case study of ards

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Reviewed By Behavioral Science Assembly

Submitted by

Lokesh Venkateshaiah, MD

Division of Pulmonary, Critical Care and Sleep Medicine

The MetroHealth System, Case Western Reserve University

Cleveland, Ohio

Bruce Arthur, MD

J. Daryl Thornton, MD, MPH

Assistant Professor

Division of Pulmonary, Critical Care and Sleep Medicine, Center for Reducing Health Disparities

Submit your comments to the author(s).

A 60-year-old man presented to the emergency department complaining of persistent right-sided chest pain and cough. The chest pain was pleuritic in nature and had been present for the last month. The associated cough was productive of yellow sputum without hemoptysis. He had unintentionally lost approximately 30 pounds over the last 6 months and had nightly sweats. He had denied fevers, chills, myalgias or vomiting. He also denied sick contacts or a recent travel history. He recalled childhood exposures to persons afflicted with tuberculosis. 

The patient smoked one pack of cigarettes daily for the past 50 years and denied recreational drug use. He reported ingesting twelve beers daily and had had delirium tremens, remote right-sided rib fractures and a wrist fracture as a result of alcohol consumption. He had worked in the steel mills but had discontinued a few years previously. He collected coins and cleaned them with mercury. 

The patient’s past medical history was remarkable for chronic “shakes” of the upper extremities for which he had not sought medical attention. Other than daily multivitamin tablets, he took no regular medications. 

Hospital course  He was initially admitted to the general medical floor for treatment of community-acquired pneumonia (see Figure 1) and for the prevention of delirium tremens. He was initiated on ceftriaxone, azithromycin, thiamine and folic acid. Diazepam was initiated and titrated using the Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWAS-Ar), a measure of withdrawal severity (1).  By hospital day 5, his respiratory status continued to worsen, requiring transfer to the intensive care unit (ICU) for hypoxemic respiratory failure. His neurologic status had also significantly deteriorated with worsening confusion, memory loss, drowsiness, visual hallucinations (patient started seeing worms) and worsening upper extremity tremors without generalized tremulousness despite receiving increased doses of benzodiazepines.

Physical Exam

White blood cell count was 11,000/mm 3 with 38% neutrophils, 8% lymphocytes, 18 % monocytes and 35% bands

Hematocrit 33%

Platelet count was 187,000/mm 3

Serum sodium was 125 mmol/L, potassium 3 mmol/L, chloride 91 mmol/L, bicarbonate 21 mmol/L, blood urea nitrogen 14 mg /dl, serum creatinine  0.6 mg/dl and anion gap of 14.

Urine sodium <10 mmol/L, urine osmolality 630 mosm/kg

Liver function tests revealed albumin 2.1 with total protein 4.6, normal total bilirubin, aspartate transaminase (AST) 49, Alanine transaminase (ALT) 19 and alkaline phosphatase 47.

Three sputum samples were negative for acid-fast bacilli (AFB).

Bronchoalveolar lavage (BAL) white blood cell count 28 cells/µl, red blood cell count 51 cells/µl, negative for AFB and negative Legionella culture.  BAL gram stain was without organisms or polymorphonuclear leukocytes.

Blood cultures were negative for growth.

Sputum cultures showed moderate growth of Pasteurella multocida.

2D transthoracic ECHO of the heart showed normal valves and an ejection fraction of 65% with a normal left ventricular end-diastolic pressure and normal left atrial size.  No vegetations were noted.

Purified protein derivative (PPD) administered via Mantoux testing was 8 mm in size at 72 hr after placement.

Human immunodeficiency virus (HIV) serology was negative. 

Arterial blood gas (ABG) analysis performed on room air on presentation to the ICU: pH 7.49, PaCO 2 29 mm Hg, PaO 2 49 mm Hg.

After admission to the ICU, the patient was noted to be in acute lung injury (ALI), a subset of acute respiratory distress syndrome (ARDS). The diagnosis of ALI requires all three of the following:  (a) bilateral pulmonary infiltrates, (b) a PaO 2 :FiO 2 ratio of ≤ 300 and (c) echocardiographic evidence of normal left atrial pressure or pulmonary-artery wedge pressure of ≤ 18 mm Hg (2). 

While patients with ALI and ARDS can be maintained with pressure-limited or volume-limited modes of ventilation, only volume assist-control ventilation was utilized in the ARDS Network multicenter randomized controlled trial that demonstrated a mortality benefit.

Noninvasive ventilation has not been demonstrated to be superior to endotracheal intubation in the treatment of ARDS or ALI and is not currently recommended (4).

This is a case of heavy metal poisoning with mercury.  The patient used mercury to clean coins.  Family members who had visited his house while he was hospitalized found several jars of mercury throughout his home.  The Environmental Protection Agency (EPA) was notified and visited the home.  They found aerosolized mercury levels of > 50,000 PPM and had the home immediately demolished. 

Alcoholic hallucinosis is a rare disorder occurring in 0.4 - 0.7% of alcohol-dependent inpatients (5).  Affected persons experience predominantly auditory but occasionally visual hallucinations.  Delusions of persecution may also occur.  However, in contrast to alcohol delirium, other alcohol withdrawal symptoms are not present and the sensorium is generally unaffected.

Delerium tremens (DT) occurs in approximately 5% of patients who withdraw from alcohol and is associated with a 5% mortality rate. DT typically occurs between 48 and 96 hr following the last drink and lasts 1-5 days.  DT is manifested by generalized alteration of the sensorium with vital sign abnormalities.  Death often results from arrhythmias, pneumonia, pancreatitis or failure to identify another underlying problem (6).  While DT certainly could have coexisted in this patient, an important initial step in the management of DT is to identify and treat alternative diagnoses.

Delirium is frequent among older patients in the ICU (7), and may be complicated by pneumonia and sepsis.  However, pneumonia and sepsis as causes for delirium are diagnoses of exclusion and should only be attributed after other possibilities have been ruled out. 

Frontal lobe stroke is unlikely, given the absence of other findings in the history or physical examination present to suggest an acute cerebrovascular event. 

In 1818, Dr. John Pearson coined the term erethism for the characteristic personality changes attributed to mercury poisoning (8).  Erethism is classically the first symptom in chronic mercury poisoning (9).  It is a peculiar form of timidity most evident in the presence of strangers and closely resembles an induced paranoid state.  In the past, when mercury was used in making top hats, the term “mad as a hatter” was used to describe the psychiatric manifestations of mercury intoxication.  Other neurologic manifestations include tremors, especially in patients with a history of alcoholism, memory loss, drowsiness and lethargy.  All of these were present in this patient. 

Acute respiratory failure (ALI/ARDS) can occur following exposure to inhalation of mercury fumes (10). Mercury poisoning has also been associated with acute kidney injury (11). 

Although all of the options mentioned above could possibly contribute to the development of delirium, only mercury poisoning would explain the constellation of findings of confusion, upper extremity tremors, visual hallucinations, somnolence and acute respiratory failure (ALI/ARDS).

Knowledge of the form of mercury absorbed is helpful in the management of such patients, as each has its own distinct characteristics and toxicity. There are three types of mercury: elemental, organic and inorganic. This patient had exposure to elemental mercury from broken thermometers. 

Elemental mercury is one of only two known metals that are liquid at room temperature and has been referred to as quicksilver (12). It is commonly found in thermometers, sphygmomanometers, barometers, electronics, latex paint, light bulbs and batteries (13).  Although exposure can occur transcutaneously or by ingestion, inhalation is the major route of toxicity.  Ingested elemental mercury is poorly absorbed and typically leaves the body unchanged without consequence (bioavailability 0.01% [13]). However, inhaled fumes are rapidly absorbed through the pulmonary circulation allowing distribution throughout the major organ systems.  Clinical manifestations vary based on the chronicity of the exposure (14).  Mercury readily crosses the blood-brain barrier and concentrates in the neuronal lysosomal dense bodies. This interferes with major cell processes such as protein and nucleic acid synthesis, calcium homeostasis and protein phosphorylation.  Acute exposure symptoms manifest within hours as gastrointestinal upset, chills, weakness, cough and dyspnea.

Inorganic mercury salts are earthly-appearing, red ore found historically in cosmetics and skin treatments.  Currently, most exposures in the United States occur from exposure through germicides or pesticides (15).  In contrast to elemental mercury, inorganic mercury is readily absorbed through multiple routes including the gastrointestinal tract.  It is severely corrosive to gastrointestinal mucosa (16).  Signs and symptoms include profuse vomiting and often-bloody diarrhea, followed by hypovolemic shock, oliguric renal failure and possibly death (12).

Organic mercury, of which methylmercury is an example, has garnered significant attention recently following several large outbreaks as a result of environmental contamination in Japan in 1956 (17) and grain contamination in Iraq in 1972 (18).  Organic mercury is well absorbed in the GI tract and collects in the brain, reaching three to six times the blood concentration (19).  Symptoms may manifest up to a month after exposure as bilateral visual field constriction, paresthesias of the extremities and mouth, ataxia, tremor and auditory impairments (12).  Organic mercury is also present in a teratogenic agent leading to development of a syndrome similar to cerebral palsy termed "congenital Minamata disease" (20).

The appropriate test depends upon the type of mercury to which a patient has been exposed.  After exposure to elemental or inorganic mercury, the gold standard test is a 24-hr urine specimen for mercury.  Spot urine samples are unreliable.  Urine concentrations of greater than 50 μg in a 24-hr period are abnormal (21).  This patient’s 24-hr urine level was noted to be 90 μg.  Elemental and inorganic mercury have a very short half-life in the blood.

Exposure to organic mercury requires testing hair or whole blood.  In the blood, 90% of methyl mercury is bound to hemoglobin within the RBCs.  Normal values of whole blood organic mercury are typically < 6 μg/L. This patient’s whole blood level was noted to be 26 μg/L.  This likely reflects the large concentration of elemental mercury the patient inhaled and the substantial amount that subsequently entered the blood.

Mercury levels can be reduced with chelating agents such as succimer, dimercaprol (also known as British anti-Lewisite (BAL)) and D-penicillamine, but their effect on long-term outcomes is unclear (22-25).

• Sullivan JT, Sykora K, Schneiderman J, et al. Assessment of alcohol withdrawal: the revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar). Br J Addict 1989;84:1353-1357.
• Bernard GR, Artigas A, Brigham KL, et al. The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994;149:818-824.
• The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000;342:1301-1308.
• Agarwal R, Reddy C, Aggarwal AN, et al. Is there a role for noninvasive ventilation in acute respiratory distress syndrome? A meta-analysis. Respir Med 2006;100:2235-2238.
• Soyka M. Prevalence of alcohol-induced psychotic disorders. Eur Arch Psychiatry Clin Neurosci 2008;258:317-318.
• Tavel ME, Davidson W, Batterton TD. A critical analysis of mortality associated with delirium tremens. Review of 39 fatalities in a 9-year period. Am J Med Sci 1961;242:18-29.
• McNicoll L, Pisani MA, Zhang Y, et al. Delirium in the intensive care unit: occurrence and clinical course in older patients. J Am Geriatr Soc 2003;51:591-598.
• Bateman T. Notes of a case of mercurial erethism. Medico-Chirurgical Transactions 1818;9:220-233.
• Buckell M, Hunter D, Milton R, et al. Chronic mercury poisoning. 1946. Br J Ind Med 1993;50:97-106.
• Rowens B, Guerrero-Betancourt D, et al. Respiratory failure and death following acute inhalation of mercury vapor. A clinical and histologic perspective. Chest 1991;99:185-190.
• Aguado S, de Quiros IF, Marin R, et al. Acute mercury vapour intoxication: report of six cases. Nephrol Dial Transplant 1989;4:133-136.
• Ibrahim D, Froberg B, Wolf A, et al. Heavy metal poisoning: clinical presentations and pathophysiology. Clin Lab Med 2006;26:67-97, viii.
• A fact sheet for health professionals - elemental mercury. Available from: http://www.idph.state.il.us/envhealth/factsheets/mercuryhlthprof.htm
• Clarkson TW, Magos L, Myers GJ. The toxicology of mercury - current exposures and clinical manifestations. N Engl J Med 2003;349:1731-1737.
• Boyd AS, Seger D, Vannucci S, et al. Mercury exposure and cutaneous disease. J Am Acad Dermatol 2000;43:81-90.
• Dargan PI, Giles LJ, Wallace CI, et al. Case report: severe mercuric sulphate poisoning treated with 2,3-dimercaptopropane-1-sulphonate and haemodiafiltration. Crit Care 2003;7:R1-6.
• Eto K. Minamata disease. Neuropathology 2000;20:S14-9.
• Bakir F, Damluji SF, Amin-Zaki L, et al. Methylmercury poisoning in Iraq. Science 1973;181:230-241.
• Berlin M, Carlson J, Norseth T. Dose-dependence of methylmercury metabolism. A study of distribution: biotransformation and excretion in the squirrel monkey. Arch Environ Health 1975;30:307-313.
• Harada M. Congenital Minamata disease: intrauterine methylmercury poisoning. Teratology 1978;18:285-288.
• Graeme KA, Pollack CVJ. Heavy metal toxicity Part I: Arsenic and mercury. J Emerg Med 1998;16:45-56.
• Aaseth J, Frieheim EA. Treatment of methylmercury poisoning in mice with 2,3-dimercaptosuccinic acid and other complexing thiols. Acta Pharmacol Toxicol (Copenh) 1978;42:248-252.
• Archbold GP, McGuckin RM, Campbell NA. Dimercaptosuccinic acid loading test for assessing mercury burden in healthy individuals. Ann Clin Biochem 2004;41:233-236.
• Kosnett MJ. Unanswered questions in metal chelation. J Toxicol Clin Toxicol 1992;30:529-547.
• Zimmer LJ, Carter DE. The efficacy of 2,3-dimercaptopropanol and D-penicillamine on methyl mercury induced neurological signs and weight loss. Life Sci 1978;23:1025-1034.

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• Published: 14 March 2019

Acute respiratory distress syndrome

• Michael A. Matthay 1 ,
• Rachel L. Zemans 2 ,
• Guy A. Zimmerman 3 ,
• Yaseen M. Arabi 4 ,
• Jeremy R. Beitler 5 ,
• Alain Mercat 6 ,
• Margaret Herridge 7 ,
• Adrienne G. Randolph 8 &
• Carolyn S. Calfee 1  

Nature Reviews Disease Primers volume  5 , Article number:  18 ( 2019 ) Cite this article

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• Respiratory distress syndrome
• Respiratory tract diseases

The acute respiratory distress syndrome (ARDS) is a common cause of respiratory failure in critically ill patients and is defined by the acute onset of noncardiogenic pulmonary oedema, hypoxaemia and the need for mechanical ventilation. ARDS occurs most often in the setting of pneumonia, sepsis, aspiration of gastric contents or severe trauma and is present in ~10% of all patients in intensive care units worldwide. Despite some improvements, mortality remains high at 30–40% in most studies. Pathological specimens from patients with ARDS frequently reveal diffuse alveolar damage, and laboratory studies have demonstrated both alveolar epithelial and lung endothelial injury, resulting in accumulation of protein-rich inflammatory oedematous fluid in the alveolar space. Diagnosis is based on consensus syndromic criteria, with modifications for under-resourced settings and in paediatric patients. Treatment focuses on lung-protective ventilation; no specific pharmacotherapies have been identified. Long-term outcomes of patients with ARDS are increasingly recognized as important research targets, as many patients survive ARDS only to have ongoing functional and/or psychological sequelae. Future directions include efforts to facilitate earlier recognition of ARDS, identifying responsive subsets of patients and ongoing efforts to understand fundamental mechanisms of lung injury to design specific treatments.

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Introduction

The acute respiratory distress syndrome (ARDS) was initially defined in 1967 with a case-based report that described the clinical presentation in critically ill adults and children of acute hypoxaemia, noncardiogenic pulmonary oedema, reduced lung compliance (increased lung stiffness), increased work of breathing and the need for positive-pressure ventilation in association with several clinical disorders including trauma, pneumonia, sepsis and aspiration 1 . In 1992, an American–European consensus conference established specific diagnostic criteria for the syndrome 2 ; these criteria were updated in 2012 in the so-called Berlin definition 3 of ARDS in adults (Box  1 ). Depending on the level of oxygenation, ‘mild’, ‘moderate’ and ‘severe’ descriptors can be added to the diagnosis of ARDS (Box  1 ). The diagnosis of ARDS depends on clinical criteria alone because it is not practical to obtain direct measurements of lung injury by pathological samples of lung tissue in most patients; furthermore, neither distal airspace nor blood samples can be used to diagnose ARDS.

ARDS develops most commonly in the setting of pneumonia (bacterial and viral; fungal is less common), nonpulmonary sepsis (with sources that include the peritoneum, urinary tract, soft tissue and skin), aspiration of gastric and/or oral and oesophageal contents (which may be complicated by subsequent infection) and major trauma (such as blunt or penetrating injuries or burns). Several other less common scenarios are also associated with the development of ARDS, including acute pancreatitis; transfusion of fresh frozen plasma, red blood cells and/or platelets (that is, transfusion-associated acute lung injury (TRALI)); drug overdose with various agents; near drowning (inhalation of fresh or salt water); haemorrhagic shock or reperfusion injury (including after cardiopulmonary bypass and lung resection); and smoke inhalation (often associated with cutaneous burn injuries). Other causes of noncardiogenic pulmonary oedema that are often considered as additional aetiologies of ARDS include primary graft dysfunction following lung transplantation, high-altitude pulmonary oedema, neurogenic oedema (following a central nervous system insult or injury) and drug-induced lung injury. The frequency of the clinical disorders associated with ARDS varies depending on the geographical location, the health-care systems that are available and whether they are resource-rich or resource-poor.

In the past 50 years, considerable progress has been made in understanding the epidemiology, pathogenesis and pathophysiology of ARDS. In addition, randomized trials to optimize mechanical ventilation and fluid therapy for ARDS have resulted in improved clinical outcomes. Although much progress has been made to improve supportive care for ARDS, effective pharmacological therapies for ARDS have not yet been identified. However, ARDS is increasingly being recognized as a heterogenous syndrome, generating momentum to identify clinical and biological features to classify patients into subphenotypes that might be more responsive to specific therapies. Furthermore, evidence of important long-term effects in survivors of ARDS is growing, driving the need for research strategies to study how these effects could be mitigated.

This Primer on adult and paediatric ARDS considers the epidemiology of ARDS from a global perspective, mechanisms of lung endothelial and alveolar epithelial injury (including experimental and clinical studies) and optimal approaches to diagnosis with a focus on screening, early recognition and evaluation for infectious and non-infectious causes. We also discuss management strategies, including mechanical ventilation, fluids and rescue therapies for severe ARDS. Finally, we describe quality of life (QOL) after recovery from ARDS. Throughout the Primer, the differences between adult and paediatric ARDS are considered.

Box 1 Definitions of ARDS in adults

2012 Berlin definition 3

Timing: respiratory failure within 1 week of a known insult or new and/or worsening respiratory symptoms

Origin: respiratory failure not fully explained by cardiac function or volume overload (need objective criterion such as echocardiography to exclude hydrostatic oedema if no risk factor is present)

Imaging: bilateral opacities on chest radiograph or CT not fully explained by effusion, collapse or nodules

Oxygenation: acute onset of hypoxaemia defined as PaO 2 /FiO 2 <300 mmHg on at least PEEP 5 cmH 2 O a

PaO 2 /FiO 2 of 201–300 mmHg is mild ARDS

PaO 2 /FiO 2 of 101–200 mmHg is moderate ARDS

PaO 2 /FiO 2 ≤100 mmHg is severe ARDS

2016 Kigali modification b (ref. 124 )

Timing and origin: as in the Berlin definition

Imaging: bilateral opacities on chest radiography or ultrasonography scan not fully explained by effusion, collapse or nodules

Oxygenation: SpO 2 /FiO 2 <315; no PEEP requirement

a PEEP may be delivered non-invasively if the criteria are in the mild category. b The Kigali definition was not directly compared with the Berlin definition in the original publication; patients in the Kigali study were not receiving mechanical ventilation. ARDS, acute respiratory distress syndrome; FiO 2 , fraction of inspired oxygen; PaO 2 , partial pressure of arterial oxygen; PEEP, positive end-expiratory pressure; SpO 2 , peripheral capillary oxygen saturation.

Epidemiology

A well-designed, prospective analysis of the incidence of ARDS in the United States was carried out in a population-based cohort study of 21 hospitals in King County, Washington, from April 1999 to July 2000, focused primarily on adults 4 . The investigators used a validated screening protocol to identify patients with ARDS (defined as a partial pressure of arterial oxygen (PaO 2 ) to fraction of inspired oxygen (FiO 2 ) ratio (PaO 2 /FiO 2 ) of <300 mmHg and bilateral chest radiographic opacities without evidence of left-sided heart failure). On the basis of these data, the authors estimated an annual incidence of 190,000 cases of ARDS in the United States with a hospital mortality of 38.5%. Subsequently, the LUNG-SAFE study provided valuable data in a cross-sectional analysis of 29,144 patients in 50 countries during the winter of 2014 (ref. 5 ); in this study, the prevalence of ARDS in patients in intensive care was 10%, and ARDS was identified in 23% of all ventilated patients. A detailed review of ARDS incidence and time-related changes in epidemiological factors has been recently published 6 .

The LUNG-SAFE study also reported that hospital mortality was 34.9% for patients with mild ARDS, 40% for those with moderate ARDS and 46.1% for those with severe ARDS (Berlin criteria 3 ; Box  1 ). However, it remains unclear how much of the reported mortality in ARDS can be attributed to ARDS as opposed to underlying comorbidities, such as cancer and immunosuppression, the associated nonpulmonary organ dysfunction (cardiovascular insufficiency as in septic shock, liver dysfunction and renal failure) and/or the older age of patients with the condition. For example, a follow-up analysis of the LUNG-SAFE study determined that 21% of patients with ARDS in the study were immunocompromised, and hospital mortality was much higher in these patients than in non-immunocompromised patients (52% versus 36%; P  < 0.0001) 7 .

Importantly, the LUNG-SAFE study revealed that clinician recognition of ARDS was low — 51% in mild ARDS and only 79% in severe ARDS. Furthermore, fewer than two-thirds of patients with ARDS were treated with an optimal tidal volume (that is, for mechanical ventilation) of <8 ml per kg predicted body weight (PBW). Thus, this study confirmed that ARDS remains common in critically ill patients and that it is under-recognized and under-treated.

Several comorbidities and exposures have been associated with increased susceptibility to ARDS, including alcohol abuse 8 , cigarette smoking 9 , 10 , air pollution 11 , 12 and hypoalbuminaemia 13 . Diabetes mellitus has been associated with a lower risk of ARDS development for reasons that remain unclear 14 , 15 , although data from the LUNG-SAFE study showed no association between diabetes and the diagnosis of ARDS, developing ARDS or outcomes of ARDS 16 . A two-centre clinical study identified the major recipient risk factors for developing TRALI, including recent liver surgery, chronic alcohol abuse, current cigarette smoking, higher peak airway pressure (that is, the highest airway pressure while being ventilated) and positive fluid balance 17 . Transfusion risk factors were receipt of whole blood or fresh frozen plasma from a female donor and the quantity of human leukocyte antigen (HLA) class II antibody or the volume concentration of anti-human neutrophil antigen in the transfused blood components. There was no risk associated with the age of the stored blood. Indeed, eliminating fresh frozen plasma or whole-blood transfusion from female donors markedly reduced the incidence of TRALI, implicating a role for allogeneic antibodies in the pathogenesis of TRALI. In blunt and penetrating trauma, the severity and duration of shock, chest injury, the number of blood product transfusions, the presence of traumatic brain injury and the quantity of crystalloid fluids (as a volume expander) can each contribute to the risk of developing ARDS 18 , 19 .

Studies of the association between ethnicity and ARDS outcomes have largely but not uniformly reported higher mortality for black and Hispanic patients with ARDS than for white patients 20 , 21 . In an analysis of patients who died with a diagnostic code for ARDS in the United States, men had higher average ARDS-related mortality than women, and black patients had higher mortality than white patients, echoing findings from similar analyses from prior decades 22 , 23 . The aetiology of these disparities remains unknown.

Studies designed to identify genetic factors that might contribute to the susceptibility for developing ARDS have been reported in the past decade. However, no specific loci with genome-wide significance for associations with ARDS have been identified, probably in part because of the phenotypic complexity of ARDS engendered by the different risk factors 24 . However, other strategies, including candidate gene and pathway analyses, have revealed potentially important mechanisms of lung injury that seem to be associated with risk of developing ARDS and, in some associations, higher mortality 25 . For example, plasma angiopoietin 2 (encoded by ANGPT2 ) is a protein marker and mediator of increased lung vascular permeability; using a quantitative trait loci analysis, five ANGPT2 genetic variants in a population with European ancestry have been associated with increased levels of plasma angiopoietin 2, and two of the five variants were associated with increased ARDS risk. No significant associations were found with this gene in people with African ancestry 26 .

From a systematic review of 29 paediatric studies 27 and the PARDIE cross-sectional study of 145 international paediatric intensive care units (PICUs) 28 , the estimated population-based incidence of ARDS in children (2 weeks to 17 years of age) is 2.2–5.7 per 100,000 person-years; most of the children in these studies were <5 years of age. ARDS is diagnosed in 2.3–3% of PICU admissions, with an estimated mortality of 17–33% 27 , 28 ; mortality is lower in highly resourced countries but was not associated with age. Over the past two decades, ARDS mortality in PICUs has been relatively stable. Although the overall number of ARDS-associated deaths is lower in children than adults, more productive life years are lost from ARDS-related paediatric deaths, as most occur in very young patients and ≥40% of these patients were previously healthy 28 .

The major risk factors and pathophysiology of ARDS are similar in adults and children 28 , but paediatric and adult ARDS epidemiology have some differences. ARDS is more frequent in boys than girls 28 , 29 , for reasons that are unknown. Over 60% of paediatric ARDS (PARDS) is also caused by pneumonia; however, viral infections such as respiratory syncytial virus and influenza virus more frequently cause life-threatening ARDS in young children 30 . Overall mortality is lowest in children with ARDS triggered by lower respiratory infection and highest in those with indirect lung injury from sepsis and/or shock 28 . ARDS occurs in only 0.5% of paediatric trauma patients, but its associated mortality is 18% 31 . The incidence, presentation and outcome of TRALI in children seems similar to that in adults. A history of prematurity, cancer or immune compromise are risk factors for mortality. The severity of hypoxaemia has consistently predicted mortality in paediatric cohorts 32 . In intubated children in the PARDIE study, severe ARDS (defined as PaO 2 /FiO 2 <100 mmHg) was associated with threefold higher mortality than in children with a PaO 2 /FiO 2 of 100–300 mmHg (ref. 28 ). In addition, a history of cancer or haematopoietic stem cell transplantation in paediatric patients with ARDS resulted in a mortality of 43% versus 11% in children without these risk factors in a prospective multicentre study 33 .

Mechanisms/pathophysiology

Here, we focus on the normal and injured lung in ARDS, the pathophysiology of ARDS and the mechanisms of injury that lead to ARDS, including the contribution of ventilator-associated lung injury (VALI). Human lung pathology and research on mechanisms of lung injury from studies of patients with ARDS are also included.

The normal lung is structured to facilitate carbon dioxide excretion and oxygen transfer across the distal alveolar–capillary unit (Fig.  1 ). The selective barrier to fluid and solutes in the uninjured lung is established by a single-layer lining of endothelial cells linked by plasma membrane structures, including adherens and tight junctions 34 . The vast surface of the alveolar epithelium is lined by flat alveolar type I (ATI) cells along with cuboidal shaped alveolar type II (ATII) cells, forming a very tight barrier that restricts even the passage of small solutes but allows diffusion of carbon dioxide and oxygen. The ATII cells secrete surfactant, the critical factor that reduces surface tension, enabling the alveoli to remain open and facilitating gas exchange. Both ATI and ATII cells have the capacity to absorb excess fluid from the airspaces by vectorial ion transport, primarily by apical sodium channels and basolateral Na + /K + -ATPase pumps 35 . Thus, when alveolar oedema develops, reabsorption of the oedematous fluid depends on junctions between ATI and ATII cells and intact ion transport channels in the epithelial cells. Once the oedematous fluid is absorbed into the lung interstitium, the fluid can be removed primarily by lymphatics and the lung microcirculation. The cellular makeup of the normal alveolus includes alveolar macrophages but not polymorphonuclear leukocytes (neutrophils), although they can be rapidly recruited from the circulation. Alveolar macrophages, neutrophils and other immune effector cells, including monocytes and platelets, are critical in defence of the normal lung and have key activities in acute lung injury.

The alveolar epithelium is a continuous monolayer of alveolar type I (ATI) cells (very thin cells that permit gas exchange) and alveolar type II (ATII) cells (which produce surfactant to enable lung expansion with a low surface tension); both cells transport ions and fluid from the alveolus to maintain dry airspaces. The intact alveolar epithelium is linked by intercellular tight junctions. Tight junctions are responsible for barrier function and regulating the movement of fluid and ions across the epithelium and are composed of transmembrane claudins and occludins and cytoplasmic zonula occludens (ZO) proteins that anchor tight junctions to the actin cytoskeleton. Alveolar epithelial cells express plasma membrane E-cadherin and β-catenin. β-Catenin also functions as a transcriptional cofactor and has a role in cell turnover in the subset of ATII cells that function as stem cells during homeostasis 80 . Endothelial cells serve to regulate the influx of fluid and inflammatory cells into the interstitial space and are connected by intercellular junctions comprising tight junctions and adherens junctions. Adherens junctions contain vascular endothelial cadherin (VE-cadherin), which mediates cell–cell contact through its extracellular domain and has a key role in barrier function. p120–catentin binds to and stabilizes VE-cadherin, which is linked to the actin cytoskeleton via α-catenin (α in the figure) and has multiple additional functional interactions 56 . TIE2 acts in concert with vascular endothelial-protein tyrosine phosphatase (VE-PTP), which dephosphorylates VE-cadherin, stabilizing it. Normally, transvascular flux of fluid out of the capillary moves water and low-molecular-weight solutes into the interstitial space and then into the lymphatics; in health, this fluid does not cross the epithelial barrier. Resident alveolar macrophages populate the airspaces, providing host defence. Large numbers of polymorphonuclear leukocytes (PMNs) reside in the alveolar capillaries and can be rapidly mobilized to the airspaces in the setting of infection. β, β-catenin; BASC, bronchioalveolar stem cell; ENaC, epithelial sodium channel; JAM, junctional adhesion molecule; RBC, red blood cell.

In ARDS, there is increased permeability to liquid and protein across the lung endothelium, which then leads to oedema in the lung interstitium. Next, the oedematous fluid translocates to the alveoli, often facilitated by injury to the normally tight barrier properties of the alveolar epithelium. Increased alveolar–capillary permeability to fluid, proteins, neutrophils and red blood cells (resulting in their accumulation into the alveolar space) is the hallmark of ARDS 36 , 37 , 38 . Arterial hypoxaemia in patients with ARDS is caused by ventilation-to-perfusion mismatch as well as right-to-left intrapulmonary shunting. In addition, impaired excretion of carbon dioxide is a major component of respiratory failure, resulting in elevated minute ventilation that is associated with an increase in pulmonary dead space (that is, the volume of a breath that does not participate in carbon dioxide excretion). Elevation of pulmonary dead space and a decrease in respiratory compliance are independent predictors of mortality in ARDS 39 .

Interstitial and alveolar oedema are key features of diffuse alveolar damage (DAD) in the acute ‘exudative’ phase (~7 days) of ARDS (Fig.  2 ). Eosinophilic depositions termed hyaline membranes are also defining features of DAD, the classic histopathological hallmark of ARDS 40 , 41 , 42 . The other findings include alveolar haemorrhage, accumulation of white blood cells (usually predominantly neutrophils), fibrin deposition and some areas of alveolar atelectasis (collapse). After the initial exudative phase, ATII cell hyperplasia follows in a ‘proliferative’ phase that can last >3 weeks in survivors; interstitial fibrosis can also occur in this phase. The original description of DAD was based heavily on analyses of lungs of patients dying with oxygen toxicity, although similar histological changes were identified in lungs from patients with a variety of conditions that underlie ARDS 40 . Recent reports reveal that DAD is present in only a subset of patients with clinical ARDS, and pathological heterogeneity is evident 41 , 42 , 43 , 44 . For example, one study carried out over two decades (1991–2010) on post-mortem samples reported that 45% of patients who met the Berlin criteria for ARDS had DAD, whereas the other 55% had alveolar inflammation consistent with acute pneumonia with infiltration of neutrophils in the alveoli and distal bronchioles 44 . Importantly, this study also found that the incidence of DAD declined in the decade after lung-protective ventilation was implemented. Recent reports also indicate key temporal features of histological progression, identify the association of DAD with severity of ARDS and provide evidence that the first 7 days after onset represent a critical window for potential therapeutic intervention 43 , 44 . In addition, one meta-analysis of open lung biopsy samples in patients with ARDS found that DAD was present in only 48% of the patients and was associated with a higher mortality 45 . Neither the severity of hypoxaemia nor the sequential organ failure assessment score were different in patients with or without DAD on lung biopsy.

In acute respiratory distress syndrome (ARDS), features of diffuse alveolar damage (DAD), such as in the acute ‘exudative’ phase (~7 days) (panel a ), are typically followed by alveolar type II (ATII) cell hyperplasia and interstitial fibrosis in a ‘proliferative’ phase. Eosinophilic depositions termed hyaline membranes are defining features of DAD (pink structure lining the central alveolus, indicated by the arrowhead in panel b ) are defining features of DAD. Leukocytes are embedded in the hyaline membranes (arrows in panel b ). Electron microscopic analyses (panel c ) demonstrate that alterations in endothelial and epithelial cells are critical features of acute alveolar injury in ARDS 37 , 46 . Focal epithelial destruction of alveolar type I (ATI) cells and denudation of the alveolar basement membrane occur early in ARDS, whereas endothelial continuity is preserved with modest alterations in most cases. The pattern shown in panel c was identified in the lungs of a patient with indirect acute lung injury resulting from sepsis 37 , 46 . A, alveolar space; BM, basement membrane; C, capillary; EC, erythrocyte; EN, endothelial cell; HM, hyaline membrane; LC, leukocyte. Reprinted with permission of the American Thoracic Society. Copyright © 2019 American Thoracic Society. Matthay, M. A. & Zimmerman, G. A. (2005) Acute lung injury and the acute respiratory distress syndrome: four decades of inquiry into pathogenesis and rational management. Am. J. Respir. Cell Mol. Biol . 33 , 319–327. The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.

Classic electron microscopic analyses demonstrate that alterations in endothelial and epithelial cells are critical features of acute alveolar injury in ARDS 37 , 46 . For example, early involvement of ATI cells is frequently dramatic and includes focal epithelial destruction and denudation of the alveolar basement membrane 40 , 46 . By contrast, alveolar endothelial cells are usually morphologically preserved and the endothelial lining is continuous, demonstrating that even ultrastructural analyses cannot precisely detect abnormalities in the normal barrier properties that regulate fluid and protein flux across the lung capillaries 37 . Epithelial cell necrosis is usually described in the exudative phase 42 , 47 , although evidence for apoptosis has also been reported 48 . Early epithelial injury is followed rapidly by ATII cell proliferation 37 , 40 , 43 , 47 . Injured but intact alveolar epithelial cells seem to drive release of pro-coagulant factors and intra-alveolar fibrin deposition 49 , 50 , which is also deposited adjacent to endothelial cells in injured alveoli 37 , 40 , 47 .

Endothelial damage

The nature of endothelial cell alteration in clinical ARDS is incompletely understood. Endothelial ‘damage’ and ‘injury’ are commonly described, and recent evidence suggests that apoptosis 36 and alternative cell death pathways such as pyroptosis 51 might be involved. Conceptually, an increase in lung vascular permeability can occur because of a functional breakdown in endothelial junctions or by death of endothelial cells. Ultrastructural alterations of alveolar endothelial cells are frequently subtle compared with the dramatic epithelial cell disruption observed in autopsy analysis 37 (Fig.  2 ), suggesting functional barrier impairment. Experimental evidence has shown that endothelial cell activation can occur, induced by inflammatory signals from microorganisms (including lipopolysaccharide and other toxins) and lung white blood cells in response to pathogens (as in pneumonia or nonpulmonary sepsis), injury from aspiration syndromes, ischaemia–reperfusion (as in trauma-induced shock) or blood product transfusions as in TRALI 36 . Endothelial cell activation may result in mediator generation (such as angiopoietin 2) and leukocyte accumulation (accompanied by upregulation of P-selectin and E-selectin (cell adhesion molecules) in the lung microvessels, especially in the post-capillary venules) 36 . Platelet and neutrophil deposition characteristically occur, often as neutrophil–platelet aggregates (Fig.  3 ), as a result of endothelial cell activation. Neutrophils and platelets seem to play a synergistic role in causing an increase in lung vascular permeability to protein (see below). Endothelial disruption can also be caused by pathogens and their toxins; endogenous danger-associated molecular patterns; barrier-destabilizing factors generated by alveolar macrophages, circulating leukocytes and platelets; and pro-inflammatory signalling molecules such as tumour necrosis factor (TNF), the inflammasome product IL-1β, angiopoietin 2, vascular endothelial growth factor, platelet-activating factor and others 36 . Increased systemic vascular permeability frequently also occurs, often contributing to hypovolaemia and multiple organ failure.

A variety of insults (such as acid, viruses, ventilator-associated lung injury, hyperoxia or bacteria) can injure the epithelium, either directly or by inducing inflammation, which in turn injures the epithelium. Direct injury is inevitably exacerbated by a secondary wave of inflammatory injury. Activation of Toll-like receptors (not shown) on alveolar type II (ATII) cells and resident macrophages induces the secretion of chemokines, which recruit circulating immune cells into the airspaces. As neutrophils migrate across the epithelium, they release toxic mediators, including proteases, reactive oxygen species (ROS) and neutrophil extracellular traps (NETs), which have an important role in host defence but cause endothelial and epithelial injury. Monocytes also migrate into the lung and can cause injury, including epithelial cell apoptosis via IFNβ-dependent release of tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), which activates death receptors. Activated platelets form aggregates with polymorphonuclear (PMN) leukocytes, which are involved in NET formation, and monocyte–platelet aggregates. Red blood cells (RBCs) release cell-free haemoglobin, which exacerbates injury via oxidant-dependent mechanisms. Angiopoietin 2 inhibits TIE2-stabilization of vascular endothelial cadherin (VE-cadherin); vascular endothelial growth factor and other permeability-promoting agonists also destabilize VE-cadherin via dissociation from p120-catenin, resulting in its internalization and enhanced paracellular permeability. Additionally, loss of cell–cell adhesion in the setting of actomyosin contraction results in the formation of occasional gaps between endothelial cells. Epithelial injury also includes wounding of the plasma membrane, which can be induced by bacterial pore-forming toxins or mechanical stretch, and mitochondrial dysfunction. Together, these effects result in endothelial and epithelial permeability, which further facilitate the transmigration of leukocytes and lead to the influx of oedematous fluid and RBCs. Airspace filling with oedematous fluid causes hypoxaemia, resulting in the need for mechanical ventilation. The vascular injury and alveolar oedema contribute to the decreased ability to excrete CO 2 (hypercapnia), accounting for the elevated pulmonary dead space in acute respiratory distress syndrome. In turn, hypoxaemia and hypercapnia impair vectorial sodium transport, reducing alveolar oedema clearance. ATI, alveolar type I cell; BASC, bronchioalveolar stem cell; ENaC, epithelial sodium channel.

Mechanistic examination of disrupted endothelial barriers has required experimental models. An extremely informative large-animal preparation demonstrated that clinically relevant insults, including intravenous bacteria, lipopolysaccharide and microemboli, cause an increase in lung endothelial permeability and filtration and that there are different responses to these insults by the endothelial and epithelial barriers 52 , 53 . Although the duration of increased lung endothelial permeability induced by specific insults in clinical ARDS is unknown, this model and more recent studies in mice suggest that it can persist for many hours to weeks 52 , 53 , 54 . In experimental models of influenza pneumonia, for example, the persistent duration of increased lung vascular permeability is associated with lung injury and slow recovery 54 . More precise understanding of the duration of barrier disruption may influence the timing of administration of candidate therapeutics aimed at reducing vascular permeability.

VE-cadherin disruption

Studies using cultured endothelium and murine models indicate that homophilic calcium-dependent vascular endothelial cadherin (VE-cadherin) bonds between adjacent endothelial cells are critical for basal lung microvascular integrity and that their ‘loosening’ is central in increased alveolar–capillary permeability in inflammatory acute lung injury 36 . VE-cadherin and TIE2, an endothelial receptor kinase, act in concert to establish junctional integrity and are regulated by vascular endothelial-protein tyrosine phosphatase (VE-PTP; also known as receptor-type tyrosine-protein phosphatase β). Genetic or pharmacological manipulation of the molecular interactions and activities of VE-cadherin, TIE2 and VE-PTP alters alveolar leak in a complex fashion in mice 36 , 55 . VE-cadherin function and adherens junction stability are also regulated by cytoskeletal interactions, small GTPases and other intracellular modulators, multiple molecular interactions (including associations with catenins, plakoglobin and VE-PTP) and phosphorylation and dephosphorylation events 36 , 56 . Destabilizing signals from pathogens or inflammatory cells and mediators responding to infectious agents induce phosphorylation of VE-cadherin and its internalization, frequently by altering activity and balance of GTPases 56 . Dissociation of VE-PTP from VE-cadherin is required for loosening of endothelial cell junctions and inflammatory alveolar protein leak in mice 57 . Recent observations indicate that inflammation-induced weakening of endothelial junctions is a process involving at least two steps, including modification of VE-cadherin contacts and alterations in the endothelial actomyosin system 55 . Genetic or pharmacological manipulation of VE-PTP can alter alveolar endothelial junctions via TIE2-dependent influences on the cytoskeleton independently of VE-cadherin 55 .

Although parallel experiments with cultured human endothelial cells suggest translational relevance 55 , direct recapitulation of these observations to alveolar endothelial barrier disruption in patients with ARDS has not been established. Nevertheless, administration to mice of an antibody against VE-cadherin resulted in intravascular sequestration of neutrophils and platelets, alveolar neutrophil accumulation and pulmonary oedema 58 — mimicking the histological pattern in clinical ARDS 37 . Of note, substantial alveolar oedema in experimental acute lung injury was not accompanied by widespread overt disruption of endothelial cell junctions detectable by electron microscopy 55 , consistent with ultrastructural observations of lung tissue from patients with ARDS in which the endothelium was found to be largely continuous and endothelial cell junctions were, for the most part, morphologically intact 37 . Thus, in animal models and human ARDS, changes in paracellular permeability to protein seem to occur in the absence of dramatic alterations in the morphology of the lung endothelium.

Immune cell recruitment to the lung

Re-establishing endothelial junctional bonds may mitigate both endothelial leak and excessive myeloid leukocyte accumulation in ARDS 36 . Indeed, genetic replacement of VE-cadherin with a fusion construct that prevented its internalization in response to inflammatory signals greatly reduced alveolar neutrophil accumulation in lipopolysaccharide-challenged mice and reduced vascular permeability 59 . Recent analysis of samples from patients and lipopolysaccharide-challenged volunteers indicates that synergistic activity of chemokines contributes to neutrophil recruitment 60 . Other signalling molecules are also likely to be involved 36 . Degranulation of neutrophils with release of intracellular enzymes such as neutrophil elastase and oxidant products contributes to the lung injury 36 .

Neutrophils in the intravascular and extravascular compartments in acute lung injury are often associated with platelets (Fig.  3 ), which have intricate thrombo-inflammatory activities including the ability to trigger deployment of neutrophil extracellular traps (NETs) 36 . NETs correlate with alveolar–capillary and epithelial barrier disruption in ARDS and experimental models 61 . NETs are filamentous chromatin fibres complexed with neutrophil-derived antimicrobial proteins, generated by a process that is not completely defined. NETs probably evolved as an innate mechanism for pathogen containment and clearance but are also involved in inflammatory insults to the lung and other organs, as illustrated in a recent experimental and clinical study of acute lung injury and ARDS 61 .

A recent observation suggests that early intravascular interactions of platelets with monocytes — which, similar to neutrophils, accumulate and have complex activities in acute lung injury — drive development of ARDS in individuals at risk 62 . Intra-alveolar macrophages play an important part in releasing chemotactic factors such as IL-8 and chemokines such as CC-chemokine ligand 2 (also known as MCP1) that enhance the recruitment of neutrophils and monocytes into the lung, particularly in response to acute pulmonary infections.

Epithelial injury and repair

In the early phase of experimental acute lung injury, the epithelium is more resistant to injury than the endothelium 53 , but as described above, some degree of epithelial injury is characteristic of ARDS. The extent of epithelial injury is also an important determinant of the severity of ARDS. The epithelium can be injured directly, for example, by bacterial products, viruses, acid, oxygen toxicity (hyperoxia), hypoxia and mechanical forces, or by inflammatory cells or their products, as in sepsis, TRALI and pancreatitis (Fig.  3 ).

As with endothelial injury 36 , 57 , 58 , 59 , epithelial injury includes dissociation of intercellular junctions 63 , 64 . Release of cell-free haemoglobin from red blood cells contributes to paracellular permeability by oxidant-dependent mechanisms. On the basis of experimental studies, the cyclo-oxygenase inhibitor acetaminophen reduces the tyrosine radical that results from oxidation of cell-free haemoglobin (Fe 4+ oxidation state to Fe 3+ oxidation state), thereby reducing the potential for lipid peroxidation 65 . In addition, epithelial cell death 37 (apoptotic or necrotic 48 , 66 , 67 ) is a key feature of alveolar injury in ARDS and can be directly caused by lytic viral infections, bacterial toxins, acid, hypoxia, hyperoxia and mechanical stretch 68 , 69 . Neutrophil-derived mediators also induce epithelial cell death via multiple mechanisms, including oxidation of soluble TNF ligand superfamily member 6 (FasL) 70 and NETs 71 , whereas inflammatory macrophages can induce cell death via mechanisms including secretion of TNF-related apoptosis-inducing ligand (TRAIL) 67 . Notably, endogenous mechanisms (such as syndecan-1-dependent MET–AKT signalling) can limit cell death 72 .

Additionally, plasma membrane wounding without cell death (that is, sublethal injury) may result from bacterial pore-forming toxins and/or overdistention from positive-pressure ventilation with high tidal volumes. A recent study demonstrated that after membrane wounding by Staphylococcus aureus toxin, calcium waves spread through gap junctions to neighbouring epithelial cells, inducing widespread mitochondrial dysfunction and loss of barrier integrity without cell death 73 . Indeed, mitochondrial dysfunction is common in lung injury and may be induced by various mechanisms, including hypercapnia 74 .

Repair of the injured epithelium is critical for clinical recovery 75 . The time frame for epithelial repair may be 2–3 days or several weeks. Because ATI cells provide >95% of the normal surface area of the alveolar epithelium and facilitate gas exchange, the process of generating new ATI cells is critical to the complete repair process. However, initially the proliferation of ATII cells can provide a provisional epithelial barrier before they transdifferentiate into ATI cells (Fig.  4 ). Many growth factors contribute to ATII cell proliferation and, although ATII cells are the default progenitors responsible for creating new alveolar epithelial cells through proliferation, in severe injury, alternate progenitor cells may be mobilized. These alternate progenitor cells include club cells 76 (secretory cells that normally line the airways), bronchoalveolar stem cells and keratin-5-expressing (KRT5 + ) cells 68 , 77 . Expansion of KRT5 + epithelial progenitors is driven by HIF–NOTCH and fibrocyte growth factor receptor 2 signalling 78 , with ATII cell fate induced by WNT–β-catenin and impeded by NOTCH and HIF 79 (Fig.  5 ). The mechanisms underlying ATII-to-ATI transdifferentiation are less well understood, but recent studies have suggested that deactivation of WNT–β-catenin is necessary 80 . Our knowledge of the regenerative role of the alternative progenitors is mainly based on mouse models of lung injury, although there is evidence that some of these progenitors exist in humans as well 79 .

Mice in which the alveolar type II (ATII) epithelial cells and all their progeny express green fluorescent protein (GFP) ( SftpcCreERT2;mTmG mice) were treated with intratracheal lipopolysaccharide to induce lung injury. Mice were euthanized 27 days later and lung sections were stained for GFP (green), the alveolar type I (ATI) cell marker T1α (purple) and 4′,6-diamidino-2-phenylindole (DAPI; for nuclear staining (blue)). Some ATII cell-derived cells (GFP-staining cells in panels a (×40) and c (×40)) expressed ATI markers (T1α-staining cells in panels b (×40) and c ), as shown by dual GFP-staining and T1α-staining cells (panel c ) — indicating transdifferentiation during repair after lung injury. Arrowheads indicate nascent ATI cells that transdifferentiated from ATII cells during repair after injury (dual GFP-staining and T1α-staining cells). Arrows indicate ATI cells that withstood the initial injury (GFP-negative but T1a-staining cells). These experimental data support the notion that ATI cells are damaged during acute lung injury and are then replaced by ATII cells that transdifferentiate into ATI cells. Reprinted with permission of the American Thoracic Society. Copyright © 2019 American Thoracic Society. Jansing, N. L. et al. (2017) Unbiased quantitation of alveolar type II to alveolar type I cell transdifferentiation during repair after lung injury in mice. Am. J. Respir. Cell Mol. Biol . 57 , 519–526. The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.

Several mechanisms promote endothelial cell junctional reassembly. Slit binds to its receptor, ROBO4, stabilizing the adherens junctions by promoting the association between p120–catenin and vascular endothelial cadherin (VE-cadherin) (not shown). Activated platelets release the lipid mediator sphingosine 1-phosphate (S1P), which activates Rho/Rac signalling to induce cytoskeletal reorganization that promotes endothelial barrier integrity (not shown). The receptor tyrosine kinase TIE2 is bound by its activating ligand, angiopoietin 1, which results in actin cytoskeletal reorganization and stability of VE-cadherin at the adherens junctions (not shown). To repair the damaged epithelium, surviving alveolar type II (ATII) cells replace lost epithelial cells via proliferation and differentiation into alveolar type I (ATI) cells. Many growth factors promote ATII proliferation, including keratinocyte growth factor (KGF), epidermal growth factor (EGF) 80 , hepatocyte growth factor (HGF) and granulocyte–macrophage colony-stimulating factor (GM-CSF); similarly, transcriptional pathways also promote ATII proliferation, including the WNT–β-catenin pathway 80 , 82 , 239 and the forkhead box protein M1 (FOXM1) pathway 240 . Toll-like receptor 4 and hyaluronan signalling also contribute 241 . In severe injury, alternate progenitors (keratin 5-expressing epithelial progenitors (KRT5 + ) and club cells) are mobilized to proliferate and differentiate into ATII cells. Withdrawal of β-catenin signalling induces ATII cells to transdifferentiate into ATI cells 80 . Fibroblasts and endothelial cells (and epithelial cells) secrete epithelial growth factors 80 , 242 ; for example, platelet-derived stromal cell-derived factor 1 (SDF1) stimulates endothelial cells to secrete matrix metalloproteinase 14 (MMP14), which cleaves heparin-bound EGF (HB-EGF), enabling it to ligate the EGF receptor and stimulate ATII cell proliferation 242 . Membrane pores can be patched and damaged mitochondria can be removed by mitophagy. Once the alveolar epithelium is regenerated, pro-resolving macrophages clear dead cells and debris and ATII and ATI epithelial cells reabsorb oedematous fluid. BASC, bronchioalveolar stem cell; ENaC, epithelial sodium channel; PMN, polymorphonuclear; RBC, red blood cell; T reg cell, regulatory T cell.

Repair of the alveolar epithelium is regulated by crosstalk between multiple alveolar cell types and the extracellular matrix. Although injury-inducing, immune cells and their mediators may also promote epithelial repair 81 , 82 . Fibroblasts secrete epithelial growth factors and deposit collagen, which, if excessive, can lead to fibrosis. Sublethal epithelial cell injury can also be repaired. For example, plasma membrane pores can be excised by endocytosis or exocytosis and patched by fusion with lipid endomembrane vesicles 83 . Additionally, damaged mitochondria are degraded via mitophagy and replaced via biogenesis or mitochondrial transfer 84 . Finally, reassembly of intercellular junctions is regulated by multiple mechanisms, including beneficial effects from angiopoietin 1 (ref. 85 ) and signals from the basement membrane 86 . The timing of endothelial and epithelial repair in various causes of acute lung injury has not been systematically worked out. Once epithelial barrier integrity is restored, oedematous fluid can be reabsorbed to the interstitium either by paracellular pathways or by diffusion through water channels driven by an osmotic gradient that is established by active apical sodium uptake, in part by the epithelial sodium channels and sodium transport through the Na + /K + -ATPase pumps (Fig.  5 ).

Unfortunately, many endogenous reparative mechanisms are specifically inhibited during ARDS. For example, influenza virus infects KRT5 + progenitors 78 . Influenza infection, hypoxaemia, hypercapnia and other factors downregulate sodium channel and/or Na + /K + -ATPase function, resulting in impaired alveolar fluid clearance in patients with ARDS 35 , 75 , 87 , 88 . Hypercapnia impairs alveolar epithelial cell proliferation 74 . Keratinocyte growth factor, while stimulating proliferation, increases the susceptibility of ATII cells to influenza virus infection and mortality in mice 89 . In addition, the many biological changes resulting from both endothelial and epithelial injury, and culminating in protein-rich oedematous fluid, contribute to surfactant dysfunction 90 . Surfactant dysfunction can then increase atelectasis, which in turn can increase the risk of biophysical injury.

Mechanical VALI

All the mechanisms that injure the lung endothelium and epithelium lead to pulmonary oedema with acute respiratory failure owing to reduced oxygenation, impaired carbon dioxide excretion and decreased lung compliance. As described in the original report of ARDS in 1967 (ref. 1 ), the use of mechanical ventilation with supplemental oxygen and positive end-expiratory pressure (PEEP) was life-saving in this context. For many years, the standard therapy with mechanical ventilation support included high tidal volumes (12–15 ml per kg PBW). Nevertheless, a potential contribution of high tidal volumes and elevated airway pressures to worsening acute lung injury was suggested by preclinical studies beginning in 1974 (refs 91 , 92 , 93 ). The clinical importance of VALI was provided by the ARMA trial in 2000 (see below, Management), in which lower tidal volume and limited airway pressure markedly reduced mortality in patients with ARDS 94 . The mechanisms for VALI have been established in both experimental and clinical studies. High tidal volume and elevated airway pressure induce biomechanical inflammatory injury and necrosis of the lung endothelium and alveolar epithelium that are associated with release of neutrophil products, including proteases, oxidants and pro-inflammatory cytokines, and a reduction in the capacity of the alveolar epithelium to remove oedematous fluid 36 , 95 , 96 . Clinical studies focused on biology and clinical factors have also confirmed the injurious effects of high tidal volume in patients with ARDS (see below). It should be emphasized that it has not been possible to eliminate VALI as it can still occur from patient–ventilator dyssynchrony and elevated plateau airway pressure (that is, the elevated pressures generated by the mechanical ventilator to the alveoli), especially in patients with severe lung injury and extensive pulmonary oedema.

Insights from clinical studies

With the exception of supportive care therapies such as lung-protective ventilation and fluid-conservative therapy (see Management), translating insights from experimental studies in animal models into effective therapies for human ARDS has proved challenging. Indeed, the search for specific pharmacotherapies that effectively treat ARDS has been fruitless, despite decades of promising preclinical research 97 . In an attempt to overcome this obstacle, investigators have sought to further understand the biology of human ARDS through studies of human samples obtained from observational and interventional clinical studies. These studies from patients with ARDS have validated several pathophysiological observations from experimental studies, led to the identification of promising prognostic biomarkers in humans (Box  2 ) and identified molecular subphenotypes of human ARDS that may have therapeutic implications.

Initial studies of ARDS pathogenesis using human samples confirmed that the biological mechanisms identified in many models are relevant. Important initial observations included confirmation in humans of the fundamental hallmark of ARDS, disruption of the alveolar–capillary barrier, by documentation of elevated protein levels in pulmonary oedematous fluid 38 , 98 . Subsequent studies of biological markers from bronchoalveolar lavage, pulmonary oedematous fluid or (most commonly) plasma (which is more readily available in most cases) demonstrated that endothelial injury 99 , 100 , 101 and an exaggerated inflammatory response 102 , 103 are consistent features of human ARDS. Endothelial activation in particular seems to occur early in the development of human ARDS, in some cases predating frank respiratory failure 104 . Lung epithelial injury in human ARDS has been identified by measurement of impaired alveolar fluid clearance 75 and more recently by measurement of specific markers of alveolar epithelial cell injury, including surfactant protein D 105 and the receptor for advanced glycation end products (RAGE), a marker of lung epithelial injury and innate immune activation 106 . Importantly, many of these markers of injury have also been linked to poor clinical outcomes in ARDS (Box  2 ), suggesting that the severity of the endothelial and epithelial injury in humans is a major determinant of clinical outcome 107 .

Biological samples from interventional clinical trials in ARDS have proved to be particularly useful in furthering understanding of ARDS pathogenesis. As one example, analysis of plasma inflammatory markers from patients enrolled in the seminal trial of low tidal volume ventilation for ARDS 94 demonstrated that a lung-protective ventilation strategy decreased circulating markers of inflammation (IL-6 and IL-8) compared with a traditional high tidal volume strategy 108 . Analyses of plasma levels of RAGE from the same trial confirmed that lung-protective ventilation also decreased alveolar epithelial cell injury compared with traditional tidal volumes 109 . Another study reported a reduction in distal airspace IL-6, TNF and neutrophils in patients treated with a lung-protective ventilation strategy 110 .

Most recently, analyses of biological samples from large clinical trials have enabled studies focused on heterogeneity in ARDS, specifically on the identification of molecular subphenotypes of ARDS that may respond differently to therapies. In many other medical disciplines, most notably in oncology, the identification of discrete molecular subtypes within broader clinical syndromes has led to remarkable therapeutic progress and a revision of diagnostic paradigms — consider, for instance, hormone receptor status in breast cancer. In ARDS, biological heterogeneity has long been suspected as a potential obstacle to successful development of therapeutics; early descriptions of the syndrome speculated whether direct (that is, pulmonary) and indirect (that is, nonpulmonary) causes of ARDS, for example, might be pathologically distinct 2 . Supporting this hypothesis, a recent analysis of direct and indirect ARDS in two clinical cohorts showed that patients with direct lung injury had higher plasma levels of biomarkers of lung epithelial injury (such as RAGE and surfactant protein D), whereas patients with indirect lung injury had higher plasma levels of biomarkers of endothelial injury and inflammation (including angiopoietin 2) 111 .

An alternative approach to deconvoluting ARDS heterogeneity has been the use of unsupervised analytical approaches, most prominently latent class analysis, to identify subphenotypes within ARDS. This approach has now been replicated in analyses of five clinical trials, finding strong evidence for two distinct subphenotypes of ARDS 112 , 113 , 114 , 115 . Approximately 30% of patients with ARDS consistently fall into the so-called hyperinflammatory subphenotype, characterized by high plasma levels of inflammatory biomarkers (IL-6, IL-8, soluble TNF receptor 1), low protein C and high prevalence of shock and metabolic acidosis. By contrast, the so-called hypo-inflammatory subphenotype comprises ~70% of patients who have lower levels of the inflammatory biomarkers, less acidosis and less vasopressor-dependent shock. Mortality was higher in the hyperinflammatory subphenotype than in the hypo-inflammatory subphenotype in all of the five clinical trials.

In secondary analyses of the completed randomized controlled trials, these two ARDS subphenotypes responded differently to PEEP, fluid management and, of most interest, simvastatin therapy 114 . Statins have been proposed as a treatment for ARDS because of their potential anti-inflammatory properties. In a randomized placebo-controlled clinical trial of simvastatin in 540 patients with ARDS, there was no effect on mortality 116 . However, a secondary analysis of the trial data revealed that the patients who were classified in the hyperinflammatory subphenotype and were treated with simvastatin had a significantly higher 28-day survival than the hyperinflammatory patients who were treated with placebo. There was no difference in 28-day survival in the hypo-inflammatory patients treated with simvastatin or placebo 114 . If validated in prospective clinical studies, this approach suggests that future clinical trials targeting patients on the basis of distinct biological subphenotype may be more successful than trials based on a clinical syndromic definition. The definitive mechanistic differences between these two subphenotypes, including whether they are driven by environmental or genetic factors, remain yet to be identified. The goal of integrating the biological and clinical variables of greatest value for predictive and prognostic enrichment in clinical trials will require more research.

In addition, research to study transcriptomics in both observational and clinical trials of ARDS will be needed to identify patterns that may help segregate pathways of lung and systemic injury. One recent study of an observational cohort of 210 patients with sepsis-related ARDS used microarray analysis to compare whole-blood gene expression in patients stratified into ‘reactive’ (61% of the cohort) and ‘uninflamed’ subphenotypes of ARDS 117 . In those with a reactive subphenotype, genes associated with neutrophils were more expressed than in those with the uninflamed subphenotype. Pathway analysis in the reactive patient group showed enrichment of oxidative phosphorylation, mitochondrial dysfunction and cholesterol metabolism whereas the uninflamed group showed patterns associated with cell proliferation. Future studies that include RNA-sequencing will reduce bias compared with the microarray approach, and studies that include samples from both the blood and distal airspaces should provide insight into the pulmonary versus systemic pathways that contribute to lung injury 118 . Studies that link gene expression to protein expression will be helpful, as illustrated in one prior study of sepsis-related ARDS 119 .

Box 2 Selected biomarkers associated with human ARDS

Epithelial markers (principal source)

Receptor for advanced glycation end products (alveolar epithelial type 1 cells)

Surfactant protein D (alveolar epithelial type 2 cells)

Club cell 16 (airway epithelial cells)

Endothelial markers (principal source)

von Willebrand factor (endothelium and platelets)

Angiopoietin 2 (endothelium and platelets)

Intercellular adhesion molecule 1 (endothelium, epithelium and macrophages)

Syndecan (endothelial glycocalyx)

Endocan (endothelium)

Inflammatory markers (principal source)

IL-6 (monocytes, macrophages, neutrophils and alveolar epithelium)

IL-8 (monocytes, macrophages, endothelium and alveolar epithelium)

Soluble tumour necrosis factor receptor 1 (alveolar epithelial type 1 and type 2 cells and macrophages)

IL-1β, IL-1 R antagonist (monocytes, macrophages and alveolar epithelium)

Neutrophil extracellular traps (neutrophils)

Coagulation and fibrinolysis markers (principal source)

Protein C (plasma)

Plasminogen activator inhibitor 1 (endothelium and macrophages)

Apoptosis markers (principal source)

FAS and FasL (endothelium, alveolar epithelium and inflammatory cells)

Selected on the basis of several clinical studies that were focused on the pathogenesis and prognosis of ARDS. ARDS, acute respiratory distress syndrome; FAS, tumour necrosis factor receptor superfamily member 6; FasL, tumour necrosis factor ligand superfamily member 6.

Diagnosis, screening and prevention

Most patients who present with the early phase of acute lung injury complain of feeling short of breath. If pneumonia is the cause, they will often have a cough that produces purulent sputum. On physical examination, they appear to be in moderate or severe respiratory distress with an elevated respiratory rate and tachycardia and they usually are working harder than normal to breathe. Hypoxaemia may manifest with evidence of cyanosis in their fingernail beds. Oxygen saturation on room air will be decreased. Respiratory deterioration in ARDS may be hyper-acute (for example, in the case of TRALI, in which respiratory failure is often fulminant) or may develop slowly over a period of hours to days.

Even after the development and refinement of the Berlin diagnostic criteria (Box  1 ), several aspects of diagnosing ARDS remain challenging. Chest radiograph interpretation is inherently (at present) subjective, and investigators studying chest radiograph interpretation in ARDS in particular have demonstrated suboptimal inter-rater reliability 120 . Similarly, differentiation of ARDS from hydrostatic pulmonary oedema due to heart failure and/or volume overload can be difficult in critically ill patients (Fig.  6 ). The 1992 consensus definition of ARDS included a requirement that the pulmonary arterial wedge pressure be <18 mmHg if measured; however, pulmonary arterial catheters are now rarely used in this setting, primarily because a randomized trial showed no clinical benefit of their use compared with central venous catheters in 1,000 patients with ARDS 121 . The Berlin definition of ARDS recommends the use of echocardiography to assess cardiac function if no clear ARDS risk factor is identified. Other tests that may be useful in this distinction include measurement of brain natriuretic peptide (BNP; which, if elevated, suggests cardiac insufficiency), assessment of the vascular pedicle width on chest radiograph (which suggests intravascular volume overload) and/or measurement of the ratio of protein in pulmonary oedema fluid to plasma (which, if <0.65, suggests elevated lung vascular pressures as in cardiogenic pulmonary oedema versus a ratio >0.65, which suggests increased alveolar–capillary permeability as in ARDS), although this test is less widely available 122 , 123 . These complexities may contribute to persistent under-recognition of ARDS by clinicians. In under-resourced settings without ready access to advanced diagnostic modalities and therapies, diagnosis of ARDS can be further hindered. Thus, in 2016, investigators proposed alternative criteria for ARDS diagnosis in the absence of chest radiography, mechanical ventilation and/or blood gas measurements — the so-called Kigali modification of the Berlin criteria 124 (Box  1 ).

Similarities in the chest radiographs from a patient with acute respiratory distress syndrome (ARDS) from influenza pneumonia (panel a ) and a patient with pulmonary oedema due to cardiac failure (panel b ) reflect the difficulty in identifying ARDS. In both cases, diffuse bilateral parenchymal opacities are consistent with alveolar filling. The cardiac silhouette (panel b ) is slightly more globular, consistent with heart failure; however, this feature is not reliable for distinguishing ARDS from cardiogenic pulmonary oedema.

Another important aspect of diagnosing ARDS depends on excluding mimics of the syndrome that may require specific treatment. Such mimics include acute eosinophilic pneumonia, diffuse alveolar haemorrhage, acute interstitial pneumonia, cryptogenic organizing pneumonia, acute exacerbations of idiopathic pulmonary fibrosis and acute heart failure (Fig.  6 ). ARDS occurs in the setting of an underlying risk factor (for example, sepsis, pneumonia or severe trauma); identification of this risk factor is required to ensure that the patient actually has ARDS and not an ARDS mimic and because treatment of the underlying risk factor is vitally important for patient care. If no ARDS risk factor is readily apparent, suspicion for an ARDS mimic should increase. In this case, bronchoscopy with bronchoalveolar lavage and cell counts and differential can be helpful diagnostically. If the aetiology remains unclear after bronchoscopy, lung biopsy (thoracoscopic or, less commonly, open) may be considered if results would change patient management. Studies on the diagnostic yield of lung biopsy samples in these settings report varying diagnostic yields (60–84%) and substantial morbidity and mortality; a recent review provides a thoughtful algorithm for when to consider lung biopsy in ARDS 125 .

Given the differences in ARDS between adults and children, the international Pediatric Acute Lung Injury Consensus Conference (PALICC) defined criteria for PARDS 126 (Box  3 ). There are major differences between the PALICC PARDS definition and the adult American–European Consensus Conference or Berlin definitions. In PARDS, as in the Kigali modification of the Berlin definition, the peripheral capillary oxygen saturation (SpO 2 ) to FiO 2 ratio is used when arterial PaO 2 is not available; however, lung ultrasonography is not incorporated into the diagnostic criteria for PARDS 126 . The presence of bilateral radiographic opacities, used to distinguish diffuse lung disease but difficult to detect with accuracy, is not required for PARDS 126 . Hypoxia assessment for intubated children requires adjustment for level of respiratory support using mean airway pressure (MAP) by calculating an oxygenation index 126 (Box  3 ).

Neonates outside of the perinatal period were included in the PARDS definition, and additional criteria for diagnosing PARDS in children with paediatric cyanotic congenital heart disease and chronic lung disease were proposed 126 . The PARDS definition was more inclusive, aiming to diagnose ARDS in the early stages. Children diagnosed with PARDS using the PALICC criteria had 24% mortality if they also met the Berlin criteria, versus <8.5% if they did not 28 . If the patients were treated with noninvasive ventilation and using the oxygen saturation (SaO 2 ) to FiO 2 ratio for diagnosis with unilateral infiltrates, the mortality was 7%. Neonatal lung disease experts have proposed a consensus definition for neonatal ARDS called the Montreaux definition 127 , which is proposed for neonates from birth to 44 weeks post-menstrual age (4 weeks if born at term). Children with respiratory distress syndrome from prematurity and surfactant deficiency and those with transient tachypnoea of the newborn or congenital anomalies causing the respiratory condition are excluded. The Montreaux definition is similar to the PALICC PARDS definition (Box  3 ) in terms of timing and uses PALICC cut-offs for oxygenation index but requires arterial or transcutaneous oxygen tension values rather than SpO 2 . Furthermore, determining origin of oedema requires use of echocardiography to verify absence of congenital heart disease as a contributor, and imaging must show diffuse bilateral infiltrates or complete lung opacification. Validation of these definitions is needed in large prospective cohorts with autopsy and pathophysiological correlates to differentiate ARDS from other causes of hypoxaemia.

Box 3 PALICC criteria for PARDS

Age: exclude patients with perinatal-related lung disease

Timing: respiratory failure within 1 week of known insult

Origin: respiratory failure not fully explained by cardiac function or fluid overload

Imaging: new unilateral or bilateral infiltrate or infiltrates consistent with acute pulmonary parenchymal disease

Oxygenation: invasive mechanical ventilation severity stratification is as follows:

OI ≥4 to <8 or OSI ≥5 to <7.5 is mild PARDS

OI ≥8 to <16 or OSI ≥7.5 to <12.3 is moderate PARDS

OI ≥16 or OSI ≥12.3 is severe PARDS

Oxygenation: noninvasive mechanical ventilation severity (not stratified) is as follows:

Full face-mask bi-level ventilation or CPAP ≥5 cmH 2 O and

PaO 2 /FiO 2 ≤300 or SaO 2 /FiO 2 ≤264

CPAP, continuous positive airway pressure; FiO 2 , fraction of inspired oxygen; MAP, mean airway pressure; OI, oxygenation index (which is (MAP × FiO 2  × 100)/PaO 2 ); OSI, oxygen saturation index (which is (MAP × FiO 2  × 100)/SpO 2 , with SpO 2 ≤97% required for assessment); PALICC, Pediatric Acute Lung Injury Consensus Conference; PARDS, paediatric acute respiratory distress syndrome; PaO 2 , partial pressure of arterial oxygen; SaO 2 , oxygen saturation; SpO 2 , peripheral capillary oxygen saturation.

Diagnostic work-up

A comprehensive history and physical examination, radiographic imaging (including a chest radiograph and sometimes abdominal imaging) and laboratory tests are required to search for a clinical risk factor that is associated with ARDS. Because bacterial and viral respiratory infections of the lung (including secondary bacterial infections after an initial viral infection) are the most common risk factors associated with ARDS, this section focuses on pulmonary infections as part of the diagnostic work-up. The typical diagnostic approach includes blood cultures and microscopic examination and culture of respiratory specimens.

When evaluating a patient with suspected ARDS for the likely causative pathogen or pathogens, several factors should be taken into consideration. Whether infection is community-acquired or healthcare-associated is an important determinant of the potential pathogens (Fig.  7 ). Other important factors include age and the presence of comorbid conditions, exposure history and vaccination status. In addition to commonly isolated organisms, physicians should consider other uncommon but important pathogens that are linked to travel or residence in certain geographic distributions or to specific exposures. Examples include the Middle East respiratory syndrome coronavirus (MERS-CoV), avian influenza H5N1 and H7N9 viruses, hantavirus, human adenovirus subtype-55 (HAdV-55), Plasmodium species, Blastomyces dermatitidis , Coxiella burnetti , coccidioidomycosis, histoplasmosis, Mycobacterium tuberculosis and Yersinia pestis (Fig.  7 ). For instance, patients who have travelled to Saudi Arabia and have been exposed to camels have a higher risk of developing MERS-CoV; patients who live in the central valley of California have a higher risk of developing coccidioidomycosis.

Common community-acquired and hospital-acquired pathogens that cause pneumonia should always be considered in patients with suspected acute respiratory distress syndrome (ARDS). Some organisms such as Streptococcus pneumoniae are more common as community-acquired infections whereas Pseudomonas aeruginosa is more common as a hospital-acquired infection in ARDS. Enterobacteriaceae include Klebsiella pneumoniae , Escherichia coli and Enterobacter species. The group ‘other respiratory viruses’ includes parainfluenza virus, human metapneumovirus virus, respiratory syncytial virus, rhinovirus, coronaviruses and adenovirus. A detailed, expanded version of this figure can be found in Supplementary Fig. 1 . COPD, chronic obstructive pulmonary disease.

In patients without an identified pathogen using traditional microbiological tests of tracheal aspirate or sputum examination, the use of bronchoalveolar lavage leads to identification of pathogens in some but not all patients. The percentage of patients with ARDS with no identified organisms, even with bronchoalveolar lavage examination, remains high (>50–60%) 128 . Pathogens, or their markers (such as DNA), can also enter the bloodstream, which may in the future enable pathogen identification without the need for bronchoalveolar lavage 129 .

Nucleic acid detection tests, such as PCR, are available to detect multiple common viruses and bacteria such as Mycoplasma spp., Chlamydia pneumoniae and Bordetella pertussis . PCR panels for identifying and quantifying common bacteria such as S. aureus and Streptococcus pneumoniae are also becoming available. However, establishing causation remains a challenge because these tests do not differentiate pathogens from colonizers, nor do they distinguish primary pathogens that trigger ARDS from pathogens that may have invaded secondarily. In addition, the variable availability of PCR testing, local testing practices and specimen timing, quality and type (sputum versus bronchoalveolar lavage) all influence pathogen identification, further influencing reported epidemiology.

Next-generation sequencing is likely to become more common to detect pathogens and may change our understanding of ARDS epidemiology 130 . Increased test sensitivity will identify pathogens that frequently colonize the respiratory tract in patients with pneumonia and ARDS 128 , 131 . However, physicians need to consider pre-test probability in interpreting these results; for example, viruses such as respiratory syncytial virus and human metapneumovirus are more likely to cause ARDS in young children, elderly individuals and immunosuppressed individuals than in those who are immunocompetent 30 , 131 , 132 . Finally, it is always important to consider nonpulmonary causes of ARDS, including intra-abdominal infections.

Screening for and predicting ARDS

At present, there is neither strong evidence nor consensus regarding whether or how patients should be screened for ARDS. ARDS occurs only in a minority of patients with a risk factor, making screening challenging 133 . Furthermore, ARDS development often occurs quite quickly, with the majority of patients who go on to develop ARDS doing so in the first 12–48 hours of hospitalization 104 , 133 , 134 , 135 .

Clinical scores have been developed to predict ARDS in at-risk patients, most prominently the Lung Injury Prediction Score (LIPS) 136 . The LIPS synthesizes available clinical data that include predisposing risk factors, comorbidities and acute physiological variables to generate a risk score; higher scores indicate greater risk of developing ARDS. The negative predictive value of the LIPS is high, but the positive predictive value even in the original description was low (18% for a LIPS ≥4); a clinical trial using this LIPS cut-off as an enrolment criterion found an even lower positive predictive value of 10% 137 . An alternative approach is the Early Acute Lung Injury (EALI) score, which aims to identify patients with incipient lung injury before frank ARDS 138 , 139 . This simpler score was developed from analysis of patients with acute bilateral radiographic opacities and is comprised of three variables: level of supplemental oxygen required; tachypnoea; and presence of immune suppression. In comparison with LIPS, the negative predictive value of the EALI score was again high, but the positive predictive value was better (53%). Although the LIPS and EALI scores have not been rigorously tested in children, the PARDIE study showed that many children with mild disease will progress to meeting the Berlin criteria within 3 days of being diagnosed with PARDS.

Biomarkers have also been evaluated as potential ARDS predictive instruments. For example, levels of von Willebrand Factor, a marker of endothelial injury, were predictive of development of ARDS in a small study of patients with nonpulmonary sepsis 100 and in a more recent, larger study in patients with severe trauma 140 . Angiopoietin 2 and IL-8 were also found to be elevated in critically ill patients before ARDS development 104 . In this analysis, angiopoietin 2 improved the positive predictive value of the LIPS. The soluble form of RAGE has been reported to be predictive of ARDS development in children undergoing cardiac surgery 141 and more recently in critically ill patients at risk of ARDS 142 , although other reports have not found soluble RAGE to be predictive in this setting 104 . These data provide important evidence that endothelial and lung epithelial injury are well underway before patients fulfil ARDS diagnostic criteria; however, as the biomarkers in question are not clinically available, their use is restricted to research settings.

Prevention and early treatment

For decades, clinicians and researchers have wondered whether preventive therapies implemented early in the progression of acute lung injury, before patients meet ARDS diagnostic criteria, could improve clinical outcomes. Unfortunately, most trials focused on prevention using pharmacotherapies have met disappointing results. In the earliest trials to test this approach, corticosteroids were evaluated for ARDS prevention in at-risk patients, with no evidence of benefit 143 , 144 . More recently, a phase IIb clinical trial testing aspirin as a preventive therapy in at-risk patients was negative 137 , although a subsequent re-analysis of the data raised interesting issues 62 . A smaller phase IIa trial of aerosolized budesonide (a corticosteroid) and formoterol (a long-acting β 2 -agonist that may improve alveolar fluid clearance) demonstrated improved oxygenation and a decreased rate of progression to ARDS in the treatment group, although baseline randomization imbalances may have affected this result 145 . In contrast to these results with pharmacotherapy trials, studies evaluating the use of low tidal volume ventilation in mechanically ventilated patients without ARDS have provided more evidence of benefit 146 , 147 , but a recent large clinical trial comparing low with intermediate tidal volumes in patients without ARDS was negative 148 . Several studies have noted reductions in nosocomial ARDS incidence thought to be associated with improvements in supportive care 149 , 150 .

Although true prevention trials have been challenging to conduct because of the rapid development and low incidence of ARDS, an alternative approach has been to test the value of early treatment in patients with incipient acute hypoxaemic respiratory failure, which in many cases progresses to ARDS. A French trial illustrated the potential value of this approach, comparing high-flow nasal cannula to noninvasive ventilation and face-mask oxygen in 310 non-intubated patients with a PaO 2 /FiO 2 <300 mmHg (ref. 151 ). The majority of patients (64%) had pneumonia, and 79% had bilateral radiographic opacities on chest radiography, indicating that they likely had early ARDS. High-flow nasal cannula did not affect the primary outcome of endotracheal intubation but did lead to statistically significantly lower mortality than both noninvasive ventilation ( P  = 0.006) and face-mask oxygenation ( P  = 0.046). This trial may serve as a useful paradigm for future early treatment trials in selected patient populations, especially emphasizing the opportunity to identify patients in the early phase of acute lung injury before endotracheal intubation (Fig.  8 ). Of note, the potential benefit of high-flow nasal cannula may not be generalizable across all patients in intensive care. A recent randomized controlled study showed that high-flow oxygen therapy did not significantly decrease 28-day mortality compared with standard oxygen therapy among critically ill immunocompromised patients with acute respiratory failure 152 .

Anterior–posterior chest radiographs in a critically ill 48-year-old man who presented to the emergency department with worsening dyspnoea, hypoxaemia (oxygen saturation of 70% on room air) and a 3-day history of fever, chills and a productive cough. He also had acute kidney failure with severe oliguria and a serum creatinine of 6.2 mg per dl. His systemic blood pressure was low, at 105/50 mmHg. He was diagnosed with acute pneumonia, acute renal failure and sepsis. a | Chest radiograph showing right lower lobe consolidation consistent with pneumonia. At this time, the patient was breathing spontaneously with 6 litres nasal oxygen that increased his oxygen saturation to 91%. b | Chest radiograph taken 24 hours later showing an endotracheal tube in place (arrows) for positive-pressure ventilation with bilateral opacities, consistent with the Berlin radiographic criteria. At this time, the patient had a partial pressure of arterial oxygen (PaO 2 ) to fraction of inspired oxygen (FiO 2 ) ratio of 125 mmHg on positive-pressure ventilation with a tidal volume of 6 ml per kg predicted body weight and a positive end-expiratory airway pressure of 15 cmH 2 O. The patient also had a central line (arrowhead) inserted for administration of fluids and vasopressors as he progressed to developing septic shock. Time elapsed between the images demonstrates the potential window for early acute respiratory distress syndrome (ARDS) detection and early administration of therapies designed to prevent progression.

Management of ARDS focuses on the diagnosis and treatment of infections, respiratory support (including oxygen supplementation and positive-pressure ventilation), careful fluid management (which is especially important if the patient is in shock) and general supportive measures such as nutritional supplementation. The details of appropriate antimicrobial therapy for the many pulmonary infections that can cause ARDS are beyond the scope of this Primer. However, as general principles, when prescribing antimicrobial therapies targeting lung infections, clinicians should consider antibiotic potency (low minimal inhibitory concentration (MIC) values against the organism), likelihood of antimicrobial resistance, ability of the antibiotic to penetrate lung tissue and speed of lung penetration 153 . Continuous infusions can increase the amount of time antibiotics exceed the MIC and have been shown to improve clinical outcomes with certain antibiotics 154 . In addition, some patients will have infections that require surgical intervention, including localized or diffuse peritonitis 155 , soft tissue infections (including necrotizing fasciitis) and empyema, which requires chest tube drainage of the pleural space.

Respiratory support

Historically, the focus of mechanical ventilation in acute respiratory failure has been to maintain adequate oxygenation and carbon dioxide elimination. Several preclinical studies indicated that the common clinical practice of using relatively high tidal volumes and elevated airway pressures for ARDS patients might exacerbate the degree of lung injury 36 . As mentioned above, in 2000, investigators supported by the US National Heart Lung and Blood Institute ARDS Network completed a randomized phase III clinical trial in which a tidal volume of 6 ml per kg PBW, compared with the more common higher tidal volume of 12 ml per kg PBW, improved survival, shortened duration of mechanical ventilation, attenuated systemic inflammation and accelerated recovery of extra-pulmonary organ failures 94 , and the biologic findings were reported in other studies 105 , 108 , 109 , 110 . Thus, with the discovery of the major role that mechanical forces play in the pathogenesis of lung injury, optimizing ventilator support to minimize VALI has become central to clinical management of ARDS, leading to the concept of lung-protective ventilation.

Tidal volume

The ARDS lung is non-uniformly aerated, with nonaerated areas predominantly in gravity-dependent regions, owing to the superimposed weight of inflammatory pulmonary oedematous fluid 156 . Aerated lung volume is much smaller than normal, a phenomenon termed baby lung, identified and illustrated first with CT scans; this concept of the baby lung accounts for the low compliance of the respiratory system because it identifies the areas of the lung that are consolidated with oedema and inflammation and associated atelectasis 157 . Thus, lower tidal volumes are needed in ARDS to prevent regional overdistension, as described above. However, scaling tidal volume to PBW targets estimated healthy lung size, although aerated baby lung volume can differ substantially between patients. Although the crucial importance of the use of a low tidal volume is now universally accepted, the best method for scaling tidal volume to patient-specific surrogates of stress or strain is still debated 158 , 159 and warrants further investigation. Targeting airway driving pressure (plateau pressure minus PEEP) is one strategy for tailoring tidal volume to patient-specific mechanics that has garnered considerable attention 159 , but a universally safe threshold has yet to be validated in a prospective trial. For patients with mild lung injury at lower risk of biophysical injury, the benefit conferred by lowering tidal volume should be weighed against risks of more aggressive sedation or use of paralytics if needed to achieve the intended tidal volumes. Real-time bedside imaging techniques such as electrical impedance tomography hold some potential to identify overdistension or tidal recruitment with each breath, which could be useful for monitoring protective ventilation and to individualize ventilator strategy.

PEEP (5–20 cmH 2 O) is a key element of protective ventilation 91 and is routinely applied in all patients with ARDS to facilitate adequate oxygenation and maintain alveolar recruitment. The ideal PEEP might be sufficiently high to prevent cyclic opening and collapse of distal airspaces during tidal ventilation yet low enough to avoid tidal overdistension. Unfortunately, there is still not a reliable method to assess at the bedside the risk-to-benefit ratio of different PEEP levels in individual patients. Titrating PEEP to offset oesophageal pressure, a surrogate of pleural pressure, showed promise in a single-centre study 160 , but the results from a follow-up multicentre trial indicate no benefit for clinical outcomes for titrating PEEP by an oesophageal-guided strategy, compared with empirical high PEEP in patients with moderate or severe ARDS 161 . No multicentre clinical trials to date have definitively shown that any one PEEP titration strategy provides superior patient-centred outcomes 162 , 163 , 164 . However, in accordance with data from studies assessing lung recruitability with CT scan 156 , a meta-analysis of these trials suggests that higher levels of PEEP might be preferable in moderate or severe ARDS but not in patients with mild ARDS 165 . Recruitability is a term used to identify distal airspaces of the lung that may be collapsed or oedematous that could be inflated with higher levels of PEEP, therefore, participating in gas exchange. However, a recent study reported worse outcomes with a strategy of aggressive recruitment manoeuvres (to open the collapsed lung) and very high PEEP in patients with moderate or severe ARDS receiving 6 ml per kg PBW tidal volume 166 . To maximize benefit and limit the risk of overdistension, further reduction in tidal volume may be necessary when using high PEEP. The role of recruitment manoeuvres in managing ARDS is uncertain at this time 167 ; whereas a brief recruitment manoeuvre (for example, 30 seconds of continuous airway pressure applied at 30 cmH 2 O) may transiently improve oxygenation in some patients, the impact of repeated manoeuvres with higher airway pressures and for a longer duration on clinical outcomes remains unclear 168 .

Prone positioning

By modifying the regional distribution of transpulmonary pressure, prone positioning decreases regional heterogeneity of lung aeration, leading to an improvement of gas exchange and a decreased risk of mechanical lung injury 169 . In the multicentre PROSEVA trial 170 , prone positioning improved survival and shortened the duration of mechanical ventilation compared with supine positioning. Unlike prior trials that yielded mixed results, PROSEVA enrolled only patients with moderate or severe ARDS (PaO 2 /FiO 2 <150 mmHg) (Box  1 ), used prone positioning early in the patient’s course, prescribed the prone position for at least 16 hours per day, tailored treatment course to patient recovery and used concomitant low tidal volume ventilation — all potential requisites for therapeutic efficacy 171 . Long sessions of the prone position are now recommended in most patients with severe ARDS 172 .

Neuromuscular blockade

In spontaneously breathing patients with acute lung injury, it is possible that elevated transpulmonary pressures may exacerbate the degree of lung injury, thereby raising the question of whether intubation and ventilation with lower tidal volumes and reduced transpulmonary pressure might be beneficial 173 . In addition, owing to a high respiratory drive, ventilated patients with ARDS frequently exhibit strong respiratory effort even when receiving high doses of sedatives. This respiratory effort may result in severe patient–ventilator dyssynchronies and increased mechanical lung injury owing to high transpulmonary pressures and/or cyclic atelectasis 173 , 174 . Paralysis can prevent these effects; thus, neuromuscular blockade may decrease mechanical lung injury. In a multicentre trial in patients with severe ARDS, infusion with the neuromuscular-blocking drug cisatracurium for 48 hours improved adjusted survival and ventilator-free days compared with deep sedation without cisatracurium 175 . Results are expected soon for a follow-up multicentre trial comparing cisatracurium to protocolized sedation managed according to usual care 176 .

Noninvasive respiratory support

For patients with mild ARDS (Box  1 ), avoiding invasive mechanical ventilation altogether may be beneficial. Invasive positive-pressure ventilation and the related co-interventions carry their own risks: sedative infusions that predispose to delirium, decreased mobility that predisposes to neuromuscular weakness and risk of ventilator-associated pneumonia, among other complications 177 , 178 . Noninvasive positive-pressure ventilation improves oxygenation 179 and is used often in patients with mild ARDS but without a clear benefit on outcome 180 ; device interface may influence patient tolerance and efficacy 181 , 182 . High-flow oxygen (for example, up to 60 l per min) via large-bore nasal cannula is safe, well tolerated and effective in supporting patients with mild ARDS, in part by providing low level PEEP and modestly increasing carbon dioxide excretion 151 , 183 . As mentioned earlier, one recent study found that high-flow nasal cannula led to lower mortality than noninvasive ventilation or usual care 151 , and additional studies are ongoing. The optimal threshold to proceed to intubation and the drawbacks of delaying invasive support in patients who are progressing towards such have not been well defined.

Fluid management

Dating back to 1978, several preclinical studies indicated that elevated lung vascular hydrostatic pressure would increase the quantity of pulmonary oedema in animal models of ARDS 184 . In 2006, a randomized clinical trial in 1,000 patients with ARDS demonstrated that adopting a fluid-conservative approach after vasopressor-dependent shock had resolved led to an increase in ventilator-free days and improved oxygenation index 185 . In the trial, the fluid-conservative arm was guided by a detailed algorithm that required measurement of central venous or pulmonary arterial wedge pressure measurements every 4 hours to determine the use of diuretics to achieve lower vascular filling pressures. Since that trial, a simplified fluid-conservative approach has been recommended to reduce overall fluid balance by 500–1,000 ml per day in patients with ARDS who no longer have shock by reducing intravenous fluids and using diuretics. In the presence of haemodynamic instability, transpulmonary thermodilution estimation of extravascular lung water could help identify risk of exacerbating pulmonary oedema with a volume challenge, potentially helping inform resuscitation. Some have cautioned against overly conservative fluid management, citing a small study that suggested that a fluid-conservative strategy might be associated with long-term cognitive impairment; however, methodological issues, potential survivorship bias and underpowering limit definitive conclusions 185 , 186 . This trial also demonstrated no value in using a pulmonary arterial catheter compared with a central venous fluid catheter to guide fluid management, as mentioned above 121 . No randomized controlled trial has assessed conservative fluid therapy in children with ARDS, but one observational study indicated that elevated cumulative fluid balance on day 3 of PARDS was associated with higher mortality, especially in patients with concomitant acute kidney injury 187 .

Rescue therapies

To maximize efficacy, therapies for ARDS should be instituted early in the patient’s course. Some patients experience continued clinical deterioration despite optimized standard therapies; in this scenario, clinicians may consider use of so-called rescue therapies. Although no rescue therapy has been definitively proved to be beneficial, several interventions described below may have value 188 .

Veno-venous extracorporeal membrane oxygenation

Veno-venous extracorporeal membrane oxygenation (ECMO) is a treatment in which blood is circulated outside of the body for oxygenation on a gas-permeable membrane. ECMO has been proposed as a rescue therapy for patients with established very severe ARDS; for these trials, patients are typically those with severe ARDS (Box  1 ) in whom sufficient correction of gas exchange is inconsistent with lung-protective ventilation 189 . Observational data from the 2009 influenza A H1N1 virus epidemic suggested that ECMO rescue may have a role for patients with refractory hypoxaemia due to isolated pulmonary failure 190 . One trial in 249 patients with very severe ARDS, refractory hypoxaemia and/or hypercapnia randomly assigned participants to ECMO or continued conventional treatment. The trial reported an 11% absolute reduction in 60-day mortality with ECMO with ventilator settings targeting very low tidal volumes to achieve a plateau airway pressure less than 24 cmH 2 O, compared with the now conventional strategy of 6 ml per kg PBW tidal volumes and plateau airway pressures up to 30 cmH 2 O 191 . However, this clinically substantial effect for survival did not achieve statistical significance ( P  = 0.09), leaving the role of ECMO in very severe ARDS open for debate 192 . The best potential candidates for ECMO are patients with very severe ARDS within the first week of mechanical ventilation and without multiple organ failure 189 , 191 . To optimize the risk-to-benefit ratio, ECMO should be provided only in centres experienced in both the care of severe ARDS and the use of extracorporeal support 189 .

Extracorporeal CO 2 removal

Extracorporeal CO 2 removal partially removes CO 2 from the venous blood using a moderate (0.5-1 l per min) extracorporeal blood flow. This method permits the use of very low tidal volume (3–4 ml per kg PBW) without causing severe respiratory acidosis 193 . This so-called ultra-protective strategy has been shown to attenuate biomarkers of inflammation in bronchoalveolar lavage and blood in pilot trials in humans 194 , 195 , indicating that some patients experience ongoing VALI with conventional protective ventilation. As with all extracorporeal methods, extracorporeal CO 2 removal carries its own risks, especially bleeding. Pending the results of ongoing studies, the benefit of ultra-protective ventilation associated with extracorporeal CO 2 removal on outcomes in patients with ARDS remains unknown.

Glucocorticoids

Methylprednisolone was among the first therapies tested in trials for preventing acute lung injury 143 , 144 , intuitively appealing for its anti-inflammatory properties. Up to one-fifth of patients with ARDS receive systemic steroids 5 , although their efficacy for attenuating lung injury remains unclear. Although some have reported a positive effect of steroids on survival 196 , a multicentre trial of methylprednisolone versus placebo for persistent moderate to severe ARDS observed no survival benefit (7–28 days duration) 197 . Steroids accelerated resolution of respiratory failure and circulatory shock but also increased risk of neuromuscular weakness; patients initiating steroids >14 days after ARDS onset experienced increased mortality. Thus, steroids should probably not be initiated 2 weeks after ARDS onset and have an uncertain risk-to-benefit ratio even when initiated earlier, unless the specific cause of ARDS is Pneumocystis carinii pneumonia 198 . The effectiveness of steroids as adjunct therapy in P. carinii pneumonia may be related to anti-inflammatory effects, although the benefit has not been demonstrated convincingly in other pathogenic causes of ARDS. On balance, the role for corticosteroids in early ARDS remains controversial owing to mixed results from existing literature and no definitive large-scale trial in the era of lung-protective ventilation.

Inhaled pulmonary vasodilators

Inhaled nitric oxide and prostaglandin achieve selective vasodilation of the pulmonary circulation, improving ventilation-perfusion matching and, transiently, oxygenation in patients with ARDS 199 . However, a benefit in patient-centred outcomes such as mortality has not been demonstrated 200 . Pulmonary vasodilation could benefit patients with ARDS in whom associated acute cor pulmonale (right heart failure) is contributing to circulatory failure 201 .

Alternative ventilator modes

High-frequency oscillatory ventilation (HFOV) is a mode of ventilation support that uses very rapid respiratory rates and very low tidal volumes in an attempt to maximize lung recruitment and avoid cyclic alveolar collapse. In two recent trials in adults with ARDS 202 , 203 , HFOV conferred no benefit compared with conventional ventilation, and in one trial mortality was increased. Thus, HFOV should be used with extreme caution, if at all, in adult ARDS. HFOV is more commonly used in children with ARDS 204 , and the PROSPECT study is currently evaluating its effectiveness using a factorial design. Ventilation modes that combine controlled breaths and unassisted spontaneous breaths, such as airway pressure release ventilation, may improve oxygenation and haemodynamics while decreasing the need for sedation 205 , 206 . However, concern for VALI risk warrants its limited use until studied further 207 .

Other pharmacological or adjunct therapies

Multiple pharmacological therapies to improve clinical outcomes in ARDS have been studied in phase II and phase III trials, but none have shown efficacy. The list of unsuccessful therapies includes surfactant replacement, aerosolized and intravenous β 2 -adrenergic agonists, prostaglandin E 1 , activated protein C, antioxidants, omega-3 supplementation, ketoconazole (an anti-fungal), lisofylline (an anti-inflammatory), recombinant human factor VIIa, IFNβ1α, granulocyte–macrophage colony-stimulating factor and statins 208 . However, it is certainly possible that one or more of these treatments might have been effective if a predictive enrichment strategy had been incorporated in the trial design, as illustrated in a recent study 114 . In addition, optimal targets for arterial oxygenation and arterial CO 2 concentration have not been defined in ARDS or other critical care conditions; once the targets are established, it may be possible to test more specific oxygenation targets in clinical trials.

Quality of life

The longitudinal evaluation of survivors of ARDS helped spark a research agenda tracking long-term morbidity after critical illness; different assessments of QOL and function have been used in ARDS survivors. Through the mid-1990s, long-term outcomes in ARDS focused primarily on the pulmonary system 209 , 210 , 211 . Over the past two decades, the assessment of longer-term outcomes has expanded to include several new methods for clinical assessments. These methods have included QOL measures focused on limitations in functional domains, including muscle weakness and quantitative walking distance, as well as neurocognitive measures that include attention, memory, concentration and mood disorders. In addition, data have been collected on caregiver burden, medical complexity and increased health-care costs. Here, we consider the evolution of outcome measures in survivors of ARDS.

Early reports observed that some survivors of ARDS experienced obstructive and restrictive ventilatory deficits that persisted for weeks to months after recovery from acute illness 209 , 210 , 211 . Variability in outcome among survivors may be related to differences in study sample selection, clinical management during the acute illness, duration and completeness of follow-up, heterogeneity in baseline pulmonary disease and variable contributions from long-term respiratory muscle and diaphragmatic muscle weakness. Nevertheless, most patients recover near-normal pulmonary function within 6–12 months after ARDS 209 , 210 , 211 .

QOL studies have consistently demonstrated a decrement in physical function domains among survivors of ARDS. Early reports postulated these decrements might be due to exercise limitation from residual pulmonary function abnormalities 212 , 213 , 214 . Later studies combined pulmonary and functional outcome measures with QOL assessments, observing that both pulmonary function and self-perceived overall health gradually improve through 6 months after the acute illness. However, the severity of disability was not wholly explained by changes in pulmonary function or respiratory symptoms 215 . The aetiology of this reported dysfunction was uncertain. A later study combined measures of pulmonary function with an evaluation of quality-adjusted life years using the Quality of Well-Being Scale (a general health questionnaire that measures well-being over the previous 3 days in terms of physical activities, social activities, mobility and symptoms) and found that ARDS survivors had poor quality-adjusted survival associated with an important illness burden. Again, the specific contributors to this dysfunction remained unclear 216 .

A subsequent study combined serial QOL, pulmonary function and 6-minute walk test (a commonly used test to assess cardiopulmonary capacity) data with in-person history and physical examination and an evaluation of pattern and cost of health-care utilization 217 . With more detailed follow-up evaluations, these investigators observed that survivors of ARDS had significant exercise limitation and poor physical QOL at 1-year follow-up related to marked muscle wasting and weakness; myriad physical disabilities including heterotopic ossification, joint contractures and tracheal stenosis; and cosmetic concerns related to scarring at tracheostomy, central line or chest tube sites. This study focused attention on muscle dysfunction as a major morbidity after ARDS and served to highlight the prevalence and persistence of medical complexity after critical illness 217 . This same group of investigators continued follow-up to 5 years after ARDS and noted persistence of disability and compromised QOL, which were associated with increased cost and health-care use 218 . These findings are robust and have been replicated by many other investigators 219 , 220 , 221 .

Hopkins and her group were the first to describe neurocognitive and mood disorder outcomes in survivors of ARDS. They noted important decrements in attention, concentration, processing speed, memory and executive function that persisted up to 2 years after discharge from intensive care 222 , 223 . Post-traumatic stress disorder in patients with ARDS has also been described and is associated with decrements in the mental health domains of the 36-Item Short Form Survey (SF-36) QOL measure 213 . These observations have led the way for other investigators to evaluate neurocognitive dysfunction and its risk factors in ARDS and other survivors of critical illness, including hypoglycaemia during the intensive care stay 224 , hypoxaemia and fluid resuscitation 186 , duration of delirium 225 and premorbid functional status 226 .

The observation of persistent muscle wasting and weakness in ARDS survivors has spawned intense interest in an entity described as intensive care unit-acquired weakness (ICUAW), which is the consequence of a myosin depletion myopathy and axonopathy occurring in isolation or together 227 . Injury to the diaphragm and muscles of the axial skeleton is due at least in part to upregulation of the ubiquitin-proteasome pathway and marked proteolysis that begins within hours of the critical illness 228 and may continue throughout the first week of the illness 229 . Recent seminal observations show that muscle repair after an episode of critical illness may be differential and the recovery of contractile force and muscle mass may be discordant at long-term follow-up 230 .

One challenge for studies of long-term outcomes is knowing the baseline status of the patients with ARDS. Thus, the extent to which the deficits manifested before developing ARDS is not always clear. In addition, the deficits may be a function of prolonged and severe critical illness rather than specifically from ARDS.

In the past two decades, outcomes from ARDS have improved considerably from the first reports of the syndrome, in which the majority of patients did not survive. However, mortality remains a serious threat, and long-term complications remain common and problematic in survivors. Additional research on several fronts may help to improve prognosis. From a mechanistic perspective, there is a need for strategies that can mitigate lung endothelial and epithelial injury and novel approaches that promote lung endothelial and epithelial repair. In addition, there is a need to optimize preclinical models for testing novel therapies in ARDS to improve the pipeline from drug discovery to improved patient outcomes.

In the clinical setting, increased recognition of ARDS in all regions of the world is important to better identify patients earlier in their clinical course so that supportive care with lung-protective ventilation and a conservative fluid approach can be implemented. Prognostic and/or predictive enrichment approaches that include biological and clinical variables in randomized trials may improve the chances of identifying responsive subsets of patients with ARDS. Some have questioned whether the syndromic definition of ARDS will continue to be useful given its lack of specificity, overlap with other distinct syndromes (that is, ARDS mimics) and the relentless failure of pharmacotherapeutics in this condition; however, there is not yet a consensus within the field on a suitable alternative approach.

There is new evidence that the degree of pulmonary oedema can be quantified on the chest radiograph 231 , a method that can applied rapidly for assessing all four quadrants of the standard anterior–posterior radiograph in the intensive care unit. In addition, a clinically practical method (the ventilatory ratio) for estimating pulmonary dead space has been validated 232 . Thus, a modified lung injury score that incorporates oxygenation abnormalities (PaO 2 /FiO 2 ), the level of PEEP, the pulmonary dead space and the degree of pulmonary oedema may prove useful to combine with the promising biological variables for risk stratification in clinical trials. Novel diagnostic approaches may improve our ability to identify and treat causative pathogens in patients with ARDS, thereby improving patient outcomes 233 . Extracorporeal therapies may provide life-sustaining support for severe ARDS 234 . Multi-pathway targeted cell-based therapies such as mesenchymal stromal cells show promise as a potential therapeutic option because they have the capacity to reduce lung vascular injury, restore alveolar epithelial fluid transport properties to remove alveolar oedematous fluid and switch the pro-inflammatory responses to a pro-resolving paradigm 235 , 236 . Finally, increased understanding of the importance of long-term patient-centred outcomes may lead to both improved mechanistic understanding of the causes of these sequelae and improved efforts to design trials that target these symptoms 237 .

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Acknowledgements

The authors declare the following grant support: M.A.M. by the US National Health Lung and Blood Institute (NHLBI; HL140026 and HL134828); C.S.C. by NHLBI (HL140026); G.A.Z. by NHLBI (HL044525, HL077671 and HL130541); Y.M.A. by the Miracle Trial; J.R.B. by NHBLI (HL133489); R.L.Z. by NHLBI (HL131608); A.G.R. by the US National Institute of Child Health and Disease (HD095228); and M.H. by the Canadian Institute of Health. The authors thank S. Ke, University of California–San Francisco, for assistance with organizing the reference list for this article.

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Introduction (M.A.M. and C.S.C.); Epidemiology (M.A.M., A.G.R. and C.S.C.); Mechanisms/pathophysiology (M.A.M., R.L.Z., G.A.Z. and C.S.C.); Diagnosis, screening and prevention (M.A.M., Y.M.A., A.G.R. and C.S.C.); Management (M.A.M., J.R.B., A.M. and C.S.C.); Quality of life (M.H.); Outlook (M.A.M. and C.S.C.); Overview of the Primer (M.A.M. and C.S.C.)

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M.A.M. declares grant support from Bayer (current), GlaxoSmithKline (prior) and Amgen (prior); has served as Data Safety and Monitoring Board chair for Roche-Genentech and has served as a consultant for GlaxoSmithKline, Bayer, Boehringer, CSL Berhring, Navigen, Quark and Cerus. G.A.Z. has served as a consultant for Navigen. Y.M.A. has served as a consultant for Gilead Sciences (past), Regeneron (past) and SAB Therapeutics (current). A.M. received fees for serving on a steering committee for Faron Pharmaceuticals, consulting fees from Air Liquide Medical Systems, grant support for research and lecture fees from Fisher & Paykel and Covidien, and lecture fees from Drager, Pfizer and ResMed. A.G.R. declares grant support from Roche-Genentech (current) and has served as a consultant for La Jolla Pharma and Bristol Meyer Squibb. C.S.C. declares grant support from Bayer (current) and GlaxoSmithKline (prior) and has served as a consultant for GlaxoSmithKline, Bayer, Boehringer, Prometic, Roche-Genentech, CSL Behring and Quark. The remaining authors declare no competing interests.

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Matthay, M.A., Zemans, R.L., Zimmerman, G.A. et al. Acute respiratory distress syndrome. Nat Rev Dis Primers 5 , 18 (2019). https://doi.org/10.1038/s41572-019-0069-0

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COVID-19 pandemic is a serious concern in the new era. Acute respiratory distress syndrome (ARDS), and lung failure are the main lung diseases in COVID-19 patients. Even though COVID-19 vaccinations are available now, there is still an urgent need to find potential treatments to ease the effects of COVID-19 on already sick patients. Multiple experimental drugs have been approved by the FDA with unknown efficacy and possible adverse effects. Probably the increasing number of studies worldwide examining the potential COVID-19 related therapies will help to identification of effective ARDS treatment. In this review article, we first provide a summary on immunopathology of ARDS next we will give an overview of management of patients with COVID-19 requiring intensive care unit (ICU), while focusing on the current treatment strategies being evaluated in the clinical trials in COVID-19-induced ARDS patients.

The 2019 novel coronavirus outbreak started in the Chinese city of Wuhan and quickly spread worldwide, leading the World Health Organization (WHO) to declare a Global Health Emergency on January 30, 2020 [ 1 ]. Later on, it was declared as a global pandemic on March 11 [ 2 , 3 ]. This latest novel coronavirus, SARS-CoV-2, spreads more quick than its two closest common ancestors, the Severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), but has lower fatality. Infection can be spread through the droplet spray produced when coughing and sneezing by both symptomatic patients and asymptomatic carriers before the onset of the symptoms [ 4 ]. The respiratory system involvement is the most frequent complication of Coronavirus disease 2019 (COVID-19) [ 5 ]. Pneumonia caused by the SARS-CoV-2 virus presents with fever, dyspnea, and acute respiratory symptoms which can lead to refractory pulmonary failure [ 6 , 7 ]. It is common among COVID-19 patients to develop acute respiratory distress syndrome (ARDS), a life-threatening form of respiratory failure [ 8 , 9 ]. According to weighted averages calculated using data from individual studies which have data available for COVID-19, approximately 1/3 (33%) of hospitalized patients develop ARDS. And nearly 3/4 (75%) of COVID-19 patients admitted to the ICU have ARDS [ 8 ]. ARDS was initially defined in 1968 with clinical symptoms including acute hypoxemia, non-cardiac pulmonary edema, low pulmonary compliance, and increased work of breathing [ 10 ].

ARDS occurs due to both direct viral effects and host cell-derived substances [ 11 ]. Activated cells of the immune system release several products such as neutrophil myeloperoxidases and other proteinases, eosinophil major basic proteins and cationic proteins, and excessive production of proinflammatory cytokines including IL-6 and TNF-α, that can ensue aggravation of ARDS and extensive tissue damage resulting in multi-organ dysfunction and mortality [ 12 , 13 ]. Although the exact mechanism of SARS-CoV-2 in ARDS is not fully understood yet, the induction of cytokine storm is considered to be one of the leading factors [ 14 ]. ARDS caused by COVID-19 differs considerably from ARDS caused by other factors based on Berlin criteria, and therefore treatment is different as well [ 5 ]. The onset time of COVID-19-associated ARDS is 8 to 12 days [ 15 ]. This is contrary to the Berlin ARDS criteria, which defined an onset limit of 1 week [ 16 ]. Patients with COVID-19 ARDS may have normal or even high lung compliance; this is not the case in patients with classic ARDS [ 5 ]. COVID-19 ARDS severity is redefined into three stages based on its specificity: mild, mild-moderate and moderate-severe [ 17 ]. Thus, the dependence on mechanical ventilation of COVID-19 ARDS is longer than that of non-COVID-19 ARDS [ 18 ]. In typical ARDS, the most frequently used adjuvant therapies are continuous neuromuscular blocking agents, high-dose corticosteroids, and recruitment maneuvers [ 19 ]. Due to the anti-inflammatory effects of corticosteroids, they are considered a possible treatment for ARDS and WHO strongly recommended systemic corticosteroid therapy for patients with severe and critical COVID-19, and recommended against corticosteroid therapy for patients with non-severe COVID-19 [ 20 ]. Several drugs including lopinavir-ritonavir, remdesivir, ruxolitinib and tocilizumab are undergoing clinical trials as a treatment for COVID-19, but yet no proven effective therapies currently exist [ 21 , 22 , 23 ].

In this review, we first describe the immunopathology of ARDS, then we intend to highlight the management of intensive care unit patients with COVID-19-related ARDS while focusing on the current status of promising emerging therapies although there is no particular recommended antiviral medication.

Search strategy

We searched the PubMed and google scholar to retrieve eligible articles of any publication status and in English from December 1, 2019, to June 20, 2021, using the following key words: Therapeutic management, Therapeutic strategy, Antiviral therapies, Immunomodulatory therapies, anti-inflammatory drugs, NSAIDs, corticosteroids, MSC therapies, Interleukin-6 inhibitors, Janus kinase inhibitors, Convalescent plasma, IVIG, anti-fibrotic therapies, Anticoagulant therapies, Anti anaemic therapies. Each key word was searched with the following string of key words (using the “AND” operator): COVID-19-related-ARDS OR coronavirus-related-ARDS OR “SARS-CoV-2-related-ARDS” OR “Severe Acute Respiratory Syndrome Coronavirus 2” OR their derivates. In addition, we identified other eligible studies by searching the reference lists of relevant articles as well as unpublished studies in ClinicalTrials.gov. Studies which provided information on the treatment of COVID-19-related ARDS were identified. After screening title and abstracts for relevant studies, full texts were carefully checked for inclusion.

Immunopathology of ARDS

It is discovered that for RNA viruses, coronavirus included, pathogen-associated molecular patterns (PAMPs) in the structure of viral RNA genomes, or the dsRNA replication intermediates, are recognized via either endosomal receptors, TLR3 (toll-like receptor 3) and TLR7 (toll-like receptor 7), or by cytosolic sensors of RNA, RIG-I/MDA (retinoic acid-inducible gene I/melanoma-differentiation-associated gene) [ 24 ]. These events lead to the transcriptional activation of interferon-stimulated genes and nuclear factor-κB-regulated genes (NF-κB) as well as immune effectors and regulatory cell recruitment [ 25 ]. Alveolar epithelial cells (AECs), alveolar macrophages (AMs), and dendritic cells (DCs) have key roles as sensor cells that detect danger signals via the receptors known as pattern recognition receptors (PRR) and initiate innate immunity. Recruitment of effector cells due to activated sensor cells lead to the secretion of a first wave of cytokines (AECs secrete IFNλ, CCL2, AMs secrete IFNα, IFNβ, IL-6, TNF, IL-12 and DCs secrete IL-12, IL-23, IL1β) to alert and stimulate resident lymphocytes [ 26 ]. The upregulation of type I IFN should be capable of suppressing the virus replication and dissemination during the early phase. In a SARS-CoV mouse model, it has been demonstrated that dysregulation of type I IFN and inflammatory monocyte macrophages cause fatal pneumonia. Consequently, exaggerated secretion of type I IFN and the infiltrated myeloid cells, negatively affect the result of the infection and are the key factors of lung damage and dysfunction [ 24 ]. Subsequently, as a part of the innate immunity the release of chemokines, including CCL2, CCL5, CXCL8, and CXCL10, results in the recruitment of neutrophils and NK cells to the lung parenchyma [ 25 ]. Neutrophils produce toxic agents, such as reactive oxygen species (ROS) and proteases. Considerable production of free radicals by neutrophils overwhelms endogenous anti-oxidant systems, leading to oxidative cell injury. This robust inflammatory reaction due to the activation of neutrophils plays a key role in the ARDS pathogenesis [ 27 ]. Similarly, NK cell recruitment during influenza virus infection exerts both pro-necrotic and -apoptotic effects through the release of granzymes and perforins; indeed, excessive NK cell–mediated cytotoxicity is linked to lethal influenza virus infection due to uncontrolled lung damage. Furthermore, infiltrating monocyte-derived macrophages and DCs by releasing other pro-inflammatory mediators such as TNF-α and nitric oxide, play key roles in influenza clearance and alveolar injury by inducing epithelial cell apoptosis [ 25 ]. DCs play important role in bridging the innate and adaptive immune systems via presenting pathogen antigens to the T cells located at lymph nodes. Once in the lung, cytotoxic T cells recognize the pathogen and kill pathogen-infected cells and remove the source of further infection. Helper T cells modulate inflammation in a myriad of strategies, including the excessive production of cytokines such as type-II interferon (IFN-II) and generate the memory against the pathogen and also activate B cells to differentiate in the germinal centers of conventional lymphoid tissues to produce antibodies specific to the pathogen [ 28 ]. Through the secretion of IL-10 and TGFβ, Treg cells suppress inflammation and restore homeostasis [ 26 ]. Comparing patients with ARDS, pneumonia, and healthy controls, researchers found that ARDS patients had increased IL-10-producing CD4 + T cells [ 29 ]. As well, ARDS survivors had more IL-10 producing CD4 + T cells than non-survivors [ 29 ]. In a small proportion of infected individuals, these immune processes can completely suppress viral replication or eliminate virus infection. Others have incomplete viral suppression and a reduction of circulating B and T cells followed by a mechanism as yet unknown. Cytokine storm, a serious condition caused by sustained viral replication, occurs in some patients and it has been shown to be the main cause of COVID-19 related ARDS [ 30 ]. Some of the cytokines and chemokines overexpressed during the cytokine storm include IL-1β, IL-2, IL-6, IL-10, TNF-α, IFN-γ, IP-10, MIP-1, and MIP-1α [ 31 ]. Serum IL-6 concentration has been associated with disease severity and mortality, suggesting IL-6 plays a central role [ 30 ]. As IL-6 circulates, it binds soluble IL-6 receptors, forming a complex with a gp130 dimer on the surface of some cells. The complex induces JAK-STAT3 activation in various cell types, including endothelial cells, leads to cytokine storm and finally may cause fatal symptoms such as ARDS in a subgroup of hospitalized COVID-19 patients [ 30 , 32 ]. So blocking these immune pathways could be beneficial against cytokine storm and ARDS in patients suffering from COVID-19 in a severe form [ 30 ].

Management of patients with ARDS in the intensive care unit (ICU)

A 1-week onset limit is defined by the ARDS Berlin criteria for a person to be diagnosed as having ARDS which is inconsistent with the onset time of COVID-19-related ARDS that is 8–12 days. So, greater attention must be paid to the ARDS development in patients with a course of longer than 1 week [ 5 ]. The management of ARDS patients is critical for survival, and should be taken into account by relevant specialists [ 33 ]. ARDS patients presenting with SpO 2  < 94% on room air at sea level, respiratory rate > 30 breaths/min, PaO 2 /FiO 2  < 300 mmHg or lung infiltrates > 50%, may require aerosol-generating procedures (AGPs). Compared to standard oxygen therapy, high-flow nasal oxygen (HFNO) decreases the requirement of endotracheal intubation in patients with ARDS. It has been suggested that HFNO may be safe in mild/moderate COVID-induced ARDS patients, and even in some moderate/severe patients [ 34 ]. Increasing lung capacity by the recruitment of previously collapsed units is often achieved by the use of high positive end-expiratory pressure (PEEP) levels, recruiting maneuvers, and prone positioning [ 35 ]. Prone positioning can improve oxygenation and survival in patients but care should be taken to turn them safely [ 36 , 37 ]. For cases with suspected bacterial pneumonia or sepsis as a secondary infection, empiric antibiotics should be administered and re-evaluated daily, and, in case of no bacterial infection, antibiotic treatment should be de-escalated or stopped [ 38 ]. The evaluation should include the imaging of pulmonary (chest x-ray, ultrasound, and, if indicated, CT) and an electrocardiogram (ECG) if necessary and A laboratory test consisting of a complete blood count (CBC) with differential, metabolic panel, liver and renal function tests [ 38 ]. Even though measurement of inflammation markers such as CRP and D-dimer is not included in standard care, it can provide valuable prognostic information. Currently, limited information is available which suggests that the intensive care management of COVID-19 patients should be substantially different from the management of other ICU patients, although safety precautions are essential to avoid viral contamination. As for every ICU patient, successful COVID-19 clinical management depends on attention to the primary conditions leading to admission to ICU, but also to other comorbidities and hospital-acquired complications [ 38 ].

Emerging therapies for COVID-19-induced ARDS

Although there is only one antiviral, Remdesivir, approved by the U.S. Food and Drug Administration (FDA) to treat hospitalized COVID-19 patients, many medications are being tested and currently, researchers are investigating other potential treatments for COVID-19 [ 38 ]. Two different strategies have been tested as potential “cures” for COVID-19, one strategy is to target the virus directly (reducing virus replication, receptor binding, etc.) and the other strategy is to modulate the innate and adaptive immune responses of the host against the virus infection (targeted or nonspecific immune-modulating drugs) [ 39 ]. A properly combined anti-inflammatory and anti-viral medication with doses adjusted according to the symptom severity and immune cell counts may help improve survival outcomes [ 28 ]. Much of the information available in research to date is based upon clinical trials, retrospective analyses, or uncontrolled case series, and so ultimate evidence of effectiveness for interventions is still required [ 39 ]. A list of drugs used for the treatment of COVID-19 patients is presented in Table 1 and a summary of the clinical trials investigating COVID-19 and COVID-19-associated ARDS management is provided in Table 2 .

Antiviral therapies /strategies

Remdesivir is an antiviral drug that exhibits potent in vitro efficacy against SARS-CoV-2 [ 40 ]. Remdesivir is the first FDA approved medication (on October 22, 2020) for COVID-19 hospitalized patients. Remdesivir (also GS-5734) was developed by Gilead Sciences for the treatment of patients with Ebola virus disease in 2016 [ 53 ]. Although it has not been proved to be effective in human clinical trials for this disease, it has shown antiviral efficacy against coronaviruses including SARS-CoV-1 and MERS-CoV. Based on this information, remdesivir has earned notable attention for its likely use as an option for the treatment of SARS-CoV-2 [ 54 , 55 ]. However, the evidence regarding the efficacy of remdesivir in treating COVID-19 is mixed.

In a randomised, double-blind, placebo-controlled, multicentre trial, Wang et al. demonstrated that remdesivir did not show statistically significant clinical improvements in hospitalized adults with severe COVID-19 [ 56 ]. The final results of a double-blind, randomized, placebo-controlled trial by Beigel et al. revealed that remdesivir is superior to placebo at reducing the duration of recovery in patients with lower respiratory tract infections who were hospitalized with Covid-19. According to their data, the remdesivir-treated patients showed a lower proportion of serious adverse events related to respiratory failure, indicating that remdesivir may have prevented the progression to more severe respiratory disease [ 57 ]. Based on a systematic review of RCTs and observational studies, Piscoya et al. investigated the effects of remdesivir in adult hospitalized patients with COVID-19 and evidence of respiratory insufficiency or pneumonia. The evidence was scarce on the efficacy and safety of 10-day remdesivir regimens, or when comparing 5-day or 10-day regimens to standard of care [ 55 ]. Regardless of the FDA approval, several ongoing RCTs need to be completed in order to evaluate if remdesivir has a clinically effectiveness and safety profile. Emdesivir cannot be concluded to be effective for treating COVID-19 until stronger evidence is available [ 55 ].

Favipiravir

Favipiravir is a viral RNA polymerase inhibitor, already demonstrated activity against influenza A and B [ 41 ]. The clinical trials of Favipiravir generally do not include patients with critical or severe conditions [ 58 ]. However, these case reports suggest that favipiravir is effective in treating patients with severe or critical conditions. Takahashia et al. shared their experiences with three COVID-19 patients: two were in critical condition, and one was in a very severe condition. All three cases required high dose oxygen therapy or ECMO. Favipiravir helped them recover from SARS-CoV-2 pneumonia, and the oxygenation treatment was tapered. According to their report of three COVID-19 cases, favipiravir may be effective in preventing pneumonia progression and cytokine production, improving respiratory function, and producing immediate effects, even in serious or critical conditions [ 58 ].

Lopinavir/ritonavir

Lopinavir/Ritonavir are inhibitors of the HIV protease and are routinely used in the treatment of AIDS [ 42 ]. In a randomized, controlled, open-label trial, Cao et al. observed that lopinavir-ritonavir therapy compared with standard care, in adult patients with severe Covid-19, did not yield any positive results. They found that Lopinavir/ritonavir treatment failed to reduce risk of death, improve clinical outcomes, or decrease throat viral RNA detectability in patients with severe Covid-19. The results of future trials in patients with severe COVID-19 may confirm or exclude the possibility that the treatment is beneficial [ 42 ].

Chloroquine and hydroxychloroquine (Clq/HClq)

ACE2 allows SARS-CoV-2 virus to enter cells, disrupting the renin-angiotensin-aldosterone axis and possibly contributing to lung damage [ 59 ]. The antimalarial medications, chloroquine, and hydroxychloroquine interrupt ACE2 binding and block viral entry, moreover, they also could affect endosomal and lysosomal pH, which can suppress the merging of the virus with the host cells [ 60 ]. These medications also inhibit the secretion of pro-inflammatory cytokines [ 43 ]. Chloroquine has especially been reported to suppress lung injury induced by influenza A H5N1 in preclinical designs [ 61 ]. In an open-label RCT, as a result of the addition of Clq/HClq to standard care, patients admitted with severe COVID-19 significantly worsened in their clinical status, were at greater risk of renal dysfunction, and required more IMV, even though mortality did not differ. This study concludes that Clq/HClq should be avoided in patients with a more severe form of COVID-19 pneumonia, and can be used to inform clinical practice and guidelines [ 62 ]. Furthermore, according to a meta-analysis, treatment with Clq/HClq does not result in any benefit in mild, moderate, or severe COVID-19 patients. When comparing treatment groups and controls in pooled analysis, no significant difference was observed in clinical recovery, viral clearance, and length of hospital stay. Based on the currently available RCTs, Clq/HClq has no added benefit in the treatment of COVID-19 patients [ 63 ]. Since the HCQ trial failed to show any benefit, WHO and the National Institute of Health discontinued the trial for hospitalized COVID patients [ 64 ].

Angiotensin receptor blockers (ARBs), such as losartan, may also alleviate some of adverse effects of ACE2 induction [ 59 ]. Losartan is currently being tested in patients with COVID-19 [ 39 , 65 ]. Among patients with COVID-19, hypertension (HTN) is a major cause of acute respiratory failure, hospitalization, and mortality [ 66 ]. Losartan and amlodipine were compared in patients with primary HTN and COVID-19 by Nouri-Vaskeh et al. in a randomised clinical trial. Losartan or amlodipine administration did not appear to have any priority for COVID-19 patients with primary HTN [ 66 ]. Further, Bolotova et al. in a feasibility study noted that losartan was well tolerated among hospitalized COVID-19 patients with HTN and did not worsen symptoms [ 67 ]. Bengtsone et al. examined the safety of using losartan to treat COVID-19-related respiratory failure in an open-label, non-randomized trial using an external, post-hoc control group. The study found that Losartan was safe for acute respiratory compromise caused by COVID-19. However, randomized trials are required to evaluate true efficacy [ 68 ].

Immunomodulatory therapies

The selection of anti-inflammatory drugs and their therapeutic doses ought to be based on the severity of the symptoms and should be monitored with the number of immune cells present in the complete blood count (CBC) [ 69 ]. Management of COVID-19 inflammation with NSAIDs and systemic corticosteroids has been controversial [ 70 ]. As overt symptoms of the cytokine storm emerge, anti-inflammatory cytokines like Interferon beta-1b (IFN-β-1b), and therapeutic antibodies targeting pro-inflammatory cytokines or their signaling pathways like Tocilizumab (anti-IL-6), Adalimumab (anti-TNFα), Anakinra (anti-IL-1), and Baricitinib (Janus kinase inhibitor) might be beneficial [ 71 , 72 ].

Corticosteroids

In consideration of the cytokine storm observed during SARS-CoV, MERS-CoV, and SARS-CoV-2 infections, corticosteroids have been commonly used to treat serious illness, for the possible recovery of lung injury induced by inflammation [ 73 ]. Despite the adverse effects of corticosteroid use, such as delayed viral clearance and opportunistic infections, and while initially WHO recommended against corticosteroid therapy, as of September 2, 2020, WHO strongly recommended systemic corticosteroid therapy for patients with severe and critical COVID-19 rather than no systemic corticosteroids [ 20 , 74 ]. The choice of corticosteroid therapy and the length of treatment can be significant and must be taken into notice [ 75 ]. Several clinical trials evaluated the effectiveness of corticosteroid and glucocorticoid therapy in critically ill patients with COVID-19 [ 45 , 76 ]. In a multicentre, randomised controlled trial done by Villar et al. high doses of dexamethasone, 20 mg per day, from day 1 to 5, then 10 mg per day from day 6 to 10 were administered in all stages of ARDS, even in the mild cases. They demonstrated that early treatment of dexamethasone could decrease overall mortality and ventilator duration in patients with established moderate-to-severe ARDS [ 44 ]. Furthermore, in a randomized clinical trial, Tomazini et al. evaluated the efficacy of i.v. dexamethasone administration in COVID-19 induced moderate to severe ARDS patients. In these patients, standard treatment plus i.v. dexamethasone led to a statistically significant increase in days alive and free of mechanical ventilation over 28 days compared with standard treatment alone [ 77 ]. Moreover, in a controlled, open-label trial, it has been determined that dexamethasone use reduced 28-day mortality in hospitalized Covid-19 patients’ who received either mechanical ventilation or oxygen, but not those receiving no respiratory support [ 78 ]. Some preliminary trial results suggest methylprednisolone and dexamethasone can be used for the severe form of COVID-19 [ 79 ]. Using a randomized control study, Ranjbar et al. assessed the efficacy of methylprednisolone in hospitalized COVID-19 patients, comparing it to regular dexamethasone treatment. Compared to the use of 6 mg/day of dexamethasone in patients admitted to hospital with COVID-19 pneumonia, the administration of 2 mg/kg per day of intravenous methylprednisolone resulted in a shorter hospital stay and less need for mechanical ventilation. Methylprednisolone demonstrated better outcomes in COVID-19 hypoxic patients when compared to dexamethasone [ 80 ]. The results of a meta-analysis of seven RCTs and 6250 severe COVID-19 cases indicated that corticosteroid therapy reduced all-cause death and disease progression rather than increasing adverse events [ 81 ]. In a systematic review and meta-analysis, Chaudhuri et al. summarized RCT findings concerning corticosteroids’ role in ARDS of any cause. Corticosteroids were proposed to be beneficial for patients with all forms of ARDS regardless of their causes. Corticosteroids might reduce mortality rates in ARDS patients and the need for mechanical ventilation. COVID-19 and non-COVID-19 ARDS patients showed the same effect across different corticosteroid types and dosages [ 82 ]. Kumakawa et al. reported a patient with severe ARDS caused by COVID-19. Treatment in this 67-year-old man was managed with late administration of i.v. steroids from day 20th of administration until 27th which was successful. The current report highlights the need for future trials to evaluate the best treatment timing and doses for ARDS induced by COVID-19, as well as selecting the optimal population for different severity COVID-19-induced ARDS [ 83 ]. Due to the affordability and accessibility of corticosteroids in healthcare systems trembling under the strain of the worldwide outbreak of this coronavirus, this area of research should be a universal priority [ 74 ].

Mesenchymal stem cell (MSC) therapies

Mesenchymal stem cells have exhibited immunoregulatory capability which can suppress inflammatory reactions. Chan et al. reported that MSC therapy has beneficial effects on H5N1- induced acute lung injury and may be beneficial to patients with a severe pulmonary illness caused by influenza viruses such as H5N1 and H7N9 [ 84 ].

Lanzoni et al., in a double-blind RCT, examined the safety and efficacy of allogenic UC-MSC infusions in patients with ARDS associated with COVID-19. Their trial results revealed that UC-MSC infusions are safe for COVID-19 patients with ARDS. Furthermore, compared to controls, UC-MSC treatment reduced SAEs, mortality, and recovery time [ 85 ]. Moreover, Shi et al. conducted a double-blind, placebo-RCT at two medical centers in Wuhan, China, assessing the safety and efficacy of iv administration of UC-MSCs in COVID-19 patients with severe lung damage. Following administration of UC-MSC, the lesions of the lung solid component were resolved faster as well as the capability of the integrated reserve improved [ 86 ]. Liang et al. noted that the optional transfer of hUCMSCs, combined with other therapeutics presented good clinical outcomes for a severely ill patient with COVID-19 and acute lung inflammation. Albeit only a case was designated there, it would further be especially valuable to inspire more clinical investigation to manage likewise critically ill patients with COVID-19 [ 87 ]. Moreover, Leng et al. [ 80 ] reported a single-dose clinical trial of MSC therapy in 7 patients with COVID-19 induced ARDS and 3 controls, and a case study by Liang et al. [ 81 ] reported the resolution of all COVID-19 manifestations in a severely ill woman on a ventilator who was administered three intravenous MSC doses. In these 2 reports, all of the 8 patients with COVID-19 induced ARDS made a good recovery following the administration of MSCs, although the follow-up periods differed, and there was no stability in the measurement of biological variables [ 88 ]. MSCs have been shown to be effective and safe in preclinical studies of ARDS models, and the results from Covid-19 clinical trials demonstrated their potential efficacy. Nevertheless, more large-scale trials are needed to verify MSC’s efficacy, particularly in patients with ARDS who have been diagnosed with Covid-19. Additionally, research is needed to establish the optimal cell source, dose and route of MSCs therapies, to develop a safe and effective treatment option for ARDS patients, particularly those who suffer from Covid-19 [ 89 ].

Interleukin-6 inhibitors

Excessive secretion of IL-6 can cause an acute systemic inflammation referred to as cytokine release syndrome (CRS). In the pathogenesis of COVID-19 pneumonia, it has been found that a CRS involving a considerable proinflammatory cytokine secretion occurred, including IL-6, IL-1, and TNF-α [ 90 ]. Xu et al. in a non-controlled retrospective study of 21 patients with SARS-CoV-2-induced ARDS demonstrated that treatment with tocilizumab (TCZ), an interleukin-6 receptor antagonist, could decrease the number of white blood cells and improve CT lung opacity and lung oxygenation [ 46 ]. Based on this data, on March 3, 2020, TCZ, an anti-IL-6 receptor monoclonal antibody, was included in the 7th edition of COVID-19 therapy recommendations by China’s National Health Commission (NHC) [ 90 ]. A single center-based study with 100 patients in Brescia, Italy evaluated the efficacy of intravenous administration of TCZ in the treatment of severe COVID-19 pneumonia and ARDS patients. They observed that more than three-quarters of patients displayed improvements in their clinical outcomes [ 91 , 92 ]. In a RCT of hospitalized patients with COVID-19 pneumonia and PaO2/FIO2 ranging from 200 to 300 mmHg, no difference was shown in the progression of disease between the tocilizumab and the standard care group [ 93 ]. A systematic review and meta-analysis was conducted by Pinzon et al. to evaluate evidence regarding the effectiveness of IL-6 inhibitors in the treatment of COVID-19. In patients with COVID-19, IL-6 inhibitors have shown to be beneficial in reducing mortality, particularly in severely ill cases [ 94 ]. However, additional blinded, placebo-controlled, RCTs should be conducted in well-established settings to evaluate the risks and benefits of IL-6 inhibitor agents across the disease spectrum [ 93 ].

Janus kinase inhibitors (e.g., baricitinib, Ruxolitinib)

Another drug that can be used to block viral entry through ACE2-mediated virus endocytosis is baricitinib, an inhibitor of JAK, that also prevents the cytokine storm and dampens the inflammatory response [ 47 ]. One meta-analysis by Chen et al. evaluated 11 studies of the safety and effectiveness of ruxolitinib and baricitinib in COVID-19 patients. They found these drugs decreased the use of IMV, had borderline effects on rates of ICU admission and ARDS and did not decrease interval of hospitalization. Among the treatments, baricitinib showed the most convincing reduction in the risk of death [ 95 ]. Capochiani et al. investigated the use of JAK inhibitors in the management of patients infected with SARS-CoV-2, including patient selection and dosing and administration information. Despite the small number of patients collected, they reported encouraging results regarding using ruxolitinib as a possible treatment option for severely ill patients with COVID-19 who develop respiratory distress [ 96 ]. In another study, Neubauer et al. have described the first successfully treated case with COVID-19-related ARDS using ruxolitinib. They observed that ruxolitinib therapy resulted in a decreased ARDS-associated inflammatory cytokines levels such as IL-6 and the acute phase protein ferritin, and also was associated with a rapid improvement in cardiac and respiratory systems [ 48 ]. Currently, clinical trials are ongoing to study both ruxolitinib and baricitinib in a prospective manner [ 48 , 74 , 97 ].

Convalescent plasma

Convalescent plasma treatment is nothing new; physicians have used it for SARS, pandemic 2009 influenza A (H1N1), avian influenza A (H5N1), several hemorrhagic fevers including Ebola, and other viral infections [ 98 ]. Convalescent plasma from the blood of people who’ve recovered contains neutralizing antibodies against viral proteins in almost all patients with COVID-19 [ 99 , 100 ]. Therefore, it might be worthwhile to investigate the safety and effectiveness of convalescent plasma therapy in COVID-19 cases [ 101 ]. A randomized controlled trial by Pouladzadeh et al. found that CP had remarkable immunomodulatory and antiviral properties, reducing the cytokine storm and improving the clinical scores in COVID-19 patients, but had little impact on mortality [ 102 ].. Furthermore, Raymond et al. in a randomized, parallel arm, phase II trial with patients with severe COVID-19 disease and mild to moderate ARDS investigated the clinical and immunological benefits of convalescent plasma transfusion. The convalescent plasma treatment arm did not demonstrate statistically significant differences in clinical outcomes across all age groups, though patients with severe ARDS aged less than 67 years were found to experience immediate hypoxia reduction, shorter hospital stays, and improved survival. This study suggested that a precise targeting of severe COVID-19 patients is necessary to achieve efficacy [ 103 ]. In a study by Shen et al., 5 critically ill patients with laboratory-confirmed COVID-19 and ARDS were treated with convalescent plasma. As assessed by Ct, treatment with convalescent plasma leads to a decline in viral load within days, and clinical improvement of patients, as indicated by body temperature reduction, improvement in P/F ratio, and chest imaging. By 9 days after plasma administration, four patients who had been receiving extracorporeal membrane oxygenation (ECMO) and mechanical ventilation no longer required breathing support [ 104 ]. Moreover, According to Allahyari et al., early administration of CP can help defuse the symptoms of severe COVID-19 patients with mild or moderate ARDS, who are at risk of progressing to critical state [ 105 ].

Intravenous immune globulin (IVIG)

Intravenous immunoglobulin (IVIG) has been investigated as an alternative immune-modulator, and IVIG therapy in a high dose has shown useful effects for immune-mediated diseases, such as Kawasaki disease and other diseases [ 106 ]. However, the exact mechanisms of action of IVIG in immune-mediated diseases are still unknown, but IVIG may act on the host’s hyperimmune reactions by binding to immune cell receptors, etiologic substances including pathogenic proteins (PPs), or other proteins that are linked to inflammation [ 106 ]. A double-blind, randomized clinical trial demonstrated that the administration of IVIg to patients with severe COVID-19 infection who failed to respond to initial treatment has significantly improved their clinical outcome. Still, several multicenter trials with larger sample sizes must be conducted to provide more information regarding the drug’s suitability as a standard treatment [ 107 ]. In recent case reports, IVIG therapy has proved beneficial for patients with COVID-19, including three cases of ARDS. In a retrospective study, early IVIG treatment of COVID-19-related ARDS resulted in a smaller mortality and shorter ventilator time [ 108 ]. With regards to IVIg’s high price, it is recommended that it should be considered for patients with > 30% lung involvement in lung CT scans, persistent dyspnea, persistent satO2 under 90%, and individuals with progressive lung involvement in serial lung CT scans, especially in younger cases [ 107 ].

Anticoagulant and anti-fibrotic therapies

Disordered coagulation, specifically, pulmonary microvascular thrombosis is increasingly in association with the pathogenesis of severe COVID-19 respiratory failure. Treatment with anticoagulants, mainly low molecular weight heparin (LMWH), has also been found to be associated with better treatment outcomes in severe coronavirus patients with evidence of activation of the coagulation system such as markedly elevated D-dimer levels [ 49 ]. A prophylactic dose of LMWH may be recommended for hospitalized patients. LMWH also exerts anti-inflammatory effects that might confer protection [ 109 ]. Currently, a clinical trial is ongoing to test its potential to reduce mortality in patients with Severe COVID-19 [ 110 ].

It has been suggested that targeting coagulation and fibrinolysis could improve the clinical outcomes of ARDS patients [ 111 ]. In particular, plasminogen activators have received strong support to limit the progression of ARDS and reduce ARDS-induced death from animal models [ 112 , 113 , 114 ] and a phase 1 human clinical trial [ 115 ]. According to Wang et al., three COVID-19 patients with ARDS being ventilated and being treated with tPA (Alteplase) showed temporally improved respiratory status, with one of them demonstrating a durable response [ 116 ]. Moore et al. have suggested that Alteplase administration can be used as compassionate salvage therapy in patients with COVID-19 related ARDS, but details remain to be determined about the dose, administration routes, and duration of treatment [ 50 ]. At the moment, clinical trials are in progress to evaluate the effects of tPA on improving the respiratory function of ARDS patients [ 117 , 118 , 119 ].

Pirfenidone

Pirfenidone which is approved for the treatment of mild to moderate idiopathic pulmonary fibrosis (IPF), may prevent the invasion and cytokine storm of COVID-19 in pneumocytes and other tissues by inhibiting apoptosis, decreasing expression of ACE receptors, suppressing inflammation through various mechanisms, and reducing oxidative stress [ 120 ]. Consequently, it can be effective against severe viral inflammation, ARDS, and ARDS fibrosis [ 51 ]. A new clinical trial aims to determine the safety and efficacy of treatment with Pirfenidone versus standard of care (SoC) in COVID-19 patients with severe ARDS (NCT04653831).

Anti anaemic drugs

Vadadustat acts as a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) and can trigger the body’s protective response to oxygen deficiency [ 52 ]. Alveolar inflammation can be dampened by stabilizing HIF, which is one of the main challenges that patients with COVID-19-related lung disease face when they develop ARDS [ 121 ]. The efficacy of vadadustat for ARDS prevention and treatment is going to be examined in a new clinical trial in hospitalized patients with COVID-19 [ 18 ].

Nitric oxide (NO)

During the SARS-CoV outbreak, in 2004, a pilot study revealed that low dose NO (max 30 ppm) inhalation could shorten the duration of the ventilator for patients diagnosed with SARS-CoV infection [ 122 ]. Furthermore, strong evidence suggests that inhaled NO can decrease inflammatory cell-mediated lung damage via suppressing activation of neutrophils and subsequent secretion of pro-inflammatory cytokines [ 123 ]. Although there is no epidemiological evidence supporting the use of inhaled NO to improve outcomes for COVID-19 patients, because of the genetic similarities between the two viruses, similar therapeutic effects of NO could be expected for COVID-19 patients [ 124 ]. Based on this experience, several medical institutes have begun clinical trials [ 125 ], and now a phase 2 clinical study of inhaled NO is being performed for COVID-19 patients who required mechanical ventilation for ARDS to confirm whether inhaled NO could be a life-saving intervention for managing COVID-19 ARDS [ 126 , 127 ].

2020 has been a challenging year for all with the COVID-19 pandemic as a live issue affecting people globally. Although 58 COVID-19 vaccines have been developed in clinical trials by several manufacturers, with some vaccines proving to be over 90% effective in preventing the disease in clinical trials [ 128 ], But it might take years for enough coverage to create herd immunity, and vaccine escape mutants are a threat to this progress [ 129 ]. So, there is still an urgent need to develop targeted therapies to combat COVID-19 and its complications [ 23 ]. In this sense, it is hoped that extensive research worldwide into possible therapies for patients suffering from COVID-19 will result in the rapid identification of effective ARDS treatments.

Availability of data and materials

Not applicable.

Abbreviations

Alveolar epithelial cells

Alveolar macrophages

Acute Respiratory Distress Syndrome

Complete blood count

Coronavirus disease 2019

Cytokine release syndrome

Dendritic cells

Electrocardiogram

Food and Drug Administration

High-flow nasal oxygen

Intensive care unit

Type-II interferon

Intravenous immune globulin

Janus kinase

Middle East respiratory syndrome coronavirus

Mesenchymal Stem Cell

Nuclear factor-κB-regulated genes

National Health Commission

Nitric oxide

Positive end-expiratory pressure

Pattern recognition receptors

Retinoic acid-inducible gene I/melanoma-differentiation-associated gene

Reactive oxygen species

Severe acute respiratory syndrome coronavirus

Toll-like receptor

Tissue plasminogen activator

World Health Organization

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Acknowledgments

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Department of Critical Care Nursing, School of Nursing and Midwifery, Tehran University of Medical Science, Tehran, Iran

Anolin Aslan

Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

Cynthia Aslan

Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

Experimental and Applied Pharmaceutical Research Center, Urmia University of Medical Sciences, Urmia, Iran

Naime Majidi Zolbanin

Department of Pharmacology and Toxicology, School of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran

Nephrology and Kidney Transplant Research Center, Clinical Research Institute, Urmia University of Medical Sciences, Shafa St., Ershad Blvd., P.O. Box: 1138, Urmia, 57147, Iran

Reza Jafari

Hematology, Immune Cell Therapy, and Stem Cell Transplantation Research Center, Clinical Research Institute, Urmia University of Medical Sciences, Urmia, Iran

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Conception and manuscript design: R J. Collection of data: A A, C A, N M Z, and R J. Manuscript writing: A A, C A, N M Z, and R J. Made important revisions and confirmed final revision: R J. All authors reviewed and approved the final version of the manuscript.

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Aslan, A., Aslan, C., Zolbanin, N.M. et al. Acute respiratory distress syndrome in COVID-19: possible mechanisms and therapeutic management. Pneumonia 13 , 14 (2021). https://doi.org/10.1186/s41479-021-00092-9

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• Acute respiratory distress syndrome

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• Rapid Reference 🚀
• Definition of ARDS
• Cardiogenic pulmonary edema vs. ARDS
• Common causes of ARDS
• Evaluating the cause of ARDS
• ARDS pathophysiology: Intrapulmonary shunting
• Treating the cause of ARDS
• Conservative fluid strategy
• High-flow nasal cannula & CPAP/BiPAP
• Awake proning
• Oxygenation goal
• Ventilation goal & permissive hypercapnia
• Volume-cycled ventilation
• Management of ventilator dyssynchrony
• Inhaled pulmonary vasodilators
• Desperate measures for refractory hypoxemia
• Therapies to avoid
• Questions & discussion

(back to contents)

intubated ARDS patient: therapeutic package ✅

Investigate & treat underlying cause ( more ).

• 🔑 Often the most important intervention!

steroid ( more )

• Consider if PaO2/FiO2 <200 mm (27 kPa) & no contraindication.
• Avoid if the cause of ARDS is known & steroid-unresponsive.
• Possible regimen: dexamethasone 20 mg qd x5d, then 10 mg qd x5d.

conservative fluid strategy ( more )

• If volume overloaded or recently fluid-loaded, consider diuresis.
• If euvolemic, target even or slightly negative balance.

lung-protective ventilation ( more )

• Usually volume-cycled ventilation utilized (although APRV is another option).
• May reduce to 4 cc/kg if needed to keep plateau <30 cm.
• May increase to 8 cc/kg if difficulty tolerating & plateau <30 cm.
• Consider high PEEP table if P/F is <200 mm (27 kPa), or in morbid obesity.

permissive hypercapnia ( more )

• Target pH roughly >~7.2 (unless elevated ICP or RV failure).
• Treat any metabolic acidoses.
• Consider IV bicarbonate to increase the bicarbonate to ~30-35 mM (if needed to achieve adequate pH without lung-injurious ventilation).

adequate multimodal analgosedation

• Moderate propofol infusion.
• Opioid boluses PRN.
• Atypical antipsychotic.
• Pain-dose ketamine gtt.
• Scheduled acetaminophen.
• Propofol and opioid will reduce respiratory drive and improve ventilator synchrony (but avoid prolonged high-dose exposure to these agents).
• (More on sedation & analgesia .)

proning ( more )

• Consider after >12 hours of optimization on ventilator.
• Indicated if PaO2/FiO2 <150 mm (20 kPa) and FiO2 ≧0.6 and no contraindications.

nutrition ( more )

• Start early enteral nutrition (even if proned and/or paralyzed).

Berlin definition requires four criteria ( 22797452 )

• Acute onset (new or worsening respiratory symptoms within <7 days).
• Diffuse bilateral pulmonary infiltrates not due to effusions, atelectasis, or nodular disease. Unfortunately, identifying ARDS on chest X-ray is notoriously subjective. ( 29438110 )
• Not exclusively due to heart failure.
• Mild ARDS: PaO2/FiO2 200-300 mm (27-40 kPa).
• Moderate ARDS: PaO2/FiO2 100-200 mm (13-27 kPa).
• Severe ARDS: PaO2/FiO2 <100 mm (<13 kPa).

noninvasive estimation of the PaO2/FiO2 ratio

• The table below may be used to roughly estimate the PaO2/FiO2 ratio, if an arterial blood gas cannot be obtained.
• The estimated PaO2/FiO2 ratio seems accurate to within roughly +/- 75 mm. For the detection of patients with PaO2/FiO2 <150 mm, this has a sensitivity of 87% and a specificity of 91%. ( 28538439 ) Performance may be worse in patients with darker skin. ( 33326721 )

some basic epidemiology

• ARDS occurs in about a quarter of intubated ICU patients (even before COVID). ( 26903337 ) So ARDS isn't a zebra – this is everyday bread and butter critical care medicine.
• In-hospital mortality associated with ARDS is ~30-40%. ( 34217425 , 33016981 ) However, most patients with ARDS do not die from refractory hypoxemia, but rather due to multiorgan failure. The exact mortality which is attributable to respiratory failure is unclear (but well below 30%).

ARDS is not a disease!

• ARDS isn't a single disease, but rather a collection of dozens of different diseases – anything which causes acute, diffuse parenchymal lung failure. In this way, ARDS is similar to “acute kidney injury.”
• Historically, ARDS has often been equated with a specific form of histological inflammation (diffuse alveolar damage with hyaline membranes). However, only ~63% of patients who meet the Berlin definition of ARDS actually have diffuse alveolar damage. ( 23370917 ) Thus, patients with diffuse alveolar damage actually constitute a subgroup of patients with ARDS (with worse outcomes). ( 27906708 )
• 💡 Always strive to identify the cause of the patient's ARDS.
• 💡 Many causes of ARDS will require specific therapy, so merely providing supportive care will fail .

pseudoARDS (a.k.a., rapidly-improving ARDS)

• Atelectasis may cause a clinical presentation which is indistinguishable from ARDS (including a CT scan appearance which closely mimics ARDS).
• The distinguishing characteristic of pseudoARDS is that when exposed to adequate airway pressures, oxygenation will improve rapidly. Following 12-24 hours of recruitment, the PaO2/FiO2 ratio improves >300 mm (40 kPa) so patients no longer meet diagnostic criteria for ARDS. ( 30359616 )
• PseudoARDS is clinically important to recognize because these patients generally respond well to high mean airway pressure, but do not benefit from interventions such as paralysis or proning. As discussed further below, patients should be optimized on the ventilator for >12 hours prior to proning, in order to sort out patients with pseudoARDS. (More on PseudoARDS here )

“ARDS mimics”

• Many authors describe patients meeting the Berlin definition of ARDS who don't have diffuse alveolar damage as “ARDS mimics” (with the concept that only diseases causing diffuse alveolar damage are “true” ARDS).
• For the purposes of this chapter, ARDS will refer to the clinical syndrome as defined by the Berlin Definition (including a diversity of histological patterns – which in clinical practice is generally unknown ). This includes what many authors would refer to as “ARDS mimics” as well as “true ARDS.”
• Historically differentiating cardiogenic vs. noncardiogenic pulmonary edema was based on wedge pressure from pulmonary artery catheter, but currently the pulmonary artery catheter is rarely used. The best ways to make this distinction are lung ultrasonography and/or chest CT scan.
• Cardiogenic pulmonary edema: diffuse edema, septal thickening, pleural effusions, evidence of heart failure (e.g., dilated left atrium).
• ARDS: patchy edema, often areas of dense consolidation interspersed with normal-appearing lung.
• Cardiogenic pulmonary edema: B-lines distributed throughout the lung, pleural effusions, pleural line is normal (thin).
• ARDS: patchy areas with B-lines intermixed with areas with A-lines (normal lung), areas of dense sub-pulmonic consolidation (small patches of severely diseased lung in contact with the pleura), pleural line may appear thick/ragged.
• In reality, it is possible to have both ARDS plus pulmonary edema (they aren't mutually exclusive). One advantage of ultrasonography and chest CT is that they are capable of diagnosing features of both processes simultaneously.

infection is the most common cause of ARDS ( 34217425 )

• Most commonly bacterial or viral.
• Pneumocystis jirovecii pneumonia is possible. ( more )
• Fungal (e.g., aspergillosis) is less common. ( more )
• (2) Non-pulmonary sepsis .

inflammation

• Diffuse alveolar hemorrhage (often due to ANCA vasculitis). ( more )
• AEP (acute eosinophilic pneumonia). ( more )
• Most often: exacerbation of IPF (idiopathic pulmonary fibrosis) or NSIP (nonspecific interstitial pneumonitis).
• Acute hypersensitivity pneumonitis (HP).
• Organizing pneumonia (OP).

medication/blood/radiation

• Chemotherapy.
• Checkpoint inhibitors.
• (Full listing on pneumotox.com ).
• Radiation pneumonitis.
• TRALI (transfusion-related acute lung injury), especially following massive transfusion .

physical insult to the lung

• Aspiration .
• Smoke inhalation.
• E-cigarette or Vaping Associated Lung Injury (EVALI).
• Pulmonary contusion, patients with multiple trauma .
• High-risk surgeries (e.g., lung resection, esophagectomy).
• Acute sickle chest syndrome. ( more )
• Fat emboli syndrome (traumatic or following orthopedic surgery).

The extent of evaluation should be tailored to the clinical context. In some cases, the cause of ARDS may be obvious, so extensive evaluation is unnecessary.

• ? Medication exposures.
• ? Blood product transfusion.
• ? Malignancy (considerations include chemotherapy, checkpoint inhibitors, radiotherapy, opportunistic infections).
• ? Infectious or rheumatologic prodrome.
• Blood cultures.
• Nasopharyngeal PCR for influenza, COVID-19, other viral pathogens.
• Sputum culture & staining for bacteria +/- fungi.
• Urinary antigens (legionella, pneumococcus) if pneumonia suspected.
• Beta-D-glucan (if fungal infection or PJP is possible).
• Procalcitonin, C-reactive protein.
• If diffuse alveolar hemorrhage is suspected: Urinalysis, Erythrocyte Sedimentation Rate (ESR), C-Reactive Protein (CRP), cANCA, pANCA, anti-MPO, anti-PR3, ANA (more on diffuse alveolar hemorrhage )
• Complete blood count with differential (? eosinophilia).

imaging (CT scan) 

Chest ct scan features to evaluate for:.

• Cavitation.
• Diffuse alveolar hemorrhage.
• Evidence of heart failure (e.g., left atrial dilation, septal thickening, bilateral pleural effusions).
• Clues to pulmonary vs. extrapulmonary etiology :  Extrapulmonary etiology may be suggested by symmetric, dependent infiltrates.

CT abdomen/pelvis

• If sepsis is possible, CT abdomen/pelvis should be performed to evaluate for a focus of infection. ( 9780323655873 )

bronchoscopy with bronchoalveolar lavage

• For most patients, bronchoscopy is relatively low-yield.
• Diffuse alveolar hemorrhage (e.g., due to ANCA vasculitis).
• Acute eosinophilic pneumonia (AEP).
• Immunocompromise with opportunistic infection (e.g., PJP, aspergillus).
• Risk of bronchoscopy include worsening hypoxemia as well as risks of barotrauma.

The histological findings in ARDS are heterogeneous (most notably, all patients do not have diffuse alveolar damage with hyaline membranes). However, one commonality which is valid across all ARDS patients is the presence of intrapulmonary shunting . Shunting results from alveolar units which receive blood flow but no ventilation, causing a shunting of deoxygenated blood into the systemic circulation.

Shunt physiology causes cardiac output to affect the oxygen saturation, based on the equations above. ( 17342520 ) If the cardiac output decreases, then the mixed venous oxygen saturation is reduced – causing blood that shunts across the lungs to have less oxygen. Hemoglobin and systemic oxygen consumption (VO2) also affects the oxygen saturation, in a similar fashion. This interplay is clinically important, because abrupt cardiac deterioration can cause a sudden drop in oxygen saturation. In extreme situations, the systemic oxygen consumption (VO2), cardiac output, and hemoglobin may be intentionally manipulated in efforts to defend systemic oxygenation. (more on this below & here )

• Many patients have ARDS due to a reversible process. Identifying the underlying process and treating it may be the single most important intervention.
• The literature on ARDS hardly mentions this, because it is impossible to study this aspect of care (among a heterogeneous group of ARDS patients, different patients will require different treatments).
• For example, in situations where bacterial infection is probable, patients may be initially covered empirically with antibiotics (until bacterial infection can be excluded).

background on steroid in ARDS

• The benefit of steroid in ARDS likely depends on the underlying etiology (since ARDS isn't a single disease process, but rather a collection of dozens of distinct diseases).
• Bacterial pneumonia. ( 29236286 )
• Viral pneumonia such as COVID-19. ( 32678530 )
• Non-pulmonary sepsis. ( 29347874 , 29490185 )
• Most interstitial lung diseases (e.g., vasculitis, cryptogenic organizing pneumonia, hypersensitivity pneumonitis).
• Drug-induced pneumonitis, radiation pneumonitis
• Consequently, it's logical to expect that steroid would benefit most patients with ARDS. However, for patients with ARDS due to a known illness that doesn't respond to steroid (e.g., aspiration pneumonitis), the use of steroid is dubious.

evidence regarding steroid administration to heterogeneous populations of ARDS patients

• Steroid has been found to be ineffective as a salvage therapy for ARDS, when applied >7 days after admission. ( 16625008 )
• An individual patient data meta-analysis that combined four RCTs evaluating prolonged methylprednisolone therapy for early ARDS found a reduction in mortality, with an improvement in ventilator-free days (13 vs. 7, p <0.001). ( 30155260 )
• The DEXA-ARDS trial found that dexamethasone improved mortality and hastened weaning from mechanical ventilation. ( 32043986 )
• All of this evidence was obtained using an older definition of ARDS that required that the PaO2/FiO2 ratio be <200 mm (27 kPa).

bottom line

• Steroid use in ARDS remains controversial. Steroid is probably beneficial for most patients, as they are likely to have a disease process which is steroid-responsive. (However, steroid is unlikely to be beneficial in patients whose disease process is known to be steroid-unresponsive.)
• Applied early in the disease process.
• Utilized in sicker patients, with PaO2/FiO2 <200 mm (27 kPa).
• Patient is known or likely to have a steroid-responsive disease process.
• Steroid is contraindicated if there is a concern for active fungal or mycobacterial infection.
• The DEXA-ARDS trial utilized 20 mg dexamethasone for 5 days, followed by 10 mg dexamethasone for 5 days (or discontinuation before 10 days, if the patient was extubated). ( 32043986 ) Dexamethasone has advantages regarding a long half-life which autotapers itself and reduced mineralocorticoid activity (which avoids problems with hypernatremia and sodium retention).
• SCCM/ESICM guidelines recommend methylprednisolone 1 mg/kg/day, with a gradual taper over 14 days. ( 28938253 )
• For patients who aren't actively in shock, the FACTT trial demonstrated that a conservative fluid strategy facilitated extubation. ( 16714767 ) The FACTT trial used a very complex scheme to determine when patients required diuresis. However, if you look at the balance of fluid input versus fluid output, what ultimately ended up happening is that patients in the conservative fluid arm achieved a net even fluid balance, whereas patients in the liberal fluid arm gained ~6 liters of fluid.
• The goal is always to target euvolemia.
• Initially, patients may require diuresis (especially if they have received large-volume resuscitation). Once patients have reached a euvolemic state, target an even or slightly negative fluid balance (with inputs roughly equal to outputs).
• Avoid fluid boluses if at all possible.

High-flow nasal cannula (HFNC)

• HFNC caused reduced mortality among patients with ARDS in the FLORALI trial. ( 25981908 ) This may be especially useful in patients with bacterial pneumonia, who have substantial sputum production. HFNC allows expectoration, which maintains patent airways.

CPAP or BiPAP

• The RECOVERY-RS trial found that CPAP reduced the requirement for intubation among patients with COVID-19. It's possible that patients with viral pneumonia benefit more from CPAP or BiPAP (because they don't produce copious secretions and require positive pressure to recruit lung tissue).
• Many patients with ARDS may be adequately supported by HFNC, CPAP, BiPAP, or some combination of these modalities (e.g., periods of HFNC to allow for airway clearance alternating with periods of CPAP/BiPAP to recruit the lungs).
• Different modalities may be optimal for various patients, depending on individual patient factors (e.g., volume of sputum production, tolerance of various interfaces, comorbid COPD).
• Patients who fail noninvasive support strategies and require intubation will often do poorly, because this failure is selecting out the sickest cohort of patients. This selection process shouldn't be interpreted to mean that noninvasive support causes patients to do worse.
• (More information on noninvasive ventilation strategies here ).
• Non-intubated patients may be maintained in a prone position for much of the time, thereby achieving the physiological benefits of proning that have been well established among intubated patients. (discussed further below )
• Awake proning may be combined with high flow nasal cannula (HFNC), CPAP, or BiPAP.
• Emerging evidence from the COVID-19 pandemic has demonstrated that this is a safe and effective technique. ( 34425070 , 32320506 )
• Based on the ARDSnet trial, the traditional 0xygenation target has been PaO2 55-80 mm or saturation of 88-95% . ( 10793162 )
• To date, RCTs comparing more liberal vs. more conservative oxygen targets have failed to detect any reproducible or robust signals of benefit, with different studies pointing in different directions. (e.g., LOCO2 , ICU-ROX , HOT-IC U , Oxygen-ICU ) Consequently, there is no compelling reason to change the oxygenation target for most patients. The ongoing Mega-ROX trial will hopefully clarify this.
• Pulse oximetry may overestimate oxygenation among patients with darker skin . ( 33326721 ) In this situation, correlation with ABG and/or targeting a saturation >90-92% could be reasonable. Further data is urgently required to clarify the performance of various devices and optimal management. (More on this here )

concept of permissive hypercapnia

• Hypercapnia is extremely well tolerated among intubated patients (hypercapnia may cause somnolence and obtundation in nonintubated patients, but this isn't a danger among intubated patients – indeed it could be beneficial for some patients).
• It's more important to achieve lung-protective ventilation than to “normalize” the pCO2. Patients ultimately die due to lung injury – not hypercapia.
• Permissive hypercapnia refers to the practice of intentionally allowing the pCO2 to rise, in order to promote lung-protective ventilation. (Further discussion of permissive hypercapnia here .)

contraindications to permissive hypercapnia

• (1) Right ventricular failure (hypercapnia increases pulmonary vascular resistance, placing additional strain on the right ventricle).
• (2) Acute neurological illness with elevated intracranial pressure (hypercapnia may cause further elevation of intracranial pressure).
• (3) Pregnancy might be a relative contraindication (with relatively little available evidence).

pH target in patients undergoing permissive hypercapnia

• This is undefined. There is no known limit of permissive hypercapnia (i.e., a pH cutoff below which patients obviously deteriorate).
• Most providers and guidelines seem comfortable with a pH over roughly 7.20 . ( 34090669 , 33526308 ) However, please note that this is an arbitrary choice. In severe cases, it is often wise to accept a lower pH.
• Perhaps more important than the pH is how well the patient is tolerating this (e.g., evidence of hemodynamic instability).

use of IV bicarbonate to achieve pH targets

• IV bicarbonate may be used to defend the pH in the face of hypercapnia. For example, this was utilized in the landmark ARDSnet trial. ( 10793162 )
• Depending on the volume and sodium status, either hypertonic or isotonic bicarbonate may be utilized. For further discussion of the techniques involved in alkalinization, see the section on this in the asthma chapter here .
• 💡 A higher bicarbonate level allows patients to be ventilated with a lower minute ventilation and a lower overall delivery of mechanical power to the lung. ( 31346828 )

Positive End Expiratory Pressure (PEEP)

• Improved oxygenation.
• Avoidance of atelectrauma (caused by repeated opening and closing of alveoli).
• Overdistension of alveoli may increase pulmonary vascular resistance (due to compression of alveolar capillaries) and impair capillary perfusion (thereby increasing the volume of dead space).
• Decreased preload may promote hypotension in some patients.
• The ARDSnet trial used a PEEP table to pair different levels of PEEP with FiO2 (figure above). ( 10793162 ) Subsequent studies have investigated the use of higher levels of PEEP. Meta-analysis of RCTs found that the higher PEEP table reduced mortality among patients with moderate to severe ARDS. ( 20197533 ) It's also notable that the high PEEP table was found to yield equivalent outcomes compared to a more sophisticated strategy utilizing esophageal manometry in the EPVent-2 trial. ( 30776290 ) Thus, the higher PEEP table is recommended by several guidelines for patients with PaO2/FiO2 <200 mm (27 kPa). ( 34035056 ) However, higher PEEP should only be continued if this appears to be safe and effective for an individual patient. ( 31197492 )
• Patients with morbid obesity may also benefit from higher levels of PEEP. ( 31060087 ) This PEEP is largely spent in counteracting pressure from the abdominal contents and isn't “felt” by the lungs (it doesn't contribute to the transpulmonary pressure). A post-hoc analysis of the ALVEOLI trial found that among all obese patients (defined as body mass index >30), the high PEEP table reduced mortality compared to standard PEEP. ( 27984004 )

tidal volume

• The ARDSnet trial showed that 6 cc/kg ideal body weight (IBW) produced a survival benefit compared to 12 cc/kg IBW. ( 10793162 )
• The safety of intermediate tidal volumes is unclear (e.g., 8 cc/kg IBW). 6 cc/kg is difficult for some patients to tolerate, so slight liberalization to 8 cc/kg may be reasonable (particularly if this can be accomplished without increasing the plateau pressure >30 cm).
• Always ensure that tidal volume is calculated from ideal body weight, rather than actual weight (e.g. using MDCalc ).

plateau pressure

• (1) Plateau pressure can only be accurately measured in a patient who is breathing passively on the ventilator (i.e., paralyzed or deeply sedated and “riding” the ventilator).
• (2) Plateau pressure is generally used as a surrogate for the transpulmonary pressure (the pressure gradient across the lungs, which is what the alveoli feel ). However, plateau pressure is a poor estimate for the transpulmonary pressure in patients with chest wall restriction or obesity (who may have increased intrapleural pressure, so that a very large plateau pressure coexists with a relatively low transpulmonary pressure).
• The ARDSnet protocol targeted a plateau pressure <30 cm . Tidal volumes were reduced as low as 4 cc/kg if necessary, to achieve this.
• Patients with morbid obesity may require high PEEP and plateau pressures to maintain lung recruitment, without causing dangerously high levels of alveolar distension (i.e., with a low transpulmonary pressure). Thus, accepting a higher plateau pressure for these patients is often beneficial. In these situations, a low driving pressure might provide some reassurance that ventilation is indeed lung protective (see below).

driving pressure

• Driving pressure = (Plateau Pressure – PEEP).
• Retrospective analysis of several ARDS studies has found a strong correlation between lower driving pressure and lower mortality. ( 25693014 ) However, there is no prospective evidence that intentionally adjusting the ventilator to reduce the driving pressure is beneficial. This correlation may partially reflect that sicker patients have worse compliance (rather than revealing that driving pressure is causally affecting mortality).
• For now, driving pressure might be a useful parameter to pay some attention to. Driving pressure might ideally be under <15 cm. ( 34090669 , 33526308 , 32735841 )

Ventilator dyssynchrony is common, especially if attempting to achieve volume-cycled ventilation with very low tidal volumes.

adjustment of ventilator

• The adage is “fit the patient to the patient, don't fit the patient to the ventilator.” When possible, ventilator settings should be adjusted to improve comfort.
• If there is evidence of flow-starvation in volume-cycled modes of ventilation, the flow rate may be increased.
• Small increases in tidal volume (e.g. from 6 cc/kg to 8 cc/kg) may improve dyssynchrony. ( 33381233 )
• If other options fail, transition to a pressure-cycled ventilator mode may be tried (e.g., pressure-controlled ventilation or APRV ).

respirolytic sedation

• Sedative agents may be helpful, especially those which directly suppress the respiratory drive (e.g., propofol and fentanyl).
• To avoid using high doses of propofol or opioids, other sedatives may be helpful as well (e.g., atypical antipsychotics for anxiety and pain-dose ketamine for pain).

management of metabolic acidosis

• The presence of any metabolic acidosis will increase the respiratory drive (in efforts to mount a compensatory respiratory alkalosis). This will make the patient feel more air-hungry and miserable. Thus, any metabolic acidosis should be treated appropriately.
• If the pH remains low, IV bicarbonate may be considered as well. (more on this here ) Mild alkalinization will reduce the respiratory drive, which may theoretically promote comfort. ( 29307724 )
• If other treatments fail, deep sedation and paralysis will eliminate ventilator dyssynchrony. This is probably most useful early in the course of ARDS, for limited periods of time (e.g., <48 hours).
• Extended periods of paralysis should be avoided.
• (More on paralysis here .)

rationale & evidence

• With conventional mechanical ventilation alone, the posterior lung tissue will often become completely atelectatic (derecruited). As alveolar units collapse, this distorts the geometry of neighboring alveoli and thereby promotes their collapse – leading to a vicious spiral of alveolar collapse which can be difficult to break. This may cause patients to develop persistent atelectasis and hypoxemia that doesn't resolve over time, despite days of mechanical ventilation – causing patients to become stuck on a ventilator indefinitely.
• Prone ventilation for prolonged periods of time (>16 hours/day) may promote recruitment of posterior lung tissue, as well as drainage of secretions from the dependent bronchi. This can break the cycle of persistent posterior atelectasis, allowing patients to make progress on the ventilator. ( 30850004 )
• The primary study demonstrating benefit from proning was the PROSEVA trial (infographic below). The main limitation of this study is that it was performed in French ICUs with >5 years of experience with proning, leaving it unclear how well this would translate into less experienced centers. ( 23688302 ) Additionally, about half of patients were excluded from the study due to various contraindications, so it is incorrect to generalize these findings to every patient with severe ARDS.

indications to initiate proning

• ⚠️ Proning should be delayed to allow for 12-24 hours of optimization on mechanical ventilation (e.g. ARDSnet ventilation with high PEEP), since many patients will respond well to supine mechanical ventilation alone. The phenomenon of patients whose oxygenation improves dramatically with positive pressure ventilation is known as rapidly improving ARDS (riARDS) or “pseudoARDS.” (discussed above ) Such patients should not be proned.
• Patients with dependent, symmetrical infiltrates.
• Patients with elevated intra-abdominal pressure. ( 9620906 )
• ARDS due to an extrapulmonary etiology. ( 11355115 )

contraindications to proning

• Unstable spine, femur, or pelvic fracture.
• Unstable rhythm that may require cardioversion.
• Refractory hypotension (e.g., persistent MAP<65 mm).
• Inability to deeply sedate the patient (e.g., due to extremely high sedative tolerance).
• Single anterior chest tube with active air leak.
• Massive hemoptysis.
• Increased intracranial pressure (ICP).
• Open abdomen.
• Abdominal compartment syndrome or extreme obesity (proning may increase intraabdominal pressure further, risking kidney and hepatic failure).
• Pregnancy (relative contraindication, depends on gestational age).
• Tracheal surgery or sternotomy within the past two weeks.
• Severe facial surgery or trauma within the past two weeks.
• Restricted mobility of the C-spine or shoulders (may increase risk of pressure ulcerations).

some technical details

• Prone patients should be either deeply sedated or paralyzed, to reduce the risk of endotracheal tube dislodgement. (Further discussion of the role of paralysis below .)
• Secure IV access should be obtained prior to proning (e.g., with a central line or PICC line if necessary).
• Enteral nutrition should be continued during prone ventilation (although some protocols may involve holding nutrition prior to turning the patient over).
• Critical care units should maintain and follow a local proning protocol that specifies additional procedural details.

when to stop proning

• Severe hemodynamic instability (including cardiac arrest).
• After proning the PaO2/FiO2 ratio fails to improve, or deteriorates (occasional patients may not respond favorably).
• (2) Due to patient improvement: Proning may be stopped if the patient is able to maintain a PaO2/FiO2 ratio >150 mm (20 kPa) with an FiO2 ≤0.6, at least four hours after supination. ( 34090669 )
• (3) Due to ineffectiveness: If proning causes no significant improvement in oxygenation or respiratory compliance, consider discontinuing further proning.
• APRV is a ventilator mode which essentially combines periods of pressure-support ventilation at high pressures (during which the patient can breathe spontaneously) with very short drops in airway pressure that provide machine-driven “dumping breaths.” Dumping breaths provide ventilator-driven CO2 clearance (thereby providing “ventilator support”).
• APRV allows for the achievement of very high mean airway pressures , without very high plateau pressures. This allows for recruitment of lung tissue while minimizing barotrauma. Maintaining alveoli in an open configuration may avoid atelectrauma (one form of the “open lung” strategy).
• APRV is generally well tolerated, because it allows patients to breathe spontaneously most of the time. This minimizes the requirement for paralytics, sedatives, and opioids compared to conventional ventilation, thereby avoiding medication side effects (e.g., delirium, myopathy, constipation, opioid dependence/withdrawal).
• Rapid-velocity dumping breaths may facilitate secretion clearance, thereby reducing the risk of ventilator-associated pneumonia. ( 31869259 )
• The combination of high mean airway pressures and diaphragmatic contraction promotes recruitment of the posterior lung tissues.

disadvantages

• Increased airway pressure may reduce cardiac preload and cause hypotension.
• Many centers and providers lack experience with APRV.
• APRV is easy to provide with some ventilators (e.g., Drager), but much harder to provide with other ventilator brands (e.g., Puritan Bennett).
• Lack of direct control over tidal volumes.
• End tidal capnography can be difficult or impossible to interpret.

evidentiary basis

• The largest RCT comparing APRV to low-tidal ventilation found that APRV caused substantial improvements in ventilator-free days, extubation, and hemodynamics (infographic below). ( 28936695 )
• A meta-analysis found evidence of benefit in other RCTs, although such studies are very small. ( 30949778 , 30307725 )

best candidates for APRV include:

• Patients with substantial posterior atelectasis.
• Patients who are unable to prone, due to contraindications.
• Morbidly obese patients (who often receive inadequate airway pressures with conventional ventilation).
• APRV may be especially useful in patients who are difficult to sedate (in some cases, it may be nearly impossible to sedate patients deeply enough to paralyze them in a humane fashion).
• APRV can be utilized in paralyzed patients, but it's most effective among patients who are making some respiratory efforts (such efforts assist in recruitment of the posterior lung tissue and improving venous return to the heart).

contraindications to APRV:

• Severe asthma or COPD (short release breaths may not allow sufficient time to exhale).
• Refractory shock (elevated intrathoracic pressure may risk hemodynamic deterioration).

optimal utilization of APRV within an overall treatment scheme for ARDS ?

• The ideal utilization of APRV remains controversial.
• APRV can be used as a primary ventilatory support mode, especially among patients who are better APRV candidates (see above). Alternatively, APRV can be used as a rescue modality for patients who fail to respond to conventional ventilation.
• APRV has replaced high-frequency oscillatory ventilation (HFOV), which is currently obsolete and should not be utilized.
• It makes sense to start APRV sooner rather than later (before the patient is in extremis).
• Failure to improve immediately on APRV shouldn't be regarded as APRV failure.

(Guide to bedside application of APRV here )

potential benefits

• Paralysis reduces metabolic activity, which reduces CO2 production and O2 consumption. This could help slightly in patients with severely impaired gas exchange.
• Complete avoidance of ventilator dyssynchrony, which may help limit peak pressures and reduce the risk of barotrauma (e.g., pneumothorax).
• May facilitate proning.
• May allow for accurate measurement of plateau pressures.

potential risks

• Paralysis mandates deep sedation, without active titration/weaning. Deep sedation may increase the risk of delirium and delayed awakening.
• Paralysis may increase the risk of critical illness neuropathy or myopathy (especially when using aminosteroid paralytics in combination with corticosteroid).
• Reduced diaphragmatic activation could promote diaphragmatic atrophy and atelectasis.
• The ACURASYS trial evaluated early paralysis with cisatracurium for 48 hours among patients with PaO2/FiO2 <150 mm (20 kPa). The study purported to show a mortality benefit, but this was only statistically significant within an adjusted analysis ( not based on the raw data). ( 20843245 )
• The larger ROSE trial subsequently found no benefit from routine cisatracurium paralysis (compared with a strategy of as-needed paralysis, that resulted in 15% of patients in the control arm receiving paralytic). ( 31112383 )
• In retrospect it's possible that both of these were actually neutral studies.

bottom line?

• Paralysis is not broadly beneficial for all patients with ARDS.
• Severe hypoxemia – and – difficulty synchronizing with the ventilator despite deep sedation.
• Refractory hypoxemia. (more on this below )
• Cisatracurium is the preferred paralytic, if available. Although cisatracurium is more expensive than aminosteroid paralytics, it seems to carry a lower risk of myopathy.
• If a paralytic is used, the lowest possible dose should be utilized, for the shortest possible duration of time.

inhaled epoprostenol

• Vasodilation of aerated lungs will improve the ventilation/perfusion matching, improving oxygen saturation.
• Acute pulmonary hypertension is common in ARDS patients due to hypoxemia and high airway pressures (which compress pulmonary capillaries, increasing pulmonary vascular resistance). Epoprostenol causes pulmonary vasodilation which reduces afterload on the right ventricle, improving right ventricular function and cardiac output.
• Evidence supporting epoprostenol in ARDS is not robust.
• (1) Refractory hypoxemia (especially in patients with an intracardiac right-to-left shunt, as with a patent foramen ovale in the context of decompensated pulmonary hypertension).
• (2) Right ventricular failure (which commonly occurs among patients who are intubated with high airway pressures).

nitric oxide

• Nitric oxide carries risks of methemoglobinemia and acute kidney injury. ( 17383982 )
• Nitric oxide rapidly causes tachyphylaxis, causing it to stop working within about two days.
• Risks with nitric oxide seem to occur with more prolonged use at higher doses. Thus, nitric oxide would still remain a very viable strategy for stabilization of a crashing ARDS patient.

(More on inhaled pulmonary vasodilators here ).

Many patients who fail to respond to conventional ventilation will respond to a combination of inhaled epoprostenol, APRV, and/or prone ventilation (or all three of these interventions applied simultaneously). For patients who fail to respond to these therapies, ECMO should be considered (see section below). If ECMO is unavailable or the patient isn't a candidate for ECMO, that constitutes a pretty desperate situation. The following interventions can be considered. Several interventions may be required simultaneously, until the patient has stabilized. (further discussion of this here )

• Discontinue systemically administered pulmonary vasodilators : Systemic administration of medications that cause pulmonary vasodilation (e.g., nicardipine) may cause V-Q mismatch, exacerbating hypoxemia. ( 27295160 )  
• Give inhaled pulmonary vasodilators: These improve ventilation/perfusion matching and may improve right ventricular function as well. In the most desperate situations, multiple different agents may be used simultaneously to target different receptors (e.g., inhaled epoprostenol plus inhaled nitric oxide). ( More on inhaled pulmonary vasodilators)
• Combination inhaled pulmonary vasodilators : The simultaneous use of epoprostenol plus nitric oxide may be more effective than either agent alone.
• Paralysis: This reduces oxygen consumption and thereby improves the oxygen saturation of the mixed venous blood. (more on paralysis above )
• Temperature control: The global metabolic activity increases ~10% with each degree centigrade of body temperature. Reducing metabolic activity will improve oxygen and CO2 levels in refractory ARDS. A simple intervention is scheduled acetaminophen to avoid fever. In refractory hypoxemia, it could be reasonable to use an adaptive cooling device to control the patient's temperature at a low-normothermic level (i.e., therapeutic temperature monitoring at 36C).
• APRV : This may be trialed if it hasn't already been. Note that recruitment often takes time, so improvement in oxygenation may occur over a period of hours rather than minutes (more on APRV ).
• Inotrope: For patients with low cardiac output, improvement in the cardiac output will improve the mixed venous saturation (thereby improving the oxygenation of blood which shunts through consolidated lung tissue).
• Effusion drainage: Evaluate for pleural effusions with bedside ultrasonography and consider therapeutic drainage. On chest X-ray effusions will often blend into the posterior atelectasis that is common in ARDS, so these may be easily overlooked.
• Thrombolysis: For patients with pulmonary embolism, thrombolysis may be considered in the context of life-threatening and refractory hypoxemia.
• Blood transfusion: This may improve oxygen carrying capacity, thereby improving oxygen delivery to the tissues. Consider administration of furosemide along with blood, to avoid volume overload. Blood transfusion is correlated with mortality outcomes in ARDS, so transfusion should be avoided if possible (it's a true act of desperation). ( 15942330 ) However, in refractory hypoxemia it could be reasonable to target a slightly higher transfusion target than usual (e.g., >8 mg/dL). The ideal approach is to avoid phlebotomy, so that a high hemoglobin level can be maintained without transfusion.
• Veno-venous ECMO allows for oxygenation and ventilation independent of the lungs, allowing support of patients whose cannot be oxygenated using other techniques.
• Precise indications need to be clarified. If the patient is a potential ECMO candidate, they should be discussed early with the ECMO team or regional ECMO referral center (as inclusion criteria may vary regionally and over time).
• ECMO circuits will rapidly be exhausted during a pandemic (indeed, they are often in short supply at baseline).

short, high-pressure recruitment maneuvers

• Traditionally, very aggressive airway pressures were applied for short periods of time in efforts to recruit the lungs (e.g., 40 cm of pressure for 40 seconds).
• Short, high-pressure recruitment maneuvers have been demonstrated to be either ineffective or harmful in several RCTs. ( 14605529 , 31356105 , 28973363 ) Very abrupt use of high airway pressures poses a risk of causing cardiac arrest or pneumothorax. The maneuver is also probably too brief to achieve extensive alveolar recruitment.
• A safer approach to recruitment is gradual recruitment over several hours using APRV (with continuous application of a high mean airway pressure). ( 30850004 )(more on this above )

high frequency oscillatory ventilation (HFOV)

• This has been demonstrated to be ineffective and potentially dangerous in RCTs. ( 23339638 , 23339639 )
• Numerous guidelines and articles warn against the use of HFOV.
• These devices are also loud and annoying, and they should be burned.

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To keep this page small and fast, questions & discussion about this post can be found on another page here .

• There is no such thing as ARDS – it's not a single entity (but rather a collection of different diseases which result in lung failure). Likewise there is single entity that is a “New Yorker” – although there are obviously millions of people living in New York. Moving beyond the notion that ARDS is a single entity is important.
• Don't be fooled into believing that your diagnostic search is done when you diagnose a patient with “ARDS.” You also need to figure out why the patient is in ARDS and treat any specific cause(s).
• For patients with ARDS and sepsis of unknown cause, search aggressively for a source of sepsis (e.g. CT scan of chest/abdomen/pelvis).

Recent guidelines

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Review of seminal studies by The Bottom Line

• RECOVERY-RS (2021) – CPAP vs. HFNC vs. conventional oxygen therapy for COVID-19.
• HOT-ICU (2021) – Lower versus higher oxygenation targets in hypoxemic respiratory failure.
• DEXA-ARDS (2020) – Dexamethasone use in ARDS.
• LOCO2 (2020) – Liberal or conservative oxygen in ARDS.
• RECOVERY-DEX (2020) – Dexamethasone for COVID-19.
• PHARLAP (2019) – Recruitment maneuvers in ARDS.
• ROSE (2019) – Early paralysis in ARDS.
• EPVent2 (2019) – Esophageal pressure to titrate PEEP in ARDS.
• EOLIA (2018) – ECMO for ARDS.
• READS (2018) – Difficulty diagnosing ARDS on chest X-ray.
• Zhou (2017) – APRV vs. conventional ventilation in ARDS.
• ART (2017) – Recruitment maneuvers in ARDS.
• Patel (2016) – Helmet interface for NIV in ARDS
• FLORALI (2015) – HFNC vs. NIV vs. conventional oxygen for acute hypoxemic respiratory failure
• PROSEVA (2013) – Proning for ARDS
• OSCILLATE (2013) – Oscillator for ARDS
• OSCAR (2013) – Oscillator for ARDS
• ACURASYS (2010) – Early paralysis for ARDS
• CESAR (2009) – ARDS patients transferred to ECMO center
• Meduri (2007) – Early methylprednisolone for ARDS
• ARMA (2000) – Original ARDSnet trial on low tidal-volume ventilation
• Meduri (1998) – Steroid for unresolving ARDS
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• Patient Care & Health Information
• Diseases & Conditions

Acute respiratory distress syndrome (ARDS) occurs when fluid builds up in the tiny, elastic air sacs (alveoli) in your lungs. The fluid keeps your lungs from filling with enough air, which means less oxygen reaches your bloodstream. This deprives your organs of the oxygen they need to function.

ARDS typically occurs in people who are already critically ill or who have significant injuries. Severe shortness of breath — the main symptom of ARDS — usually develops within a few hours to a few days after the precipitating injury or infection.

Many people who develop ARDS don't survive. The risk of death increases with age and severity of illness. Of the people who do survive ARDS , some recover completely while others experience lasting damage to their lungs.

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The signs and symptoms of ARDS can vary in intensity, depending on its cause and severity, as well as the presence of underlying heart or lung disease. They include:

• Severe shortness of breath
• Labored and unusually rapid breathing
• Low blood pressure
• Confusion and extreme tiredness

When to see a doctor

ARDS usually follows a major illness or injury, and most people who are affected are already hospitalized.

• Bronchioles and alveoli

Your bronchioles are some of the smallest airways in your lungs. Inhaled air passes through tiny ducts from the bronchioles into elastic air sacs (alveoli). The alveoli are surrounded by the alveolar-capillary membrane, which normally prevents liquid in the capillaries from entering the air sacs.

The mechanical cause of ARDS is fluid leaked from the smallest blood vessels in the lungs into the tiny air sacs where blood is oxygenated. Normally, a protective membrane keeps this fluid in the vessels. Severe illness or injury, however, can cause damage to the membrane, leading to the fluid leakage of ARDS .

Underlying causes of ARDS include:

• Sepsis. The most common cause of ARDS is sepsis, a serious and widespread infection of the bloodstream.
• Inhalation of harmful substances. Breathing high concentrations of smoke or chemical fumes can result in ARDS , as can inhaling (aspirating) vomit or near-drowning episodes.
• Severe pneumonia. Severe cases of pneumonia usually affect all five lobes of the lungs.
• Head, chest or other major injury. Accidents, such as falls or car crashes, can directly damage the lungs or the portion of the brain that controls breathing.
• Coronavirus disease 2019 (COVID-19). People who have severe COVID-19 may develop ARDS .
• Others. Pancreatitis (inflammation of the pancreas), massive blood transfusions and burns.

Risk factors

Most people who develop ARDS are already hospitalized for another condition, and many are critically ill. You're especially at risk if you have a widespread infection in your bloodstream (sepsis).

People who have a history of chronic alcoholism are at higher risk of developing ARDS . They're also more likely to die of ARDS .

Complications

If you have ARDS , you can develop other medical problems while in the hospital. The most common problems are:

• Blood clots. Lying still in the hospital while you're on a ventilator can increase your risk of developing blood clots, particularly in the deep veins in your legs. If a clot forms in your leg, a portion of it can break off and travel to one or both of your lungs (pulmonary embolism) — where it blocks blood flow.
• Collapsed lung (pneumothorax). In most ARDS cases, a breathing machine called a ventilator is used to increase oxygen in the body and force fluid out of the lungs. However, the pressure and air volume of the ventilator can force gas to go through a small hole in the very outside of a lung and cause that lung to collapse.
• Infections. Because the ventilator is attached directly to a tube inserted in your windpipe, this makes it much easier for germs to infect and further injure your lungs.
• Scarring (pulmonary fibrosis). Scarring and thickening of the tissue between the air sacs can occur within a few weeks of the onset of ARDS . This stiffens your lungs, making it even more difficult for oxygen to flow from the air sacs into your bloodstream.

Thanks to improved treatments, more people are surviving ARDS . However, many survivors end up with potentially serious and sometimes lasting effects:

• Breathing problems. Many people with ARDS recover most of their lung function within several months to two years, but others may have breathing problems for the rest of their lives. Even people who do well usually have shortness of breath and fatigue and may need supplemental oxygen at home for a few months.
• Depression. Most ARDS survivors also report going through a period of depression, which is treatable.
• Problems with memory and thinking clearly. Sedatives and low levels of oxygen in the blood can lead to memory loss and cognitive problems after ARDS . In some cases, the effects may lessen over time, but in others, the damage may be permanent.
• Tiredness and muscle weakness. Being in the hospital and on a ventilator can cause your muscles to weaken. You also may feel very tired following treatment.
• What is ARDS? National Heart, Lung, and Blood Institute. https://www.nhlbi.nih.gov/health/health-topics/topics/ards/#. Accessed Jan. 26, 2017.
• Goldman L, et al., eds. Acute respiratory failure. In: Goldman-Cecil Medicine. 25th ed. Philadelphia, Pa.: Saunders Elsevier; 2016. http://www.clinicalkey.com. Accessed Jan. 26, 2017.
• Ferri FF. Acute respiratory distress syndrome. In: Ferri's Clinical Advisor 2017. Philadelphia, Pa.: Elsevier; 2017. https://www.clinicalkey.com. Accessed Jan. 26, 2017.
• Siegel MD. Acute respiratory distress syndrome: Prognosis and outcomes in adults. http://www.uptodate.com/home. Accessed Jan. 26, 2017.
• Mason RJ, et al. Acute hypoxemic respiratory failure and ARDS. In: Murray and Nadel's Textbook of Respiratory Medicine. 6th ed. Philadelphia, Pa.: Saunders Elsevier; 2016. http://www.clinicalkey.com. Accessed Jan. 26, 2017.
• AskMayoExpert. Acute respiratory distress syndrome. Rochester, Minn.: Mayo Foundation for Medical Education and Research; 2016.
• Siegel MD. Acute respiratory distress syndrome: Clinical features and diagnosis in adults. http://www.uptodate.com/home. Accessed Jan. 26, 2017.
• Barbara Woodward Lips Patient Education Center. Acute respiratory distress syndrome (ARDS). Rochester, Minn.: Mayo Foundation for Medical Education and Research; 2013.
• AskMayoExpert. COVID-19: Outpatient. Mayo Clinic; 2020.

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Endotyping in ARDS: one step forward in precision medicine

• Open access
• Published: 14 May 2024
• Volume 29 , article number  284 , ( 2024 )

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• Andréanne Côté 1 , 2   na1 ,
• Chel Hee Lee 2 , 3   na1 ,
• Sayed M. Metwaly 4 , 5 ,
• Christopher J. Doig 2 ,
• Graciela Andonegui 6 ,
• Bryan G. Yipp 2 ,
• Ken Kuljit S. Parhar 2 &
• Brent W. Winston 2 , 6 , 7  

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The Berlin definition of acute respiratory distress syndrome (ARDS) includes only clinical characteristics. Understanding unique patient pathobiology may allow personalized treatment. We aimed to define and describe ARDS phenotypes/endotypes combining clinical and pathophysiologic parameters from a Canadian ARDS cohort.

A cohort of adult ARDS patients from multiple sites in Calgary, Canada, had plasma cytokine levels and clinical parameters measured in the first 24 h of ICU admission. We used a latent class model (LCM) to group the patients into several ARDS subgroups and identified the features differentiating those subgroups. We then discuss the subgroup effect on 30 day mortality.

The LCM suggested three subgroups ( n 1  = 64, n 2  = 86, and n 3  = 30), and 23 out of 69 features made these subgroups distinct. The top five discriminating features were IL-8, IL-6, IL-10, TNF-a, and serum lactate. Mortality distinctively varied between subgroups. Individual clinical characteristics within the subgroup associated with mortality included mean PaO 2 /FiO 2 ratio, pneumonia, platelet count, and bicarbonate negatively associated with mortality, while lactate, creatinine, shock, chronic kidney disease, vasopressor/ionotropic use, low GCS at admission, and sepsis were positively associated. IL-8 and Apache II were individual markers strongly associated with mortality (Area Under the Curve = 0.84).

Perspective

ARDS subgrouping using biomarkers and clinical characteristics is useful for categorizing a heterogeneous condition into several homogenous patient groups. This study found three ARDS subgroups using LCM; each subgroup has a different level of mortality. This model may also apply to developing further trial design, prognostication, and treatment selection.

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Introduction.

Acute respiratory distress syndrome (ARDS) is a common clinical condition in the intensive care unit (ICU) and a significant cause of morbidity and mortality [ 1 , 2 , 3 ]. ARDS represents 10.4% of all ICU admissions worldwide, affecting 23.4% of all patients requiring mechanical ventilation [ 4 ]. ARDS-related mortality before ICU discharge has been estimated at 35.3% overall, including 29.7, 35.0, and 42.9% for mild, moderate, and severe diseases, respectively. Despite ARDS's clinical, societal, and economic burden, there is no specific therapy, and the mainstay of management is supportive care [ 5 ].

ARDS is an acute onset of non-cardiogenic pulmonary edema, bilateral pulmonary infiltrates, and hypoxemia [ 5 , 6 ]. The definition, including the most recent consensus nominally known as the Berlin criteria, describes clinical characteristics without considering the pathophysiological processes leading to lung injury. Although pneumonia and sepsis are common causes, ARDS is a complex heterogeneous syndrome [ 5 , 7 , 8 ]. The most recent example of the heterogeneity of ARDS is COVID-19. Although COVID-19 patients have oxygenation and radiographic characteristics that meet the clinical criteria of ARDS, many other parameters (such as ventilatory mechanics and inflammatory mediator profiles) appear to be different [ 9 , 10 ]. In addition, despite a common etiologic cause, more than one disease subtype has been described. Although ARDS has heterogeneous causes and manifestations, diffuse alveolar damage (DAD) is the histologic hallmark [ 7 ]. However, using accepted pathologic criteria [ 11 , 12 ], DAD is identified in approximately half of the biopsy samples from patients diagnosed with ARDS [ 3 ]. Other investigators have suggested ways of subdividing the disease [ 13 , 14 , 15 ] to improve the identification of patients at risk for ARDS, improve prognostication, develop targeted therapy, and inform clinical trial design [ 16 ].

Endotyping is one approach to stratify patients. Biomarkers are an attractive tool for identifying different ARDS subtypes and have been a focus of study in the past decade [ 4 ]. Therapy-directed genotyping using circulating biomarkers has proven to be an emerging strategy for targeted oncologic therapy but is infrequently utilized in critical care, specifically in ARDS-based research. Recent studies regrouping clinical characteristics and biomarkers have identified two distinct biological subgroups of ARDS [ 15 , 17 , 18 ]. These subgroups appear to be associated with explaining differential outcomes when applied in retrospective studies. These early studies offer promise for the potential of genotyping and studying potential mechanisms of ARDS. However, studies to date have not included patients from heterogeneous regions. Our study aimed to identify clusters in a Canadian-based ARDS patient population using a combination of clinical characteristics and blood biomarkers, examine any association with mortality, and describe similarities or differences with prior published ARDS subgroups.

Study design

This is an observational, cross-sectional study of adult patients (> 17 years of age) with ARDS entered into the Critical Care Epidemiologic and Biologic Tissue Resource (CCEPTR) tissue bank at the University of Calgary. Written informed consent was obtained from each subject and/or their legal surrogates before data collection and sample storage according to the Conjoint Health Research Ethics Board of the University of Calgary, REB15-0348_MOD5).

Description of the cohort

The samples and clinical data were collected from adult subjects (> 17 years of age) following ICU admission for suspected infection/sepsis at Foothills Medical Centre or Peter Lougheed Centre; both tertiary care academic multisystem intensive care units in Calgary, Alberta, Canada.

Patients were identified as having ARDS and included in the study if they were on mechanical ventilation on the first day of their ICU stay, had PaO 2 /FiO 2 ratios ≤ 300 and had a chest X-ray confirming alveolar infiltrates in more than one quadrant. Patients were excluded if they had one of (1) a diagnosis of congestive heart failure (CHF) defined by ejection fraction (E.F.) < 40% on echocardiography or the attending team gave a diagnosis of CHF, (2) if they were immunocompromised, or (3) if the patient died within 24 h of study enrollment.

Clinical data collection

Clinical data on all patients were extracted from an ICU-specific integrated bedside clinical information system (Metavision, iMDsoft, Tel Aviv Israel), which prospectively captured clinical demographic and physiologic devices data, including ventilation parameters and measures, laboratory results, and outcome data. We have previously validated this information system by manual audit as a reliable data source for quality improvement and research. Fifty total potential clinical covariates were identified, including 13 risk factors, 12 comorbidities, 10 clinical laboratory results, eight non-respiratory clinical measures, and seven ventilatory parameters.

Biomarker selection and assay procedures

A priori, we identified 12 biomarkers for analysis. The biomarkers were selected considering four broad criteria: (1) are a potential measure of lung epithelial injury (e.g., RAGE), (2) are a marker of inflammatory injury including endothelial injury [e.g., plasminogen activator inhibitor-1 (PAI-1)], (3) assay validated in our laboratory, and/or (4) have been identified in prior work of interest in identifying hyperinflammatory or hypo-inflammatory endotypes in ARDS [ 14 ]. Plasma samples were collected within 24 h of ICU admission/ARDS diagnosis. Samples were aliquoted into 250 µl aliquots and frozen at − 80 °C for single use [ 19 ]. We measured protein C (P.C.) antigen levels quantified by a sandwich-style ELISA from plasma samples using a matched-pair antibody set (Affinity Biologicals, Ancaster, ON, Canada). The levels of the remaining biomarkers were measured by electrochemiluminescence technology using a Meso QuickPlex SQ 120 instrument (Meso Scale Discovery) equipped with Discovery Workbench 4.0 software for data acquisition and analysis.

Variables available for analysis

The variables entered in the model were chosen based on the presence of at least one of the following: (1) are routinely measured in a clinical setting, (2) are biomarkers previously identified as having a putative role in ARDS pathophysiology, and (3) represented a distinguishing feature of ARDS.

Statistical analysis

The baseline characteristics are described using descriptive statistics with measures of central tendency (median) and dispersion (interquartile range, IQR) for continuous variables and counts and percentages for categorical variables. Continuous variables with more than 20% missing values were excluded, and the MICE package was used to impute missing values. They were then transformed into a logarithm scale and standardized with mean zero and unit variance. Risk factors and comorbidity conditions with a single level were also excluded. Binary indicators for risk factors and comorbidity conditions coded positively in less than 10% of cases were removed. We also excluded highly collinear features whose Pearson correlation coefficient was greater than 0.9. Finally, functional variables were excluded. For example, APACHE II was collected as a clinical descriptor but not included in analytical models as it is derived from the other clinical variables. After following the exclusion criteria, 51 variables (33 continuous and 18 discrete variables) were available in the study, and they are listed in Table  1 . In the table, we have included variables with missing values and those that underwent imputation for information.

A latent class model (LCM) proposed by Marbec et al. was employed with the VarSelLCM package [ 20 , 21 ] since this model permits cluster analysis with mixed-type data and simultaneously identifies the most discriminative variables. In addition, the model supports two scenarios when the number of variables is smaller or larger than the number of samples. The Bayesian information criterion (BIC) and maximum integrated complete-data likelihood (MICL) criterion were utilized in choosing the optimal number of clusters. A discriminating power index ranked the input variables. A Kaplan–Meier estimator was employed to explore the difference in 30 day mortality by the clusters found by LCM. We also calculated the information value (IV) to rank the input feature in terms of the importance of predicting mortality, using 0.3 as a threshold of clinical association [ 22 ]. All analyses were carried out using standard statistical software, R-4.0.0, with the packages VarSelLCM, survival, stats, MASS, and Information.

To compare our analysis and model with previous models, we cross-classified our clustering results to the hyper- and hypo-inflammatory subphenotypes suggested by Sinha et al. (2020) [ 18 ] and this is presented in the results.

Characteristics of study cohort

Two hundred eight patients were identified with a PaO 2 /FiO 2 (P/F) ratio of less than 300, of which 28 patients were excluded as 14 had chest X-rays that did not have more than one quadrant of disease, nine were not receiving mechanical ventilatory support, and five were misclassified (CHF was present or suspected).

A description of the demographics, clinical, and biomarker characteristics of the study cohort is shown in Table  1 . 58.9% were male, with a median age [IQR] of 60 [51, 71]. The most common contributing cause of ARDS was sepsis (85.6%), of which 29.6% (44/154) was from a pulmonary source. Aspiration was the cause in 10% of patients, transfusion-associated lung injury in 6.1%, pancreatitis in 3.9%, and shock associated with trauma in 1.7%. Many patients had comorbidities, the most common including chronic respiratory disease, coronary atherosclerosis, alcohol use disorder, and diabetes. Twenty-two patients (12.2%) had a prior heart failure history (without evidence of acute hydrostatic pulmonary edema on this ICU admission). The median Apache II score was 22 [18, 28]. Vasopressors were used for 79.4% of the patients. The median P/F ratio was 170 [96, 240]. Ventilatory parameters included a median PEEP value of 10 [8, 12] cm H 2 O with a median tidal volume of 590 mL [520, 630] for men and 480 mL[430, 520] for women, and the median plateau was 26 cm H 2 0 [22, 31]. The median lactate was 1.7 mmol/L [1.2, 3.3], with a white blood cell count of 12.9 [7.8, 19.7] and a platelet count of 181 [116, 251] and serum creatinine of 98 mmol/L [67, 180]. Forty-four (24%) of patients died in ICU. The median ICU length of stay was 10 days [6, 18.3].

Cluster analysis for subgroup identification

We fitted a model to the data by changing the number of subgroups. The model with three subgroups shows the maximum BIC and MICL values (as shown in Table S1 and Figure S1). Twenty-three variables were selected as discriminatory from this model: 8 were clinical measures, 3 were risk factors, and 11 were biomarkers (Table  2 ). Patients in Group 1 (Group 1 vs. Total) appeared different across multiple variables. For example, the heart rate [median] was lower [88 vs. 100], vasopressors were used less frequently (57.1 vs. 79.4%), had better P/F ratios (197.0 vs. 172.5), lower serum lactate levels (1.10 vs. 1.7), higher platelet counts (236 vs. 181) and less kidney injury as measured by serum creatinine. Endotype subgroup 1 had evidence of lower biomarkers, including lower inflammatory markers (e.g., TNFa, TNF-R1, Il-6, IL-8), lower anti-inflammatory markers (e.g., Il-10), and lower endothelial/coagulation biomarkers (e.g., vWF, ICAM-1, PAI-1), as shown in Fig.  1 . When considered in isolation, RAGE, a lung epithelial biomarker, was comparable across sub-groups. When variables with binary results were only evaluated in the LCM, only two subgroups were evident; however, when continuous variables were also considered, there was an evident difference with three subgroups that appeared (Fig.  2 ). The three endotypes are distinct in terms of the risk of ICU-associated mortality, with Group 1 having no mortality (0%), ICU Group 2 having a 29% ICU mortality, and Group 3 having a 63% mortality before ICU discharge; Group 3 had an earlier and higher rate of death (Fig.  3 ).

Differences in a standardized score of each continuous variable and proportion of each binary variable by subtype. In terms of mortality, subtypes are referred to as mild, moderate, and severe. Variables are sorted in ascending order in the mild group. Note that IL interleukin, TNF-α tumor necrosis factor α, ANG-2 Angiopoietin 2, RAGE receptor of advanced glycation end products, vWF von Willelbrand factor, TNF-R1 tumor necrosis factor receptor 1, ICAM-1 intercellular adhesion molecule-1, PAI-1 plasminogen activator inhibitor-1, SPD surfactant protein D and Prot C Protein C

Kaplan–Meier estimate of 30-day patient survival with log-rank test p-value by subgroup

Side-by-side boxplot of cytokine concentration in logarithm scale by subgroup. Note that IL interleukin, TNF-α tumour necrosis factor α, ANG-2 Angiopoietin 2, RAGE receptor of advanced glycation end products, vWF von Willelbrand factor, TNF-R1 tumour necrosis factor receptor 1, ICAM-1 intercellular adhesion molecule-1, PAI-1 plasminogen activator inhibitor-1, SPD surfactant protein D and Prot C Protein C

We cross-classified our clustering results to the hyper- and hypo-inflammatory subphenotypes suggested by Sinha et al. (2020) [ 18 ] (Table S2). We observed 98–100% exact matches between Group 1 (mild) and hypo-inflammatory subtype and 100% between Group 3 (severe) and hyper-inflammatory subtype. For both models, 86 patients of Group 2 (moderate) are spread almost equaly between the hyper- and hypo-inflammatory groups (Table S2).

We simultaneously performed subgroup identification and variable selection using a single-step latent class model. Our work suggests that there are more than two ARDS subgroups. As has been reported in seminal studies, ARDS patients in this study appear to have an endotype that is either hypo-inflammatory (Endotype 1) or hyper-inflammatory (Endotypes 2 and 3) [ 15 ]. Our results are consistent with these findings but suggest that there may be a distinction in the hyper-inflammatory endotype identifying a group with a substantially higher mortality risk (Endotype 3). The separation between endotypes becomes evident by adding continuous variables (predominantly physiologic and biomarkers) to clinical binary variables (cause of shock, cause of ARDS, use of vasopressors) as discriminatory determinants in the model. For example, the hypo-inflammatory endotype has less vasopressor use, higher P/F ratios at baseline, lower serum lactate levels, and less evidence of kidney injury. Pro-inflammatory and anti-inflammatory marker differences between endotypes do not easily correspond with hypo- or hyper-inflammatory states. For example, IL-6 is higher in the hyperinflammatory endotype, yet IL-10 is much higher in at least the hyperinflammatory endotype three than the hypo-inflammatory endotype 1. Despite prior work by others identifying a role for RAGE—a biomarker relatively specific to lung epithelial injury, our results do not identify this biomarker in isolation as different between subgroups.

ARDS endotyping has undergone significant research over the last 10 years. Sequential findings have helped us understand how ARDS phenotypes can be detected and how they may be applied to different ARDS therapies. In 2014, Calfee et al. described the use of latent class methodology to identify two subphenotypes of ARDS, one of which was characterized as having more inflammation, shock, and metabolic acidosis, called Phenotype 2 (hyperinflammatory), and it was found to have a worse clinical outcome than Phenotype 1 (hypo-inflammatory) [ 15 ]. These phenotypes were derived from patient information from the ARMA trial (a trial of low vs high tidal volume). Three variables were found to differentiate these phenotypes (IL-6, sTNF-R1, and vasopressor use). Importantly, these phenotypes were validated and were found retrospectively to have a differential response to PEEP in patients from the ALVEOLI Trial (high vs low PEEP). In 2015, Calfee et al., using plasma biomarkers of lung epithelial and endothelial injury as well as inflammation, found two phenotypes characterized by evidence of direct lung injury (consistent with more epithelial lung injury and less severe endothelial lung injury), whereas indirect lung injury (consistent with more severe endothelial lung injury and less severe epithelial lung injury) suggestive of different molecular mechanisms of injury that may be used for potential future therapies [ 2 ]. Other studies have also examined mechanisms of injury in the direct and indirect lung injury phenotypes of ARDS using metabolomics and protein levels in serum [ 23 ]. In 2016, Famous et al. used patient information from the FACTT Trial (fluid and catheter treatment trial, a fluid management trial) to confirm two ARDS subphenotypes using latent class analysis (hyper- and hypo-inflammatory) that showed a differential response to fluid management [ 13 ]. They identified three variables that accurately classified the subphenotypes (IL-8, bicarbonate, and sTNF-R1) in keeping with previous studies. In 2017, Bos et al. used a different approach to examine ARDS subphenotypes [ 17 ]. They questioned whether plasma biomarkers (markers of inflammation, coagulation, and endothelial activation) alone could be used for subphenotype ARDS patients. They used cluster analysis and found two subphenotypes (uninflamed and reactive) based on four biomarkers (IL-6, interferon-gamma, angiopoietin 1/2, and PAI-1) with different mortality rates. They concluded that these two subpenotypes were similar to those previously identified as hyper-inflammatory and hypo-inflammatory.

To summarize and help apply the sub-phenotyping work, in 2020, Sinha et al. used patient information from 5 clinical trials (ARMA, ALVEOLI, FACTT, START, and HARP-2) to develop and validate a parsimonious classification model to accurately subphenotype ARDS meant to be used in the clinical setting [ 18 ]. They found a model having 3 or 4 variables (IL-8, bicarbonate, protein C, and vasopressor use) that could accurately identify the previously found two subphenotypes of ARDS (hyper-inflammatory and hypo-inflammatory). They propose that these markers could be used in ARDS clinical trials.

We compared our results to previously published models by cross-classifying our clustering results to the hyper- and hypo-inflammatory subphenotypes suggested by Sinha et al. (2020) [ 18 ] (Table S2). As presented in the result section, we observed 98–100% exact matches between Group 1 (mild) and the hypo-inflammatory subtype and 100% between Group 3 (severe) and the hyper-inflammatory subtype. For both models, 86 patients of Group 2 (moderate) are spread almost equaly between the hyper- and hypo-inflammatory subgroups. As a result of this comparison, we believe that our model, using more pathophysiologic biomarkers, allows more accurate grouping of patients supported by differential prediction of mortality between our two hyper-inflammatory groups. Moreover, if we apply the models of Sinha et al. (2020) [ 18 ] we have good accuracy and Kappa-agreement suggesting that our population are comparable (Table S2).

It is important to note that none of these investigators have said that only two subphenotypes exist, but their data model best fits two subphenotypes. Our data suggest a unique hyper-inflammatory subgroup may have a differential mortality risk. Although many prior studies of ARDS phenotyping have suggested only 2 clusters, other authors have also suggested that more than two phenotypes may exist [ 17 ].

Our study has numerous unique characteristics, strengths, and limitations. Our cohort of patients is unique to one region in Canada and may represent a more homogeneous cohort of patients within a complex heterogeneous disease than those previously described. For example, in the Calgary region, there are fewer African Americans and Hispanic heritage people, and there are more people of Asian heritage and Indigenous individuals than seen in most U.S. centers. Of note, we did not get information on heritage in our study. In addition, although our patients arise from 2 physically distinct ICUs, the ICUs are from the same clinical department within which there is standardized training of respiratory therapists and ICU nurses, standardized equipment (e.g., monitors, ventilators, pulse oximeters, arterial blood gas analyzers, and intravenous pumps), a singular medication library, and medical staff, including critical care fellows, that rotate between units. Therefore, it is likely that care is comparable and homogeneous between ICUs. However, differences in race and ancestral origin may limit external generalizability. Race is not routinely collected by our electronic health medical record.

One strength of our study is that the cohort is an observational cohort rather than a highly selected patient sample, such as the prior studies that used patients enrolled in randomized controlled clinical trials, suggesting that these patients were highly selected relative to a population of interest. This can have introduced a selection bias in the population analyzed, as we all know that not all comers are eligible for those studies. As such, our cohort may more reasonably represent the 'usual' population of patients with ARDS, at least in Canada. Of note, our patients excluded those with COVID-19, which some have suggested have a unique or different endotype to other causes of ARDS.

Other strengths of our study include a standardized collection of clinical, laboratory, and biomarker data at admission. However, the levels of several biomarkers in our studies differed from those obtained in comparable studies. Notably, other more recent comparative work done with ARDS caused by COVID-19 has similar numbers [ 24 ].

Again, patients in other studies were enrolled in randomized controlled studies. This could result in a difference in the populations in those studies. Also, although blood samples were collected within a standardized protocol, including comparable times from ICU admission, samples were stored and batched until they were analyzed. Despite rigorous standardized operating procedures for processing and − 80℃ storage (including alarmed freezers) until analyzed, it is possible that biological material degradation occurred over time; this may have differentially affected our analyses. However, because of the uniformity of our standard operating procedures and sample management, it is less likely that there was sample degradation than that seen in all the randomized trials from many centers in the U.S. Those different results can also be attributed to technical differences, including the measurement and analysis methods—the kits used—for the biomarkers. In addition, most other studies collected blood for biomarkers at variable time points rather than standardized at admission, like in our study. In addition, other studies measured biomarkers at different times, either during the primary analysis of the initial study or during their analysis a few years later. Finally, it is important to notice a great difference in the biomarkers introduced in the models presented in the different studies. Most prior studies introduced more biomarkers in their models compared to our work, but the justifications for each biomarker selection in their model were not provided. Our study carefully chose the biomarkers in the clustering model; the biomarkers are also close to that of the most recent work published published [ 10 , 11 ], and we used robust analytical techniques. Our findings also duplicate other recently published findings as described above [ 13 , 15 , 17 , 25 ].

Our biomarkers did not include other potential markers, such as those from genomics or metabolomics: numerous studies have suggested that patients with ARDS may have unique genomic or metabolomic profiles [ 23 ], but one of our aims was to develop a method that could be relatively easily utilized in the ICUs in North America.

Our study used an advanced LCM technique compared to those working with a conventional LCM technique. Despite the efforts to include mixed-type data, small samples in high dimensions, and variable selection (which a conventional LCM cannot do), our study still has two analytical concerns about dependency between features. The first concern is that feature redundancy and dependency between feature groups still remain. For example, consider two groups of cytokine measures. IL-6, IL-8, IL-10, and TNFa are the markers of an inflammatory group, and ICAM-1, ANG-2, and vWF are endothelium group markers. One measure per group may be much more efficient when utilizing the model as a bedside formula. In addition, the model does not fully describe the association between markers within or between groups. The second concern is that equal weight is given to all variables included in a model. This assumption ignores pathobiological pathways, that is, pathways with individual effects on biomarkers (and vice versa), and the interdependent effects between biomarkers. Although our study demonstrates important cytokines or lab results that contribute to identifying phenotypes, it is impossible to attribute a weight of effect to each input feature.

This study again highlights that patients with ARDS admitted to the ICU have heterogeneous characteristics and outcomes. Furthermore, simple characterization based on the P/F ratio alone may not be sufficient to estimate the risk of adverse outcomes such as mortality. Phenotyping studies have now been undertaken for several years. All the results of those studies are expected to be hypothesis-generating studies. In addition to other phenotyping studies, the present study also emphasizes the importance of undertaking new prospective studies with real-time measurements of biomarkers. Our study adds to the large body of evidence supporting that identifying unique endotypes using rapid diagnostics measures including a limited biomarker profiles combined with clinical variables to impact clinical trial design or prognosticate patient outcomes, remains an unrealized opportunity rather than an intervention that can be implemented in real-time. Our study revealing three endotypes in ARDS is one of many studies that may advance the detection of ARDS endotypes in developing therapies or interventions in the future.

Availability of data and materials

The data sets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

We would like to thank Dr. Matthieu Marbac, author of VarSelLCM, for the discussion. We thank Dr. Patricia Liaw (McMaster University) for doing the protein C measurement levels and the Department of Critical Care at the University of Calgary for funding the biomarker assays. We thank Josee Wong and the Critical Care Epidemiologic and Biologic Tissue Resource, a tissue bank at the University of Calgary, for managing samples and patient data. We thank the nurses, doctors, and patients who took part in the study. BWW was funded by The Lung Association of Alberta and the NWT as well as the Canadian Intensive Care Foundation. AC and BWW were funded by the Department of Critical Care, University of Calgary. The CCEPTR tissue bank was partly funded by a team grant from Alberta Innovates-Health Solutions to the Alberta Sepsis Network, a grant from Alberta's Health Research Innovation Strategy and by the Department of Critical Care, University of Calgary.

This research has been funded by the Department of Critical Care at the University of Calgary to AC and BWW, the Lung Association of Alberta and the NWT to BWW and CHL, and the Canadian Intensive Care Foundation to BWW.

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Andréanne Côté and Chel Hee Lee have co-first authors.

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Department of Medicine, Institut Universitaire de Cardiologie et de Pneumologie de Quebec-Université Laval, Quebec, Canada

Andréanne Côté

Department of Critical Care Medicine, Medicine and Biochemistry and Molecular Biology, Health Research Innovation Center (HRIC), University of Calgary, Room 4C64, 3280 Hospital Drive N.W., Calgary, AB, T2N 4Z6, Canada

Andréanne Côté, Chel Hee Lee, Christopher J. Doig, Bryan G. Yipp, Ken Kuljit S. Parhar & Brent W. Winston

Department of Mathematics and Statistics, University of Calgary, Calgary, Canada

Chel Hee Lee

School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK

Sayed M. Metwaly

Division of Internal Medicine, Aberdeen Royal Infirmary, NHS Scotland, Aberdeen, UK

Depatments of Medicine, University of Calgary, Calgary, Canada

Graciela Andonegui & Brent W. Winston

Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada

Brent W. Winston

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AC*/BW/CD—study design, manuscript writing, manuscript review. CHL*—analysis, manuscript writing, manuscript review. SMM, GA, BGY, K.P.—manuscript review. AC/CHL—co-First authors.

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Côté, A., Lee, C.H., Metwaly, S.M. et al. Endotyping in ARDS: one step forward in precision medicine. Eur J Med Res 29 , 284 (2024). https://doi.org/10.1186/s40001-024-01876-7

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Causes and attributable fraction of death from ARDS in inflammatory phenotypes of sepsis

• Bruno Evrard   ORCID: orcid.org/0000-0003-1829-4927 1 , 2 ,
• Pratik Sinha 3 , 4 ,
• Kevin Delucchi 5 ,
• Carolyn M. Hendrickson 6 ,
• Kirsten N. Kangelaris 7 ,
• Kathleen D. Liu 8 , 9 ,
• Andrew Willmore 10 ,
• Nelson Wu 10 ,
• Lucile Neyton 1 ,
• Emma Schmiege 10 ,
• Antonio Gomez 6 ,
• V. Eric Kerchberger 11 , 12 ,
• Ann Zalucky 1 ,
• Michael A. Matthay 1 , 9 , 10 ,
• Lorraine B. Ware 11 , 13 &
• Carolyn S. Calfee 1 , 9 , 10  

Critical Care volume  28 , Article number:  164 ( 2024 ) Cite this article

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Hypoinflammatory and hyperinflammatory phenotypes have been identified in both Acute Respiratory Distress Syndrome (ARDS) and sepsis. Attributable mortality of ARDS in each phenotype of sepsis is yet to be determined. We aimed to estimate the population attributable fraction of death from ARDS (PAF ARDS ) in hypoinflammatory and hyperinflammatory sepsis, and to determine the primary cause of death within each phenotype.

We studied 1737 patients with sepsis from two prospective cohorts. Patients were previously assigned to the hyperinflammatory or hypoinflammatory phenotype using latent class analysis. The PAF ARDS in patients with sepsis was estimated separately in the hypo and hyperinflammatory phenotypes. Organ dysfunction, severe comorbidities, and withdrawal of life support were abstracted from the medical record in a subset of patients from the EARLI cohort who died (n = 130/179). Primary cause of death was defined as the organ system that most directly contributed to death or withdrawal of life support.

The PAF ARDS was 19% (95%CI 10,28%) in hypoinflammatory sepsis and, 14% (95%CI 6,20%) in hyperinflammatory sepsis. Cause of death differed between the two phenotypes (p < 0.001). Respiratory failure was the most common cause of death in hypoinflammatory sepsis, whereas circulatory shock was the most common cause in hyperinflammatory sepsis. Death with severe underlying comorbidities was more frequent in hypoinflammatory sepsis (81% vs. 67%, p = 0.004).

Conclusions

The PAF ARDS is modest in both phenotypes whereas primary cause of death among patients with sepsis differed substantially by phenotype. This study identifies challenges in powering future clinical trials to detect changes in mortality outcomes among patients with sepsis and ARDS.

Acute respiratory distress syndrome (ARDS) is characterized by mortality of 35–45% [ 1 ] and considerable heterogeneity, contributing to the current challenge of developing effective treatment [ 2 ]. Two molecular phenotypes of ARDS, hypo- and hyperinflammatory, have been identified based largely on plasma levels of biomarkers reflecting inflammation, epithelial and endothelial injury and coagulation abnormalities [ 2 , 3 , 4 ]. Specifically, the hyperinflammatory phenotype, which represents about one-third of ARDS cases, is associated with high levels of inflammatory biomarkers, increased use of vasopressors, and higher mortality rates [ 2 , 3 , 4 ]. In contrast, the hypoinflammatory phenotype, representing approximately two-thirds of ARDS cases, is associated with lower levels of inflammatory biomarkers and reduced mortality rates [ 2 , 3 , 4 ]. These phenotypes have also been identified in sepsis, with similar characteristics, prognosis and differential response to activated protein C, suggesting this schema captures phenotypes of critical illness overall and not only ARDS [ 5 , 6 ].

The attributable fraction and population attributable fraction are epidemiological tools useful for estimating the potential impact of an exposure on an outcome. Population attributable fraction describes the reduction in the rate of the outcome if the exposure could be completely removed, assuming the exposure is causal. These metrics have been used in other fields to inform feasibility and design of trials [ 7 ]; for example, if population AF ARDS is low, sample size requirements for clinical trials in ARDS with primary outcome of mortality will be quite high [ 8 ]. The attributable fraction of death from sepsis-associated ARDS (AF ARDS ) is the proportion of deaths attributable to ARDS among all deaths in patients who developed sepsis-associated ARDS. The population AF ARDS (PAF ARDS ) in this context is the proportion of deaths that would be prevented following elimination of ARDS in patients with sepsis [ 9 ]. In a previous study, Auriemma et al. reported the PAF ARDS to be 16% and 18% in two independent cohorts of septic adults, with mortality mainly driven by severe ARDS (P/F ratio < 100) [ 10 ]. However, this study encompassed both hypo- and hyperinflammatory phenotypes and used sepsis patients without ARDS as the reference population. More recently, Saha et al. estimated the attributable mortality of ARDS phenotypes using a completely different reference population (either critically ill patients without acute respiratory failure or patients with a unilateral radiographic infiltrate), and without estimating the PAF ARDS [ 11 ]. The PAF ARDS for hyper- and hypoinflammatory phenotypes using a referent population of sepsis patients remains unknown. Moreover, whether causes of death differ in sepsis based on molecular phenotypes is also unknown and may inform the proportions of mortality that may be modifiable in each phenotype. In this study, we aimed to (1) estimate 60 days in hospital PAF ARDS in patients with hypo-inflammatory versus hyperinflammatory sepsis, and (2) to determine causes of death in hypo-inflammatory versus hyper-inflammatory sepsis to further contextualize our PAF ARDS analyses.

Participants

We studied patients from two prospectively enrolled cohorts of critically ill adults: (1) the Early Assessment of Renal and Lung Injury (EARLI) study, which enrolls adults admitted from the emergency department to the intensive care unit (ICU) at either an academic medical center or safety net hospital in San Francisco, California, and (2) the Validating Acute Lung Injury markers for Diagnosis (VALID) study which enrolls critically ill adults from an academic medical center in Nashville, Tennessee.

Sepsis and ARDS definition

We selected patients admitted to the ICU for sepsis [ 12 ]. Because data collection started prior to publication of the Sepsis 3 definition [ 13 ], sepsis was defined as documented or suspected infection in the presence of two or more characteristics of the systemic inflammatory response syndrome within the first two days of ICU admission [ 12 ]. Presence or absence of sepsis, and pulmonary or non-pulmonary origin of sepsis if present, was meticulously assessed by a participating study physician using all the data available from the patient’s hospitalization. Patients were defined as having ARDS if they met Berlin criteria for ARDS on at least one of the first five hospital days for EARLI and between ICU days one through four in VALID [ 14 ]. Day one was defined as the admission date in the emergency department in EARLI, whereas it was defined as the day of ICU admission in VALID. Development of ARDS was adjudicated by at least two study physicians and by review of all chest radiographs during the first 5 days of enrollment, using criteria set forth by the AECC or Berlin criteria [ 14 , 15 ]. When patients met chest radiograph and oxygenation criteria for ARDS, then the medical record was thoroughly reviewed for any evidence of a primary or contributory cardiogenic cause of pulmonary edema. We additionally identified patients who were not receiving mechanical ventilation but who met the American-European Consensus Conference (AECC) criteria for acute lung injury (ALI) during the same time frame [ 15 ]. Further information on exclusions criteria is provided in Additional file 1 : E-methods. Latent class assignments for included patients were determined in a previous study [ 6 ]. Briefly, latent class analysis (LCA) is a statistical technique that uses mixture modelling to find the best fitting model for a set of data, based on the hypothesis that the data contain several unobserved groups or classes [ 16 ].

EARLI was approved by the University of California, San Francisco Institutional Review Board (IRB) and VALID by the Vanderbilt IRB. Consent was obtained from patients or their surrogates when possible, as previously described [ 10 ].

Determination of the cause of the death

We determined cause of death in patients who died in the EARLI cohort for whom electronic health records (EHR) were available. Patients’ data were reviewed by one trained intensivist who did not participate in ARDS adjudication and was blinded to ARDS and phenotype status. Rigorous inspection of the temporal relationship of laboratory data, imaging data, hemodynamic, respiratory parameters and physician’s notes, using a standardized case ascertainment template (Additional file 1 : E-methods) [ 17 ], was carried out to define cause of death. If determination of cause was challenging, adjudication was done with a second trained intensivist (CSC). 25% of randomly patients were assessed by a third intensivist (AZ) to determine inter-rater reliability.

For each patient, we reviewed the medical record for evidence of dysfunction of eight organ systems during the 72 h prior to death (Additional file 1 : Table E1). We classified organ dysfunction as severe or irreversible using modified definitions from prior studies (Additional file 1 : Table E1) [ 17 , 18 ]. The primary cause of death was defined as the organ system that most directly contributed to death or withdrawal of life support (Additional file 1 : Figure E1). Further information regarding determination of cause of death is provided in the E-methods.

Flow chart of the study

Statistical analysis

Sample size estimation is provided in the E-methods (Additional file 1 : E-methods) and was used to support the decision to combine EARLI and VALID for most analyses. Pearson’s chi square and Wilcoxon rank sum test were used to compare baseline variables stratified by phenotypes of sepsis. The primary outcome was in-hospital 60-day mortality. AF ARDS and PAF ARDS were estimated within each phenotype separately; specifically, the mortality of hypoinflammatory sepsis with ARDS was compared to the mortality of hypoinflammatory sepsis without ARDS, without considering hyperinflammatory patients, and vice versa. To estimate the AF ARDS and the PAF ARDS within each phenotype of sepsis, we used methods outlined previously [ 9 , 10 , 19 ]. Estimates were based on indirect standardization, which computes the weighted average of stratum-specific estimates in the reference population, using weights from the study population [ 10 , 19 ]. Strata were defined by modified APACHE II quartiles; the oxygenation component of APACHE II was removed for this analysis. We also conducted multiple sensitivity analyses, one of which involved a matching approach using propensity scores, for which we used a directed acyclic graph to determine the variables to include in the model (Additional file 1 : Figure E2). Details of the sensitivity analysis are provided in the E-methods (Additional file 1 : E-methods). Pearson’s Chi Square was used to compare cause of death between patients with hypoinflammatory vs hyperinflammatory sepsis and with or without ARDS. A p-value less than 0.05 was considered statistically significant. Analyses were performed using the STDRATE procedure in SAS (Version 3.81) for the calculation of AF ARDS and the PAF ARDS using strata method and using R (Version 4.2.2) for all other analysis.

A Estimation with 95% confidence interval and sensitivity analysis of the population attributable fraction of death from ARDS in each phenotype of sepsis. B Estimation with 95% confidence interval and sensitivity analysis of the attributable fraction of death from ARDS in each phenotype of sepsis. ARDS Acute respiratory distress syndrome, LCA Latent class analysis

Patient characteristics

Overall, 1737 patients were included, 675 from EARLI and 1062 from VALID (Fig.  1 ). Patients from EARLI were significantly older (Median: 66 years, IQR [55,78] vs. 58 years, IQR [47,67], p < 0.001), more frequently required vasopressors (58% vs. 47%, p < 0.001), and less frequently required invasive mechanical ventilation (45% vs. 61%, p < 0.001) (Additional file 1 : Table E2) compared to patients from VALID. The proportion of patients who developed ARDS within five days of enrollment was also higher in EARLI (47% vs. 37%, p < 0.001). In-hospital overall mortality was similar in both cohorts (27% vs. 25%, p = 0.5) and also comparable within the ARDS subgroup in both cohorts (37% vs. 34%, p = 0.5). In both cohorts, more than 85% patients who developed ARDS did so on day 1 or day 2 of study enrollment (Additional file 1 : Figure E3A).

A Barplot showing the comparison of the cause of death between hypoinflammatory and hyperinflammatory sepsis in EARLI overall population. B Barplot showing the comparison of the cause of death between hypoinflammatory and hyperinflammatory sepsis in the subgroup of patients who developed ARDS. ARDS Acute respiratory distress syndrome, CNS Central nervous system, GI Gastro-intestinal

Considering both cohorts together, 1168 patients (67%) were allocated to the hypoinflammatory group, and 440 of these (37%) developed ARDS during their study observation period (Table  1 , Additional file 1 : Figure E4). Age and sex were similar between patients developing ARDS and those who did not, whereas proportion requiring vasopressors, pulmonary sepsis, modified APACHE II and in-hospital mortality were higher in those who developed ARDS (Table  1 ). Albumin levels and hematocrit were similar in patients who developed ARDS and those who did not, whereas patients without ARDS received more fluids in the emergency department (Table  1 ). Among hypoinflammatory patients who died, 41 (20%) died before the end of the ARDS ascertainment time frame (5 days) without having developed ARDS (Additional file 1 : Figure E3B).

In the combined cohorts, 569 patients (33%) were allocated to the hyperinflammatory phenotype, and 272 of these (48%) developed ARDS in the five days following their ICU admission (Table  1 and Additional file 1 : Figure E4). As in the hypoinflammatory phenotype, proportion of pulmonary sepsis, modified APACHE II and in-hospital mortality were higher in patients who developed ARDS. The proportion of patients requiring vasopressors was similar between those who developed ARDS and those who did not. Albumin levels were slightly lower in patients who developed ARDS, while the volume of fluids received in the emergency department and hematocrit did not differ (Table  1 ). Among hyperinflammatory patients who died, 55 (23%) died before the end of the ARDS ascertainment time frame (5 days) without having developed ARDS (Additional file 1 : Figure E3B).

AFARDS and population AFARDS

In hypoinflammatory sepsis, the AF ARDS was 36% (95%CI: 24,45%), and the PAF ARDS was 19% (95%CI: 10,28%) (Fig.  2 ). This finding indicates that eliminating ARDS in hypoinflammatory sepsis would provide a relative mortality reduction of 19%. Sensitivity analyses excluding older patients, those with intermediate probability of phenotype membership, and using propensity scores did not meaningfully alter the results (Additional file 1 : Tables E3 and E4).

In hyperinflammatory sepsis, the AF ARDS was 23% (95%CI: 14,31%) and the PAF ARDS was 14% (95% CI: 1,23%), indicating that eliminating ARDS would provide a relative mortality reduction of 14% in hyperinflammatory sepsis (Fig.  2 ). Similar to hypoinflammatory sepsis, sensitivity analyses did not meaningfully alter the results (Additional file 1 : Tables E3 and E4).

• Cause of death

Among the 179 patients who died in EARLI, 49 (27%) were excluded from analysis because no electronic medical record data was available to determine cause of death (mainly patients enrolled from 2008 to 2011). Of the 130 studied, 54 were hypoinflammatory and 76 were hyperinflammatory. Inter-rater reliability for cause of death was excellent (Kappa = 0.94, p < 0.001).

Cause of death differed by phenotype (p < 0.001) (Additional file 1 : Figs. 3A-B and E5; Table  2 ). In hypoinflammatory sepsis, patients died mainly from respiratory failure (59%) (Fig.  3 A), which was primarily characterized by failure to wean from respiratory support rather than refractory hypoxemia (Additional file 1 : Figure E6). In contrast, patients who died in the hyperinflammatory group died mainly from circulatory failure (63%) (Fig.  3 A and Additional file 1 : Figure E7). When considering only patients who developed ARDS, these proportions and differences remained similar (Fig.  3 B). Among patients who died, 53% of patients with hypoinflammatory sepsis died in the ICU versus 73% in the hyperinflammatory phenotype (p = 0.018). Underlying severe comorbidities were present in most patients but were more pronounced in hypoinflammatory sepsis: 33% of hyperinflammatory sepsis patients who died had no underlying severe comorbidities, versus 19% in hypoinflammatory sepsis (p = 0.004) (Table  2 ; Additional file 1 : Figure E5). In the overall sepsis population and in the ARDS subgroup, modified SOFA score collected on day of death or day of withdrawal of life support was significantly lower in patients with hypoinflammatory sepsis compared to patients with hyperinflammatory sepsis (Table  2 and Additional file 1 : Table E5). Further details comparing cause of death of patients who developed ARDS and those who did not in each phenotype are provided in the Additional file 1 .

To our knowledge, this study estimates for the first time the AF ARDS and PAF ARDS in inflammatory phenotypes of sepsis. While the PAF ARDS was relatively similar in hyper- and hypo-inflammatory sepsis, cause of death differed substantially between the phenotypes. Death in hypoinflammatory sepsis was mainly driven by respiratory causes, most commonly failure to wean from respiratory support, and death in hyperinflammatory sepsis was mainly driven by circulatory failure/shock.

Our analyses of cause of death in each phenotype identified several patterns of interest. First, we found that patients in the hyperinflammatory phenotype died mainly because of circulatory failure (refractory shock). We could not determine if circulatory failure was caused directly by effects of sepsis on the peripheral vasculature (e.g. vasoplegia, hypovolemia) or by pulmonary vascular dysfunction leading to right ventricular failure, which is frequently present in patients who die from ARDS [ 20 , 21 , 22 ], or a combination of the two. Second, we found that patients with hypoinflammatory sepsis died mainly because of respiratory failure, regardless of the presence of ARDS. Respiratory failure in these cases was not driven by irreversible hypoxemia but by failure to wean from ventilatory or oxygenation support. Third, more than 80% of patients with hypoinflammatory sepsis who died had severe comorbidities which contributed to the decision to withdraw or not escalate life support. Thus, deaths in hypoinflammatory sepsis may reflect at least in part a population with severe comorbidities that limit functional recovery from critical illness. Numerous studies have reported that patients with ARDS frequently die because of extrapulmonary organ failure [ 17 , 18 , 23 ], but to our knowledge, the finding that patients with hypoinflammatory sepsis died mainly because of failure to wean from respiratory support is novel.

The PAF ARDS can be defined as the proportion of death over a specified time that would be prevented following elimination of the exposure (i.e., ARDS) in the sepsis population, assuming the exposure is causal [ 9 ]. Following this definition, 19% of deaths could be avoided during hospitalization if ARDS were eliminated in hypoinflammatory sepsis, and 14% of deaths in hyperinflammatory sepsis. Surprisingly, the AF ARDS and PAF ARDS seemed relatively similar and perhaps even lower in hyperinflammatory sepsis compared to hypoinflammatory sepsis. One possible explanation for this finding is that in hyperinflammatory sepsis, the lung is only one of many failing organs; thus, treating respiratory failure is less likely to eliminate risk of death. Another explanation could be that more patients with hyperinflammatory sepsis die before they can develop ARDS. However, as ARDS occurred mainly in the first 48 h, and because only a small proportion of patients died without ARDS within the five first days, this explanation seems less likely. As a result of this low PAF ARDS , therapies that target lung-specific pathways in hyperinflammatory sepsis may require dramatic efficacy to identify a mortality benefit, while therapies that have less organ-specific effects may be more fruitful [ 8 , 10 ].

The AF ARDS and PAF ARDS in hypoinflammatory sepsis were modestly higher, with a lower prevalence of multi-system organ failure, which might imply that ARDS plays a larger role in short-term mortality in this phenotype. However, the proportion of hypoinflammatory patients who died with a high burden of severe comorbidities was very high. If confirmed by other studies, these findings may limit the utility of mortality as an endpoint for future studies in hypoinflammatory sepsis, especially when severe comorbidities persist and contribute to a short life expectancy. Using severe comorbidities as a surrogate for frailty, we speculate that the modifiable proportion of death in this phenotype may be lower. It is important to emphasize that we did not explore other important endpoints such as morbidity, quality of life and other patient-centered outcomes, or the financial impact of ARDS in patients who survived [ 24 ]. Taken together, these findings highlight challenges to achieving mortality reduction in ARDS clinical trials. Designs for future trials in both phenotypes should take account of these findings, which could indicate that a large number of patients would need to be treated in order to identify a survival benefit, or that the trial population must be more strictly selected [ 7 , 10 , 23 ]. Cooperative multinational trials may be required in order to generate studies adequately powered for mortality endpoints.

With recent data suggesting that hypoinflammatory and hyperinflammatory phenotypes are generalizable to sepsis [ 5 , 6 ], we chose to study the AF ARDS and PAF ARDS within each sepsis phenotype. This approach considers ARDS as a complication of each phenotype of sepsis, rather than considering each phenotype of ARDS as a complication of overall sepsis or more broadly of critical illness. Analyses that assess the PAF of hyperinflammatory ARDS and hypoinflammatory ARDS relative to an unselected control group (i.e., unselected patients, or ventilated controls) will likely find quite different results. In a previous study, Saha et al. estimated the attributable fraction of mortality from hyperinflammatory ARDS using a different control population (either critically ill patients without acute respiratory failure or patients with a unilateral radiographic infiltrate) [ 11 ]. In contrast with our results, they found that the AF of death from hyperinflammatory ARDS was higher than from hypoinflammatory ARDS. The observed difference may be explained by the presence of both inflammatory phenotypes within their control population.

This study has several strengths. First unlike some prior studies [ 11 ], phenotypes were assigned by LCA, a robust method [ 16 ] with consistent and well-replicated findings [ 2 , 5 , 25 , 26 , 27 ]. Moreover, sensitivity analysis provided similar results, even when using another approach (propensity scoring) to estimate attributable mortality. Second, we strictly followed established methodological guidelines for estimation and interpretation of PAF ARDS [ 28 ]. Third, it included two large, diverse prospective cohorts from distinct centers which provide a generalizable population with external validity to estimate PAF ARDS . Fourth, all patients were meticulously assessed for both sepsis and ARDS. Fifth, inter-rater reliability for cause of death was excellent.

This study also has limitations. First, we only explored cause of death in EARLI, and some patients had missing data due to timing of EHR implementation. Second, we used the Sepsis-2 criteria to define sepsis, since studies started before the Sepsis-3 definition. However, as we enrolled only critically ill patients, it is unlikely that our patients would not fulfill the more recent criteria for sepsis [ 13 ]. Third, we were not able to assess if LCA class assignment changed over time, although a previous analysis showed that ARDS phenotypes were stable over the first 3 days [ 29 ]. Fourth, while the high burden of comorbidities in hypoinflammatory patients may imply a higher prevalence of frailty, we do not have formal measures of frailty, which might shed further light on causes of death in patients with multi-comorbidity [ 30 ]. Fifth, we assumed that no ARDS patients were misclassified for the analysis. However, our systematic prospective approach to determine presence of ARDS by at least two specialists limits the risk of classification bias, and we explicitly excluded patients whose ARDS diagnosis was unclear or equivocal in one cohort. Sixth, we did not treat ARDS as a time-varying exposure, which could theoretically lead to an overestimation of the population AF ARDS [ 31 , 32 ]. However, this potential bias is limited by the fact that the vast majority of ARDS occurred on Day 1 or 2 of study enrollment. Finally, we focused here only on sepsis patients admitted in ICU, and findings may not be generalizable to patients with other risk factors for ARDS.

This study provides important new findings about PAF ARDS in each inflammatory phenotype of sepsis. The PAF ARDS was modest (< 20%) in both phenotypes and relatively similar. Patients with ARDS in hypoinflammatory sepsis died primarily from respiratory failure with a high burden of severe comorbidities contributing to decisions around end-of-life. Conversely, patients with ARDS in hyperinflammatory sepsis died primarily from circulatory failure. These findings suggest that identifying effective therapies to reduce mortality from sepsis-induced ARDS may be challenging in both phenotypes but for different reasons—namely, the higher prevalence of multiorgan failure in hyperinflammatory sepsis which may decrease the impact of treating only one organ, and the burden of comorbidities which may impact short-term prognosis for patients with hypoinflammatory sepsis.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

Acute respiratory distress syndrome

Attributable fraction of death from ARDS

Population attributable fraction of death from ARDS

Intensive care unit

Acute Physiology and Chronic Health Evaluation II

Early Assessment of Renal and Lung Injury cohort

Validating Acute Lung Injury markers for Diagnosis cohort

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BE is supported by « La Société de Réanimation de Langue Française», « Association Limousine d’Aide aux Insuffisants Respiratoires», « Philippe Fondation», « L’institut Servier» and « Fondation Monahan». CSC is supported by R35 HL140026. LBW is supported by NIH HL158906 and NIH HL164937. PS is supported by NIH GM142992.

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Contributions

BE, PS, KD, LBW and CSC designed the study. BE, NW, LN and AW performed the analysis. BE and CSC drafted the manuscript. AZ performed the inter-rater reliability. CMH, KNK, ES, AG, VEK, MAM, LBW and CSC enrolled the patients. All the authors critically reviewed the manuscript and approved the final version of the manuscript.

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Correspondence to Bruno Evrard .

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EARLI was approved by the University of California, San Francisco Institutional Review Board (IRB) and VALID by the Vanderbilt IRB.

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Consent was obtained from patients or their surrogates when possible, as previously described.

Competing interests

BE received Grants for the present work from la Société de Réanimation de la langue Française, la Fondation Monohan, L’institut Servier and L’Association Limousine d’Aide aux Insuffisants Respiratoires. VEK declares a grant from the National Heart Lung and Blood Institute to his institution for the present manuscript; grants from the American Thoracic Society and Parker B. Francis Fellowship outside the present work; being part of DSMB of MODE Trial. CSC declares a grant from NIH to her institution for the present manuscript; grants from Roche Genentech, Quantum Leap Healthcare Collaborative and NIH outside the present work; consulting fees from Vasomune, Gen1e Life Science, NGM Bio, Cellenkos, Calcimedica, Arrowhead; being a co-recipient of a patent; being a council member of the International Sepsis Forum. CMH declares a grant from NIH for the present manuscript; support from DOD, NIH-NIAID and FDA to her institution outside the present work; consulting fees from Spring Discovery; being a DSMB member for regARDS Trial. KD declares being part of the University of Vermont DSBB. KDL declares grants from NIH and Quantum Leap Healthecare collaborative; consulting fees from AM Pharma, Biomerieux, Seastar Biomedical, UpToDate, Baxter; Honoraria and support from the American Society of Nephrology; and being part of advisory Boards for BOA Medical and Novartis; being an Associate Journal Editor for the American Thoracic Society. LBW declares a grant from NIH for the present manuscript; research contracts with Department of Defense, Genentech, Boehringer Ingelheim and CSL Behring; consulting fees from Arrowhead, Akebia, Santhera, Global Blood Therapeutics and Boehringer Ingelheim; being part of DSMB for CHILL Trial and SIGNET Trial; stock in Virtuoso Surgical. MAM declares grants paid to his institution outside the present work from NHLBI, NIAID, Department of Defense, Calif Institute if Regeneration, Roche Genentec and Quantum Health; consulting fees from Citius Pharmaceuticals, Gen1LifeScience, Gilead Pharmaceuticals, Novartis, Johnson and Johnson and Pilant Therapeutics. PS declares a Grant from NIGMS/NIH for the present manuscript and consulting fees from AstraZeneca and Prenosis Inc. AG, AZ, LN, NW, KNK, ES and AW declare no conflict of interests.

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Additional file 1. e-methods:.

Participants, exclusion criteria, determination of the cause of the death and statistical analysis. E-results . Table E1: Definition of severe and irreversible organ system dysfunction derived from Stapleton et al. and Ketcham et al. Table E2: Characteristics on ICU admission between EARLI and VALID cohort. Table E3: Estimation of population attributable fraction of death from ARDS in each subphenotype of sepsis. Table E4: Estimation of attributable fraction of death from ARDS in each subphenotype of sepsis. Table E5: Details of the SOFA score without neurologic component before the day of death or at the time of withdrawal of life support, stratified by phenotype. Table E6: Characteristics of patients before the day of death or at the time of the withdrawal of life support, stratified by subphenotype and presence or not of ARDS. Figure E1: Algorithm from Ketcham et al. to determinate the primary cause of death. Figure E2: Directed Acyclic graph used for propensity score matching. Figure E3: Barplot showing the day of diagnosis of ARDS from ICU admission (Day 1) in each subphenotype of sepsis, and showing the proportion of patient who died in each phenotype and stratified by the timing of death. Figure E4: Overview of the study. Figure E5: Alluvial plot showing the relation between severe comorbidities, the origin of sepsis the phenotype of sepsis, the presence or not of ARDS and the cause of death, stratified by the subphenotype of sepsis. Figure E6: Upset plot showing the number of patients with one or multiple irreversible or severe organ dysfunction collected at the time of death or the withdrawal of life support in hypoinflammatory sepsis using the standardized case ascertainment template. Figure E7: Upset plot showing the number of patients with one or multiple irreversible or severe organ dysfunction collected at the time of death or the withdrawal of life support in hyperinflammatory sepsis using the standardized case ascertainment template. Figure E8: Results for the matching using propensity score in the hypoinflammatory sepsis. Figure E9: Results for the matching using propensity score in the hyperinflammatory sepsis. E-references . STROBE Statement .

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Evrard, B., Sinha, P., Delucchi, K. et al. Causes and attributable fraction of death from ARDS in inflammatory phenotypes of sepsis. Crit Care 28 , 164 (2024). https://doi.org/10.1186/s13054-024-04943-x

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• Respiratory distress syndrome
• Acute lung injury

Critical Care

ISSN: 1364-8535

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Research hotspots and evolving trends of barrier dysfunction in acute lung injury and acute respiratory distress syndrome

Affiliations.

• 1 The First Clinical Medical College, Gannan Medical University, Ganzhou City, Jiangxi Province, 341000, China.
• 2 Department of Rehabilitation Medicine, The First Affiliated Hospital of Gannan Medical University, Ganzhou City, Jiangxi Province, 341000, China.
• 3 Department of Critical Care Medicine, The First Affiliated Hospital of Gannan Medical University, Ganzhou City, Jiangxi Province, 341000, China.
• PMID: 38742065
• PMCID: PMC11089360
• DOI: 10.1016/j.heliyon.2024.e30579

Endothelial and epithelial barrier dysfunction due to increased permeability and heightened inflammatory reactions influences the emergence of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Nevertheless, bibliometric research comparing endothelial and epithelial barriers is limited. Therefore, this bibliometric study analyzed the Web of Science Core Collection (WoSCC) of the Science Citation Index Expanded literature to explore present research priorities and development tendencies within this field. We conducted a comprehensive search (October 18, 2023) on WoSCC from January 1, 2010, to October 18, 2023, focusing on articles related to endothelial and epithelial barriers in ALI and ARDS. Retrieved data were visualized and analyzed using R-bibliometrix, VOS viewer 1.6.19, and CiteSpace 6.2. R4. Functional enrichment analysis of gene targets identified in the keyword list using Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene ontology databases, and based on the STRING database to construct a PPI network to predict core genes. A total of 941 original articles and reviews were identified. The United States had the highest number of publications and citations and the highest H-index and G-index. According to the Collaboration Network Analysis graph, the United States and China had the strongest collaboration. Birukova AA had the most publications and citations among all authors, while eight of the top ten institutions with mediator centrality were located in the United States. The American Journal of Physiology-Lung Cellular and Molecular Physiology was the leading journal and had the most well-established publication on endothelial and epithelial barriers in ALI and ARDS. Bibliometric analysis revealed that the most frequently used keywords were acute lung injury, ARDS, activation, expression, and inflammation. RHOA appeared most frequently among gene-related keywords, and the PI3K-AKT signaling pathway had the highest count in KEGG pathway enrichment. Research on endothelial versus epithelial barriers in ALI and ARDS remains preliminary. This bibliometric study examined cooperative network connections among countries, authors, journals, and network associations in the cited references. Investigation of the functions of the endothelial and epithelial barriers in ALI/ARDS associated with COVID-19 has recently gained significant attention.

Keywords: Acute lung injury; Acute respiratory distress syndrome; Bibliometric research; Endothelial and epithelial barriers; Inflammatory reaction.

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Acute respiratory distress syndrome in COVID-19: possible mechanisms and therapeutic management

Anolin aslan.

1 Department of Critical Care Nursing, School of Nursing and Midwifery, Tehran University of Medical Science, Tehran, Iran

Cynthia Aslan

2 Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

3 Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

Naime Majidi Zolbanin

4 Experimental and Applied Pharmaceutical Research Center, Urmia University of Medical Sciences, Urmia, Iran

5 Department of Pharmacology and Toxicology, School of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran

Reza Jafari

6 Nephrology and Kidney Transplant Research Center, Clinical Research Institute, Urmia University of Medical Sciences, Shafa St., Ershad Blvd., P.O. Box: 1138, Urmia, 57147 Iran

7 Hematology, Immune Cell Therapy, and Stem Cell Transplantation Research Center, Clinical Research Institute, Urmia University of Medical Sciences, Urmia, Iran

Associated Data

Not applicable.

COVID-19 pandemic is a serious concern in the new era. Acute respiratory distress syndrome (ARDS), and lung failure are the main lung diseases in COVID-19 patients. Even though COVID-19 vaccinations are available now, there is still an urgent need to find potential treatments to ease the effects of COVID-19 on already sick patients. Multiple experimental drugs have been approved by the FDA with unknown efficacy and possible adverse effects. Probably the increasing number of studies worldwide examining the potential COVID-19 related therapies will help to identification of effective ARDS treatment. In this review article, we first provide a summary on immunopathology of ARDS next we will give an overview of management of patients with COVID-19 requiring intensive care unit (ICU), while focusing on the current treatment strategies being evaluated in the clinical trials in COVID-19-induced ARDS patients.

The 2019 novel coronavirus outbreak started in the Chinese city of Wuhan and quickly spread worldwide, leading the World Health Organization (WHO) to declare a Global Health Emergency on January 30, 2020 [ 1 ]. Later on, it was declared as a global pandemic on March 11 [ 2 , 3 ]. This latest novel coronavirus, SARS-CoV-2, spreads more quick than its two closest common ancestors, the Severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), but has lower fatality. Infection can be spread through the droplet spray produced when coughing and sneezing by both symptomatic patients and asymptomatic carriers before the onset of the symptoms [ 4 ]. The respiratory system involvement is the most frequent complication of Coronavirus disease 2019 (COVID-19) [ 5 ]. Pneumonia caused by the SARS-CoV-2 virus presents with fever, dyspnea, and acute respiratory symptoms which can lead to refractory pulmonary failure [ 6 , 7 ]. It is common among COVID-19 patients to develop acute respiratory distress syndrome (ARDS), a life-threatening form of respiratory failure [ 8 , 9 ]. According to weighted averages calculated using data from individual studies which have data available for COVID-19, approximately 1/3 (33%) of hospitalized patients develop ARDS. And nearly 3/4 (75%) of COVID-19 patients admitted to the ICU have ARDS [ 8 ]. ARDS was initially defined in 1968 with clinical symptoms including acute hypoxemia, non-cardiac pulmonary edema, low pulmonary compliance, and increased work of breathing [ 10 ].

ARDS occurs due to both direct viral effects and host cell-derived substances [ 11 ]. Activated cells of the immune system release several products such as neutrophil myeloperoxidases and other proteinases, eosinophil major basic proteins and cationic proteins, and excessive production of proinflammatory cytokines including IL-6 and TNF-α, that can ensue aggravation of ARDS and extensive tissue damage resulting in multi-organ dysfunction and mortality [ 12 , 13 ]. Although the exact mechanism of SARS-CoV-2 in ARDS is not fully understood yet, the induction of cytokine storm is considered to be one of the leading factors [ 14 ]. ARDS caused by COVID-19 differs considerably from ARDS caused by other factors based on Berlin criteria, and therefore treatment is different as well [ 5 ]. The onset time of COVID-19-associated ARDS is 8 to 12 days [ 15 ]. This is contrary to the Berlin ARDS criteria, which defined an onset limit of 1 week [ 16 ]. Patients with COVID-19 ARDS may have normal or even high lung compliance; this is not the case in patients with classic ARDS [ 5 ]. COVID-19 ARDS severity is redefined into three stages based on its specificity: mild, mild-moderate and moderate-severe [ 17 ]. Thus, the dependence on mechanical ventilation of COVID-19 ARDS is longer than that of non-COVID-19 ARDS [ 18 ]. In typical ARDS, the most frequently used adjuvant therapies are continuous neuromuscular blocking agents, high-dose corticosteroids, and recruitment maneuvers [ 19 ]. Due to the anti-inflammatory effects of corticosteroids, they are considered a possible treatment for ARDS and WHO strongly recommended systemic corticosteroid therapy for patients with severe and critical COVID-19, and recommended against corticosteroid therapy for patients with non-severe COVID-19 [ 20 ]. Several drugs including lopinavir-ritonavir, remdesivir, ruxolitinib and tocilizumab are undergoing clinical trials as a treatment for COVID-19, but yet no proven effective therapies currently exist [ 21 – 23 ].

In this review, we first describe the immunopathology of ARDS, then we intend to highlight the management of intensive care unit patients with COVID-19-related ARDS while focusing on the current status of promising emerging therapies although there is no particular recommended antiviral medication.

Search strategy

We searched the PubMed and google scholar to retrieve eligible articles of any publication status and in English from December 1, 2019, to June 20, 2021, using the following key words: Therapeutic management, Therapeutic strategy, Antiviral therapies, Immunomodulatory therapies, anti-inflammatory drugs, NSAIDs, corticosteroids, MSC therapies, Interleukin-6 inhibitors, Janus kinase inhibitors, Convalescent plasma, IVIG, anti-fibrotic therapies, Anticoagulant therapies, Anti anaemic therapies. Each key word was searched with the following string of key words (using the “AND” operator): COVID-19-related-ARDS OR coronavirus-related-ARDS OR “SARS-CoV-2-related-ARDS” OR “Severe Acute Respiratory Syndrome Coronavirus 2” OR their derivates. In addition, we identified other eligible studies by searching the reference lists of relevant articles as well as unpublished studies in ClinicalTrials.gov. Studies which provided information on the treatment of COVID-19-related ARDS were identified. After screening title and abstracts for relevant studies, full texts were carefully checked for inclusion.

Immunopathology of ARDS

It is discovered that for RNA viruses, coronavirus included, pathogen-associated molecular patterns (PAMPs) in the structure of viral RNA genomes, or the dsRNA replication intermediates, are recognized via either endosomal receptors, TLR3 (toll-like receptor 3) and TLR7 (toll-like receptor 7), or by cytosolic sensors of RNA, RIG-I/MDA (retinoic acid-inducible gene I/melanoma-differentiation-associated gene) [ 24 ]. These events lead to the transcriptional activation of interferon-stimulated genes and nuclear factor-κB-regulated genes (NF-κB) as well as immune effectors and regulatory cell recruitment [ 25 ]. Alveolar epithelial cells (AECs), alveolar macrophages (AMs), and dendritic cells (DCs) have key roles as sensor cells that detect danger signals via the receptors known as pattern recognition receptors (PRR) and initiate innate immunity. Recruitment of effector cells due to activated sensor cells lead to the secretion of a first wave of cytokines (AECs secrete IFNλ, CCL2, AMs secrete IFNα, IFNβ, IL-6, TNF, IL-12 and DCs secrete IL-12, IL-23, IL1β) to alert and stimulate resident lymphocytes [ 26 ]. The upregulation of type I IFN should be capable of suppressing the virus replication and dissemination during the early phase. In a SARS-CoV mouse model, it has been demonstrated that dysregulation of type I IFN and inflammatory monocyte macrophages cause fatal pneumonia. Consequently, exaggerated secretion of type I IFN and the infiltrated myeloid cells, negatively affect the result of the infection and are the key factors of lung damage and dysfunction [ 24 ]. Subsequently, as a part of the innate immunity the release of chemokines, including CCL2, CCL5, CXCL8, and CXCL10, results in the recruitment of neutrophils and NK cells to the lung parenchyma [ 25 ]. Neutrophils produce toxic agents, such as reactive oxygen species (ROS) and proteases. Considerable production of free radicals by neutrophils overwhelms endogenous anti-oxidant systems, leading to oxidative cell injury. This robust inflammatory reaction due to the activation of neutrophils plays a key role in the ARDS pathogenesis [ 27 ]. Similarly, NK cell recruitment during influenza virus infection exerts both pro-necrotic and -apoptotic effects through the release of granzymes and perforins; indeed, excessive NK cell–mediated cytotoxicity is linked to lethal influenza virus infection due to uncontrolled lung damage. Furthermore, infiltrating monocyte-derived macrophages and DCs by releasing other pro-inflammatory mediators such as TNF-α and nitric oxide, play key roles in influenza clearance and alveolar injury by inducing epithelial cell apoptosis [ 25 ]. DCs play important role in bridging the innate and adaptive immune systems via presenting pathogen antigens to the T cells located at lymph nodes. Once in the lung, cytotoxic T cells recognize the pathogen and kill pathogen-infected cells and remove the source of further infection. Helper T cells modulate inflammation in a myriad of strategies, including the excessive production of cytokines such as type-II interferon (IFN-II) and generate the memory against the pathogen and also activate B cells to differentiate in the germinal centers of conventional lymphoid tissues to produce antibodies specific to the pathogen [ 28 ]. Through the secretion of IL-10 and TGFβ, Treg cells suppress inflammation and restore homeostasis [ 26 ]. Comparing patients with ARDS, pneumonia, and healthy controls, researchers found that ARDS patients had increased IL-10-producing CD4 + T cells [ 29 ]. As well, ARDS survivors had more IL-10 producing CD4 + T cells than non-survivors [ 29 ]. In a small proportion of infected individuals, these immune processes can completely suppress viral replication or eliminate virus infection. Others have incomplete viral suppression and a reduction of circulating B and T cells followed by a mechanism as yet unknown. Cytokine storm, a serious condition caused by sustained viral replication, occurs in some patients and it has been shown to be the main cause of COVID-19 related ARDS [ 30 ]. Some of the cytokines and chemokines overexpressed during the cytokine storm include IL-1β, IL-2, IL-6, IL-10, TNF-α, IFN-γ, IP-10, MIP-1, and MIP-1α [ 31 ]. Serum IL-6 concentration has been associated with disease severity and mortality, suggesting IL-6 plays a central role [ 30 ]. As IL-6 circulates, it binds soluble IL-6 receptors, forming a complex with a gp130 dimer on the surface of some cells. The complex induces JAK-STAT3 activation in various cell types, including endothelial cells, leads to cytokine storm and finally may cause fatal symptoms such as ARDS in a subgroup of hospitalized COVID-19 patients [ 30 , 32 ]. So blocking these immune pathways could be beneficial against cytokine storm and ARDS in patients suffering from COVID-19 in a severe form [ 30 ].

Management of patients with ARDS in the intensive care unit (ICU)

A 1-week onset limit is defined by the ARDS Berlin criteria for a person to be diagnosed as having ARDS which is inconsistent with the onset time of COVID-19-related ARDS that is 8–12 days. So, greater attention must be paid to the ARDS development in patients with a course of longer than 1 week [ 5 ]. The management of ARDS patients is critical for survival, and should be taken into account by relevant specialists [ 33 ]. ARDS patients presenting with SpO 2  < 94% on room air at sea level, respiratory rate > 30 breaths/min, PaO 2 /FiO 2  < 300 mmHg or lung infiltrates > 50%, may require aerosol-generating procedures (AGPs). Compared to standard oxygen therapy, high-flow nasal oxygen (HFNO) decreases the requirement of endotracheal intubation in patients with ARDS. It has been suggested that HFNO may be safe in mild/moderate COVID-induced ARDS patients, and even in some moderate/severe patients [ 34 ]. Increasing lung capacity by the recruitment of previously collapsed units is often achieved by the use of high positive end-expiratory pressure (PEEP) levels, recruiting maneuvers, and prone positioning [ 35 ]. Prone positioning can improve oxygenation and survival in patients but care should be taken to turn them safely [ 36 , 37 ]. For cases with suspected bacterial pneumonia or sepsis as a secondary infection, empiric antibiotics should be administered and re-evaluated daily, and, in case of no bacterial infection, antibiotic treatment should be de-escalated or stopped [ 38 ]. The evaluation should include the imaging of pulmonary (chest x-ray, ultrasound, and, if indicated, CT) and an electrocardiogram (ECG) if necessary and A laboratory test consisting of a complete blood count (CBC) with differential, metabolic panel, liver and renal function tests [ 38 ]. Even though measurement of inflammation markers such as CRP and D-dimer is not included in standard care, it can provide valuable prognostic information. Currently, limited information is available which suggests that the intensive care management of COVID-19 patients should be substantially different from the management of other ICU patients, although safety precautions are essential to avoid viral contamination. As for every ICU patient, successful COVID-19 clinical management depends on attention to the primary conditions leading to admission to ICU, but also to other comorbidities and hospital-acquired complications [ 38 ].

Emerging therapies for COVID-19-induced ARDS

Although there is only one antiviral, Remdesivir, approved by the U.S. Food and Drug Administration (FDA) to treat hospitalized COVID-19 patients, many medications are being tested and currently, researchers are investigating other potential treatments for COVID-19 [ 38 ]. Two different strategies have been tested as potential “cures” for COVID-19, one strategy is to target the virus directly (reducing virus replication, receptor binding, etc.) and the other strategy is to modulate the innate and adaptive immune responses of the host against the virus infection (targeted or nonspecific immune-modulating drugs) [ 39 ]. A properly combined anti-inflammatory and anti-viral medication with doses adjusted according to the symptom severity and immune cell counts may help improve survival outcomes [ 28 ]. Much of the information available in research to date is based upon clinical trials, retrospective analyses, or uncontrolled case series, and so ultimate evidence of effectiveness for interventions is still required [ 39 ]. A list of drugs used for the treatment of COVID-19 patients is presented in Table ​ Table1 1 and a summary of the clinical trials investigating COVID-19 and COVID-19-associated ARDS management is provided in Table ​ Table2 2 .

Drugs used for COVID-19 respiratory distress

Therapeutic clinical trials for COVID-19 and COVID-19-associated ARDS

Antiviral therapies /strategies

Remdesivir is an antiviral drug that exhibits potent in vitro efficacy against SARS-CoV-2 [ 40 ]. Remdesivir is the first FDA approved medication (on October 22, 2020) for COVID-19 hospitalized patients. Remdesivir (also GS-5734) was developed by Gilead Sciences for the treatment of patients with Ebola virus disease in 2016 [ 53 ]. Although it has not been proved to be effective in human clinical trials for this disease, it has shown antiviral efficacy against coronaviruses including SARS-CoV-1 and MERS-CoV. Based on this information, remdesivir has earned notable attention for its likely use as an option for the treatment of SARS-CoV-2 [ 54 , 55 ]. However, the evidence regarding the efficacy of remdesivir in treating COVID-19 is mixed.

In a randomised, double-blind, placebo-controlled, multicentre trial, Wang et al. demonstrated that remdesivir did not show statistically significant clinical improvements in hospitalized adults with severe COVID-19 [ 56 ]. The final results of a double-blind, randomized, placebo-controlled trial by Beigel et al. revealed that remdesivir is superior to placebo at reducing the duration of recovery in patients with lower respiratory tract infections who were hospitalized with Covid-19. According to their data, the remdesivir-treated patients showed a lower proportion of serious adverse events related to respiratory failure, indicating that remdesivir may have prevented the progression to more severe respiratory disease [ 57 ]. Based on a systematic review of RCTs and observational studies, Piscoya et al. investigated the effects of remdesivir in adult hospitalized patients with COVID-19 and evidence of respiratory insufficiency or pneumonia. The evidence was scarce on the efficacy and safety of 10-day remdesivir regimens, or when comparing 5-day or 10-day regimens to standard of care [ 55 ]. Regardless of the FDA approval, several ongoing RCTs need to be completed in order to evaluate if remdesivir has a clinically effectiveness and safety profile. Emdesivir cannot be concluded to be effective for treating COVID-19 until stronger evidence is available [ 55 ].

Favipiravir

Favipiravir is a viral RNA polymerase inhibitor, already demonstrated activity against influenza A and B [ 41 ]. The clinical trials of Favipiravir generally do not include patients with critical or severe conditions [ 58 ]. However, these case reports suggest that favipiravir is effective in treating patients with severe or critical conditions. Takahashia et al. shared their experiences with three COVID-19 patients: two were in critical condition, and one was in a very severe condition. All three cases required high dose oxygen therapy or ECMO. Favipiravir helped them recover from SARS-CoV-2 pneumonia, and the oxygenation treatment was tapered. According to their report of three COVID-19 cases, favipiravir may be effective in preventing pneumonia progression and cytokine production, improving respiratory function, and producing immediate effects, even in serious or critical conditions [ 58 ].

Lopinavir/ritonavir

Lopinavir/Ritonavir are inhibitors of the HIV protease and are routinely used in the treatment of AIDS [ 42 ]. In a randomized, controlled, open-label trial, Cao et al. observed that lopinavir-ritonavir therapy compared with standard care, in adult patients with severe Covid-19, did not yield any positive results. They found that Lopinavir/ritonavir treatment failed to reduce risk of death, improve clinical outcomes, or decrease throat viral RNA detectability in patients with severe Covid-19. The results of future trials in patients with severe COVID-19 may confirm or exclude the possibility that the treatment is beneficial [ 42 ].

Chloroquine and hydroxychloroquine (Clq/HClq)

ACE2 allows SARS-CoV-2 virus to enter cells, disrupting the renin-angiotensin-aldosterone axis and possibly contributing to lung damage [ 59 ]. The antimalarial medications, chloroquine, and hydroxychloroquine interrupt ACE2 binding and block viral entry, moreover, they also could affect endosomal and lysosomal pH, which can suppress the merging of the virus with the host cells [ 60 ]. These medications also inhibit the secretion of pro-inflammatory cytokines [ 43 ]. Chloroquine has especially been reported to suppress lung injury induced by influenza A H5N1 in preclinical designs [ 61 ]. In an open-label RCT, as a result of the addition of Clq/HClq to standard care, patients admitted with severe COVID-19 significantly worsened in their clinical status, were at greater risk of renal dysfunction, and required more IMV, even though mortality did not differ. This study concludes that Clq/HClq should be avoided in patients with a more severe form of COVID-19 pneumonia, and can be used to inform clinical practice and guidelines [ 62 ]. Furthermore, according to a meta-analysis, treatment with Clq/HClq does not result in any benefit in mild, moderate, or severe COVID-19 patients. When comparing treatment groups and controls in pooled analysis, no significant difference was observed in clinical recovery, viral clearance, and length of hospital stay. Based on the currently available RCTs, Clq/HClq has no added benefit in the treatment of COVID-19 patients [ 63 ]. Since the HCQ trial failed to show any benefit, WHO and the National Institute of Health discontinued the trial for hospitalized COVID patients [ 64 ].

Angiotensin receptor blockers (ARBs), such as losartan, may also alleviate some of adverse effects of ACE2 induction [ 59 ]. Losartan is currently being tested in patients with COVID-19 [ 39 , 65 ]. Among patients with COVID-19, hypertension (HTN) is a major cause of acute respiratory failure, hospitalization, and mortality [ 66 ]. Losartan and amlodipine were compared in patients with primary HTN and COVID-19 by Nouri-Vaskeh et al. in a randomised clinical trial. Losartan or amlodipine administration did not appear to have any priority for COVID-19 patients with primary HTN [ 66 ]. Further, Bolotova et al. in a feasibility study noted that losartan was well tolerated among hospitalized COVID-19 patients with HTN and did not worsen symptoms [ 67 ]. Bengtsone et al. examined the safety of using losartan to treat COVID-19-related respiratory failure in an open-label, non-randomized trial using an external, post-hoc control group. The study found that Losartan was safe for acute respiratory compromise caused by COVID-19. However, randomized trials are required to evaluate true efficacy [ 68 ].

Immunomodulatory therapies

The selection of anti-inflammatory drugs and their therapeutic doses ought to be based on the severity of the symptoms and should be monitored with the number of immune cells present in the complete blood count (CBC) [ 69 ]. Management of COVID-19 inflammation with NSAIDs and systemic corticosteroids has been controversial [ 70 ]. As overt symptoms of the cytokine storm emerge, anti-inflammatory cytokines like Interferon beta-1b (IFN-β-1b), and therapeutic antibodies targeting pro-inflammatory cytokines or their signaling pathways like Tocilizumab (anti-IL-6), Adalimumab (anti-TNFα), Anakinra (anti-IL-1), and Baricitinib (Janus kinase inhibitor) might be beneficial [ 71 , 72 ].

Corticosteroids

In consideration of the cytokine storm observed during SARS-CoV, MERS-CoV, and SARS-CoV-2 infections, corticosteroids have been commonly used to treat serious illness, for the possible recovery of lung injury induced by inflammation [ 73 ]. Despite the adverse effects of corticosteroid use, such as delayed viral clearance and opportunistic infections, and while initially WHO recommended against corticosteroid therapy, as of September 2, 2020, WHO strongly recommended systemic corticosteroid therapy for patients with severe and critical COVID-19 rather than no systemic corticosteroids [ 20 , 74 ]. The choice of corticosteroid therapy and the length of treatment can be significant and must be taken into notice [ 75 ]. Several clinical trials evaluated the effectiveness of corticosteroid and glucocorticoid therapy in critically ill patients with COVID-19 [ 45 , 76 ]. In a multicentre, randomised controlled trial done by Villar et al. high doses of dexamethasone, 20 mg per day, from day 1 to 5, then 10 mg per day from day 6 to 10 were administered in all stages of ARDS, even in the mild cases. They demonstrated that early treatment of dexamethasone could decrease overall mortality and ventilator duration in patients with established moderate-to-severe ARDS [ 44 ]. Furthermore, in a randomized clinical trial, Tomazini et al. evaluated the efficacy of i.v. dexamethasone administration in COVID-19 induced moderate to severe ARDS patients. In these patients, standard treatment plus i.v. dexamethasone led to a statistically significant increase in days alive and free of mechanical ventilation over 28 days compared with standard treatment alone [ 77 ]. Moreover, in a controlled, open-label trial, it has been determined that dexamethasone use reduced 28-day mortality in hospitalized Covid-19 patients’ who received either mechanical ventilation or oxygen, but not those receiving no respiratory support [ 78 ]. Some preliminary trial results suggest methylprednisolone and dexamethasone can be used for the severe form of COVID-19 [ 79 ]. Using a randomized control study, Ranjbar et al. assessed the efficacy of methylprednisolone in hospitalized COVID-19 patients, comparing it to regular dexamethasone treatment. Compared to the use of 6 mg/day of dexamethasone in patients admitted to hospital with COVID-19 pneumonia, the administration of 2 mg/kg per day of intravenous methylprednisolone resulted in a shorter hospital stay and less need for mechanical ventilation. Methylprednisolone demonstrated better outcomes in COVID-19 hypoxic patients when compared to dexamethasone [ 80 ]. The results of a meta-analysis of seven RCTs and 6250 severe COVID-19 cases indicated that corticosteroid therapy reduced all-cause death and disease progression rather than increasing adverse events [ 81 ]. In a systematic review and meta-analysis, Chaudhuri et al. summarized RCT findings concerning corticosteroids’ role in ARDS of any cause. Corticosteroids were proposed to be beneficial for patients with all forms of ARDS regardless of their causes. Corticosteroids might reduce mortality rates in ARDS patients and the need for mechanical ventilation. COVID-19 and non-COVID-19 ARDS patients showed the same effect across different corticosteroid types and dosages [ 82 ]. Kumakawa et al. reported a patient with severe ARDS caused by COVID-19. Treatment in this 67-year-old man was managed with late administration of i.v. steroids from day 20th of administration until 27th which was successful. The current report highlights the need for future trials to evaluate the best treatment timing and doses for ARDS induced by COVID-19, as well as selecting the optimal population for different severity COVID-19-induced ARDS [ 83 ]. Due to the affordability and accessibility of corticosteroids in healthcare systems trembling under the strain of the worldwide outbreak of this coronavirus, this area of research should be a universal priority [ 74 ].

Mesenchymal stem cell (MSC) therapies

Mesenchymal stem cells have exhibited immunoregulatory capability which can suppress inflammatory reactions. Chan et al. reported that MSC therapy has beneficial effects on H5N1- induced acute lung injury and may be beneficial to patients with a severe pulmonary illness caused by influenza viruses such as H5N1 and H7N9 [ 84 ].

Lanzoni et al., in a double-blind RCT, examined the safety and efficacy of allogenic UC-MSC infusions in patients with ARDS associated with COVID-19. Their trial results revealed that UC-MSC infusions are safe for COVID-19 patients with ARDS. Furthermore, compared to controls, UC-MSC treatment reduced SAEs, mortality, and recovery time [ 85 ]. Moreover, Shi et al. conducted a double-blind, placebo-RCT at two medical centers in Wuhan, China, assessing the safety and efficacy of iv administration of UC-MSCs in COVID-19 patients with severe lung damage. Following administration of UC-MSC, the lesions of the lung solid component were resolved faster as well as the capability of the integrated reserve improved [ 86 ]. Liang et al. noted that the optional transfer of hUCMSCs, combined with other therapeutics presented good clinical outcomes for a severely ill patient with COVID-19 and acute lung inflammation. Albeit only a case was designated there, it would further be especially valuable to inspire more clinical investigation to manage likewise critically ill patients with COVID-19 [ 87 ]. Moreover, Leng et al. [ 80 ] reported a single-dose clinical trial of MSC therapy in 7 patients with COVID-19 induced ARDS and 3 controls, and a case study by Liang et al. [ 81 ] reported the resolution of all COVID-19 manifestations in a severely ill woman on a ventilator who was administered three intravenous MSC doses. In these 2 reports, all of the 8 patients with COVID-19 induced ARDS made a good recovery following the administration of MSCs, although the follow-up periods differed, and there was no stability in the measurement of biological variables [ 88 ]. MSCs have been shown to be effective and safe in preclinical studies of ARDS models, and the results from Covid-19 clinical trials demonstrated their potential efficacy. Nevertheless, more large-scale trials are needed to verify MSC’s efficacy, particularly in patients with ARDS who have been diagnosed with Covid-19. Additionally, research is needed to establish the optimal cell source, dose and route of MSCs therapies, to develop a safe and effective treatment option for ARDS patients, particularly those who suffer from Covid-19 [ 89 ].

Interleukin-6 inhibitors

Excessive secretion of IL-6 can cause an acute systemic inflammation referred to as cytokine release syndrome (CRS). In the pathogenesis of COVID-19 pneumonia, it has been found that a CRS involving a considerable proinflammatory cytokine secretion occurred, including IL-6, IL-1, and TNF-α [ 90 ]. Xu et al. in a non-controlled retrospective study of 21 patients with SARS-CoV-2-induced ARDS demonstrated that treatment with tocilizumab (TCZ), an interleukin-6 receptor antagonist, could decrease the number of white blood cells and improve CT lung opacity and lung oxygenation [ 46 ]. Based on this data, on March 3, 2020, TCZ, an anti-IL-6 receptor monoclonal antibody, was included in the 7th edition of COVID-19 therapy recommendations by China’s National Health Commission (NHC) [ 90 ]. A single center-based study with 100 patients in Brescia, Italy evaluated the efficacy of intravenous administration of TCZ in the treatment of severe COVID-19 pneumonia and ARDS patients. They observed that more than three-quarters of patients displayed improvements in their clinical outcomes [ 91 , 92 ]. In a RCT of hospitalized patients with COVID-19 pneumonia and PaO2/FIO2 ranging from 200 to 300 mmHg, no difference was shown in the progression of disease between the tocilizumab and the standard care group [ 93 ]. A systematic review and meta-analysis was conducted by Pinzon et al. to evaluate evidence regarding the effectiveness of IL-6 inhibitors in the treatment of COVID-19. In patients with COVID-19, IL-6 inhibitors have shown to be beneficial in reducing mortality, particularly in severely ill cases [ 94 ]. However, additional blinded, placebo-controlled, RCTs should be conducted in well-established settings to evaluate the risks and benefits of IL-6 inhibitor agents across the disease spectrum [ 93 ].

Janus kinase inhibitors (e.g., baricitinib, Ruxolitinib)

Another drug that can be used to block viral entry through ACE2-mediated virus endocytosis is baricitinib, an inhibitor of JAK, that also prevents the cytokine storm and dampens the inflammatory response [ 47 ]. One meta-analysis by Chen et al. evaluated 11 studies of the safety and effectiveness of ruxolitinib and baricitinib in COVID-19 patients. They found these drugs decreased the use of IMV, had borderline effects on rates of ICU admission and ARDS and did not decrease interval of hospitalization. Among the treatments, baricitinib showed the most convincing reduction in the risk of death [ 95 ]. Capochiani et al. investigated the use of JAK inhibitors in the management of patients infected with SARS-CoV-2, including patient selection and dosing and administration information. Despite the small number of patients collected, they reported encouraging results regarding using ruxolitinib as a possible treatment option for severely ill patients with COVID-19 who develop respiratory distress [ 96 ]. In another study, Neubauer et al. have described the first successfully treated case with COVID-19-related ARDS using ruxolitinib. They observed that ruxolitinib therapy resulted in a decreased ARDS-associated inflammatory cytokines levels such as IL-6 and the acute phase protein ferritin, and also was associated with a rapid improvement in cardiac and respiratory systems [ 48 ]. Currently, clinical trials are ongoing to study both ruxolitinib and baricitinib in a prospective manner [ 48 , 74 , 97 ].

Convalescent plasma

Convalescent plasma treatment is nothing new; physicians have used it for SARS, pandemic 2009 influenza A (H1N1), avian influenza A (H5N1), several hemorrhagic fevers including Ebola, and other viral infections [ 98 ]. Convalescent plasma from the blood of people who’ve recovered contains neutralizing antibodies against viral proteins in almost all patients with COVID-19 [ 99 , 100 ]. Therefore, it might be worthwhile to investigate the safety and effectiveness of convalescent plasma therapy in COVID-19 cases [ 101 ]. A randomized controlled trial by Pouladzadeh et al. found that CP had remarkable immunomodulatory and antiviral properties, reducing the cytokine storm and improving the clinical scores in COVID-19 patients, but had little impact on mortality [ 102 ].. Furthermore, Raymond et al. in a randomized, parallel arm, phase II trial with patients with severe COVID-19 disease and mild to moderate ARDS investigated the clinical and immunological benefits of convalescent plasma transfusion. The convalescent plasma treatment arm did not demonstrate statistically significant differences in clinical outcomes across all age groups, though patients with severe ARDS aged less than 67 years were found to experience immediate hypoxia reduction, shorter hospital stays, and improved survival. This study suggested that a precise targeting of severe COVID-19 patients is necessary to achieve efficacy [ 103 ]. In a study by Shen et al., 5 critically ill patients with laboratory-confirmed COVID-19 and ARDS were treated with convalescent plasma. As assessed by Ct, treatment with convalescent plasma leads to a decline in viral load within days, and clinical improvement of patients, as indicated by body temperature reduction, improvement in P/F ratio, and chest imaging. By 9 days after plasma administration, four patients who had been receiving extracorporeal membrane oxygenation (ECMO) and mechanical ventilation no longer required breathing support [ 104 ]. Moreover, According to Allahyari et al., early administration of CP can help defuse the symptoms of severe COVID-19 patients with mild or moderate ARDS, who are at risk of progressing to critical state [ 105 ].

Intravenous immune globulin (IVIG)

Intravenous immunoglobulin (IVIG) has been investigated as an alternative immune-modulator, and IVIG therapy in a high dose has shown useful effects for immune-mediated diseases, such as Kawasaki disease and other diseases [ 106 ]. However, the exact mechanisms of action of IVIG in immune-mediated diseases are still unknown, but IVIG may act on the host’s hyperimmune reactions by binding to immune cell receptors, etiologic substances including pathogenic proteins (PPs), or other proteins that are linked to inflammation [ 106 ]. A double-blind, randomized clinical trial demonstrated that the administration of IVIg to patients with severe COVID-19 infection who failed to respond to initial treatment has significantly improved their clinical outcome. Still, several multicenter trials with larger sample sizes must be conducted to provide more information regarding the drug’s suitability as a standard treatment [ 107 ]. In recent case reports, IVIG therapy has proved beneficial for patients with COVID-19, including three cases of ARDS. In a retrospective study, early IVIG treatment of COVID-19-related ARDS resulted in a smaller mortality and shorter ventilator time [ 108 ]. With regards to IVIg’s high price, it is recommended that it should be considered for patients with > 30% lung involvement in lung CT scans, persistent dyspnea, persistent satO2 under 90%, and individuals with progressive lung involvement in serial lung CT scans, especially in younger cases [ 107 ].

Anticoagulant and anti-fibrotic therapies

Disordered coagulation, specifically, pulmonary microvascular thrombosis is increasingly in association with the pathogenesis of severe COVID-19 respiratory failure. Treatment with anticoagulants, mainly low molecular weight heparin (LMWH), has also been found to be associated with better treatment outcomes in severe coronavirus patients with evidence of activation of the coagulation system such as markedly elevated D-dimer levels [ 49 ]. A prophylactic dose of LMWH may be recommended for hospitalized patients. LMWH also exerts anti-inflammatory effects that might confer protection [ 109 ]. Currently, a clinical trial is ongoing to test its potential to reduce mortality in patients with Severe COVID-19 [ 110 ].

It has been suggested that targeting coagulation and fibrinolysis could improve the clinical outcomes of ARDS patients [ 111 ]. In particular, plasminogen activators have received strong support to limit the progression of ARDS and reduce ARDS-induced death from animal models [ 112 – 114 ] and a phase 1 human clinical trial [ 115 ]. According to Wang et al., three COVID-19 patients with ARDS being ventilated and being treated with tPA (Alteplase) showed temporally improved respiratory status, with one of them demonstrating a durable response [ 116 ]. Moore et al. have suggested that Alteplase administration can be used as compassionate salvage therapy in patients with COVID-19 related ARDS, but details remain to be determined about the dose, administration routes, and duration of treatment [ 50 ]. At the moment, clinical trials are in progress to evaluate the effects of tPA on improving the respiratory function of ARDS patients [ 117 – 119 ].

Pirfenidone

Pirfenidone which is approved for the treatment of mild to moderate idiopathic pulmonary fibrosis (IPF), may prevent the invasion and cytokine storm of COVID-19 in pneumocytes and other tissues by inhibiting apoptosis, decreasing expression of ACE receptors, suppressing inflammation through various mechanisms, and reducing oxidative stress [ 120 ]. Consequently, it can be effective against severe viral inflammation, ARDS, and ARDS fibrosis [ 51 ]. A new clinical trial aims to determine the safety and efficacy of treatment with Pirfenidone versus standard of care (SoC) in COVID-19 patients with severe ARDS ( {"type":"clinical-trial","attrs":{"text":"NCT04653831","term_id":"NCT04653831"}} NCT04653831 ).

Anti anaemic drugs

Vadadustat acts as a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) and can trigger the body’s protective response to oxygen deficiency [ 52 ]. Alveolar inflammation can be dampened by stabilizing HIF, which is one of the main challenges that patients with COVID-19-related lung disease face when they develop ARDS [ 121 ]. The efficacy of vadadustat for ARDS prevention and treatment is going to be examined in a new clinical trial in hospitalized patients with COVID-19 [ 18 ].

Nitric oxide (NO)

During the SARS-CoV outbreak, in 2004, a pilot study revealed that low dose NO (max 30 ppm) inhalation could shorten the duration of the ventilator for patients diagnosed with SARS-CoV infection [ 122 ]. Furthermore, strong evidence suggests that inhaled NO can decrease inflammatory cell-mediated lung damage via suppressing activation of neutrophils and subsequent secretion of pro-inflammatory cytokines [ 123 ]. Although there is no epidemiological evidence supporting the use of inhaled NO to improve outcomes for COVID-19 patients, because of the genetic similarities between the two viruses, similar therapeutic effects of NO could be expected for COVID-19 patients [ 124 ]. Based on this experience, several medical institutes have begun clinical trials [ 125 ], and now a phase 2 clinical study of inhaled NO is being performed for COVID-19 patients who required mechanical ventilation for ARDS to confirm whether inhaled NO could be a life-saving intervention for managing COVID-19 ARDS [ 126 , 127 ].

2020 has been a challenging year for all with the COVID-19 pandemic as a live issue affecting people globally. Although 58 COVID-19 vaccines have been developed in clinical trials by several manufacturers, with some vaccines proving to be over 90% effective in preventing the disease in clinical trials [ 128 ], But it might take years for enough coverage to create herd immunity, and vaccine escape mutants are a threat to this progress [ 129 ]. So, there is still an urgent need to develop targeted therapies to combat COVID-19 and its complications [ 23 ]. In this sense, it is hoped that extensive research worldwide into possible therapies for patients suffering from COVID-19 will result in the rapid identification of effective ARDS treatments.

Acknowledgments

Abbreviations, authors’ contributions.

Conception and manuscript design: R J. Collection of data: A A, C A, N M Z, and R J. Manuscript writing: A A, C A, N M Z, and R J. Made important revisions and confirmed final revision: R J. All authors reviewed and approved the final version of the manuscript.

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