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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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ARDS Case Study (60 min)

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Mr. Martin is a 55 year old man who presents to his primary care provider (PCP) on a Tuesday with complaints of a productive cough for 3 days with fever, chills, fatigue beginning in the last 24 hours.  This clinic has capabilities for x-ray, rapid lab tests, and simple IV infusions. His PCP hears coarse rhonchi in Mr. Martin’s lungs and decides to take a chest x-ray. The x-ray shows right lower lobe infiltrates. His rapid flu swab is negative. Mr Martin’s vital signs were as follows:

BP 122/73 mmHg HR 102 bpm

RR 26 bpm Temp 38.6°C

SpO 2 94% on room air Weight 105 kg

Mr. Martin is diagnosed with pneumonia and sent home on Azithromycin.  Two days later, on Thursday, Mr. Martin still has the cough, fever, chills, and fatigue and is now having body aches on and off and is short of breath intermittently. He calls his PCP concerned that the antibiotics are not working. His PCP agrees and changes his antibiotic to Amoxicillin.

On Friday, Mr. Martin’s wife calls his PCP again because he is struggling to even get out of bed and is very fatigued and feverish. She reports a fever of 102.9°F. The PCP tells him to come into the clinic.  He arrives at the clinic 20 minutes later.

What nursing assessments should be performed at this time for Mr. Martin?

• Full set of vital signs
• Heart and lung assessment
• Skin assessment – for signs of poor perfusion or dehydration
• Subjective assessment of symptoms (OLDCARTS)
• Observe and document any sputum from productive cough

Upon further assessment, Mr. Martin has rhonchi throughout his lung fields, with occasional expiratory wheezes. He appears pale and is lethargic. His skin is tenting on his sternum and his nail beds are pale. His vital signs are as follows:

BP 108/66 mmHg HR 116 bpm

RR 30 bpm Temp 38.8°C

SpO 2 92% on room air

What diagnostic tests would you anticipate the provider ordering?

• Repeat Chest X-ray
• Possible labs – CBC, ABG if available

What would be some priority interventions for Mr. Martin at this time?

• Mr. Martin is clearly dehydrated, he could use some IV fluids
• Since he isn’t getting any better, he may need higher dose or IV antibiotics
• Concerned that Mr. Martin might be deteriorating – maybe he should be sent for a higher level of care sooner, rather than later.

Mr. Martin’s PCP believes he is suffering from dehydration related to his fever and orders 1 L of Normal Saline to be infused in the clinic before sending Mr. Martin home. The nurse starts a peripheral IV and initiates the fluid bolus, which takes 1 hour to infuse.

What evaluation information would you, as the nurse, want to obtain following the infusion of these IV fluids?

• Repeat vital signs
• Evaluate how Mr. Martin is feeling subjectively
• Re-check skin turgor to see if any improvements

Mr. Martin’s infusion completes after hours Friday, so the Medical Assistant removes his IV and tells him he can go home and to call the on-call team if he has any concerns.  Mr. Martin returns home and tells his wife he doesn’t really feel any better. For the next two days (over the weekend), Mr. Martin continues to be more and more fatigued. His wife finally calls the PCP on Sunday who says to bring him in first thing the next morning. 

On Monday morning, Mr. Martin arrives at his PCP who can immediately tell he has gotten much worse. He repeats a chest x-ray to find diffuse bilateral pulmonary infiltrates. Mr. Martin is sent straight to the Emergency Department (ED).

What step of the nursing process was skipped? What impact might that have had on Mr. Martin?

• If the nurse had seen that he wasn’t feeling any better and checked his vital signs, she could have advocated for him to go to the ER sooner rather than later.
• It’s possible this was missed because it was after hours on a Friday.

Mr. Martin arrives in the ED where providers confirm the diagnosis of bilateral pneumonia. 

Mr. Martin’s SpO 2 is 88%, so he is placed on 4L NC (36% FiO 2 ).  The provider writes the following orders, which are implemented by the nurse:

Keep sats >92%

Repeat CXR in 4 hours

Labs: ABG, CBC, BMP, blood cultures

Insert peripheral IV x 2

Give 1 L Normal Saline IV bolus now

Albuterol nebulizer 2.5mg

Mr. Martin’s blood gas results are as follows:

pH 7.30 pO 2 75 mmHg on 4L NC (36% FiO 2 )

pCO 2 58 mmHg SaO 2 96% on 4L NC (36% FiO 2 )

HCO 3 – 26 mEq/L

Interpret the ABG. Explain.

• Mr. Martin is in respiratory acidosis – his body isn’t able to get rid of the CO2 because of the fluid in his lungs.

What is Mr. Martin’s PaO2/FiO2 ratio? Explain the results.

• PaO2 75 mmHg, FiO2 36%
• 75 / 0.36 = 208.3
• This means Mr. Martin is in Mild ARDS as he isn’t responding to the oxygen as expected.

Mr. Martin’s condition continues to deteriorate. He is placed on BiPAP and sent to the ICU. The next day he is still struggling to oxygenate and the family agrees to intubate him and place him on a mechanical ventilator. He is placed on Assist Control mode, FiO 2 of 100%, Vt of 440  mL, PEEP of 5. After 1 hour, a blood gas is drawn, with the following results: 

pH 7.25 pO 2 90 mmHg

pCO 2 52 mmHg SaO 2 99% on 100% FiO 2

HCO 3 – 28 mEq/L

Interpret the ABG, including determining the PaO2/FiO2 ratio. What do these results indicate for Mr. Martin?

• Mr. Martin is still in respiratory acidosis because his lungs can’t perform gas exchange
• However, his P/F ratio is now 90 – meaning he is in Severe ARDS

What, physiologically, is going on with Mr. Martin at this time?

• Mr. Martin’s pneumonia has caused an inflammatory response within his lungs that led to the alveoli filling with fluid and inflammation and scarring of the lungs. This leads to refractory hypoxemia – or low oxygen that doesn’t respond to an increased FiO2.
• This has made gas exchange nearly impossible

Mr. Martin is in the ICU for 14 days. He has multiple bronchoscopies to attempt to clear the fluid from his lungs. He was continued on high-dose IV antibiotics after his blood cultures revealed Strep A pneumonia. His PEEP is progressively increased until it is at the max of 14 cmH2O. He is placed on lung-protective ventilator settings (APRV) to prevent barotrauma and promote opening of the alveoli. He remained in severe ARDS despite all interventions.  He was too unstable to take to the OR for a trach and ended up going into Cardiogenic Shock. Despite all interventions, Mr. Martin passed away with his family by his side on the14th day in the ICU.

What would you have done differently for Mr. Martin and when? Why?

• With pneumonia and ARDS, the sooner we can intervene, the better. In this case, the signs of ARDS were missed by the primary care team and his transfer to a higher level of care was delayed by 3 days. The evidence shows that mortality rates increased sharply with each day IV antibiotics are delayed.
• If the nurse had re-evaluated Mr. Martin on Friday, she could have advocated for him to go to the ER then, instead of waiting until Monday.
• It’s impossible to say whether this would have changed the final outcome as ARDS is a progressive, destructive disease. However, given the evidence we have, it’s likely that initiating IV antibiotics three days sooner could have slowed the inflammatory process sooner and prevented the significant decompensation we saw in Mr. Martin

Frequently Asked Questions

What are the causes of Acute Respiratory Distress Syndrome?

• Bacteremia, Sepsis
• Trauma, fat embolus
• Burns + Fluid Resuscitation
• Massive transfusion
• Pneumonia, Aspiration
• Drug overdose
• Near drowning

What are the main aspects of patient education for Acute Respiratory Distress Syndrome?

• Educate family on severity of the condition and probable course
• Possible need for tracheostomy
• Purpose for endotracheal tube and ventilator
• Recovery time, may need rehab
• Infection control precautions

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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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• Published: 18 July 2023

Management of severe acute respiratory distress syndrome: a primer

• John C. Grotberg 1 ,
• Daniel Reynolds 1 &
• Bryan D. Kraft 1  

Critical Care volume  27 , Article number:  289 ( 2023 ) Cite this article

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This narrative review explores the physiology and evidence-based management of patients with severe acute respiratory distress syndrome (ARDS) and refractory hypoxemia, with a focus on mechanical ventilation, adjunctive therapies, and veno-venous extracorporeal membrane oxygenation (V-V ECMO). Severe ARDS cases increased dramatically worldwide during the Covid-19 pandemic and carry a high mortality. The mainstay of treatment to improve survival and ventilator-free days is proning, conservative fluid management, and lung protective ventilation. Ventilator settings should be individualized when possible to improve patient-ventilator synchrony and reduce ventilator-induced lung injury (VILI). Positive end-expiratory pressure can be individualized by titrating to best respiratory system compliance, or by using advanced methods, such as electrical impedance tomography or esophageal manometry. Adjustments to mitigate high driving pressure and mechanical power, two possible drivers of VILI, may be further beneficial. In patients with refractory hypoxemia, salvage modes of ventilation such as high frequency oscillatory ventilation and airway pressure release ventilation are additional options that may be appropriate in select patients. Adjunctive therapies also may be applied judiciously, such as recruitment maneuvers, inhaled pulmonary vasodilators, neuromuscular blockers, or glucocorticoids, and may improve oxygenation, but do not clearly reduce mortality. In select, refractory cases, the addition of V-V ECMO improves gas exchange and modestly improves survival by allowing for lung rest. In addition to VILI, patients with severe ARDS are at risk for complications including acute cor pulmonale, physical debility, and neurocognitive deficits. Even among the most severe cases, ARDS is a heterogeneous disease, and future studies are needed to identify ARDS subgroups to individualize therapies and advance care.

Introduction

The acute respiratory distress syndrome (ARDS), first described in 1967 [ 1 ], is a common cause of respiratory failure in the ICU. There are approximately 190,000 ARDS cases annually in the USA alone, although cases skyrocketed in 2020 due to the COVID-19 pandemic [ 2 , 3 ]. ARDS pathophysiology is rooted in the disruption of the alveolar capillary barrier by inflammatory and oxidative insults. This results in the characteristic clinical (acute onset), radiographic (bilateral alveolar opacities), physiologic (reduced compliance, high shunt fraction), and histologic (classically diffuse alveolar damage) derangements. Severe ARDS, defined by an arterial partial pressure of oxygen (P a O 2 ) to fraction of inspired oxygen (F i O 2 ) ratio (P/F) ≤ 100, carries mortality close to 50% [ 2 ]. In moderate-to-severe ARDS, positive end expiratory pressure (PEEP) may confound the P/F ratio, and is addressed using the “P/FP ratio” ((P a O 2 *10)/(F i O 2 *PEEP)), with P/FP ≤ 100 defining severe ARDS [ 4 ]. The noninvasive ratio of pulse oximetric saturation (SpO 2 ) to F i O 2 , or the “S/F ratio”, also correlates well to P/F ratios and is readily available at the bedside. Though not clearly defined, S/F ratios of < 89 to < 120 approximate severe ARDS [ 5 , 6 , 7 ].

Patients with severe ARDS are at high risk for ventilator-induced lung injury (VILI) and may develop refractory hypoxemia and hypercapnia. Traditional treatment of severe ARDS is supportive, anchored by lung protective mechanical ventilation, proning, and conservative fluid management [ 8 , 9 , 10 ]. Adjunctive therapies (e.g., inhaled pulmonary vasodilators, glucocorticoids) can be used, and in select cases, patients may require veno-venous extracorporeal membrane oxygenation (V-V ECMO). This review will summarize the evidence-based management (Fig.  1 ) of severe ARDS emphasizing interventions that improve outcomes.

Severe ARDS Treatments. A schematic illustrating management strategies for severe ARDS and refractory hypoxemia. Green sections represent treatments that improve outcomes supported by prospective randomized controlled trials, the orange section represents a treatment that may improve outcomes based on retrospective data, the gray sections represent treatments that may improve oxygenation but have not demonstrated sustained clinical benefit in trials, and the purple sections represent treatments that likely derive benefit in a subset of patients. ARDS acute respiratory distress syndrome, IBW ideal body weight, V t , tidal volume; and V-V ECMO, veno-venous extracorporeal membrane oxygenation. Adapted from “Risk Factors of Dementia,” by BioRender.com (2023). Retrieved from https://app.biorender.com/biorender-templates

Low tidal volume ventilation

Low tidal volume ventilation using either pressure-assist control (PC) or volume-assist control (VC) modes significantly improves mortality in ARDS [ 8 , 11 , 12 , 13 ]. Neither mode is superior [ 14 ]. A VC mode controls tidal volume at the expense of controlling airway pressures, whereas a PC mode controls airway pressures at the expense of tidal volume and minute ventilation [ 15 , 16 ]. Pressure regulated volume control (PRVC) is an adaptive mode that adjusts tidal volume for set pressure limits but may be insufficient in patients with high ventilatory drives [ 17 ].

The landmark ARMA trial demonstrated that a tidal volume of 6 cc/kg ideal body weight (IBW) compared to 12 cc/kg IBW reduced mortality (31% vs. 40%) and increased ventilator-free days [ 8 ]. While tidal volume ranged from 4 to 8 cc/kg in the trial, the goal tidal volume in the protocol was 4–6 cc/kg depending on plateau pressure ( P plat ). Average tidal volume in the intervention arm was 6.2 cc/kg over the first 5 days of trial enrollment and 6.5 cc/kg was used as a cut-off to designate study-site adherence. Physiologically, lower tidal volume ventilation reduces driving pressure, mechanical power, and the risk of volutrauma on the ARDS lung [ 18 , 19 , 20 ]. However, low tidal volumes (4–6 cc/kg) may still result in barotrauma, particularly in poorly compliant lungs. Barotrauma might be mitigated by further reducing tidal volumes (to lower airway pressures) in a VC mode, or with a PC mode. While low tidal volume ventilation improves mortality in ARDS, it may be poorly tolerated in some patients, leading to increased ventilator asynchrony and deeper sedation.

Ventilator asynchrony

Patient-triggered modes of mechanical ventilation reduce work of breathing assuming matching between patient respiratory efforts and ventilator-delivered breaths [ 21 ]. Asynchrony events are common and may worsen outcomes if frequent. Asynchrony events can be quantified by the asynchrony index (AI), defined as the number of asynchrony events divided by the sum of the number of ventilatory cycles. In one study, 24% of the patients had an AI > 10% [ 21 ]. Evidence suggests AI > 10% may be associated with increased ICU and hospital mortality [ 22 ].

Common asynchronies include triggering asynchrony, cycling asynchrony and flow asynchrony. Ineffective triggering occurs when patient respiratory efforts do not result in ventilator-delivered breaths and is improved by increasing the trigger sensitivity of the ventilator or by using a flow-triggered. When ineffective triggering is due to excess intrinsic PEEP, efforts are directed to reduce intrinsic PEEP, or increase external PEEP to ~ 75% of the intrinsic PEEP to decrease the pressure gradient required by the patient to trigger the ventilator [ 23 , 24 ]. Reverse triggering is seen in deeply sedated patients in which mechanical insufflation triggers a muscular effort, generating a “patient-triggered” breath and can be resolved by decreasing the level of sedation or by adding a neuromuscular blocking agent [ 24 ]. Cycling asynchronies occur cycling from the inspiratory to expiratory phase and may be premature or delayed. In premature cycling, a patient’s respiratory effort continues during the expiratory phase resulting in double-triggering and breath stacking. This is addressed by increasing the inspiratory time in PC or by increasing the tidal volume or decreasing the flow in VC. The opposite occurs during delayed cycling and is remedied by decreasing the inspiratory time in PC or increasing the flow in VC. Finally, flow asynchronies occur when patient flow demand does not match that of the ventilator. Flow starvation more often occurs in VC where patients exhibit excessive ventilatory demand and typically “suck down” the pressure–time wave form. Increasing the flow or changing to a PC mode can improve asynchrony. Conversely, excessive flow can be improved by decreasing the flow in VC or decreasing the inspiratory pressure in PC [ 23 ].

• Positive end expiratory pressure

PEEP opens collapsed alveoli allowing for recruited lung to participate in gas exchange and reduces alveolar overdistension by increasing distribution of the tidal breath. There is no clear mortality benefit in ARDS when comparing high PEEP to low PEEP strategies in all patients receiving low tidal volume ventilation, however, there may be a benefit in patients with moderate-to-severe ARDS, particularly patients who are PEEP-responsive (defined as an increase in P/F > 25 mm Hg after higher PEEP) [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. Because of significant heterogeneity in ARDS, different phenotypes may respond differently to PEEP [ 34 ], therefore, clinicians should monitor oxygenation and lung compliance during titration. PEEP titration is performed by making stepwise increases in PEEP followed by small decremental changes of 2 cm H 2 O every 2–5 min while checking P plat and monitoring changes in lung compliance. If a patient’s oxygenation or lung compliance worsen with increased PEEP, the PEEP is too high, whereas if they improve, the titration can continue until no further improvement is observed.

More advanced methods for individualizing PEEP include the stress index (SI), electrical impedance tomography (EIT), and esophageal pressure ( P es ) guidance (Fig.  2 ). The SI is based on the pressure–time curve during constant flow (square-wave) volume-control ventilation. A linear pressure rise suggests recruited alveoli without overdistension (SI = 1). Increasing compliance as the lungs are inflated (concave down waveform, SI < 1) suggests tidal recruitment, and benefit from increased PEEP. Conversely, decreasing compliance as the lungs are inflated (concave upward waveform, SI > 1) suggests overdistension, and benefit from decreased PEEP (Fig.  2 a) [ 35 ]. SI is not superior to other PEEP titration methods [ 36 , 37 ]. EIT determines the PEEP with the least overdistended and collapsed lung (PEEP ODCL ) (Fig.  2 b) [ 38 , 39 , 40 , 41 ]. In a study of severe ARDS, EIT-guided PEEP titration improved oxygenation, compliance and driving pressure [ 38 ]. Finally, esophageal manometry can be used to guide PEEP and operates under the assumption that the esophageal pressure ( P es ) is equivalent to the intrapleural pressure ( P pl ). PEEP is titrated to a transpulmonary pressure ( P L ) of 0 cm H 2 O, where P L  =  P ao  −  P es , and P ao is the airway pressure [ 42 ]. P Plat and PEEP can represent P ao as the alveolar distending pressure at end-inspiration or end-expiration, respectively. In the EPVent trial, P es -guided PEEP titration improved oxygenation, however, when compared to empiric high PEEP in the EPVent-2 trial, there was no difference in clinical outcomes [ 43 , 44 ]. A post hoc analysis of the EPVent-2 trial demonstrated that PEEP titrated to an end-expiratory P L of 0 cm H 2 O was associated with greater survival than more positive or more negative values [ 45 ]. Ideal goals of esophageal manometry to guide PEEP include (1) end-inspiratory P L  < 15–20 cm H 2 O, (2) end-expiratory P L  = 0 cm H 2 O (± 2 cm H 2 O), and (3) transpulmonary driving pressure (end-inspiratory P L —end-expiratory P L ) < 10–12 cm H 2 O (Fig.  2 c) [ 42 ]. A newer and elegant method of determining lung recruitability by PEEP is the recruitment-to-inflation ratio, where a ratio ≥ 0.5 suggests lung recruitability at higher PEEP [ 46 ].

Advanced methods of PEEP titration. A The stress index, based on the pressure–time curve during constant flow (square-wave) volume-control ventilation. B Electrical impedance tomography with a proposed decremental PEEP titration. The top image depicts global tidal impedance where white indicates the highest volume change, and the bottom image depicts areas of alveolar over-distension (orange) and collapse (white). C Esophageal manometry and associated transpulmonary pressure targets. PEEP ODCL, PEEP with least over-distended and collapsed lung; P L , transpulmonary pressure; SI, stress index. Created with BioRender.com

Regardless of the method used for PEEP titration and the metric(s) used assessing efficacy, monitoring hemodynamic responses is also necessary. PEEP can decrease cardiac output (by decreasing preload and increasing RV afterload), which can decrease DO 2 despite an increase in oxygen saturation. Conversely, PEEP can reduce LV afterload [ 47 ]. Therefore, individualized PEEP titrations should consider oxygenation and driving pressure as well as hemodynamics.

Recruitment maneuvers

A recruitment maneuver is a technique to increase the airway pressure in the lungs temporarily. Common methods used include sustained inflation (e.g. 35–40 cm H 2 O for 30–40 s in CPAP mode with a RR of 0) or a stepwise increase in PEEP followed by a decremental PEEP titration [ 35 ]. The physiologic rationale of a recruitment maneuver is to provide static or dynamic inflation at very high pressures for a short period of time to recruit alveolar units to participate in gas exchange and improve respiratory system compliance. Most lung recruitment occurs in the first 10 s of sustained inflation, while hemodynamic instability occurs after 10 s [ 48 ]. The effects of increasing PEEP likely stabilize after 11–20 breaths [ 49 ]. Recruitment maneuvers have been shown to improve oxygenation, however, have not been shown to improve mortality, and may actually be injurious [ 50 , 51 , 52 , 53 , 54 ]. In one study, 22% of patients who received recruitment maneuvers developed non-sustained hypotension and/or hypoxemia [ 54 , 55 ]. In the ART trial, patients received a 4-min recruitment maneuver in a stepwise fashion (PC with PEEP at 25 cm H 2 O for 1 min, 35 cm H 2 O for 1 min, and 45 cm H 2 O for 2 min) followed by decremental PEEP. The recruitment maneuver strategy was modified mid-enrollment due to 3 cardiac arrests observed in the experimental arm, and overall the experimental arm showed increased mortality [ 56 ]. There is significant heterogeneity amongst studies evaluating recruitment maneuvers, making meta-analyses challenging to interpret [ 51 ]. Though some patients may show improved oxygenation with a recruitment maneuver, evidence suggests that there is no mortality benefit, and there may be associated harm. While not recommended routinely, select patients may respond favorably. If used, a stepwise increase in PEEP followed by decremental PEEP titration may be more effective [ 57 ], though more modest levels of PEEP should be used (20–25 cm H 2 O). Sustained inflation should be avoided to reduce the risk of hemodynamic instability.

• Driving pressure

In contrast to adjusting tidal volume for IBW, driving pressure adjusts tidal volume for compliance, and is the change in tidal volume relative to the static compliance of the respiratory system ( V t / C RS ), or the pressure differential required to inflate the lungs ( P plat –PEEP). High driving pressures (> 15–17 cm H 2 O) are independently linked to ARDS mortality [ 58 , 59 , 60 , 61 , 62 ]. Amato et al. re-analyzed data from 3562 patients from 9 trials and found driving pressure was the variable that best stratified risk; reductions in driving pressure were strongly associated with increased survival [ 58 ]. The association between driving pressure and mortality was also observed in the LUNG SAFE study [ 2 ]. Newer analyses suggest that the mortality benefit seen in lowering tidal volume varies with respiratory system compliance, with greater benefit seen in patients with higher lung elastance [ 61 , 62 ]. Lowering tidal volume to reduce driving pressure resulted in the greatest benefit in patients with low lung compliance. Optimizing ventilator settings to achieve a driving pressure < 15 may be the preferred target [ 2 , 58 , 59 , 63 ]. There are ongoing clinical trials to investigate a driving pressure-driven approach to ventilator management [ 18 ].

Airway pressure release ventilation

Airway pressure release ventilation (APRV) is an alternative mode of mechanical ventilation used to treat refractory hypoxemia and ARDS. APRV is a pressure-limited mode that cycles between two levels of CPAP. A higher airway pressure (P-high) is set for a certain time ( T -high) and a lower airway pressure ( P -low) (often set at 0 cm H 2 O) is set for a shorter time ( T -low). APRV utilizes an inverted inspiration:expiration ratio, as the majority of spontaneous breathing is accomplished during T -high, with the higher pressure P -high theoretically allowing for recruitment of collapsed alveoli, and T -low allowing for ventilation and complete exhalation [ 64 , 65 , 66 ]. The proposed benefits to APRV include allowing for spontaneous breathing, decreased work of breathing, and less dyssynchrony (and therefore less use of sedatives and paralytics). It is also thought that higher mean airway pressures may improve oxygenation when compared to more conventional modes of mechanical ventilation [ 66 ]. While APRV may increase mean airway pressures there is less control over tidal volume and minute ventilation. Some patients may also require deep sedation and/or paralysis, thereby eliminating spontaneous breathing, compromising adequate ventilation. These issues may be overcome using time-controlled adaptive ventilation (TCAV), where T-low is set to terminate at 75% of the expiratory flow peak, maintaining adequate alveolar inflation during the release phase. If a patient requires a higher minute ventilation, T -high is reduced to increase the frequency of releases while T -low remains set based on expiratory flow dynamics [ 67 , 68 ]. Despite its use in ARDS, high quality evidence favoring APRV is lacking, and the available studies reported mixed results. A systematic review and meta-analysis of eight studies found that use of APRV in critically ill adults with acute hypoxemic respiratory failure was associated with improved mortality and oxygenation, although the studies were small, single-center studies [ 69 ]. Another systematic review and meta-analysis of six studies with 375 patients found that APRV was associated with improved oxygenation and decreased ICU length of stay, but had no effect on mortality [ 64 ]. More recently, a randomized controlled trial of 90 adult patients with COVID-19 related ARDS compared APRV to conventional low tidal volume ventilation and found that APRV was not associated with improvements in ventilator-free days or mortality [ 70 ]. Larger, multicenter, randomized studies are needed to further clarify if APRV is beneficial in patients with severe ARDS (or in ARDS subgroups) compared with conventional ventilation.

High frequency oscillatory ventilation

High frequency oscillatory ventilation (HFOV) is a mode of IMV that employs a constant airway pressure with oscillations at extreme respiratory frequencies (e.g., 5–15 Hz or 300–900 breaths per minute), delivering tidal volumes well below that of anatomical dead space [ 71 , 72 ]. Gas exchange is by convection and diffusion: In large airways, convection predominates, where gas flow is dependent on turbulent flow, bulk convection, and central airway oscillatory pressure. In the lung periphery and alveolar units, diffusion predominates, where gas flow is dependent on Taylor dispersion, collateral ventilation, Pendelluft, and cardiogenic mixing. Higher oscillatory pressures recruit atelectatic alveoli but are dampened in aerated alveoli. In the small airways and mid-lung zones, both convention and diffusion direct gas flow and are dependent on turbulence, peripheral airways resistance, Pendelluft, and asymmetric inspiratory and expiratory velocity profiles [ 72 ]. While HFOV was previously considered a rescue mode of ventilation for severe ARDS, its use has fallen out of favor. Previous studies found mixed results among patients with moderate-to-severe ARDS [ 73 , 74 , 75 ], and a larger trial of 548 patients with moderate-to-severe ARDS demonstrated higher in-hospital mortality in patients randomized to HFOV compared with conventional high PEEP/low tidal volume ventilation [ 76 ]. However, in a meta-analysis of four studies (1552 patients total) comparing HFOV to conventional IMV, the association of HFOV on 30-day mortality varied with severity of hypoxemia: For patients with severe ARDS, HFOV was associated with improved mortality, whereas in patients with mild-to-moderate ARDS (P/F > 100), HFOV was associated with worsened mortality [ 77 ]. Though societies recommend against routinely using HFOV in patients with moderate-to-severe ARDS [ 78 ], there may be select patients with severe ARDS who benefit.

• Mechanical power

Mechanical power is the mechanical energy delivered from the ventilator to the respiratory system and has been hypothesized as a unifying driver of VILI [ 20 ]. Patients with severe ARDS receive mechanical ventilation with higher mechanical power than mild or moderate ARDS, though it is unclear if this is correlative or causative of further lung injury [ 79 ]. The power equation tidal volume, elastance, inspiratory and expiratory time, airway resistance, PEEP, and respiratory rate. This mathematical representation, however, does not necessarily address how energy is distributed to the lung parenchyma versus the respiratory system as a whole [ 80 , 81 ]. Other simplified versions of the mechanical power equation have been derived using parameters easily measured at the bedside. The most clinically useful equation is \(\mathrm{MP}=0.098\times {V}_{\mathrm{t}}\times \mathrm{RR}\times \left({P}_{\mathrm{peak}}-\frac{1}{2}\mathrm{DP}\right)\) , where MP is mechanical power, V t is tidal volume, RR is respiratory rate, P peak is peak pressure, and DP is the driving pressure. Using this representation, an analysis of two cohorts of 8207 patients with ARDS showed that higher mechanical power (> 17.0 J/min) was independently associated with higher ICU-, hospital- and 30-day mortality and decreased ventilator-free days, even in patients receiving low tidal volumes [ 82 ]. Using a simpler model, Costa et al. also showed that driving pressure and RR ( \(\left(4\times \mathrm{DP}\right)+\mathrm{RR}\) ) was equivalent to mechanical power and associated with mortality [ 83 ]. This suggests that driving pressure and RR may be the more important variables of VILI.

Prone ventilation improves oxygenation and ventilatory mechanics in many patients with severe ARDS [ 84 , 85 , 86 , 87 ]. There is often significant heterogeneity of pulmonary edema, consolidation, and atelectasis affecting dorsal lung regions. Proning improves heterogeneity allowing for increased lung recruitment, ventilation-perfusion matching, and decreased overdistension and lung stress. These physiologic effects have been demonstrated in animal models using electrical impedance tomography (EIT) [ 88 , 89 ]. The PROSEVA trial is the most notable study of early proning in patients with moderate-to-severe ARDS (P/F < 150, FIO 2  ≥ 60%). 28-day mortality in the proning group was 16% compared to 32.8% in the supine group (p < 0.001), and 90-day mortality in the proning group was 23.6% compared to 41% ( p  < 0.001). The average duration per proning session was 17 h and each patient underwent 4 proning sessions on average [ 9 ]. Meta-analyses of proning trials have shown improved oxygenation and improved mortality when proning sessions last ≥ 12 h [ 90 , 91 , 92 ]. Proning is generally indicated in moderate-to-severe ARDS (P/F < 150) after appropriate ventilator optimization. While paralysis may help to facilitate proning safely, it is not required. In PROSEVA, patients continued proning sessions until supine oxygenation improved to a P/F ≥ 150 with a PEEP ≤ 10 cm H 2 O and an FiO 2  ≤ 0.6; therefore, smaller improvements in patient oxygenation should not necessarily halt proning. If oxygenation does not improve, patients may still benefit from improved respiratory mechanics and reduced lung stress, as the mortality benefit was not directly linked to improved oxygenation [ 93 ]. This may suggest static compliance, rather than P/F, is the more physiologically relevant proning endpoint [ 94 ]. However, robust data are lacking to support compliance-guided proning strategies.

Fluid management

Acute lung injury during ARDS may be exacerbated by fluid overload. A landmark trial conducted by the ARDS Network (FACTT) compared two fluid management strategies in ARDS: a “conservative” strategy and a “liberal” strategy [ 10 ]. Treatment protocols consisted of combinations of IV fluids, diuretics, or inotropes based on the CVP or PAOP, cardiac output, and the presence or absence of shock and oliguria. While there was no effect on mortality, patients treated with conservative fluid strategy (goal CVP < 4 mm Hg and PAOP < 8 mm Hg in the presence of effective circulation) had less fluid accumulation and increased ventilator-free and ICU-free days.

Non-invasive methods, namely point-of-care ultrasonography (POCUS), can also be used to monitor hemodynamics and intravascular volume status. Venous congestion may be demonstrated by inferior vena cava (IVC) dilation with poor respiratory variability and S-wave reversal in the hepatic veins while low static filling pressures may be seen with a small IVC and a small, hyperdynamic LV cavity [ 95 , 96 ]. An E / E ’ ratio > 15 is associated with increased left-sided filling pressures, while an E / E ’ ratio < 8 is associated with normal left-sided filling pressures, particularly when coupled with lung ultrasonography [ 97 , 98 ]. Stroke volume and cardiac output can be evaluated using the left ventricular outflow tract velocity time integral (LVOT VTI) and diameter [ 96 , 99 ]. IVC respiratory variation is a poor predictor of volume-responsiveness in patients with severe ARDS as this method was validated in patients receiving > 8 cc/kg IBW tidal volumes. Respiratory variation of LVOT VTI presents a better indicator of predicting fluid responsiveness, where a difference in 15 to 20% is associated with fluid responsiveness [ 96 , 100 ].

Glucocorticoids

The administration of empiric steroids for severe ARDS has remained controversial and clinical trial results have varied significantly. One trial conducted found moderate-dose methylprednisolone significantly reduced duration of mechanical ventilation, length of ICU stay, and ICU mortality [ 101 ]. However, a larger study in 2006 by the ARDS Network showed no clinical benefit in patients treated with steroids within 7 days of ARDS onset, and increased mortality in patients treated 14 days after ARDS onset [ 102 ]. More recently, the DEXA-ARDS trial studied patients with moderate-to-severe ARDS and found that patients who received dexamethasone experienced more ventilator-free days and lower mortality [ 103 ]. Dexamethasone has also been shown to improve overall mortality in patients with hypoxemia due to moderate or severe COVID-19 pneumonia [ 104 , 105 , 106 ].

Different ARDS subphenotypes display differing responses to corticosteroid treatment. A latent class analysis of the ARMA and ALVEOLI trials revealed the existence of two distinct phenotypes: (1) hyperinflammatory and (2) hypoinflammatory [ 34 ]. The hyperinflammatory phenotype exhibits a higher overall mortality, and in a retrospective analysis of COVID-19 ARDS, had improved mortality with steroids, while the hypoinflammatory group had worse mortality with steroids [ 107 ]. While the empiric use of glucocorticoids remains controversial in all patients with severe ARDS, there are likely select ARDS subgroups that derive benefit.

Neuromuscular blockade

Neuromuscular blockade (NMB) improves oxygenation via several mechanisms. Paralysis decreases oxygen consumption, eliminates ventilator dyssynchrony, and improves thoracopulmonary compliance [ 108 ]. The ACURASYS trial in 2010 demonstrated a mortality benefit with 48 h of NMB with cisatracurium in patients with moderate-to-severe ARDS (P/F < 150) [ 109 ]. The larger multicenter ROSE trial in 2019 found no significant mortality benefit using NMB in moderate-to-severe ARDS [ 110 ]. However, patients already receiving NMB at the time of enrollment were excluded and it is possible that a subset of patients still benefit from NMB when deemed beneficial by clinician judgment. Additionally, in contrast to ACURASYS, the ROSE control arm received less sedation than the NMB group, which has been previously associated with improved ICU outcomes [ 111 ]. While it is evident that NMB improves oxygenation, it is controversial whether it confers a mortality benefit.

Prolonged use of NMB increases the risk of neuromuscular weakness and muscle loss, pressure injuries, and deep vein thromboses, and requires deep sedation which can increase delirium and neurocognitive impairment and decrease ventilator-free days [ 112 , 113 ]. When using NMB agents, train-of-four (TOF) monitoring may be used to titrate to the lowest effective dose [ 114 ]. Deep sedation is also required during NMB and may be titrated using bispectral index (BIS) to a goal of 40 to 60 [ 115 ].

Inhaled pulmonary vasodilators

Several trials have investigated the role of inhaled pulmonary vasodilators in ARDS, notably iNO and inhaled prostaglandins. Inhaled pulmonary vasodilators improve oxygenation and P/F ratio in most patients by improving ventilation-perfusion matching and may be used in patients with refractory hypoxemia [ 116 , 117 ]. However, they do not improve mortality [ 116 , 117 , 118 , 119 ].

Veno-venous extracorporeal membrane oxygenation

V-V ECMO provides extracorporeal gas exchange in patients with refractory respiratory failure [ 120 ], and plays a critical role in the care of select patients with severe ARDS, though the selection criteria and timing of its use remain controversial. Studies have shown a wide array of outcomes when comparing ECMO to conventional management [ 121 , 122 , 123 ]. Two notable prospective randomized trials for V-V ECMO in ARDS were the CESAR trial and EOLIA trial. CESAR enrolled subjects with a Murray score ≥ 3 or pH < 7.2 despite optimal ventilator settings. CESAR randomized patients to transfer to an ECMO center, rather than ECMO itself. Of the patients that were transferred, 20% did not receive ECMO (instead they received optimized conventional mechanical ventilation), of which 82% survived. There was an overall survival benefit (63% versus 47%, p  = 0.03) when transferred to an ECMO center [ 124 ]. EOLIA enrolled subjects with a P/F < 50 for > 3 h, P/F < 80 for > 6 h (with FIO 2  > 80%) with optimal ventilator settings and adjunctive measures (paralysis, proning, inhaled pulmonary vasodilators), or pH < 7.25 and pCO 2  > 60 while maintaining P Plat  < 32 and maximum RR 35 (Fig.  3 ). Though there was a non-significant trend toward improved mortality in the ECMO arm ( p  = 0.09), the study had an intention-to-treat design and 28% of the patients in the control group crossed over to receive salvage ECMO therapy, of which 43% survived [ 125 ]. The subgroup that benefitted most from ECMO were patients with excessive ventilatory pressures and refractory respiratory acidosis. A post-hoc Bayesian analysis and meta-analysis suggested ECMO may provide a ~ 10% mortality benefit [ 126 , 127 ].

V-V ECMO considerations. A flowchart illustrating indications for veno-venous ECMO, initial ventilator management, monitoring of right ventricular function and contraindications to ECMO

While optimal ventilator settings for patients on V-V ECMO are not clear, the use of ECMO allows for “lung rest” with dramatic reductions in driving pressure, P Plat , and mechanical power [ 128 , 129 , 130 , 131 , 132 ], which may reduce ongoing VILI [ 120 , 124 , 128 , 131 , 133 , 134 ] (Fig.  3 ). Higher PEEP and lower driving pressure while on ECMO has been associated with improved mortality [ 135 , 136 , 137 ] and decreased cytokine release [ 138 , 139 , 140 , 141 ]. Optimal PEEP has been evaluated in small cohorts using EIT demonstrating that most patients require a PEEP of 10–15 cm H 2 O to minimize overdistension and atelectasis and improve compliance [ 142 , 143 , 144 ]. PEEP can also be titrated at the bedside to achieve optimal compliance.

• Acute cor pulmonale

Acute cor pulmonale (ACP) is common in severe ARDS, with an estimated incidence of 25% [ 145 ], but may be higher in COVID-19 (~ 38%) [ 146 ]. The etiology of ACP is often multifactorial including pulmonary vascular dysfunction, regional hypoxemia with pulmonary vasoconstriction, and high mean airway pressures in the setting of poor lung compliance. Severe ACP, as defined by a right ventricular-to-left ventricular (RV/LV) ratio ≥ 1 with RV septal dyskinesia, is associated with even higher mortality [ 145 ]. Patients with severe ARDS should be serially monitored for the development of RV dysfunction via echocardiography or POCUS. If RV dysfunction develops, careful attention should be placed to intravascular volume status and cardiac output. Inhaled pulmonary vasodilators (e.g., iNO, epoprostenol, or systemic vasodilators (e.g., sildenafil), may be utilized to reduce pulmonary pressures. Inotropic agents may be used to augment cardiac output. The effects of PEEP on the pulmonary vascular resistance (PVR) and RV function may vary. The PVR-to-lung volume curve is generally U-shaped, with the lowest PVR at functional residual capacity [ 147 ]. Higher PEEP may induce more West zone 1 and 2 physiology resulting in increased PVR and RV dysfunction. However, hypoxic vasoconstriction in the pulmonary circulation also increases PVR, which may be addressed with higher PEEP [ 47 , 148 ]. The clinician should carefully titrate PEEP understanding this nuance. Patients requiring V-V ECMO who develop ACP may be considered for circuit adjustment such as RV assist ECMO (OxyRVAD), where a return cannula is placed in the main pulmonary artery under transesophageal guidance to bypass the failing RV [ 149 , 150 ] or veno-arterial venous ECMO (Fig.  4 ).

V-V ECMO configurations. A schematic illustrating the reconfiguration of conventional V-V ECMO to either right ventricular assist ECMO (OxyRVAD) or veno-arterial venous ECMO (V-AV ECMO). Adapted from “Extracorporeal Membrane Oxygenation (ECMO),” by BioRender.com (2023). Retrieved from https://app.biorender.com/biorender-templates

ARDS survivorship

Survivors of severe ARDS are at increased risk for physical and neurocognitive sequelae that may persist for years. Common complications include vocal cord dysfunction and tracheal stenosis due to endotracheal tube pressure-related trauma, skin pressure injuries, frailty, neuromyopathies, and cognitive dysfunction [ 113 ]. One study of 109 ARDS survivors found persistent functional disability at one year after hospital discharge including abnormal pulmonary function testing, reduced 6-min walk distance, and reduced health-related quality of life. Moreover, ARDS severity predicted exercise capacity at 6 months [ 151 ]. Lower health-related quality of life was also seen in ECMO survivors [ 152 ]. Muscular weakness is common and affects long-term functioning. Acute skeletal muscle wasting occurs within one week, and is more pronounced in patients with multiorgan failure [ 153 ]. Patients who received corticosteroids and/or NMB are at higher risk for critical illness myopathy [ 113 ], and physical decline has been shown to persist at 5 years after discharge [ 154 ].

Neurocognitive dysfunction is also common after ARDS and data suggests and > 50% of survivors have persistent cognitive impairment at one year [ 155 , 156 ]. Psychiatric morbidities, including depression, post-traumatic stress disorder (PTSD), anxiety and suicidality also occur at higher frequencies after ARDS [ 113 ].

Severe ARDS carries a high morbidity and mortality, and refractory hypoxemia can prove challenging to manage. Low tidal volume ventilation, proning, conservative fluid management, and individualized PEEP titration to minimize driving pressure improve outcomes and are the mainstays of severe ARDS therapy. Optimizing ventilator-lung mechanics as they relate to mechanical power and driving pressure may further induce secondary VILI. Patients with refractory hypoxemia may benefit from inhaled pulmonary vasodilators and neuromuscular blockade, although these interventions have not been consistently shown to improve mortality. V-V ECMO likely confers a small (~ 10%) mortality benefit in a select subset of patients and can be considered on a case-by-case basis.

Availability of data and materials

Not applicable.

Abbreviations

Asynchrony index

• Acute respiratory distress syndrome

Compliance of the respiratory system

Central venous pressure

Delivery of oxygen

• Electrical impedance tomography

Fraction of inspired oxygen

Ideal body weight

Intensive care unit

Inhaled nitric oxide

Inferior vena cava

Left ventricle

Left ventricular outflow tract velocity time integral

Right ventricular assist extracorporeal membrane oxygenation

Airway pressure

Partial pressure of oxygen in arterial blood

Pulmonary artery occlusion pressure

PEEP with least overdistended and collapsed lung

Esophageal pressure

The set high pressure during airway pressure release ventilation

Transpulmonary pressure

The set low pressure during airway pressure release ventilation

Point-of-care ultrasonography

Peak pressure

Pleural pressure

Plateau pressure

Post-traumatic stress disorder

Pulmonary vascular resistance

Respiratory rate

Right ventricle

Stress index

The set time during the low pressure of airway pressure release ventilation

The set time during the high pressure of airway pressure release ventilation

Veno-venoarterial extracorporeal membrane oxygenation

Ventilator-induced lung injury

Tidal volume

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Grotberg, J.C., Reynolds, D. & Kraft, B.D. Management of severe acute respiratory distress syndrome: a primer. Crit Care 27 , 289 (2023). https://doi.org/10.1186/s13054-023-04572-w

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

• Anolin Aslan 1 ,
• Cynthia Aslan 2 , 3 ,
• Naime Majidi Zolbanin 4 , 5 &
• Reza Jafari   ORCID: orcid.org/0000-0003-2036-9043 6 , 7  

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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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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 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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• Case Report
• Open access
• Published: 01 April 2024

Unusual presentation of miliary tuberculosis in a 12-year-old girl: a case report

• Mahsa Kamali 1 ,
• Mohammad Reza Navaeifar 1 ,
• Ali Abbaskhanian 1 ,
• Azin Hajialibeig 1 ,
• Farnaz Godazandeh 2 ,
• Mahsa Salehpour 1 &
• Mohammad Sadegh Rezai 1  

BMC Pediatrics volume  24 , Article number:  223 ( 2024 ) Cite this article

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Metrics details

Miliary tuberculosis (TB) is a lethal hematogenous spread form of mycobacterium tuberculosis with approximately 15–20% mortality rate in children. The present report highlights the clinical manifestations of an unusual presentation of miliary tuberculosis in a 12-year-old girl.

Case presentation

In this case, extensive lung involvement was presented despite the absence of respiratory symptoms. Also, some central hypo-intense with hyper-intense rim nodules were detected in the brain’s pons, right cerebral peduncles and lentiform nucleus.

The results of this study showed that severe miliary TB may occur even in a person who received the Bacille Calmette-Guérin (BCG) vaccine.

Peer Review reports

Tuberculosis (TB), caused by mycobacteria, is a preventable and curable disease with 1.5 million mortality annually most of them live in low and middle-income countries [ 1 ]. Intracranial tuberculosis (ITB) is an unusual and rare presentation of extrapulmonary tuberculosis [ 2 ]. The incidence of ITB is 5–30% of all intracranial lesions [ 3 ]. Nevertheless, it often remains underestimated [ 4 ]. Disseminated TB and miliary TB had similar pathogenesis but the anatomical-pathological findings are different [ 5 ]. Disseminated TB is an important cause of mortality and morbidity in children under 15 years old especially in developing countries [ 6 ]. Disseminated TB describing as entering the bacteria into the systemic circulation, then they multiply and infect extrapulmonary organs [ 7 ]. They account for highly variable clinical manifestations including fever, weight loss, anorexia and nocturnal sweating [ 8 ]. Miliary TB is a lethal hematogenous spread form of mycobacterium tuberculosis to several organs, diagnosed by the presence of a diffuse miliary infiltrate on a chest X-ray, CT scan and pathological evidence [ 9 ]. Peripheral lymphadenopathy and hepatosplenomegaly are the most common childhood military TB signs. The mortality rate of childhood miliary TB is approximately 15–20% [ 10 , 11 ]. As a huge challenge, the nonspecific clinical features of miliary TB often result in delayed diagnosis followed by a poor prognosis condition [ 12 ]. Also, this clinically silent TB leads to inadequate treatment in young children [ 13 ]. So, in children, considering ITB as a differential diagnosis is important. The present case report highlights the clinical presentation of unusual miliary TB evidence in a 12 years old girl.

A 12-year-old girl was admitted to a general hospital, in one of the western cities of Mazandaran province, with chief complaints of muscle atonia, and foam coming from the mouth for 20 s following fever and transient left hemiparesis. Ten minutes later, she agitated and presented generalized tonic-clonic movements lasting for 15 min and decreased consciousness following urinary incontinence. During this episode, she didn’t have foam coming from her mouth. She was intubated immediately and transferred to the PICU (Pediatric intensive care unit) of a tertiary hospital, in Sari, Mazandaran province. She had been visited by a general physician due to fever (T = 38.5 o c), vomiting (digested food particles and non-bloody), diplopia and headache one week before hospitalization and received symptomatic treatment. With relative recovery, the signs and symptoms aggravated the night before hospital admission. Her family reported unintentional weight loss accompanying anorexia and weakness from two months ago, but additional imaging was not performed.

Medical history and physical examination were as follows: The initial vital signs were blood pressure: 105/70 mmHg, the pulse rate: 110 beats per minute, respiratory rate: 22 per minute, axillary temperature: 37.4 o c and SPO2: 98% (intubated). Skin: Negative in terms of petechia, purpura and ecchymosis. Eyes: pale conjunctiva. Extremities: 1 + deep tendon reflexes. The tone and power of muscle were normal and there were not any signs of cerebellar or basal ganglion involvement. Lymph node: No lymphadenopathy. Chest and lung: No chest deformity, she was intubated, and symmetric lung sounds. Abdomen: No distention and organomegaly. No sign and symptom of increased intracranial pressure. She had no history of contact with Coronavirus disease 2019 (COVID-19) patients, contaminated water, rice field and trauma. She had fainted in her childhood period following excessive activity (medical follow-up showed cardiac chamber defect) and improved spontaneously when she was 3 years old. She completed all doses of recommended childhood vaccines but did not receive the COVID-19 vaccine. She had a drug allergy to Cefixime and penicillin and a food allergy to eggplant. Initially, her family did not report a positive family history of TB, but after the final diagnosis, they declared that her uncle died following TB 3 years ago.

Para-clinical investigations: The result of COVID-19 Reverse transcription polymerase chain reaction (RT-PCR) and galactomannan level was negative. Also, the levels of HIV (human immunodeficiency virus) antibody, Venereal disease research laboratory (VDRL), CD4 (cluster of differentiation 4), CD19 and Complement hemolysis (CH50) were normal. The echocardiography showed mild Tricuspid valve regurgitation and mild pulmonary valve insufficiency. Also, there was no pulmonary hypertension. Based on the possible COVID-19 bilateral involvement in chest X-ray and lung CT scan, Pro-BNP, D-dimer and troponin levels were requested. Only the D-dimer level was high. It was 1710. The lumbar puncture (LP) was done on the first day of the PICU admission. The Cerebrospinal fluid (CSF) analysis results are presented in Table  1 . Although, the girl had no signs and symptoms of meningitis including Brudzinski’s and Kernig’s signs, there was CSF involvement. CSF analysis showed increased levels of protein and WBC. The patient had not the coughing or sputum, so the gastric aspirate culture PCR (three times) had been done and the result was positive for miliary TB. Findings of the chest X-ray (Fig.  1 ), lung CT scan (Figs.  2 and 3 ) and brain MRI (Fig.  4 ) were suggestive of caseating tuberculomas. Finally, the miliary TB was diagnosed based on brain MRI, positive gastric aspirate culture and also two organs involvement. AP chest x-ray demonstrates wide spread tiny nodular opacities distributed throughout both lungs. The PPD test were normal.

A pediatric infectious diseases specialist prescribed rifampin, ethambutol, pyrazinamide, isoniazid and vitamin B6 (For prevention of the side effect of isoniazid) based on the miliary TB evidence in MRI. The anti-tuberculosis medication dosage was adjusted due to elevated AST and ALT levels 10 days later. So, the rifampin and isoniazid were discontinued and in the follow-up due to the normal levels of AST and ALT, the rifampin and isoniazid were added to the medication regimen. At the time of discharge, approximately one month later, the gastric aspiration result was negative. She was discharged in stable condition with fixed-dose combination anti-TB medication (III), acid folic and vitamin B6 tablets daily. On her follow-up, AST and ALT levels were normal. Also, her medication changed to two-drug formulations. The girl had been follow-up for at least one year and the MRI finding and gastric aspirate on follow-up were normal.

CXR. PICU admission: AP chest x-ray demonstrates wide spread tiny nodular opacities distributed throughout both lungs

a, b ) Chest CT scan without contrast (mediastinal window): Some calcified lymphadenopathies in the right paratracheal and subcarinal space of the middle mediastinum (white arrows)

a, b ) Chest CT scan without contrast (Lung window): Diffuse multiple miliary nodules (black circle) and some scattered micronodules in a random distribution (black triangle) in both lungs associated with patchy consolidation (black arrows) in lower lobes, in favor of pulmonary TB

Brain MRI without contrast: 4- a & 4- b ) Flair sequence: some central hypo-intense with hyper-intense rim nodules in the pons, right cerebral peduncles and lentiform nucleus (white arrows). 4- c ) DWI/ADC: no restricted diffusion. 4- d ) Contrast–enhanced MRI: Diffuse Multiple rim-enhancing nodules in both cerebral, cerebellar hemispheres and brainstem. These findings are suggestive of caseating tuberculomas with tuberculous meningitis. DWI: Diffusion-weighted imaging – ADC: Apparent diffusion coefficient

In the present case report, the miliary TB evidence was presented in a 12 years old girl. Miliary TB has been more prevalent in middle age and older people than children [ 14 , 15 ]. Also, 60% of the cases are male with a mean age of 55 years in studies [ 16 , 17 , 18 ]. Although the mean age of miliary TB patients has increased, the rates remain relatively low in children [ 19 , 20 ]. In the present study, the unusual miliary TB pattern was seen in a 12 years old girl. The miliary TB in young patients is reported in TB-endemic countries [ 21 ]. Based on the results of a retrospective descriptive study in South Africa, 32.7% of children were TB meningitis. Also, the recent study reported 43.3% of children drug resistant was the main reason for hospitalization [ 22 ]. But, in our case, the girl had no drug resistance. Approximately 13% of the TB cases suffer from HIV infections [ 23 ]. TB becomes more generalized and affects more than one organ when progressive immunosuppression occurs [ 24 ]. However, the present case didn’t have HIV infection as co-infection or other immunodeficiency condition. Corticosteroid therapy can reactivate cryptic TB [ 25 ]. Song et al. reported a 36-year-old man who underwent corticosteroid therapy and two weeks later, he experienced an acute exacerbation of miliary TB [ 26 ]. But in our study, the patient had no history of recent corticosteroid therapy. Considering increased the number of BCG-vaccinated children and improving the diet status of children, we see the modified clinical profile of neurotuberculosis including TB meningitis nowadays with wide varieties of clinical manifestations according to the site of the brain lesion [ 27 ]. The clinical presentation of neurotuberculosis may be nonspecific leading to delayed treatment and poor clinical outcome [ 28 ]. The present case had diffuse multiple rim-enhancing nodules in both cerebral, cerebellar hemispheres and brainstem in the brain. The brain and central nervous systems are two target organs of mycobacterium tuberculosis that cause serious and dangerous forms of extrapulmonary tuberculosis [ 29 ]. The most obvious initial clinical symptoms of our case were fever, weight loss, anorexia and seizure. Other studies reported fever, cough, seizure, diarrhea, hepatomegaly, splenomegaly, jaundice, anorexia and weight loss as the most common clinical presentations in children [ 6 , 30 , 31 ]. A male three-months Brazilian infant was admitted with nocturnal fever, sweating and coughing 10 days before hospitalization and he was not responsive to antibiotic therapy. The results of the chest X-ray showed bilateral miliary TB and also CNS TB based on the CT-scan report [ 32 ]. Similar to our case, the recent case showed early diagnosis and treatment in endemic areas. Delayed diagnosis in miliary TB patients can cause serious complications including cranial nerve involvement, convulsions and death [ 16 ] as a seizure occurred in our case. Machida et al.’s report showed 1% of TB patients had CNS involvement which is about a high mortality rate and permanent neurological sequelae [ 33 ]. Fortunately, in the present case, follow-up interventions showed no neurological sequelae and she was in good general condition. Multiple diagnostic tests are provided to detect miliary TB, including PCR, sputum smear and acid-fast staining, in addition to histopathological findings but radiology plays a major role in this regard [ 34 ]. In this case, despite the absence of respiratory symptoms and non-significant lung involvement in chest X-ray, extensive lung involvement was seen including diffuse multiple miliary nodules. Also, a chest CT scan revealed some scattered micronodules in a random distribution in both lungs associated with patchy consolidation in lower lobes in favor of pulmonary TB. Additionally, in the brain, some central hypo-intense with hyper-intense rim nodules in the pons, right cerebral peduncles and lentiform nucleus, multiple diffuse rims enhancing nodules in both cerebral, cerebellar hemispheres and brainstem were obvious.

The COVID-19 pandemic has emerged new conditions, including neuro-COVID which has presented by lung involvement and seizure [ 35 ]. During the COVID-19 pandemic, miliary TB should be considered in TB endemic areas due to neuro-COVID diagnosis.

Our study showed that teenage patients might present extensive lung involvement in favor of miliary TB even in the absence of respiratory symptoms. Also, we found that severe miliary TB may occur even in a person who received the bacille Calmette-Guérin (BCG) vaccine. In an Iranian study, in 15 children aged under 72 months, disseminated BCG infection occurred after BCG vaccination [ 36 ]. Also, in patients with CNS symptoms including seizure especially in TB endemic areas, miliary TB should be considered as a differential diagnosis, to prevent delay in diagnosis and treatment. We live in the TB endemic area. So, when a patient is admitted with a decreased level of consciousness and there is no reasonable cause, we should consider TB as a differential diagnosis. In the current case report, due to early diagnosis and treatment, neurological sequelae were not observed.

Data Availability

Due to the privacy of the patients, the data generated during the current study are not publicly available but are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors would like to extend their gratitude to all the healthcare providers who were involved in the treatment of the present case.

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Pediatric Infectious Diseases Research Center, Communicable Diseases Institute, Mazandaran University of Medical Sciences, Sari, Iran

Mahsa Kamali, Mohammad Reza Navaeifar, Ali Abbaskhanian, Azin Hajialibeig, Mahsa Salehpour & Mohammad Sadegh Rezai

Department of Radiology, Faculty of Medicine, Mazandaran University of medical sciences, Sari, Iran

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MR: critically edited the manuscript. MK: Drafting the manuscript. MN, AA, AH, MS, MR: Involved in treatment. FG: Interpreting the CXR, MRI and CT-scan. All authors approved final version of the manuscript.

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Correspondence to Mohammad Sadegh Rezai .

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Kamali, M., Navaeifar, M.R., Abbaskhanian, A. et al. Unusual presentation of miliary tuberculosis in a 12-year-old girl: a case report. BMC Pediatr 24 , 223 (2024). https://doi.org/10.1186/s12887-023-04427-x

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Received : 18 February 2023

Accepted : 16 November 2023

Published : 01 April 2024

DOI : https://doi.org/10.1186/s12887-023-04427-x

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