sample case study on asthma

Case Study: Managing Severe Asthma in an Adult

—he follows his treatment plan, but this 40-year-old male athlete has asthma that is not well-controlled. what’s the next step.

By Kirstin Bass, MD, PhD Reviewed by Michael E. Wechsler, MD, MMSc

This case presents a patient with poorly controlled asthma that remains refractory to treatment despite use of standard-of-care therapeutic options. For patients such as this, one needs to embark on an extensive work-up to confirm the diagnosis, assess for comorbidities, and finally, to consider different therapeutic options.

Case presentation and patient history

Mr. T is a 40-year-old recreational athlete with a medical history significant for asthma, for which he has been using an albuterol rescue inhaler approximately 3 times per week for the past year. During this time, he has also been waking up with asthma symptoms approximately twice a month, and has had three unscheduled asthma visits for mild flares. Based on the  National Asthma Education and Prevention Program guidelines , Mr. T has asthma that is not well controlled. 1

As a result of these symptoms, spirometry was performed revealing a forced expiratory volume in the first second (FEV1) of 78% predicted. Mr. T then was prescribed treatment with a low-dose corticosteroid, fluticasone 44 mcg at two puffs twice per day. However, he remained symptomatic and continued to use his rescue inhaler 3 times per week. Therefore, he was switched to a combination inhaled steroid and long-acting beta-agonist (LABA) (fluticasone propionate 250 mcg and salmeterol 50 mcg, one puff twice a day) by his primary care doctor.

Initial pulmonary assessment Even with this step up in his medication, Mr. T continued to be symptomatic and require rescue inhaler use. Therefore, he was referred to a pulmonologist, who performed the initial work-up shown here:

• Spirometry, pre-albuterol: FEV1 79%, post-albuterol: 12% improvement
• Methacholine challenge: PC 20 : 1.0 mg/mL
• Chest X-ray: Within normal limits

Continued pulmonary assessment His dose of inhaled corticosteroid (ICS) and LABA was increased to fluticasone 500 mcg/salmeterol 50 mcg, one puff twice daily. However, he continued to have symptoms and returned to the pulmonologist for further work-up, shown here:

• Chest computed tomography (CT): Normal lung parenchyma with no scarring or bronchiectasis
• Sinus CT: Mild mucosal thickening
• Complete blood count (CBC): Within normal limits, white blood cells (WBC) 10.0 K/mcL, 3% eosinophils
• Immunoglobulin E (IgE): 25 IU/mL
• Allergy-skin test: Positive for dust, trees
• Exhaled NO: Fractional exhaled nitric oxide (FeNO) 53 parts per billion (pbb)

Assessment for comorbidities contributing to asthma symptoms After this work-up, tiotropium was added to his medication regimen. However, he remained symptomatic and had two more flares over the next 3 months. He was assessed for comorbid conditions that might be affecting his symptoms, and results showed:

• Esophagram/barium swallow: Negative
• Esophageal manometry: Negative
• Esophageal impedance: Within normal limits
• ECG: Within normal limits
• Genetic testing: Negative for cystic fibrosis, alpha1 anti-trypsin deficiency

The ear, nose, and throat specialist to whom he was referred recommended only nasal inhaled steroids for his mild sinus disease and noted that he had a normal vocal cord evaluation.

Following this extensive work-up that transpired over the course of a year, Mr. T continued to have symptoms. He returned to the pulmonologist to discuss further treatment options for his refractory asthma.

Diagnosis Mr. T has refractory asthma. Work-up for this condition should include consideration of other causes for the symptoms, including allergies, gastroesophageal reflux disease, cardiac disease, sinus disease, vocal cord dysfunction, or genetic diseases, such as cystic fibrosis or alpha1 antitrypsin deficiency, as was performed for Mr. T by his pulmonary team.

Treatment options When a patient has refractory asthma, treatment options to consider include anticholinergics (tiotropium, aclidinium), leukotriene modifiers (montelukast, zafirlukast), theophylline, anti-immunoglobulin E (IgE) antibody therapy with omalizumab, antibiotics, bronchial thermoplasty, or enrollment in a clinical trial evaluating the use of agents that modulate the cell signaling and immunologic responses seen in asthma.

Treatment outcome Mr. T underwent bronchial thermoplasty for his asthma. One year after the procedure, he reports feeling great. He has not taken systemic steroids for the past year, and his asthma remains controlled on a moderate dose of ICS and a LABA. He has also been able to resume exercising on a regular basis.

Approximately 10% to 15% of asthma patients have severe asthma refractory to the commonly available medications. 2  One key aspect of care for this patient population is a careful workup to exclude other comorbidities that could be contributing to their symptoms. Following this, there are several treatment options to consider, as in recent years there have been several advances in the development of asthma therapeutics. 2

Treatment options for refractory asthma There are a number of currently approved therapies for severe, refractory asthma. In addition to therapy with ICS or combination therapies with ICS and LABAs, leukotriene antagonists have good efficacy in asthma, especially in patients with prominent allergic or exercise symptoms. 2  The anticholinergics, such as tiotropium, which was approved for asthma in 2015, enhance bronchodilation and are useful adjuncts to ICS. 3-5  Omalizumab is a monoclonal antibody against IgE recommended for use in severe treatment-refractory allergic asthma in patients with atopy. 2  A nonmedication therapeutic option to consider is bronchial thermoplasty, a bronchoscopic procedure that uses thermal energy to disrupt bronchial smooth muscle. 6,7

Personalizing treatment for each patient It is important to personalize treatment based on individual characteristics or phenotypes that predict the patient's likely response to treatment, as well as the patient's preferences and practical issues, such as adherence and cost. 8

In this case, tiotropium had already been added to Mr. T's medications and his symptoms continued. Although addition of a leukotriene modifier was an option for him, he did not wish to add another medication to his care regimen. Omalizumab was not added partly for this reason, and also because of his low IgE level. As his bronchoscopy was negative, it was determined that a course of antibiotics would not be an effective treatment option for this patient. While vitamin D insufficiency has been associated with adverse outcomes in asthma, T's vitamin D level was tested and found to be sufficient.

We discussed the possibility of Mr. T's enrollment in a clinical trial. However, because this did not guarantee placement within a treatment arm and thus there was the possibility of receiving placebo, he opted to undergo bronchial thermoplasty.

Bronchial thermoplasty  Bronchial thermoplasty is effective for many patients with severe persistent asthma, such as Mr. T. This procedure may provide additional benefits to, but does not replace, standard asthma medications. During the procedure, thermal energy is delivered to the airways via a bronchoscope to reduce excess airway smooth muscle and limit its ability to constrict the airways. It is an outpatient procedure performed over three sessions by a trained physician. 9

The effects of bronchial thermoplasty have been studied in several trials. The first large-scale multicenter randomized controlled study was  the Asthma Intervention Research (AIR) Trial , which enrolled patients with moderate to severe asthma. 10  In this trial, patients who underwent the procedure had a significant improvement in asthma symptoms as measured by symptom-free days and scores on asthma control and quality of life questionnaires, as well as reductions in mild exacerbations and increases in morning peak expiratory flow. 10  Shortly after the AIR trial, the  Research in Severe Asthma (RISA) trial  was conducted to evaluate bronchial thermoplasty in patients with more severe, symptomatic asthma. 11  In this population, bronchial thermoplasty resulted in a transient worsening of asthma symptoms, with a higher rate of hospitalizations during the treatment period. 11  Hospitalization rate equalized between the treatment and control groups in the posttreatment period, however, and the treatment group showed significant improvements in rescue medication use, prebronchodilator forced expiratory volume in the first second (FEV1) % predicted, and asthma control questionnaire scores. 11

The AIR-2  trial followed, which was a multicenter, randomized, double-blind, sham-controlled study of 288 patients with severe asthma. 6  Similar to the RISA trial, patients in the treatment arm of this trial experienced an increase in adverse respiratory effects during the treatment period, the most common being airway irritation (including wheezing, chest discomfort, cough, and chest pain) and upper respiratory tract infections. 6

The majority of adverse effects occurred within 1 day of the procedure and resolved within 7 days. 6  In this study, bronchial thermoplasty was found to significantly improve quality of life, as well as reduce the rate of severe exacerbations by 32%. 6  Patients who underwent the procedure also reported fewer adverse respiratory effects, fewer days lost from work, school, or other activities due to asthma, and an 84% risk reduction in emergency department visits. 6

Long-term (5-year) follow-up studies have been conducted for patients in both  the AIR  and  the AIR-2  trials. In patients who underwent bronchial thermoplasty in either study, the rate of adverse respiratory effects remained stable in years 2 to 5 following the procedure, with no increase in hospitalizations or emergency department visits. 7,12  Additionally, FEV1 remained stable throughout the 5-year follow-up period. 7,12  This finding was maintained in patients enrolled in the AIR-2 trial despite decreased use of daily ICS. 7

Bronchial thermoplasty is an important addition to the asthma treatment armamentarium. 7  This treatment is currently approved for individuals with severe persistent asthma who remain uncontrolled despite the use of an ICS and LABA. Several clinical trials with long-term follow-up have now demonstrated its safety and ability to improve quality of life in patients with severe asthma, such as Mr. T.

Severe asthma can be a challenge to manage. Patients with this condition require an extensive workup, but there are several treatments currently available to help manage these patients, and new treatments are continuing to emerge. Managing severe asthma thus requires knowledge of the options available as well as consideration of a patient's personal situation-both in terms of disease phenotype and individual preference. In this case, the patient expressed a strong desire to not add any additional medications to his asthma regimen, which explained the rationale for choosing to treat with bronchial thermoplasty. Personalized treatment necessitates exploring which of the available or emerging options is best for each individual patient.

Published: April 16, 2018

• 1. National Asthma Education and Prevention Program: Asthma Care Quick Reference.
• 2. Olin JT, Wechsler ME. Asthma: pathogenesis and novel drugs for treatment. BMJ . 2014;349:g5517.
• 3. Boehringer Ingelheim. Asthma: U.S. FDA approves new indication for SPIRIVA Respimat [press release]. September 16, 2015.
• 4. Peters SP, Kunselman SJ, Icitovic N, et al. Tiotropium bromide step-up therapy for adults with uncontrolled asthma. N Engl J Med . 2010;363:1715-1726.
• 5. Kerstjens HA, Engel M, Dahl R. Tiotropium in asthma poorly controlled with standard combination therapy. N Engl J Med . 2012;367:1198-1207.
• 6. Castro M, Rubin AS, Laviolette M, et al. Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial. Am J Respir Crit Care Med . 2010;181:116-124.
• 7. Wechsler ME, Laviolette M, Rubin AS, et al. Bronchial thermoplasty: long-term safety and effectiveness in patients with severe persistent asthma. J Allergy Clin Immunol . 2013;132:1295-1302.
• 8. Global Initiative for Asthma: Pocket Guide for Asthma Management and Prevention (for Adults and Children Older than 5 Years).
• 10. Cox G, Thomson NC, Rubin AS, et al. Asthma control during the year after bronchial thermoplasty. N Engl J Med . 2007;356:1327-1337.
• 11. Pavord ID, Cox G, Thomson NC, et al. Safety and efficacy of bronchial thermoplasty in symptomatic, severe asthma. Am J Respir Crit Care Med . 2007;176:1185-1191.
• 12. Thomson NC, Rubin AS, Niven RM, et al. Long-term (5 year) safety of bronchial thermoplasty: Asthma Intervention Research (AIR) trial. BMC Pulm Med . 2011;11:8.

More On This Topic

Treatable traits and future exacerbation risk in severe asthma, baker’s asthma, the long-term trajectory of mild asthma, age, gender, & systemic corticosteroid comorbidities, ask the expert: william busse, md, challenges the current definition of the atopic march, considering the curveballs in asthma treatment, do mucus plugs play a bigger role in chronic severe asthma than previously thought, an emerging subtype of copd is associated with early respiratory disease.

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Case 1 diagnosis: allergy bullying, clinical pearls.

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Case 1: A 12-year-old girl with food allergies and an acute asthma exacerbation

• Article contents
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Lopamudra Das, Michelle GK Ward, Case 1: A 12-year-old girl with food allergies and an acute asthma exacerbation, Paediatrics & Child Health , Volume 19, Issue 2, February 2014, Pages 69–70, https://doi.org/10.1093/pch/19.2.69

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A 12-year-old girl with a history of asthma presented to the emergency department with a three-day history of increased work of breathing, cough and wheezing. She reported no clear trigger for her respiratory symptoms, although she had noted some symptoms of a mild upper respiratory tract infection. With this episode, the patient had been using a short-acting bronchodilator more frequently than she had in the past, without the expected resolution of symptoms.

On the day of presentation, the patient awoke feeling ‘suffocated’ and her mother noted her lips to be blue. In the emergency department, her oxygen saturation was 85% and her respiratory rate was 40 breaths/min. She had significantly increased work of breathing and poor air entry bilaterally to both lung bases, with wheezing in the upper lung zones. She was treated with salbutamol/ipratropium and received intravenous steroids and magnesium sulfate. Her chest x-ray showed hyperinflation and no focal findings.

Her medical history revealed that she was followed by a respirologist for her asthma, had good medication adherence and had not experienced a significant exacerbation for six months. She also had a history of wheezing, dyspnea and pruritis with exposure to peanuts, chickpeas and lentils; she had been prescribed an injectible epinephrine device for this. However, her device had expired at the time of presentation. In the past, her wheezing episodes had been seasonal and related to exposure to grass and pollens; this presentation occurred during the winter. Further history revealed the probable cause of her presentation.

Although reluctant to disclose the information, our patient later revealed that she had been experiencing significant bullying at school, which was primarily related to her food allergies. Three days before her admission, classmates had smeared peanut butter on one of her schoolbooks. She developed pruritis immediately after opening the book and she started wheezing and coughing later that day. This event followed several months of being taunted with peanut products at school. The patient was experiencing low mood and reported new symptoms of anxiety related to school. The review of systems was otherwise negative, with no substance use.

The patient's asthma exacerbation resolved with conventional asthma treatment. Her pulmonary function tests were nonconcerning (forced expiratory volume in 1 s 94% and 99% of predicted) after her recovery. The trigger for her asthma exacerbation was likely multifactorial, related to exposure to the food allergen as well as the upper respiratory infection. A psychologist was consulted to assess the symptoms of anxiety and depression that had occurred as a result of the bullying. During the hospitalization, the medical team contacted the patient's school to provide education on allergy bullying, treatment of severe allergic reactions and its potential for life-threatening reactions with exposure to allergens. The medical team also recommended community resources for further education of students and staff about allergy bullying and its prevention.

Allergy bullying is a form of bullying with potentially severe medical outcomes. In recent years, it has gained increasing notoriety in schools and in the media. Population-based studies have shown that 20% to 35% of children with allergies experience bullying. In many cases (31% in one recent study [ 1 ]), this bullying is related directly to the food allergy. From a medical perspective, there are little published data regarding allergy bullying, and many health care providers may not be aware of the issue.

Allergy bullying can include teasing a child about their allergy, throwing food at a child, or even forcing them to touch or eat allergenic foods. Most episodes of allergy bullying occur at school, and can include episodes perpetrated by teachers and/or staff ( 2 ).

Allergy bullying can lead to allergic reactions, which may be mild or severe (eg, urticaria, wheezing, anaphylaxis), but may also lead to negative emotional consequences (sadness, depression) ( 2 ) and an overall decrease in quality of life measures ( 1 ). Adolescents commonly resist using medical devices, such as injectible epinephrine devices, and bullying may be a contributing factor for this ( 3 ). Attempting to conceal symptoms in a bullying situation may place children at risk for a worse outcome.

Physicians can play a key role in detecting allergy bullying and its health consequences. In many cases, children have not discussed this issue with their parents ( 1 ). Given the prevalence of bullying, its potential to lead to severe harm, including death, and the lack of awareness of this issue, clinicians should specifically ask about bullying in all children and teens with allergies. Physicians can also work with families and schools to support these children, educate their peers and school staff, and help prevent negative health outcomes from allergy bullying.

Online resources

www.anaphylaxis.ca − A national charity that aims to inform, support, educate and advocate for the needs of individuals and families living with anaphylaxis, and to support and participate in research. This website includes education modules for schools and links to local support groups throughout Canada.

www.whyriskit.ca/pages/en/live/bullying.php − A website for teenagers with food allergies; includes a segment that addresses food bullying.

www.foodallergy.org − Contains numerous resources for children and their families, including a significant discussion on bullying and ways to prevent it.

Allergy bullying is common but is often unrecognized as a factor in clinical presentations of allergic reactions.

Physicians should make a point of asking about bullying in patients with allergies and become familiar with resources for dealing with allergy bullying.

Physicians can play roles as advocates, educators and collaborators with the school system to help make the school environment safer for children with allergies who may be at risk for allergy bullying.

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• Published: 16 October 2014

A woman with asthma: a whole systems approach to supporting self-management

• Hilary Pinnock 1 ,
• Elisabeth Ehrlich 1 ,
• Gaylor Hoskins 2 &
• Ron Tomlins 3  

npj Primary Care Respiratory Medicine volume  24 , Article number:  14063 ( 2014 ) Cite this article

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• Health care

A 35-year-old lady attends for review of her asthma following an acute exacerbation. There is an extensive evidence base for supported self-management for people living with asthma, and international and national guidelines emphasise the importance of providing a written asthma action plan. Effective implementation of this recommendation for the lady in this case study is considered from the perspective of a patient, healthcare professional, and the organisation. The patient emphasises the importance of developing a partnership based on honesty and trust, the need for adherence to monitoring and regular treatment, and involvement of family support. The professional considers the provision of asthma self-management in the context of a structured review, with a focus on a self-management discussion which elicits the patient’s goals and preferences. The organisation has a crucial role in promoting, enabling and providing resources to support professionals to provide self-management. The patient’s asthma control was assessed and management optimised in two structured reviews. Her goal was to avoid disruption to her work and her personalised action plan focused on achieving that goal.

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A 35-year-old sales representative attends the practice for an asthma review. Her medical record notes that she has had asthma since childhood, and although for many months of the year her asthma is well controlled (when she often reduces or stops her inhaled steroids), she experiences one or two exacerbations a year requiring oral steroids. These are usually triggered by a viral upper respiratory infection, though last summer when the pollen count was particularly high she became tight chested and wheezy for a couple of weeks.

Her regular prescription is for fluticasone 100 mcg twice a day, and salbutamol as required. She has a young family and a busy lifestyle so does not often manage to find time to attend the asthma clinic. A few weeks previously, an asthma attack had interfered with some important work-related travel, and she has attended the clinic on this occasion to ask about how this can be managed better in the future. There is no record of her having been given an asthma action plan.

What do we know about asthma self-management? The academic perspective

Supported self-management reduces asthma morbidity.

The lady in this case study is struggling to maintain control of her asthma within the context of her busy professional and domestic life. The recent unfortunate experience which triggered this consultation offers a rare opportunity to engage with her and discuss how she can manage her asthma better. It behoves the clinician whom she is seeing (regardless of whether this is in a dedicated asthma clinic or an appointment in a routine general practice surgery) to grasp the opportunity and discuss self-management and provide her with a (written) personalised asthma action plan (PAAP).

The healthcare professional advising the lady is likely to be aware that international and national guidelines emphasise the importance of supporting self-management. 1 – 4 There is an extensive evidence base for asthma self-management: a recent synthesis identified 22 systematic reviews summarising data from 260 randomised controlled trials encompassing a broad range of demographic, clinical and healthcare contexts, which concluded that asthma self-management reduces emergency use of healthcare resources, including emergency department visits, hospital admissions and unscheduled consultations and improves markers of asthma control, including reduced symptoms and days off work, and improves quality of life. 1 , 2 , 5 – 12 Health economic analysis suggests that it is not only clinically effective, but also a cost-effective intervention. 13

Personalised asthma action plans

Key features of effective self-management approaches are:

Self-management education should be reinforced by provision of a (written) PAAP which reminds patients of their regular treatment, how to monitor and recognise that control is deteriorating and the action they should take. 14 – 16 As an adult, our patient can choose whether she wishes to monitor her control with symptoms or by recording peak flows (or a combination of both). 6 , 8 , 9 , 14 Symptom-based monitoring is generally better in children. 15 , 16

Plans should have between two and three action points including emergency doses of reliever medication; increasing low dose (or recommencing) inhaled steroids; or starting a course of oral steroids according to severity of the exacerbation. 14

Personalisation of the action plan is crucial. Focussing specifically on what actions she could take to prevent a repetition of the recent attack is likely to engage her interest. Not all patients will wish to start oral steroids without advice from a healthcare professional, though with her busy lifestyle and travel our patient is likely to be keen to have an emergency supply of prednisolone. Mobile technology has the potential to support self-management, 17 , 18 though a recent systematic review concluded that none of the currently available smart phone ‘apps’ were fit for purpose. 19

Identification and avoidance of her triggers is important. As pollen seems to be a trigger, management of allergic rhinitis needs to be discussed (and included in her action plan): she may benefit from regular use of a nasal steroid spray during the season. 20

Self-management as recommended by guidelines, 1 , 2 focuses narrowly on adherence to medication/monitoring and the early recognition/remediation of exacerbations, summarised in (written) PAAPs. Patients, however, may want to discuss how to reduce the impact of asthma on their life more generally, 21 including non-pharmacological approaches.

Supported self-management

The impact is greater if self-management education is delivered within a comprehensive programme of accessible, proactive asthma care, 22 and needs to be supported by ongoing regular review. 6 With her busy lifestyle, our patient may be reluctant to attend follow-up appointments, and once her asthma is controlled it may be possible to make convenient arrangements for professional review perhaps by telephone, 23 , 24 or e-mail. Flexible access to professional advice (e.g., utilising diverse modes of consultation) is an important component of supporting self-management. 25

The challenge of implementation

Implementation of self-management, however, remains poor in routine clinical practice. A recent Asthma UK web-survey estimated that only 24% of people with asthma in the UK currently have a PAAP, 26 with similar figures from Sweden 27 and Australia. 28 The general practitioner may feel that they do not have time to discuss self-management in a routine surgery appointment, or may not have a supply of paper-based PAAPs readily available. 29 However, as our patient rarely finds time to attend the practice, inviting her to make an appointment for a future clinic is likely to be unsuccessful and the opportunity to provide the help she needs will be missed.

The solution will need a whole systems approach

A systematic meta-review of implementing supported self-management in long-term conditions (including asthma) concluded that effective implementation was multifaceted and multidisciplinary; engaging patients, training and motivating professionals within the context of an organisation which actively supported self-management. 5 This whole systems approach considers that although patient education, professional training and organisational support are all essential components of successful support, they are rarely effective in isolation. 30 A systematic review of interventions that promote provision/use of PAAPs highlighted the importance of organisational systems (e.g., sending blank PAAPs with recall reminders). 31 A patient offers her perspective ( Box 1 ), a healthcare professional considers the clinical challenge, and the challenges are discussed from an organisational perspective.

Box 1: What self-management help should this lady expect from her general practitioner or asthma nurse? The patient’s perspective

The first priority is that the patient is reassured that her condition can be managed successfully both in the short and the long term. A good working relationship with the health professional is essential to achieve this outcome. Developing trust between patient and healthcare professional is more likely to lead to the patient following the PAAP on a long-term basis.

A review of all medication and possible alternative treatments should be discussed. The patient needs to understand why any changes are being made and when she can expect to see improvements in her condition. Be honest, as sometimes it will be necessary to adjust dosages before benefits are experienced. Be positive. ‘There are a number of things we can do to try to reduce the impact of asthma on your daily life’. ‘Preventer treatment can protect against the effect of pollen in the hay fever season’. If possible, the same healthcare professional should see the patient at all follow-up appointments as this builds trust and a feeling of working together to achieve the aim of better self-management.

Is the healthcare professional sure that the patient knows how to take her medication and that it is taken at the same time each day? The patient needs to understand the benefit of such a routine. Medication taken regularly at the same time each day is part of any self-management regime. If the patient is unused to taking medication at the same time each day then keeping a record on paper or with an electronic device could help. Possibly the patient could be encouraged to set up a system of reminders by text or smartphone.

Some people find having a peak flow meter useful. Knowing one's usual reading means that any fall can act as an early warning to put the PAAP into action. Patients need to be proactive here and take responsibility.

Ongoing support is essential for this patient to ensure that she takes her medication appropriately. Someone needs to be available to answer questions and provide encouragement. This could be a doctor or a nurse or a pharmacist. Again, this is an example of the partnership needed to achieve good asthma control.

It would also be useful at a future appointment to discuss the patient’s lifestyle and work with her to reduce her stress. Feeling better would allow her to take simple steps such as taking exercise. It would also be helpful if all members of her family understood how to help her. Even young children can do this.

From personal experience some people know how beneficial it is to feel they are in a partnership with their local practice and pharmacy. Being proactive produces dividends in asthma control.

What are the clinical challenges for the healthcare professional in providing self-management support?

Due to the variable nature of asthma, a long-standing history may mean that the frequency and severity of symptoms, as well as what triggers them, may have changed over time. 32 Exacerbations requiring oral steroids, interrupting periods of ‘stability’, indicate the need for re-assessment of the patient’s clinical as well as educational needs. The patient’s perception of stability may be at odds with the clinical definition 1 , 33 —a check on the number of short-acting bronchodilator inhalers the patient has used over a specific period of time is a good indication of control. 34 Assessment of asthma control should be carried out using objective tools such as the Asthma Control Test or the Royal College of Physicians three questions. 35 , 36 However, it is important to remember that these assessment tools are not an end in themselves but should be a springboard for further discussion on the nature and pattern of symptoms. Balancing work with family can often make it difficult to find the time to attend a review of asthma particularly when the patient feels well. The practice should consider utilising other means of communication to maintain contact with patients, encouraging them to come in when a problem is highlighted. 37 , 38 Asthma guidelines advocate a structured approach to ensure the patient is reviewed regularly and recommend a detailed assessment to enable development of an appropriate patient-centred (self)management strategy. 1 – 4

Although self-management plans have been shown to be successful for reducing the impact of asthma, 21 , 39 the complexity of managing such a fluctuating disease on a day-to-day basis is challenging. During an asthma review, there is an opportunity to work with the patient to try to identify what triggers their symptoms and any actions that may help improve or maintain control. 38 An integral part of personalised self-management education is the written PAAP, which gives the patient the knowledge to respond to the changes in symptoms and ensures they maintain control of their asthma within predetermined parameters. 9 , 40 The PAAP should include details on how to monitor asthma, recognise symptoms, how to alter medication and what to do if the symptoms do not improve. The plan should include details on the treatment to be taken when asthma is well controlled, and how to adjust it when the symptoms are mild, moderate or severe. These action plans need to be developed between the doctor, nurse or asthma educator and the patient during the review and should be frequently reviewed and updated in partnership (see Box 1). Patient preference as well as clinical features such as whether she under- or over-perceives her symptoms should be taken into account when deciding whether the action plan is peak flow or symptom-driven. Our patient has a lot to gain from having an action plan. She has poorly controlled asthma and her lifestyle means that she will probably see different doctors (depending who is available) when she needs help. Being empowered to self-manage could make a big difference to her asthma control and the impact it has on her life.

The practice should have protocols in place, underpinned by specific training to support asthma self-management. As well as ensuring that healthcare professionals have appropriate skills, this should include training for reception staff so that they know what action to take if a patient telephones to say they are having an asthma attack.

However, focusing solely on symptom management strategies (actions) to follow in the presence of deteriorating symptoms fails to incorporate the patients’ wider views of asthma, its management within the context of her/his life, and their personal asthma management strategies. 41 This may result in a failure to use plans to maximise their health potential. 21 , 42 A self-management strategy leading to improved outcomes requires a high level of patient self-efficacy, 43 a meaningful partnership between the patient and the supporting health professional, 42 , 44 and a focused self-management discussion. 14

Central to both the effectiveness and personalisation of action plans, 43 , 45 in particular the likelihood that the plan will lead to changes in patients’ day-to-day self-management behaviours, 45 is the identification of goals. Goals are more likely to be achieved when they are specific, important to patients, collaboratively set and there is a belief that these can be achieved. Success depends on motivation 44 , 46 to engage in a specific behaviour to achieve a valued outcome (goal) and the ability to translate the behavioural intention into action. 47 Action and coping planning increases the likelihood that patient behaviour will actually change. 44 , 46 , 47 Our patient has a goal: she wants to avoid having her work disrupted by her asthma. Her personalised action plan needs to explicitly focus on achieving that goal.

As providers of self-management support, health professionals must work with patients to identify goals (valued outcomes) that are important to patients, that may be achievable and with which they can engage. The identification of specific, personalised goals and associated feasible behaviours is a prerequisite for the creation of asthma self-management plans. Divergent perceptions of asthma and how to manage it, and a mismatch between what patients want/need from these plans and what is provided by professionals are barriers to success. 41 , 42

What are the challenges for the healthcare organisation in providing self-management support?

A number of studies have demonstrated the challenges for primary care physicians in providing ongoing support for people with asthma. 31 , 48 , 49 In some countries, nurses and other allied health professionals have been trained as asthma educators and monitor people with stable asthma. These resources are not always available. In addition, some primary care services are delivered in constrained systems where only a few minutes are available to the practitioner in a consultation, or where only a limited range of asthma medicines are available or affordable. 50

There is recognition that the delivery of quality care depends on the competence of the doctor (and supporting health professionals), the relationship between the care providers and care recipients, and the quality of the environment in which care is delivered. 51 This includes societal expectations, health literacy and financial drivers.

In 2001, the Australian Government adopted a programme developed by the General Practitioner Asthma Group of the National Asthma Council Australia that provided a structured approach to the implementation of asthma management guidelines in a primary care setting. 52 Patients with moderate-to-severe asthma were eligible to participate. The 3+ visit plan required confirmation of asthma diagnosis, spirometry if appropriate, assessment of trigger factors, consideration of medication and patient self-management education including provision of a written PAAP. These elements, including regular medical review, were delivered over three visits. Evaluation demonstrated that the programme was beneficial but that it was difficult to complete the third visit in the programme. 53 – 55 Accordingly, the programme, renamed the Asthma Cycle of Care, was modified to incorporate two visits. 56 Financial incentives are provided to practices for each patient who receives this service each year.

Concurrently, other programmes were implemented which support practice-based care. Since 2002, the National Asthma Council has provided best-practice asthma and respiratory management education to health professionals, 57 and this programme will be continuing to 2017. The general practitioner and allied health professional trainers travel the country to provide asthma and COPD updates to groups of doctors, nurses and community pharmacists. A number of online modules are also provided. The PACE (Physician Asthma Care Education) programme developed by Noreen Clark has also been adapted to the Australian healthcare system. 58 In addition, a pharmacy-based intervention has been trialled and implemented. 59

To support these programmes, the National Asthma Council ( www.nationalasthma.org.au ) has developed resources for use in practices. A strong emphasis has been on the availability of a range of PAAPs (including plans for using adjustable maintenance dosing with ICS/LABA combination inhalers), plans for indigenous Australians, paediatric plans and plans translated into nine languages. PAAPs embedded in practice computer systems are readily available in consultations, and there are easily accessible online paediatric PAAPs ( http://digitalmedia.sahealth.sa.gov.au/public/asthma/ ). A software package, developed in the UK, can be downloaded and used to generate a pictorial PAAP within the consultation. 60

One of the strongest drivers towards the provision of written asthma action plans in Australia has been the Asthma Friendly Schools programme. 61 , 62 Established with Australian Government funding and the co-operation of Education Departments of each state, the Asthma Friendly Schools programme engages schools to address and satisfy a set of criteria that establishes an asthma-friendly environment. As part of accreditation, the school requires that each child with asthma should have a written PAAP prepared by their doctor to assist (trained) staff in managing a child with asthma at school.

The case study continues...

The initial presentation some weeks ago was during an exacerbation of asthma, which may not be the best time to educate a patient. It is, however, a splendid time to build on their motivation to feel better. She agreed to return after her asthma had settled to look more closely at her asthma control, and an appointment was made for a routine review.

At this follow-up consultation, the patient’s diagnosis was reviewed and confirmed and her trigger factors discussed. For this lady, respiratory tract infections are the usual trigger but allergic factors during times of high pollen count may also be relevant. Assessment of her nasal airway suggested that she would benefit from better control of allergic rhinitis. Other factors were discussed, as many patients are unaware that changes in air temperature, exercise and pets can also trigger asthma exacerbations. In addition, use of the Asthma Control Test was useful as an objective assessment of control as well as helping her realise what her life could be like! Many people with long-term asthma live their life within the constraints of their illness, accepting that is all that they can do.

After assessing the level of asthma control, a discussion about management options—trigger avoidance, exercise and medicines—led to the development of a written PAAP. Asthma can affect the whole family, and ways were explored that could help her family understand why it is important that she finds time in the busy domestic schedules to take her regular medication. Family and friends can also help by understanding what triggers her asthma so that they can avoid exposing her to perfumes, pollens or pets that risk triggering her symptoms. Information from the national patient organisation was provided to reinforce the messages.

The patient agreed to return in a couple of weeks, and a recall reminder was set up. At the second consultation, the level of control since the last visit will be explored including repeat spirometry, if appropriate. Further education about the pathophysiology of asthma and how to recognise early warning signs of loss of control can be given. Device use will be reassessed and the PAAP reviewed. Our patient’s goal is to avoid disruption to her work and her PAAP will focus on achieving that goal. Finally, agreement will be reached with the patient about future routine reviews, which, now that she has a written PAAP, could be scheduled by telephone if all is well, or face-to-face if a change in her clinical condition necessitates a more comprehensive review.

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Pinnock, H., Ehrlich, E., Hoskins, G. et al. A woman with asthma: a whole systems approach to supporting self-management. npj Prim Care Resp Med 24 , 14063 (2014). https://doi.org/10.1038/npjpcrm.2014.63

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Clinical case study - asthma, clinical case study - asthma, resource information.

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• Published: 21 February 2018

Pediatric severe asthma: a case series report and perspectives on anti-IgE treatment

• Virginia Mirra 1 ,
• Silvia Montella 1 &
• Francesca Santamaria 1  

BMC Pediatrics volume  18 , Article number:  73 ( 2018 ) Cite this article

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The primary goal of asthma management is to achieve disease control for reducing the risk of future exacerbations and progressive loss of lung function. Asthma not responding to treatment may result in significant morbidity. In many children with uncontrolled symptoms, the diagnosis of asthma may be wrong or adherence to treatment may be poor. It is then crucial to distinguish these cases from the truly “severe therapy-resistant” asthmatics by a proper filtering process. Herein we report on four cases diagnosed as difficult asthma, detail the workup that resulted in the ultimate diagnosis, and provide the process that led to the prescription of omalizumab.

Case presentation

All children had been initially referred because of asthma not responding to long-term treatment with high-dose inhaled steroids, long-acting β 2 -agonists and leukotriene receptor antagonists. Definitive diagnosis was severe asthma. Three out four patients were treated with omalizumab, which improved asthma control and patients’ quality of life. We reviewed the current literature on the diagnostic approach to the disease and on the comorbidities associated with difficult asthma and presented the perspectives on omalizumab treatment in children and adolescents. Based on the evidence from the literature review, we also proposed an algorithm for the diagnosis of pediatric difficult-to-treat and severe asthma.

Conclusions

The management of asthma is becoming much more patient-specific, as more and more is learned about the biology behind the development and progression of asthma. The addition of omalizumab, the first targeted biological treatment approved for asthma, has led to renewed optimism in the management of children and adolescents with atopic severe asthma.

Peer Review reports

Children with poor asthma control have an increased risk of severe exacerbations and progressive loss of lung function, which results in the relevant use of health resources and impaired quality of life (QoL) [ 1 ]. Therefore, the primary goal of asthma management at all ages is to achieve disease control [ 2 , 3 , 4 ].

According to recent international guidelines, patients with uncontrolled asthma require a prolonged maintenance treatment with high-dose inhaled corticosteroids (ICS) in association with a long-acting β 2 -agonist (LABA) plus oral leukotriene receptor antagonist (LTRA) (Table  1 ) [ 5 ].

Nevertheless, in the presence of persistent lack of control, reversible factors such as adherence to treatment or inhalation technique should be first checked for, and diseases that can masquerade as asthma should be promptly excluded. Finally, additional strategies, in particular anti-immunoglobulin E (anti-IgE) treatment (omalizumab), are suggested for patients with moderate or severe allergic asthma that remains uncontrolled in Step 4 [ 5 ].

Herein, we reviewed the demographics, clinical presentation and treatment of four patients with uncontrolled severe asthma from our institution in order to explain why we decided to prescribe omalizumab. We also provided a review of the current literature that focuses on recent advances in the diagnosis of pediatric difficult asthma and the associated comorbidities, and summarizes the perspectives on anti-IgE treatment in children and adolescents.

Case presentations

Table  2 summarizes the clinical characteristics and the triggers/comorbidities of the cases at referral to our Institution. Unfortunately, data on psychological factors, sleep apnea, and hyperventilation syndrome were not available in any case. Clinical, lung function and airway inflammation findings at baseline and after 12 months of follow-up are reported in Table  3 . In the description of our cases, we used the terminology recommended by the ERS/ATS guidelines on severe asthma [ 6 ].

A full-term male had severe preschool wheezing and, since age 3, recurrent, severe asthma exacerbations with frequent hospital admissions. At age 11, severe asthma was diagnosed. Sensitization to multiple inhalant allergens (i.e., house dust mites, dog dander, Graminaceae pollen mix, and Parietaria judaica ) and high serum IgE levels (1548 KU/l) were found. Body mass index (BMI) was within normal range. Combined treatment with increasing doses of ICS (fluticasone, up to 1000 μg/day) in association with LABA (salmeterol, 100 μg/day) plus LTRA (montelukast, 5 mg/day) has been administered over 2 years. Nevertheless, persistent symptoms and monthly hospital admissions due to asthma exacerbations despite correct inhaler technique and good adherence were reported. Parents refused to perform any test to exclude gastroesophageal reflux (GER) as comorbidity [ 6 ]. However, an ex-juvantibus 2-month-course with omeprazole was added to asthma treatment [ 7 ], but poor control persisted. Anterior rhinoscopy revealed rhinosinusitis that was treated with nasal steroids for six months [ 8 ], but asthma symptoms were unmodified. Treatment with omalizumab was added at age 12. Reduced hospital admissions for asthma exacerbations, no further need for systemic steroids, and improved QoL score (from 2.0 up to 6.7 out of a maximum of 7 points) were documented over the following months. Unfortunately, after one year of treatment, adherence to omalizumab decreased because of family complaints, and eventually parents withdrew their informed consent and discontinued omalizumab. Currently, by age 17, treatment includes inhaled salmeterol/fluticasone (100 μg/500 μg∙day -1 , respectively) plus oral montelukast (10 mg/day). Satisfactory symptom control is reported, with no asthma exacerbations.

A full-term male, who had a recurrent severe preschool wheezing, at 6 years of age developed exercise-induced asthma. At age 10, severe asthma was diagnosed. High serum IgE levels (1300 KU/l) and skin prick tests positive to house dust mites were found. Despite a 3-year treatment with progressively increasing doses of inhaled fluticasone (up to 1000 μg/day) combined with salmeterol (100 μg/day) and oral montelukast (5 mg/day), monthly hospital admissions with systemic steroids use were reported. At age 13, a 24-h esophageal impedance/pH study demonstrated the presence of acid and non-acid GER [ 7 ]. Esomeprazole was added to asthma medications, but with an incomplete clinical benefit for respiratory symptoms. Esomeprazole was withdrawn after 3 months, and parents refused to re-test for GER. As respiratory symptoms persisted uncontrolled despite treatment, severe asthma was definitively diagnosed [ 6 ]. BMI was within the normal range and anterior rhinoscopy excluded rhinosinusitis. Inhaler technique and adherence were good; thus we considered the anti-IgE treatment option [ 9 ]. Subcutaneous omalizumab was started, with fast improvement of both symptoms and QoL score (from 3.9 up to 6.5). Seventeen months later, the dose of ICS had been gradually tapered and oral montelukast definitely discontinued. Currently, at age 14, treatment includes the combined administration of bimonthly subcutaneous omalizumab and of daily inhaled salmeterol/fluticasone (50 μg/100 μg∙day - 1 , respectively). Asthma control is satisfactory and no side effects are reported. Omalizumab has been continuously administered for 2.6 years and is still ongoing.

A full-term male had severe preschool wheezing and, since age 3, recurrent, severe asthma exacerbations with acute respiratory failure that frequently required intensive care unit (ICU) admission. At age 6, sensitization to multiple perennial inhalant (i.e., house dust mites, dog and cat danders, Alternaria alternata , Graminaceae pollen mix, Artemisia vulgaris , Parietaria judaica , and Olea europaea pollen) and food allergens (i.e., egg, milk, and peanut) was diagnosed. Serum IgE levels were 2219 KU/l. Weight and height were appropriate for age and sex. The patient has been treated over 3 years with a combined scheme of high-dose inhaled fluticasone (up to 1000 μg/day) plus salmeterol (100 μg/day) and oral montelukast (5 mg/day), with correct inhaler technique and good adherence. Despite this, monthly hospital admissions with systemic steroids use were recorded. Rhinosinusitis and GER were excluded on the basis of appropriate testing; thus treatment with omalizumab was started when the patient was 9 years old. At age 11, adherence to treatment is satisfactory, with no side effects. More importantly, reduced hospital admissions for asthma exacerbations, no further need for systemic steroids, and improved QoL score (from 6.4 to 6.8) were reported. Finally, progressive step-down of anti-asthma treatment was started, and at present (by 11.5 years) inhaled fluticasone (200 μg/day) plus bimonthly subcutaneous omalizumab provide good control of symptoms. Omalizumab has been continuously administered for 2.6 years and is still ongoing.

A full-term male had severe preschool wheezing and, since age 4, recurrent, severe asthma exacerbations with frequent hospital admissions. At age 8, multiple perennial inhalants and food sensitization (i.e., house dust mites, dog dander, Graminaceae pollen mix, Olea europaea pollen, tomatoes, beans, shrimps, and peas) and high serum IgE levels (1166 KU/l) were found. The patient has been treated over 5 years with inhaled fluticasone (up to 1000 μg/day) in association with salmeterol (100 μg/day) and oral montelukast (5 mg/day). Despite this, monthly hospital admissions with systemic steroids need were recorded. After checking the inhaler technique and adherence to treatment, comorbidities including obesity, rhinosinusitis and GER were excluded. Omalizumab was proposed, but parents refused it. By 13.6 years, despite a treatment including the association of inhaled salmeterol/fluticasone (100 μg/1000 μg∙day − 1 , respectively) plus oral montelukast (10 mg/day), monthly exacerbations requiring systemic steroids are reported.

Discussion and conclusions

Most children and adolescents with asthma respond well to inhaled short-acting beta 2 -agonists (SABA) on demand if symptoms are intermittent, or to low dose controller drugs plus as-needed SABA if the risk of exacerbations increases [ 1 ]. Nevertheless, a proportion of patients is referred to specialists because this strategy is not working and asthma is persistently uncontrolled [ 4 ]. For these children, assessment is primarily aimed at investigating the reasons for poor control. Indeed, when the child is initially referred, before the label of “severe, therapy-resistant asthma” (i.e., not responding to treatment even when factors as exposure to allergens and tobacco smoke have been considered) is assigned, three main categories need to be identified: 1) “not asthma at all”, in which response to treatment is suboptimal because the diagnosis is wrong; 2) “asthma plus ”, when asthma is mild but exacerbated by one or more comorbidities; and 3) “difficult-to-treat asthma”, when asthma is uncontrolled because of potentially reversible factors [ 10 ].

The reported cases highlight some aspects of the disease process that may expand the diagnosis and improve patients’ care. At our institution, the severe asthma program includes a multidisciplinary approach with consultations by gastroenterologists as well as ear, nose and throat experts. Recently, sleep medicine experts joined this multidisciplinary team; thus, unfortunately, sleep-disordered breathing (SDB) could not be excluded at the time of our patients’ assessment. Inhalation technique is periodically evaluated by nurses or doctors in each patient. Unfortunately, in Italy an individual prescription database is not available and thus we cannot assess patients’ use of medication. In two cases, the filtering process eventually identified GER and rhinosinusitis, but poor control of asthma persisted even after comorbidities were treated. In all subjects, inhaler skills, treatment adherence, and environmental exposure to indoor/outdoor allergens as well as to second- and third-hand smoke were excluded as cause of lack of control. Eventually, three out of four patients started anti-IgE treatment; asthma control was obtained and maintenance drugs were progressively reduced. In the case that refused omalizumab therapy, pulmonary function, clinical features and controller treatment including high-dose ICS were unchanged.

Previous studies have highlighted an association between increasing asthma severity in children and reduced QoL [ 11 , 12 , 13 ]. Uncontrolled asthma symptoms not only affect children physically, but can impair them socially, emotionally, and educationally [ 13 ]. In line with previous observations, 3 out 4 of our cases had poor QoL, assessed by a standardized questionnaire [ 14 ]. It is well known that improving QoL in difficult asthma is not an easy task, despite a variety of treatments aimed at achieving control [ 12 ], and much more remains to be done to address the problem. Nevertheless, 2 of our 3 cases showed a remarkable improvement of QoL after one year of treatment with omalizumab.

Reduction in forced expiratory volume in the first second (FEV 1 ) is often used to define childhood asthma severity in treatment guidelines and clinical studies [ 5 , 11 , 15 ]. Nevertheless, children with severe asthma often have a normal FEV 1 that does not improve after bronchodilators, indicating that spirometry may be a poor predictor of asthma severity in childhood [ 6 , 16 , 17 ]. Actually, children with a normal FEV 1 , both before and after β 2 -agonist, may show a bronchodilator response in terms of forced expiratory flow between 25% and 75% (FEF 25–75 ) [ 18 ]. However, the utility of FEF 25–75 in the assessment or treatment of severe asthma is currently unknown. Interestingly, all the reported cases showed normal or slightly reduced values of FEV 1 but severe impairment of FEF 25–75 . Two cases showed a bronchodilator response in terms of FEV 1 (subjects 3 and 4), while 3 patients had a significant increase of FEF 25–75 (cases 1, 3 and 4). Unfortunately, we could not provide the results of bronchodilator response during or after the treatment with omalizumab in any case.

Available literature on the diagnostic approach to difficult asthma in children offers a number of reviews which basically summarize the steps needed to fill the gap between a generic diagnosis of “difficult asthma” and more specific labels (i.e., “severe” asthma, “difficult-to-treat” asthma, or even different diagnoses) [ 3 , 5 , 6 , 8 , 10 , 19 , 20 , 21 ]. So far, few original articles and case reports have been published, probably due to the peculiarity of the issue, which makes retrospective discussion of cases easier than the design of a prospective clinical study [ 4 , 22 , 23 , 24 , 25 , 26 ]. Available knowledge mainly derives from the experience of specialized centers.

The evaluation of a child referred for uncontrolled asthma should start with a careful history focused on typical respiratory symptoms and on the definition of possible triggers. In the “severe asthma” process, it is crucial for clinicians to maintain a high degree of skepticism about the ultimate diagnosis, particularly in the presence of relevant discrepancies between history, physical features and lung function, as many conditions may be misdiagnosed as asthma. In order to simplify this process, herein we propose an algorithm for the diagnosis of difficult-to-treat and severe asthma (Fig.  1 ). Confirmation of the diagnosis through a detailed clinical and laboratory re-evaluation is important because in 12–50% of cases assumed to have severe asthma this might not be the correct diagnosis [ 10 ]. Several documents have indicated the main steps of the process that should be followed in children with uncontrolled asthma [ 3 , 8 , 10 ]. The translation of these procedures into real life practice may deeply change from one subject to another due to the variability of individual patients’ history and clinical features, which will often lead the diagnostic investigations towards the most likely reason for uncontrolled asthma. For children with apparently severe asthma, the first step is to confirm the diagnosis and, before proceeding to broader investigations, to verify that the poor control is not simply determined by poor adherence to treatment, inadequate inhaler skills and/or environmental exposure to triggers. A nurse-led assessment, including a home visit, despite not being applicable in all settings, may be useful for identifying potentially modifiable factors in uncontrolled pediatric asthma [ 27 ].

A practical algorithm for the diagnosis of difficult-to-treat and severe asthma. ICS, inhaled corticosteroids; OCS, oral corticosteroids

A number of comorbidities have been increasingly recognized as factors that may impact asthma clinical expression and control in childhood [ 10 , 28 ]. Children with uncontrolled disease should be investigated for GER, rhinosinusitis, dysfunctional breathing and/or vocal cord dysfunction, obstructive sleep apnea, obesity, psychological factors, smoke exposure, hormonal influences, and ongoing drugs [ 3 , 6 , 8 , 20 ]. Indeed, the exact role played by comorbidities in pediatric asthma control is still debated [ 28 ]. The most impressive example is GER. Several pediatric documents recommend assessing for GER because reflux may be a contributing factor to problematic or difficult asthma [ 7 , 29 ]. Nevertheless, GER treatment might not be effective for severe asthma [ 30 , 31 ], as confirmed by current cases 1 and 2. There is an established evidence that chronic rhinosinusitis is associated with more severe asthma in children [ 32 , 33 , 34 ]. Therefore, examination of upper airways and ad hoc treatment if rhinosinusitis is evident are recommended in children with severe asthma [ 3 , 8 , 35 ]. However, intranasal steroids for rhinitis resulted in a small reduction of asthma risk in school-aged children [ 36 ], and actual placebo-controlled studies on the effect of treatment of rhinosinusitis on asthma control in children are lacking [ 10 , 37 ].

Dysfunctional breathing, including hyperventilation and vocal cord dysfunction, is associated with poorer asthma control in children [ 8 , 10 , 38 , 39 ]. Unfortunately, there is scarce literature on the effect of its treatment on the control of severe asthma in children [ 40 ]. SDB ranging from primary snoring to obstructive sleep apnea syndrome is very common in children [ 41 ], and an increased prevalence of SDB together with increasing asthma severity has been reported [ 42 ]. Interestingly, GER may also be worsened by recurrent episodes of upper airway obstruction associated with SDB, and this may further trigger bronchial obstruction. Asthma guidelines recommend the assessment of SDB through nocturnal polysomnography in poorly controlled asthmatics, particularly if they are also obese [ 5 ]. There are no studies examining whether pediatric asthma improves after SDB has been treated, for example, with nasal steroids, adenotonsillectomy, continuous positive airway pressure or weight reduction if the child is also obese [ 43 ]. The parallel increase in obesity and asthma suggests that the two conditions are linked and that they can aggravate each other [ 44 , 45 ], even though the exact mechanisms that underlie this association remain unclear [ 46 ]. Indeed, other coexisting comorbidities such as SDB or GER may play a confounding role in the development of the interactions between obesity and the airways [ 47 , 48 ]. Obesity is associated with increased markers of inflammation in serum and adipose tissue and yet decreased airway inflammation in obese people with asthma [ 49 ]. Several interventions, including behavioral and weight reduction programs or bariatric surgery, may result in improved asthma control, quality of life and lung function in adult obese asthmatics [ 50 ]. Although reports of adolescent bariatric surgery demonstrate a significant body weight decrease, this approach is not widely available and there are no published reports on its effect on pediatric severe asthma control [ 51 ]. Finally, although it is still unclear whether food allergy is causative or shares a common pathway with difficult asthma, it might explain the loss of asthma control at least in some children and thus be considered as a comorbid condition [ 10 , 16 , 52 ].

In conclusion, establishing the impact of comorbidities on asthma control may be cumbersome, and an ex-juvantibus treatment is sometimes necessary to assess their role. Comorbid conditions can also worsen each other, and symptoms arising from some of them may mimic asthma [ 6 ]. Although the ability to improve pediatric severe asthma by treating comorbidities remains unconfirmed, they should be treated appropriately [ 9 ].

The vast majority of asthmatic children exhibit a mild or at most a moderate disease that can be fully controlled with low-to-medium dose ICS associated or not with other controllers [ 5 , 6 ]. However, a subset of asthmatics remains difficult-to-treat [ 5 , 6 ]. With the advent of biologics, these severe steroid-dependent asthmatics have alternative options for treatment, as steroid-related adverse events are common in severe asthma [ 53 ]. Omalizumab, an anti-IgE monoclonal antibody, is the only biologic therapy recommended in children with moderate-to-severe asthma by the recent guidelines [ 5 , 6 ]. In Italy, this treatment is fully covered by the National Health System. Therefore, there is no influence by any funding on treatment decisions. It was approved by the US (Food and Drug Administration) in 2003 and by the European Union (European Medicines Agency) in 2005 as an add-on treatment for patients aged > 12 years with severe persistent allergic asthma and who have a positive skin test or in-vitro reactivity to a perennial aeroallergen, FEV 1  < 80% predicted, frequent daytime symptoms or nighttime awakenings, and multiple documented severe asthma exacerbations despite daily ICS plus a LABA [ 54 , 55 ]. In 2009, it also received approval in Europe for treating patients aged 6–12 years. Figure  2 illustrates current indications for treatment with omalizumab in children and adolescents with severe asthma.

Indications for omalizumab in children and adolescents with severe asthma

IgE antibodies, Th 2 -derived cytokines and eosinophils play a major role in the development of chronic airway inflammation in asthmatic subjects [ 56 ]. Once released from plasma cells, IgE binds principally to the high-affinity IgE receptor (FcεRI) on mast cells, triggering different effector responses, including the release of mediators leading to allergic inflammatory reactions [ 56 ]. The activation of the allergic cascade by IgE, under constant allergen stimulation, leads to the establishment of chronic allergic inflammation in the airways of asthmatic patients, with IgE being a key element of the vicious circle that maintains it. Cytokines produced during the late phase and subsequent chronic inflammation stage have been directly associated with the induction of airway remodelling, indirectly implicating IgE in the process [ 56 ]. At present, omalizumab is the only commercially available recombinant humanized anti-IgE monoclonal antibody that specifically binds serum free IgE at its CH 3 domain, in the proximity of the binding site for FcεRI, thus preventing IgE from interacting with its receptor on mast cells, basophils, antigen-presenting cells and other inflammatory cells [ 57 ]. The rapid reduction of free IgE levels leads to a downregulation of the FcεRI expression on inflammatory cells and an interruption of the allergic cascade, which results in the reduction of peripheral and bronchial tissue eosinophilia and of levels of granulocyte macrophage colony stimulating factor, interleukin (IL)-2, IL-4, IL-5, and IL-13 [ 58 ]. Moreover, basophils have a relevant role in the initiation and progression of allergic inflammation, suggesting that they may represent a viable therapeutic target. Indeed, in children with severe asthma, it has been reported that omalizumab therapy is associated with a significant reduction in circulating basophil numbers, a finding that is concurrent with improved clinical outcomes [ 59 ]. This finding supports a mechanistic link between IgE levels and circulating basophil populations, and may provide new insights into one mechanism by which omalizumab improves asthma symptoms.

Several clinical controlled and real-life studies of adults with severe, inadequately controlled allergic asthma have demonstrated the efficacy and safety of omalizumab in reducing asthma-related symptoms, corticosteroid use, exacerbation rates, and healthcare resource utilization, and in improving QoL and lung function [ 60 , 61 , 62 , 63 ]. Fewer studies have been published in children. In two double-blind, randomized, placebo-controlled trials (RCTs) of children aged 6 to 12 years with moderate-to-severe allergic asthma, treatment with omalizumab reduced the requirement for ICS and protected against disease exacerbations, but there was little change in asthma symptom scores or spirometry [ 9 , 64 ]. These findings were confirmed and extended in older children [ 65 , 66 , 67 ].

The results of the ICATA study, a multicenter RCT of 419 inner-city children, adolescents and young adults with persistent allergic asthma, showed that, compared to placebo, omalizumab reduces the number of days with asthma symptoms and the proportion of participants with at least one exacerbation by approximately 25% and 19%, respectively ( p  < 0.001), thus reducing the need for asthmatic symptom controllers [ 68 ]. Another multicenter RCT of inner-city children and adolescents showed that the addition of omalizumab to ongoing guidelines-based care before patients return to school reduces fall asthma exacerbations (odds ratio, 0.48), particularly in subjects with a recent exacerbation [ 69 ]. Moreover, in a real-life study of 104 children and adolescents with severe allergic refractory asthma followed over 1 year, treatment with omalizumab resulted in good asthma control in 67% of the cases ( p  < 0.001), while FEV 1 improved by 4.9% ( p  = 0.02) and exacerbation rates and healthcare utilisation decreased approximately by 30% ( p  < 0.001) [ 70 ]. The same authors also showed that, after two years of treatment, exacerbation rate and healthcare utilisation were further decreased by 83% and 100%, respectively, while level of asthma control, steroid use and lung function remained unchanged [ 71 ].

A systematic review of pediatric RCTs pooled the data of 1381 children and adolescents with moderate-to-severe allergic asthma in order to establish the efficacy of omalizumab as an add-on therapy [ 72 ]. During the stable-steroid phase, omalizumab decreased the number of patients with at least one exacerbation (risk ratio, 0.69; p  < 0.001), the mean number of asthma exacerbations per patient (risk ratio, 0.35; p  < 0.001), and the asthma symptom score (mean difference, 0.12; p  = 0.005) when compared to placebo. During the steroid reduction phase, omalizumab further reduced the number of patients with at least one exacerbation (risk ratio, 0.48; p  < 0.001) and the mean number of asthma exacerbations per patient (mean difference, 0.12; p  < 0.05).

Given the cost of omalizumab, many authors have argued for the importance of identifying specific asthma populations who will have significant benefit from it [ 68 , 73 , 74 ]. In the ICATA study, baseline predictors of good response to treatment were sensitization and exposure to cockroach allergen, sensitization to house dust mite allergens, a serum IgE level of more than 100 IU per milliliter, a BMI of 25 or more, and a history of at least one unscheduled medical visit in the previous year [ 68 ].

Several studies have assessed the long-term safety of omalizumab in children and adults. A pooled analysis of 67 RCTs conducted over 2 decades on 4254 children and adults treated with omalizumab showed no association between omalizumab treatment and risk of malignancy [ 75 ]. In an RCT evaluating 225 school-aged children, omalizumab was well tolerated, there were no serious adverse events, and the frequency and types of all adverse events were similar to the placebo group [ 9 ]. These results have been further confirmed by a recent systematic review of RCTs that concluded that treatment with omalizumab does not result in increased risk of malignancy or hypersensitivity reactions [ 72 ].

While the rationale for long-term treatment with omalizumab is supported by pharmacokinetic-pharmacodynamic models [ 76 ], the duration of treatment is still under discussion. Results from published studies suggest that omalizumab should be continued for > 1 year [ 77 , 78 ]. In a retrospective study of adults and children with uncontrolled severe asthma treated with omalizumab, the response to treatment was ‘excellent’ in 52.5% of patients, particularly in the subgroup of children aged 6 to 11 years [ 77 ]. After the discontinuation of treatment, loss of asthma control was documented in 69.2% of the patients who had received omalizumab for < 1 year, 59.1% of the subjects treated for 1–2 years, and 46.1% of the cases treated for > 2 years. Time to loss of control was shorter in younger children and longer in patients with an ‘excellent’ response compared with patients with a ‘good’ response. No early loss of control (within 6 months) was observed among patients with > 3.5 years of continuous treatment with omalizumab. Finally, 20% of patients in whom omalizumab was re-prescribed because of loss of control did not respond to the treatment anymore [ 77 ]. Despite these encouraging findings, the impact of omalizumab on the natural history of severe asthma in children deserves to be further investigated by long-term studies that will also define the criteria and timing for discontinuing the treatment.

It is well known that asthma pharmacotherapy is effective in controlling symptoms and bronchial inflammation, but cannot affect the underlying immune response, thus leading to the possibility of symptom reappearance after its discontinuation [ 79 ]. In this scenario, allergen-specific immunotherapy (AIT) has been proposed as the only therapeutic method that can modulate the underlying immune pathophysiology in allergic asthma [ 80 ].

AIT is currently indicated in children and adults with mild-moderate allergic asthma that is completely or partially controlled by pharmacotherapy and with the evidence of a clear relationship between symptoms and exposure to a specific allergen [ 81 , 82 , 83 , 84 ]. However, according to recent guidelines, the efficacy of AIT in asthmatic subjects is limited, and its potential benefits must be weighed against the risk of side effects and the inconvenience and costs of the prolonged therapy [ 5 ]. Moreover, severe or uncontrolled asthma (regardless of its severity) is a major independent risk factor for non-fatal or even fatal adverse reactions, thus representing a contraindication for AIT [ 85 , 86 , 87 ]. Finally, children with severe asthma are often sensitized to multiple allergens, thus making AIT prescription even more complicated [ 88 ].

In subjects with uncontrolled and/or severe allergic asthma, a combination of omalizumab and AIT has been proposed [ 88 ]. Surprisingly, only a few studies have addressed this issue [ 89 , 90 , 91 , 92 ]. However, pre-treatment with omalizumab seems to improve the efficacy and tolerability of subcutaneous AIT in children and adults with severe allergic asthma both during omalizumab treatment and after its discontinuation [ 89 , 91 , 92 ]. Omalizumab has also been successfully used as a supplementary treatment to AIT in order to improve asthma control in children ≥6 years with severe persistent allergic asthma [ 90 ]. Given the scarcity of studies on AIT plus omalizumab in children with severe allergic asthma, further research is warranted to assess risks and benefits of the combined treatment.

Children with severe asthma require a detailed and individualized approach including re-assessment for differential diagnoses, comorbidities and contributory factors, environmental triggers, lung function and inflammation, adherence and response to therapy, and QoL. Treatment of pediatric severe asthma still relies on the maximal optimal use of corticosteroids, bronchodilators and other controllers recommended for moderate-to-severe disease. However, the management of asthma is becoming much more patient-specific, as more and more is learned about the biology behind the development and progression of asthma.

In the current paper, we described the characteristics of four children with severe asthma in whom omalizumab was prescribed. A review of the relevant literature on the topic was also performed. Finally, we provided an algorithm for the diagnosis of difficult-to-treat and severe asthma in children and adolescents, based on the evidence from the literature review. As all algorithms, it is not meant to replace clinical judgment, but it should drive physicians to adopt a systematic approach towards difficult and severe asthma and provide a useful guide to the clinician.

The addition of omalizumab, the first targeted biological treatment approved for asthma, has led to renewed optimism of outcome improvements in patients with allergic severe asthma. As severe asthma is a heterogeneous condition consisting of different phenotypes, the future of asthma management will likely involve phenotypic and potentially even genotypic characterization in selected cases in order to determine appropriate therapy and thus to provide the highest possible benefit, especially if specific responder phenotypes can be identified and selected for this highly specific treatment.

Abbreviations

Anti-immunoglobulin E

Body mass index

IgE receptor

Forced expiratory flow between 25% and 75%

Forced expiratory volume in the first second

Gastroesophageal reflux

Inhaled corticosteroids

Intensive care unit

Interleukin

Long-acting β 2 -agonist

Oral leukotriene receptor antagonist

Quality of life

Randomized controlled trials

Short-acting β 2 -agonists

Sleep-disordered breathing

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Chung KF. Targeting the interleukin pathway in the treatment of asthma. Lancet. 2015;386:1086–96.

Jensen RK, Plum M, Tjerrild L, Jakob T, Spillner E, Andersen GR. Structure of the omalizumab Fab. Acta Crystallogr F Struct Biol Commun. 2015;71:419–26.

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Molimard M, Mala L, Bourdeix I, Le Gros V. Observational study in severe asthmatic patients after discontinuation of omalizumab for good asthma control. Respir Med. 2014;108:571–6.

Busse WW, Trzaskoma B, Omachi TA, Canvin J, Rosen K, Chipps BE, et al. Evaluating Xolair persistency of response after long-term therapy (XPORT). Am J Respir Crit Care Med. 2014;189:A6576.

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Acknowledgements

The authors gratefully thank Dr. Marco Maglione for his contribution in the clinical assessment of the described cases. Medical writing assistance was provided by Stephen Walters on behalf of City Hills Proofreading.

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VM, SM and FS, authors of the current manuscript, declare that they have participated sufficiently in the work to take public responsibility for appropriate portions of the content. VM and SM carried out the initial investigations, drafted the initial manuscript, revised the manuscript, and approved the final manuscript as submitted. FS conceptualized and designed the study, and critically reviewed and approved the final manuscript as submitted. All authors read and approved the final manuscript.

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Correspondence to Francesca Santamaria .

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Mirra, V., Montella, S. & Santamaria, F. Pediatric severe asthma: a case series report and perspectives on anti-IgE treatment. BMC Pediatr 18 , 73 (2018). https://doi.org/10.1186/s12887-018-1019-9

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Submitted by

Cathy Benninger, RN, MS, CNP

The Ohio State University

Columbus, OH

John Mastronarde, MD

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A 29-year-old man with mild persistent asthma presented to an outpatient office for a follow-up visit.  He was originally referred 6 months ago by his primary care provider after having an asthma exacerbation which required treatment in an emergency room.

At his initial visit, he reported wheeze and cough 4 days a week and nocturnal symptoms three times a month.   Spirometry revealed forced vital capacity (FVC) 85% predicted, forced expiratory volume in 1 second (FEV 1 ) 75% predicted, FEV 1 /FVC 65%, and an increase in FEV 1 of 220 ml or 14% following an inhaled short-acting bronchodilator.   He was placed on a low-dose inhaled corticosteroid twice a day and a short-acting inhaled beta-agonist as needed.  He returned 4 weeks later improved, but with continued daytime symptoms 2 days a week.  He also had symptoms of rhinitis; therefore he was referred to an allergist for evaluation. Skin testing was positive for trees, ragweed, dust mites, and cats, and he was prescribed a nasal steroid spray and nonsedating oral antihistamine.   He presents today and reports no asthma exacerbations since his last visit.  Furthermore, during the past 4 weeks, he has not been awakened by his asthma, experienced morning breathing symptoms, missed work, had any limitations in activities due to asthma, or required the use of rescue albuterol.  He currently denies shortness of breath or wheezing.  He performs aerobic exercise 4 days a week for 45 minutes per session without symptoms, provided he premedicates with a short-acting inhaled beta-agonist.  His review of symptoms is otherwise unremarkable.  His current medications include low-dose inhaled corticosteroid, 1 puff twice a day ; steroid nasal spray, 2 puffs each nostril daily; a nonsedating antihistamine, 1 tablet daily; and inhaled beta-agonist, 2 puffs as needed.    His past medical history is significant for intermittent asthma diagnosed at age 13 and frequent “colds.”  He has never required hospitalization for an asthma exacerbation .  He works as a hospital microbiologist and does not smoke, drink alcohol, or use illicit drugs.  He recently moved to a pet-free apartment complex and instituted dust mite protective barriers for his bedding .  His family history is noncontributory.

Physical Exam

The goal of asthma therapy is to minimize risk and maintain asthma control with the least amount of medication (1).   In patients with mild persistent asthma, recent studies have demonstrated several options for "step-down therapy."  The American Lung Association Asthma Clinical Research Centers network study found that patients who stepped down from twice daily low-dose fluticasone to once daily combination therapy with fluticasone/salmeterol had equivalent asthma control scores, FEV 1 , and frequency of exacerbations compared with continued therapy with twice daily fluticasone (2).  Once-daily montelukast demonstrated a slightly higher treatment failure compared with either of the regimens containing inhaled steroids.   Despite the slight increase in treatment failure with montelukast, each of the treatment groups had equivalent symptom-free days and rates of clinically significant asthma exacerbations.   Thus, while either regimen would be appropriate, stepping down to once-daily combination therapy with fluticasone/salmeterol appears to be more beneficial.

Recent studies also suggest that those with mild persistent asthma taking inhaled corticosteroids in combination with either a long-acting beta-agonist or a short-acting beta-agonist when symptomatic, had no increase in adverse outcomes compared with those taking scheduled daily inhaled doses.   Boushey et al. (3) compared patients with mild persistent asthma using twice-daily budesonide versus twice-daily zafirlukast verses placebo. All three groups used budesonide as-needed following a symptom-based action plan. The study found that in comparison with patients on a daily controller (budesonide or zafikulast), participants using only as-needed budesonide had no significant difference in morning peak expiratory flow, postbronchodilator FEV 1 , quality of life, or frequency of asthma exacerbations. Results of this study raise the possibility of treating mild persistent asthmatics with as-needed inhaled corticosteroids.   More recently, Papi et al. (4) found as-needed use of an inhaler containing both beclomethasone and albuterol for symptom relief was associated with fewer exacerbations and higher morning peak flow readings than using an inhaler with albuterol alone.   The morning peak flow readings in the as-needed combination beclomethasone/albuterol group was equivalent to those taking scheduled daily doses of beclomethasone alone, or scheduled daily doses of beclomethasone/albuterol combined.   The combination of an inhaled steroid and a short-acting beta-agonist in a single inhaler is not currently available in the United States.

In the mild persistent asthmatic there is now strong evidence to support multiple treatment approaches which provide good asthma control.   Matching the drug regimen with the patient’s preferences, lifestyle, comorbidities, and financial limitations will help ensure drug adherence and maintain asthma control.

When spirometry is used to diagnose or confirm asthma, testing must include pre- and post-bronchodilator readings (1).   A change in FEV 1 of >200 ml and ≥ 12% from the baseline measure following the administration of a short-acting bronchodilator is indicative of significant airway reversibility which has been shown to correlate with airway inflammation (7).  

The Expert Panel (1) classifies asthma severity by FEV 1 , FEV 1 /FVC, short-acting beta-agonist use, or frequency of asthma symptoms.    Parameters are measured at baseline with asthma severity determined by the worse parameter, e.g., daily symptoms with normal FEV 1 is classified as moderate persistent asthma.   Correct identification of asthma severity guides the provider in choosing the appropriate type and amount of therapy.  

Asthma symptoms should be assessed at each office visit to determine asthma control.   Validated self-assessment tools such as the Asthma Control Test (ACT), Asthma Therapy Assessment Questionnaire (ATAQ), or Asthma Control Questionnaire (ACQ) can facilitate consistent measurement and documentation of asthma symptoms during office visits (1, 8).   All asthmatics are at risk for a severe asthma attack regardless of their asthma classification; therefore, providers are encouraged to teach patients to recognize symptoms of inadequate asthma control and provide them with specific instructions for adjusting their medications or seeking medical care (1).  

When studied, only approximately 25% of patients are able to properly demonstrate use of a meter dose inhaler when asked.   The remaining 75% improved with specific instruction and practice which reinforces the need to incorporate proper inhaler use during the office visit (9,10).   The use of a spacer significantly improves accuracy and dose delivery, particularly in patients with poor coordination skills (9,10).

Assessing patient adherence is best approached with a nonjudgmental attitude.   Adherence to inhaled corticosteroids is estimated at < 50% (11).   Causes of nonadherence are multifactorial but may be improved by providing asthma education, encouraging self management through use of an asthma action plan, and facilitating open communication (11).   Financial barriers often transcend all other efforts to improve adherence and must be taken into account when prescribing asthma therapy (11).

Methacholine challenge testing is useful to demonstrate airway hyperresponsiveness in those with normal spirometry and a suspicion of asthma, but is not recommended as a serial procedure.   Biomarkers for inflammation such as eosinophils or nitric oxide are being investigated in clinical trials but currently have no indication in routine asthma care (1).   Peak flow monitoring is useful for long-term home assessment of asthma control and medication response, but is not indicated for regular office assessment or diagnostic purposes (1).

• Expert Panel Report 3 (EPR 3). Guidelines for the Diagnosis and Management of Asthma. Bethesda, Md: National Institutes of Health; 2007. NIH Publication No. 08-4051.
• The American Lung Association Asthma Clinical Research Centers. Randomized comparison of strategies for reducing treatment in mild persistent asthma. N Engl J Med 2007;356:2027-2039.
• Boushey HA, Sorkness CA, King TS, et al. Daily versus as-needed corticosteroids for mild persistent asthma. N Engl J Med 2005;352:1519-1528.
• Papi A, Giorgio GW, Maestrelli P, et al. Rescue use of beclomethasone and albuterol in a single inhaler for mild asthma. N Engl J Med 2007;356:2040-2052.
• Gibson PG, Powell H. Written action plans for asthma: an evidence-based review of the key components. Thorax 2007;59:94-99.
• Miller MR, Hankinson J, Brusasco V, et al. Series ATS/ERS Task Force: Standardization of lung function testing. Eur Respir J 2005;26:319-338.
• Pellegrino R, Viegi G, Brusasco V, et al. Interpretative strategies for lung function tests. N Engl J Med 2005;26:948-968.
• Global Initiative for Asthma. Pocket guide for asthma management and prevention. Bethesda, Md: National Institutes of Health; 2006.
• Giraud V, Roche N. Misuse of corticosteroid metered-dose inhaler is associated with decreased asthma stability. Eur Respir J 2002;19(2):246-251.
• Johnson DH, Robart P. Inhaler technique of outpatients in the home. Respir Care 2000;45(10):1182-1187.
• Elliott RA. Poor adherence to anti-inflammatory medication in asthma reasons, challenges, and strategies for improved disease management. Dis Manage Health Outcomes 2006;14(4):223-233.

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Asthma Case Study

Asthma affects about 6.1 million children in the US under 18 years of age, making it one of the most common chronic childhood disorders (American Lung Association, 2021). Asthma occurs as a result of a stimulus which can range from allergens, cigarette smoke, changes in temperature, stress, or exercise. In this case we’ll experience an asthma attack and subsequent treatment with 16-year-old Ben Mason.

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Ben was struggling to breathe when he reached the ER...

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Ben was also given an additional breathing treatment...

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Case Summary

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Patient Presentation

A 12 year old girl, Annie, enters the Pediatrician’s office with complaints of dyspnea, wheezing, and chest tightness.

The history of the illness from the family includes:

A recent upper respiratory infection with cough, congestion and runny nose with a low grade fever of 100.8 degrees Fahrenheit.

Mother also states this has happened the last few times Annie had cold symptoms and does seem to get relief from Albuterol that was prescribed previously. Annie is behind on her well checks and usually only comes in for sick visits.

Family/Social History

Family history revealed that mother has asthma and because of this uses a lot of hand sanitizer for herself and family to keep them from “catching colds”.

In the home lives Annie, her mother, father and little brother age 6. Annie’s father is a smoker but mother states he smokes outside.

The family is living in a home currently under renovations.

Upon assessment Annie has the following:

(Parakh, 2019)

• intermittent coughing
• expiratory wheezing
• subcostal retractions
• temperature of 100.8 PO
• heart rate of 100 bpm
• respiratory rate of 40
• pulse oximetry 92 %
• purulent mucous from  bilateral nares
• catching her breath often while speaking

Case of Acute Severe Asthma

Kane guthrie.

• Dec 2, 2022

A 25-year-old lady Miss. Poor Compliance is rushed into your Emergency Department as a Priority 1. She is a brittle asthmatic and has been given 3x 5mg salbutamol nebs, and 0.5mg of adrenaline IM prehospital. On arrival Miss PC is sitting forward in the tripod position , using her accessory muscles to breath. She is tachypnoeic, agitated and unable to talk.

Vital signs: Pulse 143, BP 138/95, RR 42, Sp02 91% on neb, GCS 14/15.

Past Medical and Medication History

• Smoker. Severe asthmatic. Intubated twice in past 2 years
• Currently taking seritide 250/50mg, salbutamol MDI PRN and prednisolone 50mg PRN

Asthma Epidemiology

• Over 2.2 million Australians have currently diagnosed asthma
• 406 deaths attributed to asthma in 2006
• Highest risk of dying from asthma is in the elderly over 70
• The emergency clinician’s goal in treating acute severe asthma is preventing intubation
• Severe/Critical asthma is a life threatening condition

Asthma Pathophysiology

• Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role, in particular, mast cells, eosinophils, T lymphocytes, macrophages, neutrophils, and epithelial cells.
• Smooth muscle hypertrophy and hyperplasia
• Inflammatory cell infiltration and oedema
• Goblet cell and mucous gland hyperplasia with mucous hypersecretion
• Protein deposition including collagen
• Epithelial desquamation
• Most common, responsible for 80-85% of all fatal events is characterised by eosinophilic inflammation associated with gradual deterioration over days-weeks occurring in patients with severe or poorly controlled asthma, and is slow to respond to therapy.
• The second phenotype, with neutrophilic inflammation, has both rapid onset and response to therapy.

Markers of severe asthma:

• Inability to speak in full sentences
• Use of accessory muscles or tracheal tugging
• Cyanosis and sweating
• Pulsus paradoxus (>15mmHg decreased with inspiration). With severe muscle fatigue might be absent
• Quiet chest on auscultation (The “Silent Chest”)
• Confusion or decreased level of consciousness
• Hypotension or bradycardia
• FEV 1<40% predicted
• PEF <40% of predicted or best (<25% in life threatening asthma)
• Oxygen saturation <90-92%
• PaO2 <60mmHg
• PaCO2 >45mmHg

Complications of Asthma :

• Pneumothorax, Pneumomediastinum, Pneumopericardium and Pneumoretroperitoneum
• Cardiac Arrhythmias, Myocardial ischaemia or infarction
• Electrolyte disturbances (hypokalaemia, hypomagnesaemia, hypophosphataemia)
• Lactic Acidosis
• Hyperglycaemia

Conditions that may mimic acute asthma:

• Upper airway obstruction
• Foreign-body aspiration
• Vocal cord dysfunction syndrome
• Pulmonary oedema
• Acute exacerbations of COPD
• Hysterical conversion reaction
• Munchausen syndrome

Diagnostic Test:

• Hyperinflation 5-10%
• Infiltrate 5%
• Pneumothorax <1%
• Pneumomediastinum <1%
• Respiratory alkalosis typical
• Inaccurate predictor of outcome
• Will seldom alter your treatment plan
• An objective measure of lung function
• Useful to assess response to treatment
• Impossible to obtain in the dying patient
• <25% Severe
• 25-50% Moderate
• 50-70% Mild
• >70% Discharge Goal
• Simple, and less painful than ABG
• Provides continuous oxygenation measurements
• Needs to placed on well-perfused site, difficult to obtain readings if global hypoperfusion or peripheral vasoconstriction present.
• Aim to keep sp02 >92%

Management of Acute Severe Asthma

• Hypoxia is the main cause of death in asthma
• Oxygen should be given to keep Sp02 above 92%
• A slight Pco2 rise may occur with oxygen therapy but this is of no clinical significance.

Beta-agonists:

• Rapid acting inhaled beta-agonists (bronchodilators) are the first line therapy for acute asthma.
• Nebulisers should generally be used in acute severe asthma, as provide easier delivery of medication to patient, multi dose inhalers have a role in mild to moderate asthma.
• IV salbutamol gives you the advantage of hitting the beta 2 receptors from the back door, while continuing nebulizer treatment, and should be trialed in patients not responding to nebulisers.
• Continuous nebuliser therapy appears to be more effective than intermittent nebulisers for delivering beta-agonist drugs to relieve airway spasm in acute severe asthma.  (Cochrane Review, 2009)
• Salbutamol toxicity can caused a lactic acidosis which is often unrecognized in asthma patients, the lactic acidosis has been hypothesized to adversely affect ventilation by increasing ventilatory demand, increasing dead space ventilation, worsening dynamic hyperinflation and intrinsic PEEP. Management is to discontinue salbutamol at the earliest opportunity.
• Dose:  Salbutamol Nebuliser Ampoule 5mg
• Dose: Salbutamol IV 5mg in 500mL of 0.9% sodium chloride or 5% dextrose start at 30mL/hr titrating up to 120mL/hr

Anticholinergics:

• Anticholinergics agents block muscarinic receptors in airway smooth muscles, inhibit vagal cholinergic tone and result in bronchodilation.
• Dose: Ipratropium bromide (Atrovent) 500ug to second dose of salbutamol via neb, can be repeated every 4hours
• Use of corticosteroids within 1 hour of presentation to an ED significantly reduces the need for hospital admission in patients with acute asthma. Benefits appear greatest in patients with more severe asthma, and those not currently receiving steroids
• Dose: Prednisolone 50mg PO
• Dose: IV Hydrocortisone 100-200mg
• Note: Parenteral route is indicated in ventilated patient or patient unable to swallow, eg. Vomiting

Adrenaline:

• Can be give either intravenously or via nebulizer
• Bronchoconstriction is the major pathology in asthma; airway oedema might also make a significant contribution. Both the a-agonist and B-agonist effects of adrenaline might be beneficial, with the alpha effect decreasing oedema and the beta effect responsible for bronchodilation.
• Dose:  IV 6mg in 100mls 5% dextrose start at 1-15mLs/hour
• Dose: Nebulizer 1mg in 3ml normal saline

Aminophylline:

• The popularity of aminophylline in asthma exacerbations has diminished in recent years.
• Systematic reviews have shown that IV aminophylline in severe acute asthma does not produce additional bronchodilation above that achieved with beta-agonist and corticosteroids.
• Side effects; cardiac arrhythmia’s, vomiting, toxicity.
• Dose : 5mg/kg over 20min followed by infusion of 500mg aminophyline n 500mL of 5% dextrose at 0.5mg/kg per hour

Magnesium Sulphate:

• Magnesium potential role is asthma may involve a combination of smooth muscle relaxation, inhibition of histamine release and acetylcholine release from nerve endings.
• Most evidence to support the use of magnesium in asthma is in the acute severe asthmatic were it has been shown to be safe and beneficial.
• Dose : IV 2-4g over 30-60mins
• Heliox Mixture 80% helium/20% oxygen
• There is evidence that helium and oxygen mixtures (heliox) may provide additional benefits to patients with acute asthma.
• Heliox mixtures have the potential to decrease airway resistance, and therefore decrease the work of breathing for the severe acute asthma patient.

Antibiotics:

• Antibiotics are not indicated in the management of severe acute asthma.
• Antibiotics should only be used in the setting of an underlying pneumonia, respiratory tract infection or to aid in the prevention of ventilator-associated pneumonia in ICU.

Airway Management

Non-Invasive Positive Pressure Ventilation:

Good quality evidence and trails to support the use of NPPV in asthma are lacking, however it is worth trying when intubation is not immediately indicated. Remember the goal of the emergency clinician’s in treating asthma is to prevent intubation.

• Positive pressure is generally less than 15cmH2O
• Benefit between CPAP vs BiPAP is unknown
• Tachypnea caused by severe asthma can make it difficult for the patient to coordinate they’re breathing with machine making BiPAP uncomfortable
• Need a large randomised control trial to determine the effectives properly of NIV, in acute severe asthma.

“Asthmatic on BiPAP before being Intubated”

Mechanical Ventilation:

1-3% of acute severe asthma requires intubation. Prevention of intubation and mechanical ventilation are the goals of managing acute severe asthma, this can be achieved by maximising pre-intubation therapy, however you don’t want to wait too long or let the severe asthmatic tire before trying to intubate them. Once an asthmatic is intubated and ventilated their morbidity and mortality increasing dramatically, and it can be difficult to wean from the ventilator.

Criteria for Intubation:

• Cardiac or Respiratory arrest
• Altered mental status
• Progressive exhaustion
• Severe hypoxia despite maximal oxygen delivery
• Failure to reverse severe respiratory acidosis despite intensive therapy
• pH <7.2, carbon dioxide pressure increasing by more than 5mmHg/hr or greater than 55 to 70mm/Hg, or oxygen pressure of less than 60mm/Hg.

Challenges:

• Effective pre-oxygenation impossible
• No margin for error or delay
• Need to be intubated by most experienced person available
• High intrathoracic pressure after RSI

Recommendations:

• Fluid bolus before intubation if possible
• RSI preferred
• Ketamine for bronchodilator effects
• Permissive hypercapnea essential

Initial Ventilator settings in paralysed patients:

• FiO2 1.0, then titrate to keep SpO2 >94%
• Tidal Volume 5-6ml/kg
• Ventilator rate 6-8 breaths/min
• Long expiratory time (I:E ratio >1:2)
• Minimal PEEP < 5cmH2O
• Limit peak inspiratory pressure to <40cmH2O
• Target plateau pressure <20cmH2O
• Ensure effective humidification

• Brenner, B. Corbridge, T. & Kazzi, A. (2009). Intubation and mechanical ventilation of the asthmatic patient in respiratory failure. The Journal of Emergency Medicine. 37(2s), s23-s34.
• Camargo, C. Rachelefsky, G. & Schatz, M. (2009). Managing Asthma Exacerbation in the Emergency Department: Summary of the National Asthma Education and Prevention Program Expert Panel Report 3 Guidelines for the Management of Asthma Exacerbation.The Journal of Emergency Medicine. 37 (2S), S6-S17.
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• Creagh-Brown, B. & Ball, J. (2007). An under-recognized complication of treatment of acute severe asthma. American Journal of Emergency Medicine. 26, 513-515.
• Hodder, R. et al. (2009). Management of acute asthma in adults in the emergency department: nonventilatory management.  CMAJ. 182(2), E55-E67.
• Holley, A. & Boots, R.(2009). Review article: Management of acute severe and near-fatal asthma. Emergency Medicine Australasia, (21) 259-268.
• Jones, L. & Goodacre, S. (2009). Magnesium sulphate in the treatment of acute asthma: evaluation of current practice in adult emergency departments. Emergency Medicine Journal. 26, 783-785.
• Melnick, E. & Cottral, J. (2010). Current Guidelines for Management of Asthma in the Emergency Department.  http://www.ebmedicine.net. 2(2). 1-13.
• Morris, F. & Fletcher, A. (Ed). (2009). ABC of Emergency Differential Diagnosis. Oxford: Blackwell Publishing
• National Asthma Council of Australia. Asthma management handbook: 2006. Accessed http://www.nationalasthma.org.au/cms/images/stories/amh2006_web_5.pdf, 12/02/2010
• Nowak, R. Corbridge, T. & Brenner, B. (2009). Noninvasive Ventilation. The Journal of Emergency Medicine. 37(2S), S18-S22.
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• Rowe, B. Spooner, C. Ducharme, F. Bretzlaff, J. Bota, G. (2008). Early emergency department treatment of acute asthma with systemic corticosteroids (Review). http://www.thecochranelibrary.com.
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• Open access
• Published: 03 April 2020

Determinants of Acute Asthma Attack among adult asthmatic patients visiting hospitals of Tigray, Ethiopia, 2019: case control study

• Melaku Negash 1 ,
• Hagos Tsegabrhan 2 ,
• Teklit Meles 3 ,
• Degena Bahrey Tadesse 1 ,
• Gebreamlak Gidey 4 ,
• Yemane Berhane 5 ,
• Kibrom Berhanu 6 &
• Tsgalem Haylemaryam 7  

Asthma Research and Practice volume  6 , Article number:  1 ( 2020 ) Cite this article

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Introduction

Acute asthma attack is one of the most common causes of visits to hospital emergency departments in all age groups of the population and accounts for the greater part of healthcare burden from the disease. Despite, Acute asthma attack is an important public health problem that affects not only the patients, but also to the family, health professionals, health care institutions and development of the nation, little is known about the risk factors of acute asthma attack.

Therefore, this study is aimed to investigate the determinants of acute asthma attack among.

The aim of this study was to assess the determinant factors of acute asthma attack among adult asthmatic patients visiting general hospitals of central zone, Tigray, Ethiopia, 2019.

Hospital based unmatched case control study design was conducted in general hospitals of central zone of Tigray, Ethiopia 2019. Data were collected using pretested interviewer administered questionnaire. A total of 289 study subjects (96 cases &193 controls) were selected by systematic random sampling. Data were entered to Epi data version 3.1 then exported to SPSS version 23 for analysis. Bivariate logistic regression was employed to examine the statistical association between dependent and independent variables. Variables with p value < 0.25 in binary logistic regression were entered to multivariable logistic regression model and variables with p value < 0.05 was taken as significant determinants of the outcome variable.

A total of 96 adult asthmatic patients who have acute asthma attack (cases) and 193 adult asthmatic patients without attack (controls)) with 100% response rate were participated in this study. Upper Respiratory tract Infection [AOR = 6.835,95% CI = 3.285,14.222], Season [AOR =2.204,95% CI = 1.011,4.805] kitchen smoke [AOR = 2.307,95%CI1.010,5.272]& sleep apnea [AOR = 9.254, 5%CI =3.563,25.460] were significantly associated with acute asthma exacerbation.

Asthma is a long-term inflammatory disease of the respiratory system which is characterized by wheezing, shortness of breath, chest tightness. Globally it affects approximately 300 million people and is estimated to rise to 400 million by 2025 globally [ 1 , 2 ]. And it is ranked 16th among the leading causes of disability and 28th among the leading causes of burden of disease, as measured by disability adjusted life years (DALYs) [ 3 ].

According to Croatian medical journal 2013, an estimate of asthma prevalence in Africa, was 49.7 million in the age of < 15 years (13.9%), < 45 years 102.9 million (13.8%), and in total population 119.3 million (12.8%) in 2010 [ 4 ].

Asthma exacerbation is defined as a worsening of shortness of breath, cough, wheezing, or chest tightness. If not treated immediately there will be increase in flow resistance causing increased work of breathing, gas exchange inefficiency, respiratory muscle tiredness and finally hypercapnic and hypoxemic respiratory failure [ 5 ]. This implies that acute asthma attack is a significant public health problem that affects patients with their parents or families and the community through labor and school loss, frequent emergency clinic visits, a poor quality of life hospitalizations and finally death [ 6 ]. According to Centers for Disease Control and prevention (CDC) report, More than 11 million people reported having an acute asthma attack [ 7 ].

Despite, in Ethiopia little is known about how risk factors are associated with exacerbation, according to asthma severity and the relative importance of the risk factors. This may be the reason for no policy and strategy to ascertain and acting out of effective intervention in order to reduce the burden of acute asthma attack [ 8 ]. Therefore, this study is aimed to full fill this gap.

Study setting and study design

Hospital based unmatched case control study was conducted in the selected general Hospitals of Central zone of Tigray from November 2018 to July 2019.

Study population and sample size determination

Source population.

All adult asthmatic patients visited to emergency unit who have acute asthma attack.

All adult patients diagnosed as asthma but without acute asthmatic attack who visited the OPD and the regular follow-up unit during the data collection period.

Study population

All selected adult asthmatic patients visited to emergency unit who have acute asthma attack during the data collection period.

All selected adult patients diagnosed as asthma but without acute asthmatic attack who visited the OPD and the regular follow-up unit during the data collection period.

Eligibility criteria

Inclusion criteria.

Adult asthmatic patients who have acute asthma attack during the data collection period.

Adult asthmatic patient without acute asthma attack during the data collection period.

Exclusion criteria

Patients with any history of pulmonary embolism, chronic obstructive pulmonary disease, active pulmonary TB, known congestive heart failure and known mechanical obstruction.

Sample size determination

Sample size was calculated from Previous study conducted in Uganda [ 9 ],using Epi info version 7. sample size was determined based on the assumption of confidence level = 95%; Power = 80%; Odds ratio = 2.132 with case to control ratio = 1:2, proportion of among controls 37.2%, proportion of among cases = 55.8%.

Therefore, the required sample size for cases was =92 where as for the controls =183 and the overall sample size was = 275 then after adding 5% non-response rate, the total sample size was 289. Finally, a sample size for cases was 96 and for controls 193.

Sampling technique and procedure

The total sample size was allocated to each hospital proportionally based on the number of patients who attend in the selected hospitals. A total number of 585(case 165, control.420) patients attended at the selected Hospitals with in 2 months of the previous year (April 1 to May 30–2018). Systematic random sampling method was applied in each hospital to select 289 participants.

Study Variables

Dependent variable.

Acute asthma attack.

Independent variables

Socio-demographic variables.

Age, Gender, Marital status, Residence, Educational level, Employment status and Occupational status.

Behavioral factors

Exercise, vigorous activity Smoking cigarette.

Environmental factors

Humidity, Kitchen smoke, dust, Season.

Medical and Clinical characteristics

URTI, Sleep apnea, Missing follow-up / appointments,

Operational definitions

Those who present with cough, wheezing and difficulty of breathing and diagnosed asthma by physician [ 10 ].

Acute Asthma Attack

Those who present with worsening of wheezing, shortness of breath, cough, chest tightness and diagnosed as acute asthma attack by physician [ 10 ].

Smoker:( daily smoker and non-daily smoker) those who currently smokes or those who quit smoking less than 1 year before the assessment [ 10 ].

Passive smoker: Smoke inhaled involuntarily by non-smokers [ 11 ].

Nonsmoker: Respondents who report never smoke those who quit smoking greater than 1 year before the assessment.

Vigorous activity: participants doing activity more than 10 min continuously, that increases breathing, like carrying or lifting heavy loads, digging or construction work, cutting fire wood [ 11 ].

Data collection tool

Structured questionnaire was used to collect the data which was adapted from different literatures [ 9 , 12 , 13 , 14 ]. The questionnaire contains four parts: socio-demographic, environmental factors, behavioral factors, and Medical &Clinical characteristics.

Data collection procedures

Data were collected from cases and controls using structured questionnaire and checklists through face-to-face interview and from patients chart review respectively.

Twelve BSc nurses as data collectors and three senior nurse supervisors were recruited for the data collection, Then data from cases were collected after they take all the necessary medical care and they recover from their attack whereas from the controls data were collected after they have completed their assessment by physician and at the last record reviews from their chart. Participants were identified as having upper respiratory tract infection and Obstructive sleep apnea from their medical charts which was diagnosed by senior physicians. This is to mean that, it was just suspected clinically by the time of the acute event. The reason we obeyed to use clinically diagnosis for obstructive sleep apnea is that, there is no accesses of modern diagnostic modality like polysomnography in the study area which was Tigray regional state not only in the study area but also in the country Ethiopia as a whole. The evaluation protocol that we use were a single evaluation visit for each case and even those who have follow-up and developed acute asthma attack were included .

Data quality control techniques

Data quality was ensured by training of data collectors and supervisors before data collection period. 5% of the questionnaire was pre-tested in Shire Hospital which was not included in the actual data collection. Based on the findings of the pre-test, questionnaire was modified. The filled questionnaire was checked for completeness and accuracy by data collectors, supervisors and principal investigator each day.. The questionnaire was translated into Tigrigna language for better understanding to both the data collectors and respondents and then back translated into English by another expert to ensure accuracy and consistency.

Data analysis procedures

Data were entered in to Epi data version 3.1 and analyzed using SPSS version 23.0. The degree of association between independent and dependent variables were assessed using adjusted odds ratio with 95% confidence interval. Variables < 0.25 p -value in binary logistic regression were entered to multivariable logistic regression model to control the potential confounding variables. Variables with p-value less than 0.05 in multivariable logistic regression model were taken as significantly associated factors. Variance inflation factor (VIF) was used to assess Multicollinearity between the independent variables. Hosmer and Lemeshow goodness fit model were used to check model fitness.

Ethical consideration

Ethical clearance was obtained from Mekelle University College of health sciences institutional review board (IRB). A subsequent permission was also obtained from Tigray teaching hospitals. Respondents were informed about the purpose of the study and the interview was conducted after receiving the written consent from participants. Confidentiality of the data/information was secured and was not used for other purposes.

Sociodemographic characteristic of study participants

Among the participants, 67.7% (65) of the cases and 60.6% (117) of the controls were females. The median ages of participants were 43 years with interquartile range (IQR) of 26.5 years among cases and 43 median ages with interquartile range (IQR) of 22 for control.

The educational status, one third 33.3% (32) of the cases and 24.9% (48) of the controls were collage and above, where as 14.6% (14) of the cases and 16.6% (32) of the controls were unable to read and write. The majority of the cases 63.5% (61) and 60.1% (116) of the controls were married (Table  1 ).

Behavioral characteristics of study participants

Among the participants, 2.1% (2) of the cases and 1.1% (6) of the controls were smokers.in parallel with this 3.1% of the cases and 4.7% of the control were passive smokers. Regarding vigorous activity 37.5% (36) of the cases and 23.8% (46) of the controls were do vigorous activity. Majority of the participants 72.9% (70) of the cases and 58% (112) of the controls were doing exercise.

Medical & clinical characteristics of study participants

Among the participants, 44.8% (43) of the cases and 13.5% (26) of the controls had Upper Respiratory Tract Infections (URTI) and 29.2% (28) of the cases and few of the controls 5.2% (10) had obstructive sleep apnea.

Among the participants, 31.3% (30) of the cases and 20.7% (40) of the controls had Missing follow up.

Environmental characteristics of study participants

Regarding the seasons of a year, spring season (April, May, June) were the season with high percentage 37.7% (109) of acute asthma attack than the autumn season. Majority of the participants 79.5% (230) were open their window/door while they were cooking. Concerning the kitchen of the participants 32.3% (31) of the cases and 20.2% (39) of the control’s kitchen have no kitchen smoke (chimney) (Table  2 ).

Unmatched case control study with 96 cases and 193 controls was conducted to show the determinants of acute asthma attack among adult asthmatic patients visiting general hospitals of central zone, Tigray, Ethiopia.

Having URTI increases the occurrence of acute asthma attack 6.8 times [AOR = 6.835,95% CI = 3.285,14.222] than those who have not upper respiratory tract infection (URTI) (Table 3 ).

This is consistent with the studies conducted in Gondar, Uganda and Ireland [ 9 , 12 , 15 ].

The association might be due to the mechanism of airway inflammation,mucus hyper secretion, and bronchial hyper responsiveness [ 16 ]. In contrast to this study upper respiratory tract infections was no risk factor for acute asthma exacerbation on the study conduct in Pretoria and New Zealand [ 14 , 17 ]. This difference might be due to difference in health care seeking behavior of the participants in this study.

This study revealed that, sleep apnea was strongly associated with the occurrence of acute asthma exacerbation. Those who have sleep apnea are 9.5 times more likely to run in to acute asthma exacerbation than those who have not sleep apnea [AOR = 9.524, 95% CI = 3.563, 25.460].

This findings is comparable with a study done in Gondar and USA [ 12 , 18 ].

The possible reason is the fact that sleep apnea lead to the worsening of asthma control in patients with concomitant sleep apnea secondary to bronchoconstriction as a result of increase vagal tone while sleeping [ 19 ].

The result of this study shows that the odds of having acute asthma in Spring season was 2.2 times higher than the odds of having acute asthma attack in the autumn season [AOR = 2.204,95% CI = 1.011,4.805]. This is consistent with a study conducted in Canada in which spring season was triggering factor for asthma exacerbation [ 20 ]. Seasonal variation is the risk factors for acute asthma attack especially pollens appearing seasons like spring season exacerbates acute asthma attack. This may be due to the reason that during the spring, tree pollen, mold spores and grass have the power to inflame and narrow the air passages of people who have asthma [ 21 ].

The result of this study was different from a study conducted in Spain which was resulting winter season as higher risk of developing acute asthma attack [ 22 ]. The difference could be arisen from seasonal variation between the study areas, due to the influence of temperature and humidity.

In this study, Kitchen smoke (chimney) is highly associated with risk of acute asthma exacerbation.

Those who have no kitchen smoke in their kitchen were 2.3 times at risk to develop acute asthma exacerbation [AOR = 2.307,95%CI = 1.010,5.2725] than those who have kitchen smoke. This finding is comparable with the study conducted in India [ 13 ]. This is due to the fact that kitchen smoke (chimney) is a way that helps in removing the smokes and fumes from the kitchen and making it clean and smoke free which result in reduction of indoor air pollution and prevents acute asthma exacerbation [ 23 ]. Inhaling harmful smoke can inflame lungs and airway, causing them to swell and block oxygen. This can lead to acute asthma exacerbation [ 24 ]

In this study the determinant factors of acute asthma attack were spring season, presence of upper respiratory tract infection (URTI), having no Kitchen smoke in their kitchen and having obstructive sleep apnea.

Limitations

The diagnosis of respiratory tract infections and sleep apnea was empirical (without laboratory) and all measures used were based on self-reporting, this might end up with social desirability bias. This study may have recall bias, since some of the information was based on the recall of the study participants. Unavailability of studies on acute asthma exacerbation.

Availability of data and materials

The datasets used and analyzed during the current study are presented within the manuscript and available from the corresponding author on reasonable request.

Abbreviations

Adjusted Odds Ratio

Confidence Interval

Crude Odds Ratio

Central Statistical Agency

Interquartile Range

National Health Interview Survey

Out Patient Department

Tigray Region Health Development Agency

Upper Respiratory Tract Infection

Variance Inflation Factor

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Acknowledgments

Authors thanks to public general hospitals of central zone Tigray, Ethiopia for their co-operation, to data collectors, supervisors, for the health staffs of the hospitals and to the study participants for their valuable information.

Not applicable.

Author information

Authors and affiliations.

Department of adult health nursing ,school of Nursing, Aksum University, Aksum, Ethiopia

Melaku Negash & Degena Bahrey Tadesse

Department of Psychiatric, Mekelle University, Mekelle, Ethiopia

Hagos Tsegabrhan

Adwa General Hospital, Adwa, Ethiopia

Teklit Meles

Department of midwifery, Aksum University, Aksum, Ethiopia

Gebreamlak Gidey

college of medicine and health science, Adigrat university, Adigrat, Ethiopia

Yemane Berhane

Maternity and reproductive health nursing, Mekelle University, Mekelle, Ethiopia

Kibrom Berhanu

Department of Emergency and critical care nursing, Mekelle University, Mekelle, Ethiopia

Tsgalem Haylemaryam

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Contributions

MN: was made substantially contributions to conceived and designed the study, analysis the data, methodology, data interpretation and wrote the final manuscript.TM, DB, GG,YB, had equally contributed to analysis and interpretation of the data. Whereas HT, TH and KB substantial contribution in reviewing overall the study in analysis, interpretation of data, have drafted the manuscript and substantively revised the work. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Melaku Negash .

Ethics declarations

Ethics approval and consent to participate.

Ethical clearance was obtained from Mekelle University College of health sciences institutional review board (IRB). Official supportive letters were obtained from Regional Health Bureau (TRHB) and central zone health office. Respondents were informed about the purpose of the study and the interview was conducted after receiving the written consent from participants. The right of participants to withdraw from the study at any time, without any precondition were secured and participants were informed. Confidentiality of the data/information was secured and was not used for other purposes. No personal identifiers was used on the questionnaire. To maintain confidentiality, data collector was recruited from the study unit.

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Competing interests.

The authors declare that they have no competing interests.

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Supplementary information

Additional file 1..

Annex I: English version structured interview questionnaire.

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Negash, M., Tsegabrhan, H., Meles, T. et al. Determinants of Acute Asthma Attack among adult asthmatic patients visiting hospitals of Tigray, Ethiopia, 2019: case control study. asthma res and pract 6 , 1 (2020). https://doi.org/10.1186/s40733-020-00054-w

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• Acute asthma attack
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Asthma Research and Practice

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Higher Prevalence of Asthma Exacerbations Found in Patients With Insomnia

Underlying mood and sleep disorders may negatively affect asthma control, researchers find.

Insomnia, depression, and obstructive sleep apnea were more common among patients with asthma in a retrospective analysis published in the Journal of Asthma . 1 The fundings suggest an underlying association between mood and sleep disorders and asthma control.

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“Asthma control, sleep quality, and mood are all critical factors in affecting an individual’s overall quality of life, and our study suggests a strong relationship among all three areas,” said Michael Wechsler, MD, pulmonologist, Professor of Medicine, director of The Cohen Family Asthma Institute at National Jewish Health and senior author of the paper, in a statement . 2 “Individuals with asthma should be regularly screened for sleep quality as well as for co-existing mood disorder.”

Asthma is a common chronic disease, with an estimated 262 million people affected worldwide. Additionally, individuals with asthma often report sleep disturbances that are associated with worse asthma control and worse quality of life.

Despite this knowledge, there is still little understanding of how underlying sleep disorders impact asthma control. Therefore, researchers aimed to evaluate impact of concurrent obstructive sleep disorder and mood disorders on exacerbation frequency among patients with asthma.

The study was conducted among 659 adult patients enrolled in a long-term study at National Jewish Health, beginning in October 2017. Patients with asthma were evaluated based on the presence of concurrent obstructive sleep disorder, mood disorders, asthma exacerbation frequency, and asthma control test (ACT) scores. Patients with and without insomnia were matched by age, sex, Charlson comorbidity index, and biologic therapy.

Exacerbations were defined as the need for oral corticosteroids, hospitalization, or documentation of exacerbation by a physician in electronic medical record (EMR).

Of the 659 patients, 89 (13.5%) had a concurrent diagnosis of insomnia. The average age of patients was 57 years, most patients were female (76%), and 35.9% were on a biologic therapy for asthma. Among those with insomnia, 57.3% had a concurrent diagnosis of obstructive sleep apnea, compared with 18% of individuals without insomnia ( P < .001).

Additionally, patients with insomnia were more likely to have a diagnosis of depression or anxiety (68.5%), compared with those without insomnia (11.4%). Individuals with insomnia also had a significant overlap between patients who were diagnosed with obstructive sleep apnea and depression (34.8%), compared with individuals without insomnia (2.2%).

Patients with insomnia experienced an average of 0.93 exacerbations in the year preceding data collection, compared with 0.59 exacerbations among those without insomnia ( P = .039). Patients with insomnia also had worse asthma control, with an average ACT score of 16 compared with 18.9 in those without insomnia ( P = .0029).

However, the researchers acknowledged some limitations to the study. First, they noted that the study had a small sample size and was also retrospective in design. Other limitations included difficulty identifying the presence of additional comorbid conditions and details regarding an individual’s insomnia diagnosis.

Despite these limitations, the researchers believe the study demonstrated an association between insomnia and increased asthma exacerbations, as well as decreased ACT score. Additionally, the study suggests the prevalence of obstructive sleep apnea may also be significantly higher in individuals with asthma who have insomnia.

“It is important for us as physicians to treat asthma comorbidities like sleep and mood disorders similarly to what we do with other conditions that impact asthma management, such as reflux, sinus disease and vocal cord dysfunction,” Wechsler said in a statement. 2

1. Rhoads SL, Edinger J, Khatiwada A, Zimmer J, Zelarney P, Wechsler ME. The impact of insomnia and depression on asthma control. Journal of Asthma . Published online April 4, 2024:1-4. doi:10.1080/02770903.2024.2335367

2. Researchers show impact of insomnia and depression on asthma control. EurekAlert! News Release. May 8, 2024. Accessed May 16, 2024. https://www.eurekalert.org/news-releases/1044053 .

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Efficacy and safety of subcutaneous dupilumab in participants with asthma/asthmatic wheeze aged 2 to <6 years

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• Observational study — observes people and measures outcomes without affecting results.
• Interventional study (clinical trial) — studies new tests, treatments, drugs, surgical procedures or devices.
• Medical records research — uses historical information collected from medical records of large groups of people to study how diseases progress and which treatments and surgeries work best.

Study phase

During the early phases (phases 1 and 2), researchers assess safety, side effects, optimal dosages and risks/benefits. In the later phase (phase 3), researchers study whether the treatment works better than the current standard therapy. They also compare the safety of the new treatment with that of current treatments. Phase 3 trials include large numbers of people to make sure that the result is valid. There are also less common very early (phase 0) and later (phase 4) phases. Phase 0 trials are small trials that help researchers decide if a new agent should be tested in a phase 1 trial. Phase 4 trials look at long-term safety and effectiveness, after a new treatment has been approved and is on the market.

• Rochester, Minnesota: 23-010243

About this study

This study is a placebo-controlled, double-blind, randomized trail enrolling children aged 2 to <6 years old with uncontrolled asthma and/or recurrent severe asthmatic wheeze despite stand of care therapy with inhaled corticosteroids.   The study is desgined to evaluate the efficacy and safety of subcutaneous duplimab treatment over a 52-week treatment period.  This study will be conducted in 2 parts.  Part A, a randomized, double-blind, placebo-controlled phase will evaluate efficacy and safety data over 52 weeks.  Participants who satisfy the inclusion/exclusion criteria will be randomized (2:1) to one of the following study intervention groups:  dupilumab 200mg or 300 mg every 4 weeks, or matching placebo.  Eligible participants who complete the randomized treatment period will be offered the opportunity to participate in the Part B 1-year open-label extension study with dupilumab.  All participants whould complete a 12-week post-treatment observational period at the end of their treatment period (Either Part A or Part B).

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Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

Inclusion Criteria:  

• Participant must be 2 to < 6 years of age inclusive, at the time of signing the informed consent form by participants’ parent(s)/caregiver(s)/legal guardian(s).

Type of participant and disease characteristics

• Diagnosis of asthma or recurrent severe asthmatic wheeze that is not controlled with chronic ICS for at least 3 months with stable use of at least low dose ICS for ≥ 1 month prior to Screening Visit 1 with evidence of uncontrolled asthma and/or recurrent severe asthmatic wheeze*. * Uncontrolled asthma and/or recurrent severe asthmatic wheeze is defined as participants with at least 2 episodes of asthma exacerbations (defined as acute worsening of respiratory symptoms/wheeze that required treatment for at least 5 days with an increase in ICS dose or 3 days of SCS in the previous year or 1 episode of hospitalization in the past year for asthma) during which the participant required treatment with ICS or SCS.
• Physician diagnosed Atopic Dermatitis.
• Allergic sensitization to at least 1 aeroallergen (with a positive serum immunoglobulin E (IgE) defined as a value ≥ 0.35 kU/L). OR 2 minor critieria:
• Wheezing unrelated to colds.
• Peripheral blood eosinophilia ≥ 4%.
• Allergic sensitization to milk, eggs, or peanuts (defined by serum specific IgE > 0.35 kU/L.
• Blood eosinophils ≥ 300 cells/µL at screening.
• Parent(s)/caregiver(s)/legal guardian(s) willing and able to comply with clinic visits and study-related procedures.
• Parent(s)/caregiver(s)/legal guardian(s) able to understand the study requirements. Participants/parent(s)/caregiver(s)/legal guardian(s), as appropriate, must be able to understand and complete study-related questionnaires.
• Body weight at screening and randomization > 5 kg and < 30 kg.

Informed Consent

• Parents or caregivers or legal guardian capable of giving signed informed consent as described in Appendix 1 (Section 10.1.3) of the protocol which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

Exclusion Criteria: 

Medical conditions

• Severe asthma with the need for chronic oral/systemic corticosteroid use ( > th continuous) at the time of screening enrollment.
• History of a systemic hypersensitivity reaction or anaphylaxis to dupilumab or any other biologic therapy, including any excipient.
• History of prematurity ( < 34 weeks gestation).
• Any other chronic lung disease that would impair lung function (eg, cystic fibrosis, broncopulmonary dysplasia) or chronic lung disease of prematurity or need for oxygen for more than 5 days in the neonatal period.
• History of life-threatening asthma (eg, requiring intubation).
• Other significant medical conditions including but not limited to: major congenital anomalies, chest wall deformities such as spondylocostal dysplasia, cystic fibrosis, interstitial pulmonary disease, bronchopulmonary dysplasia, thoracic surgery, immunodeficiency (primary or secondary), seizure disorders.
• Severe concomitant illness(es) that, in the Investigator’s judgment, would adversely affect the participant’s participation in the study. Examples include but are not limited to participants with short life expectancy, participants with uncontrolled diabetes (hemoglobin A1c ≥ 9%), severe renal, hepato-biliary, neurological conditions autoimmune diseases (eg, lupus, inflammatory bowel disease, rheumatoid arthritis, etc), other severe endocrinological, gastrointestinal, metabolic, pulmonary, psychiatric, or lymphatic diseases. The specific justification for participants excluded under this criterion will be noted in study documents (chart notes, case report forms [CRFs], etc).
• Participants with active tuberculosis (TB) or non-tuberculous mycobacterial infection, or a history of incompletely treated TB will be excluded from the study unless it is well documented by a specialist that the participant has been adequately treated and can now start treatment with a biologic agent, in the medical judgment of the Investigator and/or infectious disease specialist. Tuberculosis testing will be performed on a country-by-country basis, according to local guidelines if required by regulatory authorities or ethics boards.
• History of malignancy of any kind.
• Diagnosed with, suspected of, or at high risk of endoparasitic infection (helminths); and/or use of antiparasitic drug within 2 weeks before Screening Visit (Visit 1) or during the Screening period.
• Known or suspected immunodeficiency, including invasive opportunistic infections (eg, TB, histoplasmosis, listeriosis coccidiomycosis, pneumocystosis, aspergillosis), despite infection resolution; or otherwise, recurrent infections of abnormal frequency or prolonged duration suggesting an immune-compromised status, as judged by the Investigator.
• Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, or antifungals within 2 weeks before the Screening Visit (Visit 1) or during the screening period.
• Participants with autoimmune disease or participants using immunosuppressive therapy for autoimmune disease (eg, juvenile idiopathic arthritis, inflammatory bowel disease, systemic lupus erythematosus, etc.).
• History of human immunodeficiency virus (HIV) infection or positive HIV serology at Visit 1.
• At any time: Participants with positive (or indeterminate) test for hepatitis B surface antigen (HBsAg), positive Immunoglobulin M (IgM) hepatitis B core antibody (HBcAb); positive total HBcAb confirmed by positive total hepatitis B virus DNA (HBV DNA); positive hepatitis C virus antibody (HCVAb) confirmed by positive hepatitis C virus RNA (HCV RNA).
• Creatine phosphokinase (CPK) > 3 ULN; or,
• Platelets < 100 000 cells/mm^3 .
• Eosinophils ≥ 1500 cells/µL.

Prior/concomitant therapy

• Need for systemic corticosteroids or a hospitalization for respiratory symptoms within 4 weeks prior to Screening and during Screening period.
• Non-compliance with the use of mandatory background therapy during the Screening period, as defined by < 80% of the total number of prescribed background medications for this period. Compliance is verified based on background medication use recorded by caregivers in the participant eDiary.
• Any biologic therapy/immunosuppressant to treat inflammatory disease, allergic disease, or autoimmune disease (eg, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus as well as other diseases) within 2 months or 5 half-lives prior to Visit 1, whichever is longer.
• Initiation of allergen immunotherapy within 3 months prior to Visit 1 or dose change from 1 month prior to Visit 1 or a plan to begin allergen immunotherapy or to change its dose during the screening period or the randomized treatment period.
• Exposure to another investigational antibody within a time-period prior to Visit 1 that is less than 5 half-lives of the antibody. In case the half-life is not known, then the minimum interval since exposure to the prior investigational antibody is 6 months. The minimum interval since exposure to any other (non-antibody) investigational study medication is 30 days prior to Visit 1.
• Either intravenous immunoglobulin therapy within 30 days prior to Screening Visit (Visit 1).
• Participants for whom administration of live (attenuated) vaccine can be safely postponed would be eligible to enroll into the study.
• Participants who have their vaccination preponed can enroll in the study only after a gap of 4 weeks following administration of the vaccine.

Prior/concurrent clinical study experience

• Participants who have previously been treated with dupilumab.

Other exclusion criteria

• Individuals accommodated in an institution because of regulatory or legal order; prisoners or participants who are legally institutionalized.
• Any country-related specific regulation that would prevent the participant from entering the study – see Appendix Section 10.8 of the protocol (country-specific requirements).
• Participant not suitable for participation, whatever the reason, as judged by the Investigator, including medical or clinical conditions, or participants potentially at risk of noncompliance to study procedures.
• Participant’s parent(s)/caregiver(s)/legal guardian(s) is related to the Investigator or are employees of the clinical study center or other individuals directly involved in the conduct of the study, or immediate family members of such individuals (in conjunction with Section 1.61 of the ICH-GCP Ordinance E6).
• Any specific situation during study implementation/course that may raise ethics considerations.
• Sensitivity to any of the study interventions, or components thereof, or drug or other allergy that, in the opinion of the Investigator, contraindicates participation in the study.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 10/3/23. Questions regarding updates should be directed to the study team contact.

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Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

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ORIGINAL RESEARCH article

Pathogenic role of different phenotypes of immune cells in airway allergic diseases: a study based on mendelian randomization.

• 1 Department of Otolaryngology, Head and Neck Surgery, Second Hospital, Shanxi Medical University, Taiyuan, Shanxi, China
• 2 Shanxi Key Laboratory of Rapid Diagnosis and Precision Treatment of Airway Allergic Diseases, Head & Neck Surgery, Second Hospital, Shanxi Medical University, Taiyuan, Shanxi, China
• 3 Shanxi Airway Inflammatory Diseases Neuroimmunity Laboratory, Head & Neck Surgery, Second Hospital, Shanxi Medical University, Taiyuan, Shanxi, China
• 4 Shanxi Medical University, Taiyuan, Shanxi, China
• 5 Department of Environmental Health, School of Public Health, Shanxi Medical University, Taiyuan, Shanxi, China

Background: Airway allergic disease (AAD) is a class of autoimmune diseases with predominantly Th2-type inflammation, mainly including allergic rhinitis (AR), allergic asthma (AS), and chronic sinusitis (CRS). There are very complex regulatory mechanisms between immune cells and AAD; however, previous reports found that the functions of the same immune cells in AAD are not identical.

Objective: The aim of this study was to explore the causal relationship between different phenotypic immune cells and their association with AAD.

Method: Utilizing the publicly available Genome-Wide Association Studies (GWAS) database, this study conducted a bidirectional Mendelian randomization (MR) to assess the causal relationship between immune cells of 731 different immunophenotypes and AAD. The primary assessment methods included inverse variance weighting, weighted median, and MR Egger. Additionally, sensitivity analyses such as MR-PRESSO, leave-one-out, and scatter plots were employed to eliminate the interference of heterogeneity and pleiotropy, ensuring the stability of the causal inference.

Result: A total of 38 immune cells with different immunophenotypes were found to be positively and causally associated with AR, of which 26 were protective factors and 12 were risk factors. Positive associations were found between 33 immune cells and AS, of which 14 were protective factors and 19 were risk factors, as well as between 39 immune cells and CRS, of which 22 were protective factors and 17 were risk factors. Finally, the results of all relevant immune cells for the three diseases were taken and intersected, and it was found that CD3 on CD39+-activated Treg (IVW AR = 0.001, IVW CRS = 0.043, IVW AS = 0.027) may be the key immune cell that inhibits the development of AAD (OR AR = 0.940, OR AS = 0.967, OR CRS = 0.976).

Conclusion: This study reveals that different immune phenotypes of immune cells are closely related to AAD at the genetic level, which provides a theoretical basis for future clinical studies.

1 Introduction

Airway allergic disease (AAD) is a class of allergic disease types characterized by infiltration of T helper 2 (Th2) cells; this mainly includes allergic rhinitis (AR), allergic asthma (AS), and chronic sinusitis (CRS) (especially CRS with nasal polyps) ( 1 , 2 ). Th1/Th2 immune imbalance is an important factor leading to AAD. Th1 mainly mediates cellular immunity and secretes cytokines such as IFN-γ, IL-2, and so forth. IFN-γ inhibits the differentiation of Th2 cells as well as the synthesis of IgE by B cells and attenuate allergic reactions; Th2 mainly mediates humoral immunity and secretes cytokines such as IL-4/5. IL-4 further induces the differentiation of Th2 cells, which leads to the release of Th2-associated cytokines (IL-4/5/13), inhibits the proliferation of Th1 cells, and enhances the degranulation of mast cells, thereby exacerbating allergic reactions. When the body is exposed to allergens, antigen presenting cells secrete IL-10 to activate downstream CD4+T cells (Th0 cell) towards Th2 differentiation ( 3 ), Disruption of the Th1/Th2 balance is highly likely to result in allergic diseases.

The development of AAD involves multiple immune cell regulation, and eosinophils (EOS) are common tissue infiltrating cells in AAD; when the body is sensitized, EOS not only converges toward the inflammatory response and releases heterophilic basic proteins to kill bacteria or helminths but also causes damage to surrounding tissues. EOS can also release a variety of inflammatory mediators that exacerbate inflammation (IL-3, IL-5, Colony stimulating factors) ( 4 ); B cell is also one of the key cells in the development of AAD. After activation of B cell, it produces IgE, which binds to and activates mast cell degranulation, releasing active mediators such as leukotrienes and histamine, and triggering an Type I–hypersensitivity reaction. Regulatory T cells (Treg) are crucial immunoregulatory cells that carry out immunosuppressive functions, which are crucial in maintaining the body’s immune balance and reducing Th2-type inflammation. The expression level and function of Treg and their key transcription factor Foxp3 are significantly reduced under the stimulation of multiple pathogenic factors ( 5 ), Accordingly, the immunosuppressive function of Treg is diminished, which is one of the pathogenic mechanisms of many allergic diseases, including AAD.

Different subsets of the same immune cells have different functions, such as T cells, which have the potential to differentiate into CD4+ T cells and CD8+ T cells, and CD4+ T cells can further differentiate into Th1, Th2, Th17, Treg, and other T-helper cell subsets. The mainstream view is that Th2 and Th17 are associated with an increased risk of AAD, while Treg has immunosuppressive effects; in addition, it has been found that the same immune cell subpopulations but different immune phenotypes have inconsistent roles in disease ( 6 ). As research on immune cells continues to deepen, the functional heterogeneity among subsets of the same immune cells has gradually been discovered by researchers; in order to achieve better therapeutic outcomes, people have begun to explore the changes in the roles of immune cells with different immunophenotypes. Many recent studies have found that the same immune cells with different phenotypes have inconsistent roles in diseases. For example, in patients with plasma cell hepatitis, significant phenotypic heterogeneity of regulatory B cells (Bregs) was observed in the blood, spleen, and tonsils. Two main suppressive Breg subpopulations, CD24hiCD38hi transitional B cells (Trb) and CD24hiCD27+ human equivalent of B10 cells, also exhibit differences in immune suppressive function, with the latter expressing more IL-10, TGF-β, and granzyme B, resulting in better inhibition of CD4+ T-cell immune responses. In addition, compared with CD24hiCD38hi Trb, CD24hiCD27+ human equivalent of B10 cells also express more CD49d and CD11a, further indicating that the two subpopulations may primarily function in different tissues ( 7 ). As mentioned above, Tregs are well-known immune suppressive cells, but with in-depth research on cell phenotypes, people have begun to discover that Tregs may not only have immune suppressive functions. Bin and his team found that Helios- Foxp3+ Tregs can secrete pro-inflammatory factors such as IFN-γ, IL-2, and IL-17, which is significantly different from the functions of Helios+ Foxp3+ Tregs ( 8 ). Similarly, Alvarez and his team found that overexpression of IL-1 receptor (IL1R1) in Tregs leads to a decrease in Foxp3 expression and promotes Tregs to shift towards the Th17 phenotype, becoming pro-inflammatory Treg cells ( 9 ). It can be seen that the same subpopulation of immune cells with different phenotypes play different or even opposite cellular functions. Clarifying the functional differences between different phenotypes of immune cells can better serve clinical treatment, adapting to the needs of precision medicine in recent years.

Thanks to the advancement of technologies such as flow cytometry and single-cell RNA analysis, researchers can delve deeper into the functional differences of immune cells with different phenotypes, providing new theoretical guidance for further exploration of disease pathogenesis, development of corresponding targeted drugs, and discovery of new biomarkers. To date, the role of immune cells with different phenotypes in AAD has been less studied, and due to the limitations of traditional analysis methods (potential confounding factors and reverse causality), the correlation between different phenotype immune cells and AAD remains unclear. Mendelian randomization is an analytical method based on the random allocation of genes to infer causal relationships in epidemiology. It can greatly avoid the interference of confounding factors and intuitively provide evidence of causal relationships between exposure and outcome ( 10 ); therefore, our team used two-sample Mendelian randomization (TSMR) analysis to estimate the causal relationship between immune cells of different phenotypes and AAD, with the aim of providing potential theoretical foundations for clinical treatment and research.

2 Materials and methods

2.1 study design.

We used TSMR as a basis for assessing the causal association of 731 immune cells with AR, AS, and CRS; the use of single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) and analysis of causality between exposure and outcome using MR must satisfy the following points: (I) IV is directly related to exposure; (II) IVs are not associated with any known or unknown confounding factors; and (III) In addition to influencing outcomes through exposure, IVs do not influence outcomes through any other pathways or directly. The flowchart of the specific study is shown in the figure ( Figure 1 ).

Figure 1 Research flowchart.

2.2 Airway allergic disease data sources

The data for the AAD genome-wide association study were obtained from FinnGen ( www.finngen.fi/en ), a large Finnish biological database which launched in Finland in 2017; it brings together genomic meta-analyses of hundreds of thousands of people from universities, hospitals, biobanks, and so forth in Finland and combines information from the Finnish Health Registry population. The Genome-Wide Association Studies (GWAS) data for AR, AS, and CRS are all Finngen R9 version ( https://r9.risteys.finngen.fi/ ), little overlap with education or any intermediary GWAS to ensure the lowest possible Type I error rate ( 11 ). The AR-GWAS data contained a total of 370,158 Finnish individuals ( N case = 11,009, N control = 359,149). The AS-GWAS data contain a total of 219,753 Finnish individuals ( N case = 9,631, N control = 210,122). The CRS-GWAS data contained a total of 299,737 Finnish individuals ( N case = 16,395, N control = 283,342). The diagnostic criteria for all three diseases are based on the international code of diseases ( 12 ).

2.3 Immune cell data sources

GWAS data for 731 immune cells with different immune phenotypes from a sequence of 3,757 individual European data from Sardinia, Italy, these immune cell-associated genetic variants were identified by a reference panel based on 3,514 individuals in the Sardinian sequence or after analyzing nearly 20 million SNPs by high-density arrays, subsequently adjusted for gender, age, age squared ( 13 ), and the immune cell populations were preliminarily divided based on staining with seven major flow cytometry panels (B cell panel, Dendritic Cell (DC) panel, Maturation stages of T-cell panel, Monocyte panel, Myeloid cell panel, T lymphocytes, B lymphocytes, and Natural Killer cells (TBNK) panel, Regulatory T cell (Treg) panel). After the initial classification of cell types, the immune cells are further categorized into more detailed functional classifications based on the expression of other phenotypes on the cells. For instance, Treg cells (CD25hi CD127lo) identified in the Treg panel were further subdivided into activated Treg (CD25+++CD45RA−), resting Treg (CD25++CD45RA+), and secreting Treg (CD25++CD45RA−) (for more details, please refer to reference 13). GWAS statistics for each immune cell population are available from the GWAS Catalog (GCST90001391-GCST90002121).

2.4 IVs selection

To minimize the influence of weak instrumental variables, all SNPs are assessed with the F -statistic for strength; those with F > 10 are deemed robust enough for MR analysis. When using AAD as exposure, SNP threshold selected for significant correlation with exposure was set at p < 5 × 10 −8 (AR = 386, CRS = 2,425, AS = 4,840, after sieving), when using immune cells as exposure, due to the challenges faced by most immune cell GWAS in achieving genome-wide significance levels ( p < 5 × 10 −8 ), the threshold for significance for IVs was established at p < 1 × 10 −5 . SNPs in a state of linkage disequilibrium from the remaining SNPs were excluded as tools for further analysis to ensure the independence between the selected SNPs ( r 2 < 0.001, distance threshold > 10000 kb).

2.5 Statistical analysis

All statistical analyses were performed in R 4.3.1 software ( http://www.Rproject.org ).

Inverse variance weighted (IVW) was performed to assess the causal relationship between immune cells of different immunophenotypes and AAD ( 14 ), mainly using the “TwoSampleMR” package. IVW is the primary reference index for MR analysis, assuming all SNPs serve as valid instrumental variables without horizontal pleiotropy, thus delivering stable and valid causal estimates based on this. The IVW is prone to bias due to the difficulty in practical application to achieve complete absence of horizontal pleiotropy in the included SNPs. Considering the above, the MR-Egger method and the weighted median method were used to complement the results of the IVW method. The MR-Egger method allows for the presence of (intercept term) pleiotropy, allowing for IVs that are all invalid, thus identifying potential pleiotropic bias, but with poor precision. The weighted median method (WM) selects the median for the overall MR estimation, particularly when 50% of the weights are derived from valid IVs, MR-Egger can still make causal effect inferences consistent with IVW and with similar efficiency ( 15 ). If the null hypothesis ( p < 0.05) is rejected, the Cochran’s Q test ( Q p -value) is used to include heterogeneity between SNPs, heterogeneity was considered to be present, and the results were evaluated using the WM ( 13 ). When the results of the WM method are also not significant, it indicates that there is no causal relationship between the exposure and the outcome, and it is considered negative and removed. To remove the effect of horizontal pleiotropy on the results, we used MR-PRESSO to assess whether the results were pleiotropic or not ( 16 ), direct exclusion of causal inference effects if there is pleiotropy. When the same exposure exists for three allergic diseases, if there is pleiotropy, the “cause” package is used to determine whether the pleiotropy affects the stability of causal inference, the model with a fixed causality of zero (sharing model) is compared with the model with a causal relationship (causal model), and the expected log pointwise posterior density (ELPD) is used to assess the degree of fit of the two models (delta_ELPD = ELPDsharing - ELPDcasual). If delta_ELPD is less than 0, the causal model is better than sharing model, conversely, the sharing model outperforms the causal model, subsequently further looking at the p -value. When there is significance in the p -value ( p < 0.05) and delta_ELPD is negative, it can be assumed that horizontal multiplicity does not affect the inference of causal effects ( 17 ). In addition, we also used scatterplots to assess causality, which can visualize the heterogeneity of all causal assessment methods and show whether outliers have a large impact on the results; funnel plots and leave-one-out methods were used to evaluate the sensitivity and stability of the results.

3.1 Causal analysis of immunophenotypes and airway allergic diseases

To investigate the effect of different immune cell phenotypes on AADs, we performed TSMR on 731 immune cell phenotypes in relation to AR, AS, and CRS, respectively, with IVW as the primary analytical method, while the WM method was applied in cases of substantial heterogeneity. A p -value of less than 0.05 indicated a significant causal relationship. All IVs included in the final analysis had F -values greater than 10, and all results were tested for stability by funnel plots and leave-one-out tests.

3.2 Allergic rhinitis

A total of 47 immune cell phenotypes with clearly significant IVW were identified in the AR; all of them were free of heterogeneity. We excluded Mo MDSC AC (absolute count) due to horizontal pleiotropy (MR-PRESSO p = 0.044). Scatter plots were taken to see if there was a difference in the trends of the 46 immune cell analysis methods (beta), and five immune cells were markedly different, unstable for causal inference, and were removed. Reverse Mendelian randomization was then performed to explore whether there was reverse causality between AR and the remaining 41 immune cells, with AR as the exposure and 731 immune cells as the endpoints. The analysis revealed bidirectional causality for CD4 on CD39+ activated Treg, FSC-A on CD8br (bright), and CD45 on lymphocyte, which were excluded. The final screen identified 38 immunophenotypes of immune cells ( Supplementary Table S1 ), 12 different phenotypes of immune cells as risk factors for AR. Immune cells of 26 different phenotypes are protective against AR ( Figure 2 ).

Figure 2 Forest plot showing all immune cells with a positive causal relationship with AR. (A) immune cells with pathogenic effects. (B) Immune cells with protective effects; CI, confidence interval; br, bright cell; %, relative count; AC, absolute count; IVW, inverse variance weighted.

3.3 Allergic asthma

A total of 47 different cellular immunophenotypes significantly associated with AS were identified, among which 10 were removed due to significant heterogeneity. Despite the presence of heterogeneity in HVEM on CD45RA− CD4+ (Cochran’s Q p = 0.017, WM = 0.018), HLA DR on plasmacytoid DC (Cochran’s Q p < 0.001, WM < 0.001), and HLA DR on DC (Cochran’s Q p < 0.001, WM < 0.001), the results of the WM method were statistically significant and thus retained. CD20 on IgD− CD27− (beta MR-Egger = −0.016, beta WM = 0.014, beta IVW = 0.067) and CD14 on CD33dim HLA DR+ CD11b+ (beta MR-Egger = -0.016, beta WM = 0.022, beta IVW = 0.040) were removed due to inconsistent trends in analytical results, HVEM on CD45RA− CD4+ (MR-PRESSO p = 0.029), HLA DR on plasma cell DCs (MR-PRESSO p = 0.002), HLA DR on DCs (MR-PRESSO p = 0.017) significant levels of multiplicity were present and were excluded, reverse Mendelian results suggesting bidirectional causation of FSC-A on CD8br, CD4 on secreting Treg were eliminated, resulting in 33 remaining immune cells ( Supplementary Table S2 ), 19 immune cells are risk factors for AS, and 14 immune cells as protective factors in AS ( Figure 3 ).

Figure 3 Forest plot showing all immune cells with a positive causal relationship with AS. (A) immune cells with protective effects. (B) Immune cells with protective effects; CI, confidence interval; br, bright cell; %, relative count; AC, absolute count; IVW, inverse variance weighted; DP, double positive; EM, effector memory.

3.4 Chronic sinusitis

A total of 62 immune cells with different immunophenotypes associated with chronic rhinosinusitis were identified, of which 19 were heterogeneous, and 10 immune cells with significant WM results such as CM CD4+ AC (Cochran’s Q p < 0.001, WM = 0.024), CD4+ AC(Q p < 0.001, WM = 0.017) were retained, excluding nine highly heterogeneous immune cells; scatter plots to observe the trend of results for the remaining 53 immune cells, CD127− CD8br %T cell (beta MR-Egger = −0.003, beta WM = 0.028, beta IVW = 0.056), CD27 on IgD- CD38br (beta MR-Egger = −0.097, beta WM = 0.071, beta IVW = 0.068) had inconsistent trends; the inference of causality was not robust. Further assessment was performed for the presence of horizontal pleiotropy among the remaining immune cells. A total of 12 immune cells such as CM CD4+ AC (MR-PRESSO p = 0.001) and CD4+ AC (MR-PRESSO p = 0.001) were excluded due to the presence of horizontal pleiotropy. Subsequently, reverse Mendelian randomization of the remaining immune cells did not reveal the existence of significant reverse causality and, finally, 39 immune cells remained ( Supplementary Table S3 ), 17 immune cells are risk factors for CRS, and 22 immune cells are protective factors for CRS ( Figure 4 ).

Figure 4 Forest plot showing all immune cells with a positive causal relationship with CRS. (A) immune cells with protective effects. (B) Immune cells with protective effects; CI, confidence interval; br, bright cell; %, relative count; DN, double negative; DC, dendritic cell; HSC, hematopoietic stem cells; %, relative count; AC, absolute count; IVW: inverse variance weighted; TD, terminally differentiated; CM, central memory; DN, double negative.

3.5 Causal analysis of immune cells and AAD

To explore the immune cell phenotypes that are most likely to have an impact on AADs, three immune cell populations significantly associated with AADs, AS, AR, and CRS were taken for intersectional processing, and CD3 on CD39+ activated Treg was the only immune cell type that had positive causality for all three different AADs (IVW AR = 0.001, IVW CRS = 0.043, IVW AS = 0.027) and was protective in all three diseases (OR AR = 0.940, OR AS = 0.967, OR CRS = 0.976) without heterogeneity or horizontal pleiotropy ( Figure 5 ).

Figure 5 Forest plot showing the immune cells with positive causal relationship with three AAD; CI, confidence interval; AC, absolute cell counts.

When the screening conditions were relaxed moderately (considering only the presence or absence of significance of IVW, heterogeneity and trend inconsistency were acceptable), Mo MDSC AC (Myeloid cell, IVW AR = 0.014, IVW AS = 0.043, IVW CRS = 0.004) appeared to be a potentially critical immune cell phenotype for AADs. Mo MDSC AC is pleiotropic in all three diseases, and to determine whether pleiotropy actually affects the inference of causal effects, we validated it using the CAUSE package ( Figure 5 ). The results suggest that horizontal pleiotropy of the three disease species can influence the inference of causality, and no causality exists between Mo MDSC AC and AAD ( Table 1 ).

Table 1 Cause method of determining the effect of horizontal pleiotropy on causality.

4 Discussion

Building on Finland’s publicly available biogenetic data, we investigated potential causal relationships between a total of 731 phenotypes of immune cells and AR, AS, and CRS. A total of 101 immune cells showed positive causality for AR, AS, and CRS (AR = 38, AS = 33, CRS = 39), involving seven immune cell populations.

Classical Treg is a subpopulation of CD4+ T cells producing FOXP3 and CD25, with immunosuppressive functions, which could be further categorized into natural Treg (nTreg) and induced Treg (iTreg), with nTreg develop directly derived from the thymus, whereas iTreg are mainly produced by naïve CD4+ T cells after peripheral antigen stimulation and can differentiate into iTreg of different phenotypes ( 18 ), both of which require Foxp3 to maintain functional stability. Treg performs its immunosuppressive function by secreting inhibitory cytokines such as IL-10, TGF-β, IL35, and perforin. Classical Tregs with immunosuppressive functions are often characterized as CD4+ CD25+ CD127- Foxp3+ Treg cells. CD127 is also a key phenotype used to distinguish Tregs from other types of CD4+ T cells, and the expression of CD127 is negatively correlated with the expression of Foxp3 ( 19 ). When Treg function is suppressed, it can easily lead to the onset and exacerbation of many autoimmune diseases ( 20 ). In addition to Th1/Th2 imbalance, Treg/Th17 is an important influence on the pathogenesis of airway allergic inflammation ( 21 , 22 ); there is a very complex link between Th17 and Treg, which both diverge from naïve CD4+ T cells, which can differentiate into Treg only when induced by TGF-β. When TGF-β and IL-6 are present at the same time, the CD4 + T cells will turn to differentiate into Th17, this process is in a state of dynamic equilibrium, which maintains a stable immune state of the organism, when there is an imbalance of the cytokine environment in the surroundings, the production of Treg decreases, and the production of Th17 increases, which aggravate the allergic inflammation and the high reaction of the airways ( 23 , 24 ). In conclusion, classical Treg is important for keeping immune stability and suppressing the onset of autoimmune diseases. Our study found that CD3 on CD39+-activated Tregs (CD4+ CD39+ CD25+++ CD45RA- CD127 lo Treg) played a protective role in three types of AAD. CD39 has been identified as an E-NTPD enzyme, predominantly expressed on the surface of Treg cells, which can degrade extracellular ATP into AMP, thereby reducing the pro-inflammatory effects of extracellular ATP and enhancing the immunosuppressive effects of Tregs ( 25 , 26 ). Aberrant CD39 expression can suppress the function of Tregs, increase the expression of sensitized CD8+ T cells, leading to increased allergic symptoms, and can also alter the distribution of NKT in the lungs of mice, exacerbating AAD ( 27 , 28 ). Similarly, a significant decrease in the proportion of CD3+ CD39+ Tregs was also observed in the peripheral blood of patients with severe asthma. In addition, in recent years, CD39 has also been used to identify and recognize high-functioning Tregs ( 29 ). The above evidence proves the importance of CD39+ for the immunosuppressive function of Tregs. CD3+ is a phenotype shared by T cells, which can promote the activation and differentiation of Tregs and enhance their immunosuppressive function. During the activation process of T cells, the CD3-TCR complex must first bind to antigenic peptide fragments presented by MHC on the surface of other antigen-presenting cells, subsequently activating the proliferation and inhibitory functions of T cells. Once T cells are activated, to limit the intensity of T-cell activation, cells achieve the recycling and degradation of the CD-TCR complex through endosomal recycling ( 30 ). This self-regulatory process occurs in almost all T cells, including Tregs. Therefore, the expression level of CD3 determines the quantity of CD3-TCR and the surface density level of endosomal recycling, which also represents the intensity of T-cell activation to a certain extent. Treatment with anti-CD3 can significantly inhibit the proliferation of CD4+ T cells in the peripheral blood of patients with AS and, in mice, anti-CD3 treatment was observed to inhibit CD4+ T-cell activity in lung tissue and blood vessels, significantly reducing the level of asthma inflammation ( 31 ). Although there are few reports on the relationship between CD3 expression levels and Treg function and activation, the above evidence also provides us with certain insights, that is, an increase in CD3 expression levels may help enhance the immunosuppressive function of Tregs and promote Treg activation. Our other Treg results also suggest that the expression level of CD3 on different phenotypic Tregs may be key to Treg treatment of AAD ( Figures 2 – 4 ). In summary, our research results further emphasize the importance of CD3 on CD39+-activated Tregs in the development of AADs from a causal perspective and provide new insights and a basis for further exploration of new AAD treatment targets based on CD3 and CD39 in the future.

However, not all Treg in all states have immunosuppressive functions. CD4+ CD25+ Treg isolated from patients with SLE were unable to inhibit effector T cells and monocytes from releasing inflammatory cytokines, although they remained cellularly active, probably because tumor necrosis factor α (TNF-α) causes Treg to impair the function of Treg ( 32 , 33 ). In addition, Treg can also express inflammatory cytokines from other types of Th cells through internal reprogramming, a behavior known as Treg plasticity, which has been identified in multiple autoimmune diseases ( 23 , 34 ), This Th2-like Treg cell production was observed in the sensitized state, the Th2-like Treg is triggered by IL-4 and IL-13 and is associated with significant cellular phenotypic changes, which can secrete a large number of sensitizing pro-inflammatory factors, but still have some inhibitory activity of Th1 and Th2 ( 35 ). The above evidence suggests that Treg does not simply exercise an immunosuppressive function, but may also contribute to disease exacerbation in different environments and with different phenotypes. Human CD4+ Foxp3+ T cells can generally be classified into Foxp3 lo CD25++ CD45RA+ (resting Treg), Foxp3 hi CD25+++ CD45RA− (activated Treg), and Foxp3 lo CD25++ CD45RA− (cytokine-secreting T cells). Unlike resting and activated Tregs, Foxp3 lo CD25++ CD45RA− cytokine-secreting T cells do not have an immunosuppressive function but can exacerbate inflammation by secreting cytokines such as IL-17 and IFN-γ ( 36 ). Some scholars currently consider it to be a subtype of Tregs, and this type of Cytokine-Secreting Treg has been observed to have significantly higher expression in the peripheral blood of asthma patients compared to healthy individuals, with expression levels increasing as the severity of asthma increases ( 37 ). Our research did not identify any specific Treg phenotypes that promote AS. However, we noted that the secreting Treg AC (CD25++ CD45RA- CD127lo) have a protective effect against AS. The primary distinction in phenotype between it and cytokine-secreting T cells lies in the opposite levels of expression of CD127 and Foxp3, highlighting to some extent the importance of Foxp3 and CD127 expression levels in maintaining the suppressive function of Tregs. Furthermore, in AR, we found that CD28 on CD39+ secreting Treg (CD28 on CD4+ CD39+ CD25++ CD45RA- CD127 lo ) has a pathogenic role. CD28 is a protein receptor expressed on the surface of T cells that can bind to CD80/CD86 to activate T cells, and CD28 plays an important role in maintaining Treg proliferation and homeostasis ( 38 ). However, Zheng and his team have found that using anti-CD28 antibodies to block CD28 can enhance the inhibitory function of Tregs, possibly due to the blockade of CD28 altering the interaction between Tregs and dendritic cells (DCs) ( 39 ). Although our findings suggest that CD28 on CD39+ secreting Treg may be a risk factor for AR, the absence of literature directly linking this specific phenotype with AR, together with the potential risk of false positives due to the selection of analysis thresholds in our study, necessitates further confirmation through clinical and cellular experimentation. The role of Tregs in CRS remains complex, with studies reporting that CD25+/CD4+ FOXP3+ T cells are significantly higher in CRS with nasal polyps than in CRS without nasal polyps. However, reports also indicate that Treg dysfunction can lead to Th1/Th2 imbalance, exacerbating CRS ( 40 , 41 ). Moreover, the immunological process of CRS varies among different ethnicities and regions; for instance, patients with CRS with nasal polyps in Western countries tend to have Th2-type inflammation, while patients in Southeast Asia tend to have Th1/Th17 immune imbalance ( 42 ). Among protective factors, we have found that the expression level of CD3 significantly affects the protective role of Tregs in CRS. Our research also discovered that activated and secreting Treg AC is the only Treg phenotype combination that has a pathogenic effect on CRS. Consistent with our findings, Ickrath and his team discovered that the expression of activated Treg in nasal polyp tissues of chronic rhinosinusitis is significantly higher than in peripheral blood ( 43 ). Tregs have a strong suppressive effect on inflammation, and we consider that the main reason for the dysfunction of Tregs in CRS may be the functional plasticity of Tregs. In summary, this provides important insights for exploring the functional diversity of Tregs in CRS and innovation in future treatment strategies.

B cells develop by differentiation from bone marrow hematopoietic stem cells and are most well known for their function of producing antibodies. B cells are very important to the immune system and are the primary effector cells of humoral immunity. B cells are categorized into different subpopulations based on their function and origin, which includes naive B cells, transitional B cells, plasma cells, and others. Similarly, immune phenotypes and functions differ between subtypes ( 44 ). It has been established that B cells can act and activate Th2 cells as antigen-presenting cells. Significantly elevated nasal mucosal and blood species–specific IgE antibodies were observed in AR patients, expression of CD23+ B cells was markedly elevated in AR patients in comparison to normal subjects ( 45 ). A recent study discovered that CD38+ B cells cause Treg/Th17 imbalance and exacerbate allergic symptoms through the secretion of IL-6, and that the combined application of CD38-antibody may enhance the therapeutic effect of AIT ( 46 ). Apart from the sensitizing effect through IgE, Breg is a subpopulation of B cells involved in modulating immune tolerance, promotion of naive CD4+ T-cell differentiation into Treg cells, and suppression of Th1 and Th17 cell differentiation ( 47 ); as a major IL-10 secreting cell, Breg can effectively inhibit allergic inflammation and suppress eosinophil production; as with Treg described earlier, there has been insufficient study of the function of Breg in AAD, which may be due in part to its different immunophenotypes ( 48 ). Trb are immature B cell types in transition that have just acquired a functional B-cell antigen receptor and from the bone marrow; it migrates to the peripheral lymphoid organs, awaiting activation and maturation. Different subtypes of Transitional B cells also have different functions, for example, the T2/T3 type produces IL-10 to reduce CD4 + T-cell proliferation but, in some autoimmune diseases, Trb also secretes anti-inflammatory factors (IL-6 and TNF-α) that disrupt the Treg/Th17 balance ( 49 , 50 ). Our results suggest that CD19 on transitional may be a risk factor for AS; however, a recent study found that after 6 months of treatment with Dupilumab in patients with severe asthma, the number of TrB cells in the patients was elevated and the total serum IgE was significantly decreased, but the paper did not explore the specific functions and immunophenotypes of TrB; this difference may also be due to different immunophenotypes ( 51 ), in addition, in AR, the relative count of Trb may be a potential risk factor (Transitional %B cell, p IVW = 0.003, OR=1.156), whereas the absolute count (AC) of Trb may be a risk factor for being a CRS (Transitional AC, p IVW = 0.014, OR = 1.04).

Maturation stages of T cells mainly include CD4+/CD8+ T cells. CD4+ T cells, CD45RA is primarily expressed on the surface of naïve T cells and is one of their surface markers. The expression of CD45RA gradually decreases during the maturation process of T cells ( 52 ), also known as Th0 cells, can differentiate into different subtypes such as Th1, Th2, Th3, Treg, Th17, and Tfh. CD8+ T cells are also known as cytotoxic T cells, and their special antiviral and antitumor capabilities are well recognized. Different subtypes have different impacts on the immune system; different T cells cooperate with each other through promotion or suppression to coordinate the immune balance in the body. Myeloid cells include granulocytes, monocytes, dendritic cells, and other cells ( 53 ). Myeloid-derived suppressor cells (MDSCs) consist of myeloid-derived myeloid progenitor cells and immature cells; MDSC expression was markedly increased in acute inflammation, severe infections and tumors, and negatively regulates immune function, a recent study showed that MDSCs are engaged in the invigoration of Th2 cells, which induces airway hyperresponsiveness and asthma, and MDSC levels have been reported in AR, AS, and other allergic diseases. Elevated MDSC is reported in AR, AS, and other allergic diseases, but MDSC expression is also elevated in healthy individuals after exposure to allergens, suggesting the possibility that MDSCs may have both inhibitory and pro-validating roles, and that the roles of different phenotypes of MDSCs and chemokines may be the key factors influencing the function of MDSCs ( 54 ).Our research only found that one MDSC phenotype has a protective effect against AAD (CD14 on Mo MDSC, p IVW-AR = 0.025, beta AR = -0.032, OR AR = 0.968). No other causal relationship between MDSCs and AAD was identified.

Monocytes are also an important part in the immune system. The most studied monocyte in AAD is the macrophage, which can be polarized by stimuli from the surrounding environment into subpopulations with different phenotypes and functions ( 55 ), for example, M2-type macrophages can promote Th2 cell differentiation, leading to Th1/Th2 imbalance and recruitment of eosinophilic infiltration, leading to exacerbation of AAD symptoms. It is worth noting that no monocyte type was found to have a direct causal relationship with CRS in our results, in addition; cDC are important immune cells with strong antigen phagocytosis and can promote Treg differentiation. It has also been shown that cDC can exacerbate AAD by modulating Th2 cells through the p38α and Fas pathways ( 56 – 58 ); however, in our results, no cDC cells were found to have a positive causal relationship with AR. It is noteworthy that some studies have found that high expression of CD62L in plasmacytoid dendritic cells of AS patients can promote Th2-type inflammatory responses ( 59 ). Our research has discovered that low expression of CD62L in cDCs can also promote AS. This result suggests that even the same phenotype may have different effects on different types of DC cells, and the expression and function of CD62L may be crucial in DCs and AAD.

5 Conclusion

To our knowledge, it is the first research to explore the causal relationship between immune cells of different immunophenotypes and AAD; we demonstrated the causal relationship between the three AAD disorders and different phenotypes of immune cells through a rigorous two-way two-sample Mendelian randomization analysis, which reduces confounding bias and improves the reliability of our results. As our results demonstrate, different phenotypes of immune cells have different effects on AAD, and perhaps there is a difference in just a single phenotype, but the functions may be completely opposite, suggesting a complex regulatory model between the immune system and AAD. In addition, our study results provide a theoretical foundation for the development of more personalized and precise treatment plans for AAD and can also help clinicians better understand the pathophysiological mechanisms of patients and formulate more effective treatment strategies. By gaining a deeper understanding of the interactions between immune cells and AAD, we can further explore new therapeutic targets. Although further research is needed to validate our results and explore their clinical application value, we believe that this study will provide valuable reference and guidance for the prevention and treatment of AAD.

However, some limitations of our study exist, firstly, we appropriately expanded the inclusion when immune cells were used as exposure ( p < 1 × 10 −5 ), which may somewhat contribute to biased results and false positives; second, all our data sources are based on European populations, and extrapolation to other races should be construed with caution and, last, because of the lack of personal information, we were unable to stratify the population analysis any further. Additionally, it is regrettable that there is still a lack of expression Quantitative Trait Loci (eQTL) data for different phenotype immune cells in publicly available databases, which to some extent limits our ability to better understand and explore the role of different phenotype immune cells in AAD. Therefore, we will continue to focus on and explore the eQTL data of different phenotype immune cells in our future research to improve our study results. We believe that with the continuous improvement of public databases and the efforts of more researchers, the role of different phenotype immune cells in AAD will be better understood in the future, and new biomarkers and therapeutic targets will be discovered.

In conclusion, we expect that this study will help researchers to explore the role of different immunophenotypes of immune cells for AAD and provide valuable clues for the development of further immunotherapeutic approaches for AAD.

Data availability statement

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

Ethics statement

The studies involving humans were approved by Sardinian Regional Ethics Committee The Coordinating Ethics Committee of the Hospital District of Helsinki and Uusimaa (HUS). The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and institutional requirements.

Author contributions

ZX: Conceptualization, Data curation, Formal analysis, Methodology, Project administration, Resources, Software, Validation, Visualization, Writing – original draft, Writing – review & editing. RL: Conceptualization, Data curation, Formal analysis, Methodology, Resources, Software, Validation, Visualization, Writing – review & editing. LW: Data curation, Formal analysis, Investigation, Methodology, Resources, Software, Validation, Writing – review & editing. YiW: Data curation, Methodology, Resources, Writing – review & editing. YT: Data curation, Writing – review & editing. YS: Data curation, Writing – review & editing. YM: Data curation, Writing – review & editing. RL: Data curation, Writing – review & editing. YaW: Data curation, Writing – review & editing. CZ: Data curation, Writing – review & editing. SH: Data curation, Writing – review & editing. SD: Data curation, Writing – review & editing. HP: Data curation, Writing – review & editing. JX: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – review & editing.

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The authors received research grants from The National Natural Science Foundation of China(81970865) and Four “Batches” Innovation Project of Invigorating Medical through Science and Technology of Shanxi Province(2022XM06) and Research Project Supported by Shanxi Scholarship Council of China (2021-172), The funder had no role in the study design, data collection and analysis, decision to publish, or manuscript preparation.

Acknowledgments

We would like to thank every member of our team.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2024.1349470/full#supplementary-material

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Keywords: airway allergic disease, immunophenotype, immune cell, MR analysis, causal inference

Citation: Xu Z, Li R, Wang L, Wu Y, Tian Y, Su Y, Ma Y, Li R, Wei Y, Zhang C, Han S, Duan S, Peng H and Xue J (2024) Pathogenic role of different phenotypes of immune cells in airway allergic diseases: a study based on Mendelian randomization. Front. Immunol. 15:1349470. doi: 10.3389/fimmu.2024.1349470

Received: 04 December 2023; Accepted: 25 April 2024; Published: 15 May 2024.

Reviewed by:

Copyright © 2024 Xu, Li, Wang, Wu, Tian, Su, Ma, Li, Wei, Zhang, Han, Duan, Peng and Xue. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Jinmei Xue, [email protected]

† These authors have contributed equally to this work

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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Educational Case: Asthma: Clinical Features and Morphologic Findings

Maria kamal.

1 Department of Pathology, The University of Chicago, IL, USA

Mariam Ghafoor

Urooba nadeem, aliya n. husain.

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040 . 1

Primary Objective

Objective: RS4.4: Asthma . Compare and contrast the clinicopathological features and causes of asthma and describe the morphologic changes and consequences that result in airflow obstruction.

Competency 2: Organ System Pathology; Topic: Respiratory System (RS); Learning Goal 4: Obstructive Diseases of the Lung.

Patient Presentation

A 13-year-old male presents to the emergency department with acute onset of breathlessness. He has had recurrent, episodic attacks of wheezing, cough, dyspnea, itchy red eyes, nasal discharge, stuffiness, and occasional chest tightness for past 2 years. Initially, his symptoms were relieved by short-acting β-blocker, albuterol. However, the frequency and the severity of the symptoms have increased for the past 1 month with the patient waking up with these symptoms. He has a history of eczema. His family history is significant for asthma in his mother.

Diagnostic Findings

Physical examination reveals respiratory rate of 22/min and diffuse wheezing all over the lung fields. Pulmonary function test (PFT) shows FEV1/FVC (forced expiratory volume at 1 second [FEV1]/forced ventilatory capacity [FVC]) of 0.65. Forced expiratory volume at 1 second is 60% of predictive and post-bronchodilator therapy the FEV1 increases to 74% of predictive. Chest X-ray is normal.

Question/Discussion Points

What is the diagnosis based on clinical findings and pulmonary function test.

Clinical presentation (recurrent, episodic attacks of wheezing, cough, dyspnea, itchy red eyes, nasal discharge, stuffiness, and chest tightness), and PFT findings (FEV1/FVC of 0.65, FEV1 is 60% of predictive and post-bronchodilator therapy the FEV1 increases to 74% of predictive) are consistent with the diagnosis of asthma. Diagnosis of asthma can be confirmed if the evidence of airway obstruction is seen on PFT, especially if it is reversible with a bronchodilator as seen in our case.

What Type of Lung Disease Is Asthma, and What Are Other Diseases in That Category?

Obstructive diseases of lung are characterized by an increased airflow resistance due to partial or complete obstruction of airway at any level from the trachea to the respiratory bronchioles. In contrast, restrictive diseases show reduced lung parenchymal expansion leading to decreased total lung capacity. Obstructive pulmonary diseases can be distinguished from restrictive diseases based on pulmonary function tests. Obstructive disorders show decreased maximal airflow rates during forced expiration, usually expressed as the FEV1 over the FVC. Obstructive pulmonary diseases generally show a FEV1/FVC ratio of less than 0.7 contrasting with restrictive diseases that are characterized by a proportionate reduction in both total lung capacity and FEV1, resulting in normal FEV1/FVC ratio.

Asthma, emphysema, chronic bronchitis, and bronchiectasis are common obstructive lung diseases. Each has distinct clinical and pathologic characteristics ( Table 1 ). 2 Emphysema and chronic bronchitis are frequently grouped as chronic obstructive pulmonary disease (COPD), as the majority of patients share features of both. Also, both entities are triggered by cigarette smoking. Asthma can be distinguished from COPD by the presence of reversible bronchospasm.

Types of Obstructive Pulmonary Disease.

What Are the Differential Diagnoses Based on Clinical Findings?

Cystic fibrosis and noncystic fibrosis bronchiectasis.

Both cystic fibrosis (CF) and diffuse non-CF bronchiectasis present with chronic cough and abundant sputum production that is atypical for an asthmatic child. Furthermore, recurrent chest infections are seen in CF patients from a very young age. Patients with non-CF bronchiectasis frequently report productive cough with sputum expectoration, respiratory distress, growth retardation, and night sweats.

Primary ciliary dyskinesia

Primary ciliary dyskinesia (PCD) commonly involves lower airways. It may present as chronic asthma which is usually unresponsive to maintenance therapy. Patients with unexplained respiratory distress at birth and recurrent upper and lower respiratory infections should be screened for PCD.

Protracted bacterial bronchitis

It presents as chronic cough (lasting ≥ 4 weeks) not responding to asthma treatment and require a prolonged (minimum of 2 weeks) course of antibiotic treatment.

Airway foreign body

The sudden onset of respiratory symptoms is more suggestive of an accidental foreign body aspiration than a sudden onset of asthma. It is more common in young children. The patient may present with choking, persistent cough, unilateral and monophonic wheeze, and respiratory distress.

Vocal cord dysfunction

It is characterized by inappropriate adduction of the vocal cords during inspiration induced by exercise, psychological stress, or local irritation like reflux. It frequently coexists with asthma but is unresponsive to bronchodilator therapy. Patients present with breathlessness, intermittent aphonia or dysphonia, choking sensation, chest tightness or pain, difficulty swallowing, and throat clearing. Direct visualization of the vocal cords by endoscopy is the gold standard for the diagnosis. Abnormal shape of the inspiratory loop is seen on spirometry consistent with a variable extrathoracic obstruction.

Bronchiolitis obliterans

Bronchiolitis obliterans occurs secondary to viral and mycoplasma pneumonia infections. It frequently presents as persistent wheezing, rather than paroxysmal symptoms. Computed tomography scan shows a characteristic mosaic pattern and air trapping.

What Is Asthma?

Asthma is a chronic, episodic, inflammatory disorder of the airways associated with bronchoconstriction and airflow limitation that is at least partly reversible, either spontaneously or with treatment. The hallmarks of the disease are as follows 2 :

• ○ Increased airway responsiveness resulting in episodic bronchoconstriction
• ○ Inflammation of the bronchial walls
• ○ Increased mucus secretion

How Does It Present Clinically?

Patients with asthma present with dyspnea, cough, and wheezing due to sudden episodes of bronchospasm. 2 According to the latest National Asthma Education and Prevention Program guidelines, correctly diagnosing asthma is important by establishing the following 3 :

• ○ Episodic symptoms of airflow obstruction or airway hyperresponsiveness
• ○ Airflow obstruction or symptoms are at least partially reversible
• ○ Exclusion of alternative diagnoses.

What Is Acute Severe Asthma (Formerly Known as Status Asthmaticus)?

It is defined as a state of unrelieved attacks of asthma, formerly known as status asthmaticus. It is rare and may prove to be fatal. Usually, it is seen in patients with a long history of severe asthma. Patients may be asymptomatic between episodes. 2

What Are the Risk Factors of Asthma?

Certain factors contribute to the development of airway hyper-reactivity, leading to asthma. These are given as follows 2 :

• ○ Environmental allergens
• ○ Exercise, hyperventilation
• ○ Viral respiratory infections
• ○ Exposure to cold
• ○ Aspirin or nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity
• ○ Inhaled air pollutants such as smoking, sulfur dioxide, ozone, and nitrogen dioxide. Occupational exposure including fumes (epoxy resins, plastics), organic and chemical dusts (wood, cotton, platinum), gases (toluene), or other chemicals (formaldehyde, penicillin products)

What Are the Different Types of Asthma?

Asthma is classified as atopic or non-atopic based on presence or absence of an evidence of allergen sensitization. It may also be categorized according to the triggers that lead to bronchoconstriction. Table 2 shows various types of asthma. 2

Types of Asthma.

Abbreviations: IgE, immunoglobulin E; NSAIDs, nonsteroidal anti-inflammatory drugs.

What Is the Pathogenesis of Asthma?

Asthma results from an interplay between genetic factors, environmental factors, and immune response. Airway inflammation forms the core pathophysiologic mechanism. The pathogenesis of asthma is depicted in Figure 1 . Atopic asthma is characterized by a TH2 and immunoglobulin E (IgE) response to allergens in genetically predisposed individuals. The asthma related genetic polymorphisms possibly influence immune process. Some of the genetic associations are described below 2 :

• ○ Chromosome 5q has a susceptibility locus for asthma close to the gene cluster encoding the cytokines IL-3, IL-4, IL-5, IL-9, and IL-13 and IL-4 receptor among which IL13 gene polymorphisms have the strongest and most consistent association.
• ○ Alleles of class II HLA are associated with production of IgE antibodies against some antigens, like ragweed pollen.
• ○ ADAM33 (a metalloproteinase) gene polymorphisms may be related to increased proliferation of bronchial smooth muscle cells and fibroblasts.
• ○ β2-adrenergic receptor gene variants are linked to differential in vivo airway hyper-responsiveness and in vitro response to β-agonist stimulation.
• ○ IL-4 receptor gene variants are linked to elevated total serum IgE, atopy, and asthma.

Pathogenesis of asthma.

What Are the Morphologic Changes Seen in Asthma?

Gross appearance.

In patients with severe asthma, the lungs appear overinflated showing atelectatic areas. The most prominent gross finding includes airways (bronchi and bronchioles) occluded by thick, tenacious mucus plugs. 2

Microscopic Appearance

A characteristic microscopic finding is Curschmann Spiral ( Figure 2 ) seen in sputum or bronchoalveolar lavage samples of asthma patients. It is the result of mucus plugs extruding from subepithelial mucous gland or bronchioles. Numerous eosinophils with Charcot-Leyden crystals ( composed of an eosinophil protein called galectin-10) are also present. 2 There are other typical microscopic findings of asthma, collectively known as “airway remodeling” that result in airway obstruction, which include ( Figures 3 ​ – 5 ) 2 :

Curschmann spiral (1000×).

Sub-basement membrane fibrosis and submucosal eosinophilic infiltration (×200 magnification).

Squamous metaplasia, sub-basement membrane fibrosis and intraepithelial and submucosal eosinophilic infiltration (×400 magnification).

Goblet cell hyperplasia and smooth muscle hypertrophy (×100 magnification).

• ○ Airway wall thickening
• ○ Subbasement membrane fibrosis (due to type I and III collagen deposition)
• ○ Increase in vascularity and squamous metaplasia
• ○ An increase in the size of the submucosal glands and number of airway goblet cells
• ○ Hypertrophy and/or hyperplasia of the bronchial wall muscle

What Causes Airflow Obstruction in Asthma?

Airflow obstruction is a result of the following changes in asthma 4 :

• Acute bronchoconstriction due to IgE dependent release of mediators (early asthmatic response)
• Airway edema associated with allergen challenge that occurs 6 to 24 hours later (late asthmatic response)
• Exudation of serum proteins and cellular debris resulting in chronic mucus plug formation
• Airway remodeling resulting from structural changes due to chronic inflammation that impacts the extent of airway obstruction reversibility

Airway obstruction leads to increased airflow resistance and expiratory flow rate reduction. These changes result in reduced air expulsion and may lead to hyperinflation of the lung. This overdistention helps preserve airway patency, thus improving expiratory flow. However, it also increases the work of breathing by altering pulmonary mechanics.

Teaching Points

• Asthma results in reversible bronchoconstriction due to hyper-responsiveness of the airway to various stimuli.
• Atopic asthma is the result of an immunologic reaction to environmental allergens and is characterized by acute-phase (immediate) and late-phase reactions.
• Nonatopic asthma has less clear triggers but some viral infections and inhaled air pollutants are known to cause it.
• Almost all subtypes of asthma show eosinophils as key inflammatory cells but other inflammatory cells, for example, mast cells, neutrophils, and T lymphocytes can also be found.
• The irreversible component is the result of extensive airway remodeling (sub-basement membrane fibrosis, bronchial glands hypertrophy, and hyperplasia of smooth muscle).

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.

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Roula Khalaf, Editor of the FT, selects her favourite stories in this weekly newsletter.

The case studies below, featuring the most innovative legal teams in the Asia-Pacific region highlight examples of their work in the following areas:

Operational transformation

New product and services

Sustainability and impact

Commercial and strategic advice, digital solutions, using generative artificial intelligence, people and skills.

All the case studies were researched, compiled and ranked by RSGI. “Winner” indicates that the organisation won an FT Innovative Lawyers Asia-Pacific award for 2024

Read the other FT Innovative Lawyers Asia-Pacific ‘Best practice case studies’, which showcase the standout innovations made for and by people working in the legal sector:

Practice of law Business of law

Winner: Telstra Originality: 9; Leadership: 8; Impact: 8; Total: 25 The legal team at the Australian telecoms company has built on previous improvements to the way it prioritises work from the rest of the business. It created a tool that measures capacity and provides the team with a system for discussing its scope to take on work — deciding how to prioritise tasks within the team, or justifying putting them out to external counsel. The resulting transparency on capacity and costs has enhanced relationships with the rest of the business.

HSBC O: 8; L: 8; I: 8; Total: 24 In 2023, the bank’s regional legal team built and deployed several tools, including a digital portal to receive legal requests from the business, a centralised system for approving marketing campaigns, and a chatbot to handle responses to routine queries. They are, so far, used by the digital legal team, the litigation department, and one of the banking teams.

Highly commended

Boston Consulting Group O: 8; L: 8; I: 7; Total: 23 As part of BCG’s strategy to increase artificial intelligence and digital consulting fees significantly by 2026, its legal department in the region is collaborating with counterparts across the firm in initiatives such as overhauling risk and contractual frameworks. Internally, it is adopting workload management software and trialling generative AI automation tools.

IAG O: 7; L: 8; I: 8; Total: 23 In 2023, the Australian insurance company’s legal team improved its operations by automating the generation of complex contracts and by extending its programme for managing external spending to its teams in New Zealand. The team also introduced a dashboard that displays quarterly and monthly reports on legal expenditures and how external law firms perform.

Zongteng Group O: 7; L: 8; I: 8; Total: 23 Lawyers at the Chinese logistics business built a database that collects details of global legislation, legal commentaries and cases, and names of recommended external counsel in countries where the business operates. The resource helps the small legal team, mainly based in China, to provide global legal advice.

WiseTech Global O: 6; L: 8; I: 7; Total: 21 To gain support from the business for several operational changes, lawyers recorded precisely how they spent their time — an unusual practice for in-house teams. The scrutiny helped identify where alterations, such as introducing a contract management system, would help improve efficiency. The improvements have saved the team hundreds of hours in answering routine queries.

BHP O: 6; L: 7; I: 7; Total: 20 In preparation for making use of generative AI, the mining group’s legal team has upgraded its systems to store documents in one place and to collect structured data. The team estimates that the move has already cut lawyers’ time spent on administrative tasks by a quarter.

Toll Group O: 6; L: 7; I: 7; Total: 20 The legal team at the global logistics business introduced an automation tool to speed up contract approval. Some 3,000 requests have been yielding valuable insights, such as how often negotiators deviate from standard contract terms.

Dentsu O: 6; L: 7; I: 6; Total: 19 The Japanese-led global advertising group’s Asia-Pacific legal team worked with the chief technology officer and other departments to improve and extend oversight of new products’ commercial viability and any potential data privacy questions, as well as other legal risks.

Equinix O: 6; L: 7; I: 6; Total: 19 The regional section of the data centre operator’s global legal team has centralised and streamlined several processes to enhance its contract management systems.

New products and services

Joint winners: Hong Kong Exchanges and Clearing and HSBC Both legal teams: Originality: 8; Leadership: 8; Impact: 9; Total: 25 Launched in May 2023, the stock exchange operator’s Swap Connect programme allows offshore investors access to China’s $5tn interest rate swaps market, and is similar to existing programmes in Hong Kong that allow offshore investors to trade mainland bonds and stocks.

At Hong Kong Exchanges and Clearing (HKEX), the legal team helped structure the link-up, backed by the Shanghai Clearing House and the China Foreign Exchange Trade System, and worked to secure regulatory approval in the territory and mainland. At HSBC, lawyers drafted the contracts used by both the onshore and offshore investors.

DBS Bank O: 7; L: 9; I: 7; Total: 23 In 2023, the Singaporean bank set up a group to improve its handling of customer safety, led by a senior member of the legal team. It created an enhanced anti-malware tool for DBS to prevent users of its banking app logging in remotely if it detects signs of fraudulent activity. The bank says this change has stopped S$14mn ($10.3mn) being taken fraudulently from accounts. Another product enables digital deposits but only in-person withdrawals.

CIMB O: 6; L: 7; I: 8; Total: 21 Lawyers at the Malaysian banking group advised it on the rollout of online business loans and personal loans to domestic customers in the country.

Westpac O: 6; L; 7; I; 8; Total: 21 Lawyers at the Australian bank supported the product team in redesigning its mobile banking app, advising on new features, consumer rights and data protection.

Winner: Asian Development Bank Originality: 8; Leadership: 9; Impact: 8; Total: 25 The bank is working with UN agencies to send aid to people in Afghanistan without money passing through the Taliban. Usually, ADB works directly with governments to provide funding but, because the Taliban is not generally recognised as a government by the international community, aid had to be delivered through other channels.

The legal team successfully argued to stakeholders that, because Afghanistan does not exercise jurisdiction over UN agencies, those organisations are appropriate entities through which to deliver aid.

The lawyers negotiated with the UN agencies to ensure the arrangement met ADB’s strict transparency requirements, such as it being able to inspect any suppliers the UN contracted with as part of the collaboration.

DBS Bank O: 7; L: 8; I: 8; Total: 23 Since 2020, the legal and compliance team at the Singapore bank has run “hackathons”, alongside other organisations, to try to address wider social problems. The 2023 edition focused on mental resilience. Some 27 ideas were generated, two of which are being explored for further development.

MTR Corporation O: 6; L: 8; I: 7; Total: 21 The Hong Kong railway operator’s legal team helped it to execute its environmental, social and governance strategy. This included developing a new corporate structure and working to secure a patent for a product that uses cameras and AI to prevent damage to escalators from discarded objects.

Standard Chartered Bank O: 7; L: 7; I: 6; Total: 20 Sustainability experts in the Apac region’s legal team developed a process whereby the bank can assess and mitigate competition and antitrust risk when working on sustainable projects with counterparts in the banking industry.

Klook O: 7; L: 6; I: 7; Total: 20 After the travel company came under criticism over animal welfare standards at wildlife attractions, it took action to improve them. The legal team piloted a programme, working with accreditation business Asian Captive Elephant Standards, to help five elephant visitor attractions that sold tickets through Klook to meet the new standards. Some venues listed on Klook may still offer close-quarter wildlife experiences, but these are not promoted or sold through the Klook site itself.

Winner: SoftBank Originality: 8; Leadership: 9; Impact: 9; Total: 26 The legal team advised the Japanese investment group on last September’s initial public offering of its UK chip designer Arm in the US. To expedite the deal, lawyers also helped SoftBank acquire an additional 25 per cent of Arm from its Saudi-backed investment partner Vision Fund, the $100bn vehicle that is managed by SoftBank itself.

The lawyers negotiated with investors and dealt with scrutiny over this related-party transaction. The legal team also dealt with the US Securities and Exchange Commission in preparation for Arm’s IPO, which saw the Japanese company raise nearly $5bn while retaining 90 per cent of the business — making it the largest US listing in almost two years.

Asian Development Bank O: 7; L: 8; I: 8; Total: 23 The legal team at the Manila-based institution advised on the arrangement, structuring and syndication of a $692mn financing package signed last March to fund the construction of Monsoon Wind Power Project — the largest wind power plant in south-east Asia. Electricity generated from the plant under construction, the first wind farm in Laos, will be sold to neighbouring Vietnam. Features such as a $50mn concessional financing package, in case of delays, provide additional reassurance for commercial lenders.

Hong Kong Exchanges and Clearing (HKEX) O: 6; L: 9; I: 8; Total: 23 Lawyers at the stock exchange operator advised on narrowing the period between pricing and the start of share trading in an IPO from five days to two, via its new settlement platform Fast Interface for New Issuance, which was launched last year. The team worked with different stakeholders to digitise the previously paper-based system.

Australian Nuclear Science and Technology Organisation O: 7; L: 7; I: 7; Total: 21 The public research body’s lawyers worked with Australian legal design firm Inkling to improve the project agreements it uses when collaborating with a range of industry and academic partners. New contracts that clearly set out expectations and undertakings of projects are designed to improve the relationships between the organisation, including ANSTO scientists, and external researchers when working together on collaborations.

HSBC O: 7; L: 7; I: 7; Total: 21 Lawyers designed the documentation for HSBC’s role as sole settlement bank for a scheme to link Hong Kong’s Faster Payment System with PromptPay in Thailand. Nine banks and payment providers have so far signed up to use the scheme.

Recruit O: 7; L: 7; I: 7; Total: 21 Legal and data teams at Japan’s biggest recruitment agency, which has been expanding AI services for job searches and matching, have developed a new governance and review process to ensure compliance with AI and anti-discrimination laws globally.

Winner: Tencent Originality: 8; Leadership: 8; Impact: 9; Total: 25 The legal team at the Chinese technology company has set up a platform to simplify and speed up the review process when artificial intelligence features are added to Tencent apps. Product developers answer a series of questions about how they plan to use AI in an app and where the data will come from, which allows the legal team to say within a day if it should go ahead.

UBS O: 8; L: 9; I: 7; Total: 24 A tool devised by the Swiss bank’s lawyers in collaboration with the IT team assists in approval for data-transfer requests. It saves an estimated 1,000 hours of lawyer time annually and allows for faster approval of outsourcing projects at the bank.

Flex O: 7; L: 8; I: 7; Total: 22 To comply with the US-based manufacturing company’s data-security requirements, the China legal team bought a licence outright for a contract lifecycle management platform in order to be able to customise it. The tool works on English- and Chinese-language documents and has cut the review time required for procurement contracts from days to hours.

Fazz O: 7; L: 7; I: 7; Total: 21 The legal team at the Singaporean fintech is collaborating with police and government agencies in the city state to help prevent cyber crime. The lawyers have created a tool that streamlines responses to requests for information from the police.

AS Watson O: 6; L: 7; I: 7; Total: 20 The group legal team at the Hong Kong-based global health and beauty retailer has customised a legal operations management platform to act as a contract management system. The new system automates document drafting, streamlines the approvals process and cuts contract review times by up to 50 per cent.

Klook O: 6; L: 7; I: 7; Total: 20 The legal team at the Hong Kong-based travel company adopted a contract management system, for both sales and procurement, to handle a year-on-year doubling in contracts without adding more lawyers.

Winner: DBS Bank Originality: 9; Leadership: 8; Impact: 8; Total: 25 As a proof-of-concept exercise, the legal team used an application to retrieve news articles about customers that it wished to scrutinise over potential illicit or illegal activities. It then used generative artificial intelligence to summarise the items to highlight relevant coverage. The full version of this tool went live earlier this year and the team is piloting several other uses for generative AI in detecting money laundering and fraud.

Telstra O: 9; L: 8; I: 7; Total: 24 The legal team at the Australian telecoms business is testing a generative AI tool’s accuracy for translating laws, such as those regarding billing, into obligation statements for the business. The AI assesses Telstra’s processes for ensuring compliance and suggests measures to improve them.

Westpac O: 8; L: 8; I: 8; Total: 24 In collaboration with law firms, technology companies and other professional services businesses, the legal team at the Australian bank tested several generative AI tools in different scenarios. The team says it is already seeing productivity gains. One of the most promising tools links the bank’s underlying regulations and policies to its supplier contracts, which allows users to better understand the reasoning behind certain contract clauses.

Lazada O: 7; L: 8; I: 8; Total: 23 The legal team at the south-east Asian ecommerce business used generative AI to accelerate its contract review process and to identify common risks across different agreements. The team estimates that contract review is already 20 per cent to 30 per cent faster on its standard work.

GLP O: 7; L: 7; I: 7; Total: 21 The legal team at the Singapore-based international logistics company worked with colleagues, including the chief financial officer and the IT team, to store financial and legal documents centrally. This will give the business’s generative AI tool better access to data.

LG Chem O: 7; L: 8; I: 6; Total: 21 The legal team at the South Korean chemical company is using generative AI tools on Chinese and Korean-language documents, to help review the contents of contracts and redraft clauses more easily. It is currently used for simple contracts, such as non-disclosure agreements.

McKinsey & Company O: 7; L: 7; I: 7; Total: 21 Asia-Pacific lawyers at the consulting business are using its internal generative AI tool, Lilli, to help craft responses to external counsel, to critique their own legal arguments, and to assist in translation as the business uses more than 10 languages in the region.

Winner: Boston Consulting Group Originality: 8; Leadership: 9; Impact: 9; Total: 26 The US-based consultancy is aiming to double the proportion of fees it gets from AI and digital consulting to 40 per cent of its global revenues by 2026 (last year, revenues were $12.3bn). To help with this, BCG’s legal team in the region has hired a range of experts in technology, intellectual property, the metaverse, and AI ethics. To keep abreast of the latest developments in the field, the team has designated individuals to gather and update information across their practice areas to feed into different parts of the business.

Nanyang Technological University O: 7; L: 8; I: 9; Total: 24 At the start of 2024, the Singaporean university’s 22-person legal team established a “360” structure that expects all its lawyers to have a working knowledge of all areas that the institution may need advice on. There are still specialists, but most queries can now be answered by anyone in the department.

DBS Bank O: 8; L: 9; I: 6; Total: 23 The legal and compliance team at Singapore’s biggest bank has developed a strategy for coping with the anticipated disruption of generative AI in its business. It plans to move those doing work that becomes obsolete into new areas, while other jobs will be redesigned to create pooled resources that can better serve multiple business teams, assisted by AI tools. As many as 80 per cent of the legal team now use generative AI tools regularly.

HSBC O: 7; L: 8; I: 8; Total: 23 The bank’s legal team in the region centralised its training programmes on a single platform that allows lawyers to track their progress, view past materials, and create a customised development plan. Topics range from sustainability to digital and personal banking.

FedEx O: 7; L: 8; I: 7; Total: 22 Ten lawyers at the package delivery business used their training in more flexible working to introduce new practices to the rest of the region’s legal team.

Another 20 team members joined a workshop to help develop a chatbot that can assist in answering routine legal queries and accessing template documents.

Telstra O: 6; L: 8; I: 8; Total: 22 The legal team at the Australian telecoms business launched a training scheme for new graduate recruits and paralegals, where successful applicants rotate through several areas of Telstra’s in-house department and can spend six months to a year on secondment at an external law firm.

Uber O: 7; L: 8; I: 7; Total: 22 Members of the ride-hailing app’s regional legal team are now obliged to work as taxi drivers or food delivery riders one day per quarter, and share feedback with operations and product teams on how the business can be improved.

Airbnb O: 7; L: 7; I: 7; Total: 21 The holiday rental website set up a training scheme to prepare lawyers with skills required for senior roles. It comprises a dozen training sessions on key areas of legal expertise. Sessions include role-playing a presentation to a board of directors.

Macquarie O: 7; L: 7; I: 7; Total: 21 Lawyers at the Australia-based financial services group created an intranet for the business. It provides regularly updated resources about various areas of legal advice and identifies the best person to contact for each topic.

MSD (Merck) O: 7; L: 8; I: 6; Total: 21 The multinational pharmaceutical company’s legal team in China has launched a diversity and inclusion programme for five law firms it works with. The programme pairs in-house counsel and private practice lawyers at different seniority levels to discuss ideas and challenges in the field.

Jera O: 6; L: 7; I: 7; Total: 20 The legal team at the Japanese power company has adopted a new system for the intake and allocation of work. It uses the resulting data to identify skills gaps and shape training and hiring.

McCain Foods O: 6; L: 8; I: 6; Total: 19 The Asia-Pacific legal team at the global frozen foods company rebranded internally, with the aim of making its communications, such as legal notifications, more immediately noticeable to the rest of the business.

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