case study bronchial asthma in acute exacerbation

Acute asthma exacerbation in adults

• Overview  
• Theory  
• Diagnosis  
• Management  
• Follow up  
• Resources  

When viewing this topic in a different language, you may notice some differences in the way the content is structured, but it still reflects the latest evidence-based guidance.

An acute asthma exacerbation in adults presents as an acute or subacute episode of progressive worsening of asthma symptoms, such as shortness of breath, wheezing, cough, and chest tightness.

Pulse rate, respiratory rate, subjective assessment of respiratory distress, accessory muscle use, and auscultation of the lung fields are key factors to assess during physical examination.

An increase in airway obstruction that can be quantified objectively by peak flow measurement is typical in an acute exacerbation.

Early administration of bronchodilators and corticosteroids relieves airflow obstruction and helps to prevent future relapses. Severe exacerbations often require additional therapy including oxygen, magnesium, and, in some circumstances, mechanical ventilation.

Pneumonia, pneumothorax, pneumomediastinum, and respiratory failure are complications.

An asthma exacerbation is an acute or subacute episode of progressive worsening of symptoms of asthma, including shortness of breath, wheezing, cough, and chest tightness. Exacerbations are marked by decreases from baseline in objective measures of pulmonary function, such as peak expiratory flow rate. [1] Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention. 2023 [internet publication]. https://ginasthma.org/2023-gina-main-report

This topic covers the management of adults. Children 12 years and older are generally treated the same as adults. However, consult your local paediatric guidance as there may be some differences in the treatment approach and weight-based dosing may be recommended in some adolescents.

History and exam

Key diagnostic factors.

• shortness of breath
• risk factors
• progressive chest tightness
• progressive decrease in lung function
• tachycardia
• silent chest
• accessory muscle use
• sleep disturbance

Other diagnostic factors

• exercise limitation
• altered consciousness
• skin symptoms
• hypotension

Risk factors

• viral infection
• uncontrolled asthma symptoms
• high use of short-acting beta-2 agonists
• inadequate use of inhaled corticosteroids
• incorrect inhaler technique
• low forced expiratory volume in 1 second (FEV1)
• high bronchodilator reversibility
• current smoker (including e-cigarettes) or exposure to second-hand cigarette smoke
• exposure to allergens (including history of seasonal allergic rhinitis)
• air pollution
• poor indoor air quality
• chronic rhinosinusitis
• gastro-oesophageal reflux disease
• confirmed food allergy
• history of asthma
• history of hospitalisation for asthma exacerbations
• one or more severe exacerbations in the last 12 months
• use of oral corticosteroids
• poor adherence to asthma treatment
• psychological or socioeconomic problems
• blood eosinophils
• elevated fractional exhaled nitric oxide (FeNO)
• respiratory bacterial infection

Diagnostic investigations

1st investigations to order.

• arterial blood gas (in hospital)
• peak flow (in the community and in hospital)
• pulse oximetry (in the community and in hospital)
• chest x-ray (in hospital)

Investigations to consider

• full blood count (in hospital)
• urea and electrolytes (in hospital)
• C-reactive protein (in hospital)
• theophylline levels (in hospital)
• ECG (in hospital)

Treatment algorithm

Life-threatening exacerbation or impending respiratory failure, acute severe exacerbation, moderate exacerbation, symptomatic asthma post-stabilisation, contributors, expert advisers, jonathan bennett, md.

Honorary Professor of Respiratory Sciences

University of Leicester

Respiratory Consultant

Glenfield Hospital

JB is deputy medical director of the Royal College of Physicians (RCP) Invited Service Reviews, and speaker at national society meetings including the British Thoracic Society, the Primary Care Respiratory Society, and the Society for Cardiothoracic Surgery.

Disclosures

JB is deputy medical director of RCP Invited Service Reviews.

Richard Russell, MBBS, PhD, MRCP

Specialty Registrar in Respiratory Medicine

RR has received support from Chiesi, covering registration fee, travel, and accommodation, to attend a conference.

Acknowledgements

BMJ Best Practice would like to gratefully acknowledge the previous expert contributors, whose work has been retained in parts of the content:

Sourav Majumdar, MD

Clinical Assistant Professor (Affiliated)

Division of Pulmonary, Allergy and Critical Care Medicine

Department of Medicine

Stanford University School of Medicine

Lauren Eggert, MD

SM and LE declare that they have no competing interests.

Peer reviewers

Pujan h patel, md.

Consultant in Respiratory Medicine

Royal Brompton Hospital

PP has received speaker fees for educational lecture events from GlaxoSmithKline.

Emma Quigley

Section Editor, BMJ Best Practice

EQ declares that she has no competing interests.

Tannaz Aliabadi-Oglesby

Lead Section Editor, BMJ Best Practice

TAO declares that she has no competing interests.

Julie Costello

Comorbidities Editor, BMJ Best Practice

JC declares that she has no competing interests.

Adam Mitchell

Drug Editor, BMJ Best Practice

AM declares that he has no competing interests.

Differentials

• Acute bronchiolitis
• Foreign body/obstruction
• Global strategy for asthma management and prevention
• British guideline on the management of asthma

Calculators

Glasgow Coma Scale

Peak flow measurement animated demonstration

Patient information

Asthma in adults: what is it?

Asthma in adults: what treatments work?

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• Assessment and...

Assessment and management of adults with asthma during the covid-19 pandemic

Read our latest coverage of the coronavirus pandemic.

• Related content
• Peer review
• Thomas Beaney , academic clinical fellow in primary care 1 ,
• David Salman , academic clinical fellow in primary care 1 ,
• Tahseen Samee , specialist registrar in emergency medicine 2 ,
• Vincent Mak , consultant in respiratory community integrated care 3
• 1 Department of Primary Care and Public Health, Imperial College London, London, UK
• 2 Barts Health NHS Trust, London, UK
• 3 Imperial College Healthcare NHS Trust, London, UK
• Correspondence to: T Beaney Thomas.beaney{at}imperial.ac.uk

What you need to know

In patients with pre-existing asthma, a thorough history and structured review can help distinguish an asthma exacerbation from covid-19 and guide management

In those with symptoms of acute asthma, corticosteroids can and should be used if indicated and not withheld on the basis of suspected covid-19 as a trigger

Assessment can be carried out remotely, ideally via video, but have a low threshold for face-to-face assessment, according to local arrangements

A 35 year old man contacts his general practice reporting a dry cough and increased shortness of breath for the past three days. He has a history of asthma, for which he uses an inhaled corticosteroid twice daily and is now using his salbutamol four times a day. Because of the covid-19 outbreak, he is booked in for a telephone consultation with a general practitioner that morning.

Asthma is a condition commonly encountered in primary care, with over five million people in the UK prescribed active treatment. 1 While seemingly a routine part of general practice, asthma assessment is a particular challenge in the context of the covid-19 pandemic, given the overlap in respiratory symptoms between the two conditions and the need to minimise face-to-face assessment. Over 1400 people died from asthma in 2018 in England and Wales, 2 while analyses of non-covid-19 deaths during the covid-19 outbreak have shown an increase in deaths due to asthma, 31 highlighting the need to distinguish the symptoms of acute asthma from those of covid-19 and manage them accordingly.

This article outlines how to assess and manage adults with exacerbations of asthma in the context of the covid-19 outbreak ( box 1 ). We focus on the features differentiating acute asthma from covid-19, the challenges of remote assessment, and the importance of corticosteroids in patients with an asthma exacerbation.

Asthma and covid-19: what does the evidence tell us?

Are patients with asthma at higher risk from covid-19.

Some studies, mostly from China, found lower than expected numbers of patients with asthma admitted to hospital, suggesting they are not at increased risk of developing severe covid-19. 3 4 5 However, these reports should be viewed cautiously, as confounding by demographic, behavioural, or lifestyle factors may explain the lower than expected numbers. Recent pre-print data from the UK suggest that patients with asthma, and particularly severe asthma, are at higher risk of in-hospital mortality from covid-19. 6 In the absence of more conclusive evidence to indicate otherwise, those with asthma, particularly severe asthma, should be regarded as at higher risk of developing complications from covid-19. 7

Can SARS-CoV-2 virus cause asthma exacerbations?

Some mild seasonal coronaviruses are associated with exacerbations of asthma, but the coronaviruses causing the SARS and MERS outbreaks were not found to be. 8 9 In the case of SARS-CoV-2 virus, causing covid-19, data from hospitalised patients in China did not report symptoms of bronchospasm such as wheeze, but the number of patients with pre-existing asthma was not reported. 10 More recent pre-print data from hospitalised patients in the UK identified wheeze in a minority of patients with Covid-19. 11 Given the overlap of symptoms, such as cough and shortness of breath, until further published data emerges, SARS-CoV-2 may be considered as a possible viral trigger in patients with an asthma attack.

What you should cover

Challenges of remote consultations.

Primary care services have moved towards telephone triage and remote care wherever possible to minimise the risk of covid-19 transmission. This brings challenges to assessment as visual cues are missing, and, unless the patient has their own equipment, tests involving objective measurement, such as oxygen saturation and peak expiratory flow, are not possible. In mild cases, assessment via telephone may be adequate, but, whenever possible, we recommend augmenting the consultation with video for additional visual cues and examination. 12 However, many patients, particularly the elderly, may not have a phone with video capability. If you are relying on telephone consultation alone, a lower threshold may be needed for face-to-face assessment.

Presenting symptoms

Start by asking the patient to describe their symptoms in their own words. Note whether they sound breathless or struggle to complete sentences and, if so, determine whether immediate action is required. If not, explore what has changed, and why the patient has called now. The three questions recommended by the Royal College of Physicians—asking about impact on sleep, daytime symptoms, and impact on activity—are a useful screening tool for uncontrolled asthma. 13 Alternative validated scores, such as the Asthma Control Questionnaire and Asthma Control Test, which include reliever use, are also recommended. 14 In assessing breathlessness, the NHS 111 symptom checker contains three questions—the answers may arise organically from the consultation, but are a useful aide memoire:

Are you so breathless that you are unable to speak more than a few words?

Are you breathing harder or faster than usual when doing nothing at all?

Are you so ill that you’ve stopped doing all of your usual daily activities?

Consider whether an exacerbation of asthma or covid-19 is more likely. Both can present with cough and breathlessness, but specific features may indicate one over the other (see box 2 ). Do the patient’s current symptoms feel like an asthma attack they have had before? Do symptoms improve with their reliever inhaler? Do they also have symptoms of allergic rhinitis? Pollen may be a trigger for some people with asthma during hay fever season.

History and examination features helping distinguish asthma exacerbation from covid-19 10 11 14 15 16

Exacerbation of asthma*.

Improvement in symptoms with reliever inhaler

Diurnal variation

Absence of fever

Coexisting hay fever symptoms

Examination:

Reduced peak expiratory flow

Close contact of known or suspected case

Dry continuous cough

Onset of dyspnoea 4-8 days into illness

Flu-like symptoms including fatigue, myalgia, headache

Symptoms not relieved by inhaler

Absence of wheeze

Peak expiratory flow may be normal

*Note SARS-CoV-2 infection may be a trigger for an asthma exacerbation

Risk factors and medications

To assess the risk of deterioration, ask specifically about any previous hospital admissions for asthma and about oral corticosteroid use over the past 12 months. Does the patient have any other high risk conditions or are they taking immunosuppressive drugs? Ask the patient if they smoke and take the opportunity to offer support to quit.

Are they prescribed an inhaled corticosteroid (ICS) or a long acting β agonist (LABA) and ICS combination inhaler? Are they using this regularly? Are they using a spacer device, and do they have a personal asthma action plan to guide management?

Psychosocial factors

Taking a psychosocial history can be more challenging over the telephone, where cues are harder to spot. Lessons from asthma deaths have shown that adverse psychosocial factors are strongly associated with mortality. 14 17 These include a history of mental health problems, lack of engagement with healthcare services, and alcohol or drug misuse, along with employment and income problems. Social isolation is also a risk factor, which may be exacerbated during social distancing measures. 17 The covid-19 outbreak is an anxious time for many patients, and symptoms of anxiety can contribute to the overall presentation.

Examination

In remote assessment, video can help guide decision making, and we recommend its use in asthmatic patients presenting with acute symptoms. First, assess the general appearance of the patient. A fatigued patient sitting up in bed, visibly breathless, and anchoring their chest will raise immediate concerns, as opposed to someone who is walking around while talking. Vocal tone and behaviour may indicate any contributing anxiety. Observe if the patient can speak in complete sentences, listen for audible wheeze, and count the respiratory rate. Assess the work of breathing, including the use of accessory muscles, and consider the use of a chaperone where appropriate. The Roth score is not advocated for assessment of covid-19 or asthma. 18

Further objective assessment can be made, such as measuring peak expiratory flow (PEF). If the patient does not have a PEF device at home, one can be prescribed, though this may not be feasible in an acute scenario. We recommend that PEF technique be witnessed via video to assess reliability. Silent hypoxia may be a feature of covid-19, and oxygen saturations should be measured if this is a concern. 19 In some regions, oxygen saturation probe delivery services are being implemented, which may facilitate this. Heart rate can also be provided by the patient if they use conventional “wearable” technology, although, given the potential inaccuracies with different devices, the results should not be relied on. 20 If time allows, inhaler technique can also be checked.

What you should do

Determine the most likely diagnosis.

Decide on the most likely diagnosis on the basis of the history and clinical features (see box 2 and fig 1 ) or consider whether an alternative or coexisting diagnosis is likely, such as a bacterial pneumonia or pulmonary embolus. If you suspect covid-19 without asthmatic features, manage the patient as per local covid-19 guidance.

Assessment and management of patients with known asthma during the covid-19 outbreak 14

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Determine severity and decide if face-to-face assessment is necessary

If asthmatic features are predominant, determine severity and treat according to Scottish Intercollegiate Guidelines Network (SIGN) and British Thoracic Society (BTS) guidance ( fig 1 ). 14 If the patient cannot complete sentences or has a respiratory rate ≥25 breaths/min, treat the case as severe or life threatening asthma and organise emergency admission. A peak expiratory flow (PEF) <50% of best or predicted or a heart rate ≥110 beats/min also indicate severe or life threatening asthma. If the patient does not meet these criteria, treat as a moderate asthma attack—a PEF of 50-75% of best or predicted helps confirm this. If they do not have a PEF meter, or if you are unsure as to severity, brief face-to-face assessment to auscultate for wheeze and assess oxygen saturations can help confirm the degree of severity and determine if the patient may be suitable for treatment at home with follow-up. Do not rely solely on objective tests and use clinical judgment to decide on the need for face-to-face assessment, based on knowledge of the patient, risk factors, and any adverse psychosocial circumstances.

Wheeze has been reported as a presenting symptom in a minority of patients with confirmed covid-19, and it may be difficult to rule out the presence of SARS-CoV-2 via remote assessment. 11 We recommend that, when a face-to-face assessment is needed, it should take place via local pathways in place to safely assess patients with suspected or possible covid-19—for example, at a local “hot” clinic. At present, performing a peak flow test is not considered to be an aerosol generating procedure, but the cough it may produce could be, so individual risk assessment is advised. 21 Consider performing PEF in an open space or remotely in another room via video link. Any PEF meter should be single-patient use only and can be given to the patient for future use.

Initial management when face-to-face assessment is not required

For moderate asthma exacerbations, advise up to 10 puffs of a short acting β agonist (SABA) inhaler via a spacer, administered one puff at a time. There is no evidence that nebulisers are more effective: 4-6 puffs of salbutamol via a spacer is as effective as 2.5 mg via a nebuliser. 22 Alternatively, if the patient takes a combined inhaled corticosteroid and long acting β agonist (LABA) preparation, then maintenance and reliever therapy (MART) can be used according to their action plan. 14 Management of an acute exacerbation should not rely solely on SABA monotherapy, so advise patients to follow their personal asthma action plan and continue corticosteroid treatment (or start it if they were not taking it previously) unless advised otherwise ( box 3 ). Antibiotics are not routinely recommended in asthma exacerbations.

Risks and benefits of inhaled and oral corticosteroids in asthma and covid-19

There is substantial evidence for the benefits of steroids in asthma. Regular use of inhaled steroids reduces severe exacerbations of asthma 23 and the need for bronchodilators, 24 while the prompt use of systemic corticosteroids during an exacerbation reduces the need for hospital admissions, use of β agonists, 25 and relapses. 26

The evidence for corticosteroid use in early covid-19 is still emerging. A systematic review of steroid use in SARS reported on 29 studies, 25 of which were inconclusive and four of which suggested possible harm (diabetes, osteoporosis, and avascular necrosis) but no reported effects on mortality. 27 WHO have cautioned against the use of systemic corticosteroids for the treatment of covid-19 unless indicated for other diseases. 28

In light of the strong evidence of benefits in patients with asthma, inhaled and oral corticosteroids should be prescribed if indicated in patients with symptoms of bronchoconstriction. Steroids should not be withheld on the theoretical risk of covid-19 infection, in line with guidance from the Primary Care Respiratory Society (PCRS), British Thoracic Society (BTS), and Global Initiative for Asthma (GINA). 15 22 29

Response to initial SABA or MART treatment can be assessed with a follow-up call at 20 minutes. If there is no improvement, further treatment may be necessary at a local hot clinic for reviewing possible covid-19, emergency department, or direct admission to an acute medical or respiratory unit depending on local pathways. For those who do respond, BTS-SIGN and GINA advise starting oral corticosteroids in patients presenting with an acute asthma exacerbation (such as prednisolone 40-50 mg for 5-7 days). 14 15 There is an increasing move in personalised asthma action plans to early quadrupling of the inhaled corticosteroid dose in patients with deteriorating control for up to 14 days to reduce the risk of severe exacerbations and the need for oral steroids. 15 30 However, there may be a ceiling effect on those who are already on a high dose of inhaled corticosteroid (see BTS table 14 ), so quadrupling the dose may not be effective in this group of patients. A personalised asthma action plan is an extremely helpful guide to treatment and should be completed or updated for all patients.

Follow-up and safety-netting

We recommend that all patients with moderate symptoms are followed up via remote assessment within 24 hours. Asthma attacks requiring hospital admission tend to develop relatively slowly over 6-48 hours. 14 However, deterioration can be more rapid, and symptoms can worsen overnight. Patients should be advised to look out for any worsening breathing or wheeze, lack of response to their inhalers, or worsening PEF. They should receive clear advice on what to do, including use of their reliever, and who to contact (such as the local out-of-hours GP provider, 111, or 999). With potential long waits for remote assessment, particularly out of hours, they should be advised to have a low threshold to call 999 if their symptoms deteriorate. If covid-19 infection is also suspected, advise them to isolate for seven days from onset of symptoms and arrange testing, according to the latest guidance. 7

How this article was created

We performed a literature search using Ovid, Medline, and Global Health databases using the search terms (asthma OR lung disease OR respiratory disease) AND (coronavirus OR covid-19)). Articles from 2019-20 were screened. We also searched for specific guidelines, including NICE, British Thoracic Society, Scottish Intercollegiate Guidelines Network, Primary Care Respiratory Society, European Respiratory Society, International Primary Care Respiratory Group, Global Initiative for Asthma, and the American Academy of Allergy, Asthma and Immunology.

Education into practice

Do you feel confident in completing personalised asthma plans in collaboration with patients?

How often do you start or increase inhaled corticosteroids in patients at initial presentation with an exacerbation of asthma?

If you manage a patient with acute asthma remotely, what safety netting advice would you give and how could you check understanding?

How patients were involved in the creation of this article

No patients were involved in the creation of this article.

This is part of a series of occasional articles on common problems in primary care. The BMJ welcomes contributions from GPs.

Contributors: TB and TS conceived the article. TB, DS, and TS carried out the literature review and wrote the initial drafts. All four authors contributed to editing and revision, and VM provided expert advice as a respiratory specialist. All authors are guarantors of the work.

Competing interests: We have read and understood BMJ policy on declaration of interests and have no relevant interests to declare.

Provenance and peer review: Commissioned, based on an idea from the author; externally peer reviewed.

• Mukherjee M ,
• Stoddart A ,
• ↵ Asthma UK. Asthma facts and statistics. https://www.asthma.org.uk/about/media/facts-and-statistics/ .
• Scabini S ,
• Mornese Pinna S ,
• Di Perri G ,
• De Rosa FG ,
• Williamson E. ,
• Walker AJ ,
• Bhaskaran KJ ,
• ↵ Public Health England. Guidance on social distancing for everyone in the UK [Withdrawn]. 2020. https://www.gov.uk/government/publications/covid-19-guidance-on-social-distancing-and-for-vulnerable-people/guidance-on-social-distancing-for-everyone-in-the-uk-and-protecting-older-people-and-vulnerable-adults .
• Shaker MS ,
• Oppenheimer J ,
• Grayson M ,
• China Medical Treatment Expert Group for Covid-19
• Docherty AB ,
• Harrison EM ,
• Greenhalgh T ,
• Pinnock H ,
• Campbell S ,
• ↵ Scottish Intercollegiate Guidelines Network & British Thoracic Society. Sign 158 British guideline on the management of asthma. 2019. https://www.sign.ac.uk/sign-158-british-guideline-on-the-management-of-asthma .
• ↵ Primary Care Respiratory Society. PCRS Pragmatic Guidance: Diagnosing and managing asthma attacks and people with COPD presenting in crisis during the UK Covid 19 epidemic. 2020. https://www.pcrs-uk.org/sites/pcrs-uk.org/files/resources/COVID19/PCRS-Covid-19-Pragmatic-Guidance-v2-02-April-2020.pdf .
• Rapoport AB
• Royal College of Physicians
• ↵ Centre for Evidence-Based Medicine. Question: Should the Roth score be used in the remote assessment of patients with possible COVID-19? Answer: No. 2020. https://www.cebm.net/covid-19/roth-score-not-recommended-to-assess-breathlessness-over-the-phone/ .
• Goldstein BA ,
• ↵ Public Health England. Guidance: COVID-19 personal protective equipment (PPE). 2020. https://www.gov.uk/government/publications/wuhan-novel-coronavirus-infection-prevention-and-control/covid-19-personal-protective-equipment-ppe .
• ↵ British Thoracic Society. Advice for healthcare professionals treating people with asthma (adults) in relation to COVID-19. 2020. https://www.brit-thoracic.org.uk/about-us/covid-19-information-for-the-respiratory-community/ .
• Pauwels RA ,
• Pedersen S ,
• START Investigators Group
• Bestall JB ,
• Lasserson TJ ,
• Spooner C ,
• Ducharme FM ,
• Bretzlaff JA ,
• Spooner CH ,
• Stockman LJ ,
• Bellamy R ,
• ↵ World Health Organization. Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected: Interim guidance 13th March 2020. 2020. https://www.who.int/docs/default-source/coronaviruse/clinical-management-of-novel-cov.pdf .
• ↵ Global Initiative for Asthma (GINA). 2020 GINA report, global strategy for asthma management and prevention. 2020. https://ginasthma.org/gina-reports/ .
• McKeever T ,
• Mortimer K ,
• ↵ Office for National Statistics. Analysis of death registrations not involving coronavirus (COVID-19), England and Wales: 28 December 2019 to 1 May 2020. Release date: 5 June 2020. https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/deaths/articles/analysisofdeathregistrationsnotinvolvingcoronaviruscovid19englandandwales28december2019to1may2020/technicalannex .

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Article Contents

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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• Supplementary Data

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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• Spontaneous pneumomediastinum complicating asthma exacerbation
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• Chukwudumebi Okafor ,
• http://orcid.org/0000-0003-2714-5923 Sarthak Soin and
• Joao Francisco Figueiredo Marcondes Ferraz
• Department of Internal Medicine , Presence Saint Joseph Hospital , Chicago , Illinois , USA
• Correspondence to Dr Sarthak Soin, sarthaksoin{at}gmail.com

https://doi.org/10.1136/bcr-2018-229118

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• pneumomediastinum

Description

Pneumomediastinum is an uncommon condition characterised by the accumulation of air in the mediastinum. Pneumomediastinum is frequently associated with other forms of extra-alveolar air, including pulmonary interstitial emphysema, pneumopericardium, pneumothorax, subcutaneous emphysema, pneumoretroperitoneum and pneumoperitoneum. 1 The majority of patients with spontaneous pneumomediastinum have predisposing factors that cause increase in airway pressure, which leads to alveolar rupture. Most commonly, this results from straining against a closed glottis (Valsalva manoeuvre) as during vomiting, coughing, or exercising. 2  Oesophageal perforation (OE) is another important cause of spontaneous pneumomediastinum. However, these individuals are more likely to present with history of multiple or severe episodes of emesis and retching along with features of shock such as hypotension and tachycardia. 3 OE are often complicated by mediastinitis and sepsis, early diagnostic imaging is the goal in order to improve survival. 4 5 The incidence of pneumomediastinum in adult patients with asthma exacerbations is unknown. 6 7 Vianello et al published a study of 45 patients with severe acute asthma exacerbations who underwent radiologic imaging on admission and found that 11% had pneumomediastinum. 8

Blood work-up showed elevated white cell count 20×10 9 /L, lactate 6.6 mmol/L and anion gap of 13mEq/L. Blood cultures and influenza/respiratory syncytial virus (RSV) PCR were unremarkable. Chest X-ray showed linear lucencies traversing the mediastinum and low neck consistent with pneumomediastinum. CT chest showed a very large pneumomediastinum throughout the chest extending well into the neck  (figures 1 and 2 ). There was air surrounding the oesophagus although no focal oesophageal abnormality was noted effectively ruling out OE in absence of features of shock. There was prominent pneumopericardium and air extending into the spinal canal at the level of the thoracic and cervical spine. Repeat chest X-rays showed persistent subcutaneous emphysema with pneumomediastinum but no evidence of pneumothorax.

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CT chest axial showing large pneumomediastinum in the pericardial region.

CT chest sagittal showing prominent pneumomediastinum extending throughout the middle mediastinum and superior mediastinum well into the soft tissues of the neck.

He was managed with high-flow oxygen, nebulised bronchodilators, intravenous steroids, fluids and morphine for pain and was subsequently discharged on day three of admission.

Learning points

Spontaneous mediastinum occurs as a result of sudden rise in the intra-alveolar pressure resulting in rupture of alveoli.

Management is conservative, however high flow oxygen might enhance the reabsorption of air from the mediastinum.

CT chest imaging is an important initial diagnostic tool if spontaneous pneumomediastinum secondary to oesophageal perforation is suspected.

Acknowledgments

Dr. William M. Sanders MD, Department of Pulmonology at Presence Saint Joseph Hospital Chicago

• Meireles J ,
• Castro A , et al
• Akinyemi R ,
• Akisanya C , et al
• Brinster CJ ,
• Singhal S ,
• Lee L , et al
• Koullias GJ ,
• Korkolis DP ,
• Wang XJ , et al
• Ng TT , et al
• Greenstone MA , et al
• Vianello A ,
• Caminati M ,
• Chieco-Bianchi F , et al

Patient consent for publication Not required.

Contributors CO, SS and JFFMF have contributed equally in writing and reviewing of the manuscript. SS is the article guarantor.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests None declared.

Provenance and peer review Not commissioned; externally peer reviewed.

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Am Fam Physician. 2024;109(1):43-50

Author disclosure: No relevant financial relationships.

Asthma exacerbations, defined as a deterioration in baseline symptoms or lung function, cause significant morbidity and mortality. Asthma action plans help patients triage and manage symptoms at home. In patients 12 years and older, home management includes an inhaled corticosteroid/formoterol combination for those who are not using an inhaled corticosteroid/long-acting beta 2 agonist inhaler for maintenance, or a short-acting beta 2 agonist for those using an inhaled corticosteroid/long-acting beta 2 agonist inhaler that does not include formoterol. In children four to 11 years of age, an inhaled corticosteroid/formoterol inhaler, up to eight puffs daily, can be used to reduce the risk of exacerbations and need for oral corticosteroids. In the office setting, it is important to assess exacerbation severity and begin a short-acting beta 2 agonist and oxygen to maintain oxygen saturations, with repeated doses of the short-acting beta 2 agonist every 20 minutes for one hour and oral corticosteroids. Patients with severe exacerbations should be transferred to an acute care facility and treated with oxygen, frequent administration of a short-acting beta 2 agonist, and corticosteroids. The addition of a short-acting muscarinic antagonist and magnesium sulfate infusion has been associated with fewer hospitalizations. Patients needing admission to the hospital require continued monitoring and systemic therapy similar to treatments used in the emergency department. Improvement in symptoms and forced expiratory volume in one second or peak expiratory flow to 60% to 80% of predicted values helps determine appropriateness for discharge. The addition of inhaled corticosteroids, consideration of stepping up asthma maintenance therapy, close follow-up, and education on asthma action plans are important next steps to prevent future exacerbations.

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The Global Asthma Report 2022. Int J Tuberc Lung Dis. 2022;26(supp 1):1-104.

Centers for Disease Control and Prevention. Most recent national asthma data. Accessed January 17, 2023. https://www.cdc.gov/asthma/most_recent_national_asthma_data.htm

McCoy K, Shade DM, Irvin CG, et al.; American Lung Association Asthma Clinical Research Centers. Predicting episodes of poor asthma control in treated patients with asthma. J Allergy Clin Immunol. 2006;118(6):1226-1233.

Meltzer EO, Busse WW, Wenzel SE, et al. Use of the Asthma Control Questionnaire to predict future risk of asthma exacerbation. J Allergy Clin Immunol. 2011;127(1):167-172.

Schatz M, Zeiger RS, Yang SJ, et al. The relationship of asthma impairment determined by psychometric tools to future asthma exacerbations. Chest. 2012;141(1):66-72.

Loymans RJB, Honkoop PJ, Termeer EH, et al. Identifying patients at risk for severe exacerbations of asthma: development and external validation of a multivariable prediction model [published correction appears in Thorax . 2018; 73(8): 795–796]. Thorax. 2016;71(9):838-846.

National Heart, Lung, and Blood Institute. National Asthma Education and Prevention Program. Expert panel report 3: guidelines for the diagnosis and management of asthma. 2007. Accessed June 15, 2023. https://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm

Reddel HK, Taylor DR, Bateman ED, et al. An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice. Am J Respir Crit Care Med. 2009;180(1):59-99.

Jackson DJ, Bacharier LB. Inhaled corticosteroids for the prevention of asthma exacerbations. Ann Allergy Asthma Immunol. 2021;127(5):524-529.

Pollart SM, Compton RM, Elward KS. Management of acute asthma exacerbations. Am Fam Physician. 2011;84(1):40-47.

Global Initiative for Asthma. Global strategy for asthma management and prevention. 2023. Accessed June 15, 2023. https://ginasthma.org/wp-content/uploads/2023/07/GINA-2023-Full-report-23_07_06-WMS.pdf

Gibson PG, Powell H. Written action plans for asthma: an evidence-based review of the key components. Thorax. 2004;59(2):94-99.

Abramson MJ, Bailey MJ, Couper FJ, et al.; Victorian Asthma Mortality Study Group. Are asthma medications and management related to deaths from asthma?. Am J Respir Crit Care Med. 2001;163(1):12-18.

Salazar G, Tarwala G, Reznik M. School-based supervised therapy programs to improve asthma outcomes: current perspectives. J Asthma Allergy. 2018;11:205-215.

Cicutto L, To T, Murphy S. A randomized controlled trial of a public health nurse-delivered asthma program to elementary schools. J Sch Health. 2013;83(12):876-884.

Sobieraj DM, Weeda ER, Nguyen E, et al. Association of inhaled corticosteroids and long-acting β-agonists as controller and quick relief therapy with exacerbations and symptom control in persistent asthma: a systematic review and meta-analysis. JAMA. 2018;319(14):1485-1496.

Raymond TJ, Peterson TA, Coulter J. Chronic asthma treatment: common questions and answers. Am Fam Physician. 2023;107(4):358-368.

Cloutier MM, Baptist AP, Blake KV, et al. Expert Panel Working Group of the National Heart, Lung, and Blood Institute administered and coordinated National Asthma Education and Prevention Program Coordinating Committee. 2020 focused updates to the asthma management guidelines [published correction appears in J Allergy Clin Immunol . 2021; 147(4): 1528–1530]. J Allergy Clin Immunol. 2020;146(6):1217-1270.

Szefler SJ. Update on the NAEPPCC asthma guidelines: the wait is over, or is it?. J Allergy Clin Immunol. 2020;146(6):1275-1280.

Kim LHY, Saleh C, Whalen-Browne A, et al. Triple vs dual inhaler therapy and asthma outcomes in moderate to severe asthma: a systematic review and meta-analysis. JAMA. 2021;325(24):2466-2479.

Kew KM, Flemyng E, Quon BS, et al. Increased versus stable doses of inhaled corticosteroids for exacerbations of chronic asthma in adults and children. Cochrane Database Syst Rev. 2022(9):CD007524.

O’Byrne PM, FitzGerald JM, Bateman ED, et al. Inhaled combined budesonide-formoterol as needed in mild asthma. N Engl J Med. 2018;378(20):1865-1876.

Bateman ED, Reddel HK, O’Byrne PM, et al. As-needed budesonide-formoterol versus maintenance budesonide in mild asthma. N Engl J Med. 2018;378(20):1877-1887.

Crossingham I, Turner S, Ramakrishnan S, et al. Combination fixed-dose beta agonist and steroid inhaler as required for adults or children with mild asthma. Cochrane Database Syst Rev. 2021(5):CD013518.

Nwaru BI, Ekström M, Hasvold P, et al. Overuse of short-acting β 2 -agonists in asthma is associated with increased risk of exacerbation and mortality: a nationwide cohort study of the global SABINA programme. Eur Respir J. 2020;55(4):1901872.

Sturdy PM, Victor CR, Anderson HR, et al.; Mortality and Severe Morbidity Working Group of the National Asthma Task Force. Psychological, social and health behaviour risk factors for deaths certified as asthma: a national case-control study. Thorax. 2002;57(12):1034-1039.

Pumphrey RSH, Gowland MH. Further fatal allergic reactions to food in the United Kingdom, 1999–2006. J Allergy Clin Immunol. 2007;119(4):1018-1019.

Alvarez GG, Schulzer M, Jung D, et al. A systematic review of risk factors associated with near-fatal and fatal asthma. Can Respir J. 2005;12(5):265-270.

Chang YL, Ko HK, Lu MS, et al. Independent risk factors for death in patients admitted for asthma exacerbation in Taiwan. NPJ Prim Care Respir Med. 2020;30(1):7.

Roberts G, Patel N, Levi-Schaffer F, et al. Food allergy as a risk factor for life-threatening asthma in childhood: a case-controlled study. J Allergy Clin Immunol. 2003;112(1):168-174.

Nowak RM, Tomlanovich MC, Sarkar DD, et al. Arterial blood gases and pulmonary function testing in acute bronchial asthma. Predicting patient outcomes. JAMA. 1983;249(15):2043-2046.

White CS, Cole RP, Lubetsky HW, et al. Acute asthma. Admission chest radiography in hospitalized adult patients. Chest. 1991;100(1):14-16.

Perrin K, Wijesinghe M, Healy B, et al. Randomised controlled trial of high concentration versus titrated oxygen therapy in severe exacerbations of asthma. Thorax. 2011;66(11):937-941.

Rowe BH, Spooner CH, Ducharme FM, et al. Corticosteroids for preventing relapse following acute exacerbations of asthma. Cochrane Database Syst Rev. 2007(3):CD000195.

Edmonds ML, Milan SJ, Camargo CA, et al. Early use of inhaled corticosteroids in the emergency department treatment of acute asthma. Cochrane Database Syst Rev. 2012(12):CD002308.

Kirkland SW, Vandenberghe C, Voaklander B, et al. Combined inhaled beta-agonist and anticholinergic agents for emergency management in adults with asthma. Cochrane Database Syst Rev. 2017(1):CD001284.

Kew KM, Kirtchuk L, Michell CI. Intravenous magnesium sulfate for treating adults with acute asthma in the emergency department. Cochrane Database Syst Rev. 2014(5):CD010909.

Weber EJ, Silverman RA, Callaham ML, et al. A prospective multicenter study of factors associated with hospital admission among adults with acute asthma. Am J Med. 2002;113(5):371-378.

Grunfeld AF, Fitzgerald JM. Discharge considerations for adult asthmatic patients treated in emergency departments. Can Respir J. 1996;3(5):322-327.

Arnold DH, Gebretsadik T, Minton PA, et al. Assessment of severity measures for acute asthma outcomes: a first step in developing an asthma clinical prediction rule. Am J Emerg Med. 2008;26(4):473-479.

Hasegawa T, Ishihara K, Takakura S, et al. Duration of systemic corticosteroids in the treatment of asthma exacerbation; a randomized study. Intern Med. 2000;39(10):794-797.

Jones AM, Munavvar M, Vail A, et al. Prospective, placebo-controlled trial of 5 vs 10 days of oral prednisolone in acute adult asthma. Respir Med. 2002;96(11):950-954.

Chang AB, Clark R, Sloots TP, et al. A 5- versus 3-day course of oral corticosteroids for children with asthma exacerbations who are not hospitalised: a randomised controlled trial. Med J Aust. 2008;189(6):306-310.

Krishnan JA, Davis SQ, Naureckas ET, et al. An umbrella review: corticosteroid therapy for adults with acute asthma. Am J Med. 2009;122(11):977-991.

Higgins JC. The ‘crashing asthmatic.’. Am Fam Physician. 2003;67(5):997-1004.

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ERS/EAACI statement on severe exacerbations in asthma in adults: facts, priorities and key research questions

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Despite the use of effective medications to control asthma, severe exacerbations in asthma are still a major health risk and require urgent action on the part of the patient and physician to prevent serious outcomes such as hospitalisation or death. Moreover, severe exacerbations are associated with substantial healthcare costs and psychological burden, including anxiety and fear for patients and their families. The European Academy of Allergy and Clinical Immunology (EAACI) and the European Respiratory Society (ERS) set up a task force to search for a clear definition of severe exacerbations, and to also define research questions and priorities. The statement includes comments from patients who were members of the task force.

ERS/EAACI statement on severe exacerbations in asthma in adults http://bit.ly/2Hl8sqf

• Introduction

Asthma is one of the most common chronic diseases and its worldwide prevalence has risen around three-fold in recent decades [ 1 ]. With the recognition of the inflammatory nature of the disease and the introduction of inhaled corticosteroids, asthma control and the quality of life of asthma patients have substantially improved and many deaths have been prevented. Nevertheless, patients still face exacerbations of varying severity, ranging from increased symptoms to life-threatening episodes. Any asthmatic patient may suffer a severe exacerbation and even die from one; in fact, most exacerbations present in mild asthmatics, who are the majority of asthma sufferers [ 2 , 3 ]. The causes leading to exacerbations may be exposure to a triggering agent, lack of adherence to treatment or the inherent severity and hyperresponsiveness of the disease, and may be affected by comorbidities. Severe exacerbations of asthma likely carry most of the burden of the disease through their immediate and delayed associated risks. Severe exacerbations expose patients to immediate and delayed side-effects of high doses of bronchodilators and systemic corticosteroids, and quite often to antibiotics. Absenteeism, presenteeism, care-associated risks if admitted (nosocomial infection for example), anxiety and many other issues insufficiently describe all components of the burden of severe exacerbations. Epidemiological data remain heterogenous as very different definitions are used in cohorts and in clinical trials. For example, in TENOR II, 25.8% of the population reported a severe exacerbation [ 4 ]. In the MENSA study, among enrolled patients who reported 3.5±2.2 exacerbations before entering the study, 17–21% were admitted. During the trial, the mean rate of clinically significant exacerbation and exacerbation requiring admission fell to 1.74 and 0.10 respectively [ 5 ]. Unfortunately, asthma deaths still exist. Their rates are low and most of them are seen as preventable [ 6 , 7 ] in westernised countries. This also implies that some are not preventable, suggesting a place for new drugs to treat refractory episodes of near fatal asthma.

Accordingly, both the European Respiratory Society (ERS) and the European Academy of Allergy and Clinical Immunology (EAACI) elicited a task force in 2016 that aimed to review the most relevant research evidence and the current practice on definition, clinical identification of severe exacerbations, triggers and risk factors, management, and prevention. Subsequently, this document does not contain recommendations for clinical practice but offers recommendations for future research.

• Methodology

After the initial meetings, the task force members decided to address four main research questions related to serious exacerbations. 1) What are the available definitions for severe exacerbations in asthmatics and what would be an accurate definition? 2) Which are the trigger factors related to the initiation and severity of exacerbations? 3) What is the best way to manage severe exacerbations? 4) What is the best strategy to prevent them? Specific keywords and MeSH terms were identified based on several key references provided by the task force members, and the corresponding literature search was initiated for all sections using the MEDLINE and CENTRAL (Cochrane Library) Databases. Search results were extracted in .txt file formats and imported in a specially designed reference management software (Reference Manager Version 12) in order to screen for duplicates. Further processing of the search results was made in a stepwise approach (as shown in the supplementary material flow charts) based on the title, the abstract, and finally after reading the whole text, filtering for date (2000 and onwards), age (adults only), language (only English), and type (included: randomised and observational studies, and systematic reviews/meta-analyses; excluded: case reports and letters to the editor). All articles remaining after final processing for each section were sent back to the corresponding task force members for final evaluation (corresponding flow charts are available in the supplementary material ). From this sorting of the relevant literature, leaders of the four sections drafted a first version and each statement was kept or removed if any concern was expressed and no consensus could be found. During the subsequent dedicated meetings, research needs were identified, and tables and figures were reviewed.

• Definition of severe exacerbations of asthma

Asthma severity and control have more or less been defined and graded over the years so that the definitions are equally understood by all stakeholders [ 3 , 8 – 10 ]. This is not yet the case for asthma exacerbations, where exacerbations are defined as episodes characterised by more or less rapid increase in symptoms, sufficient to require a change in treatment [ 3 , 11 ]. Severe exacerbations are usually defined based on use of systemic, usually oral, corticosteroids (OCS), emergency care visits and/or hospitalisations [ 1 ], while in some clinical studies reductions in lung function (peak expiratory flow (PEF) or forced expiratory volume in 1 s of more than 20 or 30% have also been included in the definition ( table 1 ). It must be noted that patient perception and easy access to rescue corticosteroids and emergency care facilities may confound the definition and so may the retrospective collection of data. The ERS/American Thoracic Society (ATS) statement on exacerbations released in 2009 [ 12 ] defines severe exacerbations as events that require urgent action on the part of the patient and physician to prevent a serious outcome, i.e. hospitalisation or death. However, there is subjectivity in the perception of severity and moreover, many studies have shown that the risk of severe exacerbation is associated with a multitude of factors. These factors include 1) the level of asthma control, 2) asthma severity based on ERS/ATS definition [ 3 ], 3) lung function, 4) the presence of comorbidities, 5) the psychosocial status (to assess the ability to seek help in case of clinical worsening), 6) previous history of near fatal attacks and 7) response to treatment. Such factors seem important in guiding treatment decisions and, importantly, decisions regarding hospitalisations. Moreover, prediction models assessing future risk of exacerbations in adult asthma patients have been proposed, such as the one published by M iller et al. [ 13 ], based on the TENOR cohort. However, the applicability of such models has not been examined in large studies and needs to be assessed prospectively. Composite scores have been developed for use in other acute respiratory conditions, for example the CURB-65 (confusion, blood urea nitrogen greater than 7 mmol·L −1 , respiratory rate ≥30 breaths·min −1 , blood pressure <90 mmHg (systolic) or ≤60 mmHg (diastolic), age ≥65 years) or Pneumonia Severity Index score for pneumonia or GENEVA score for pulmonary embolism, and they greatly help clinicians in treatment decisions and are important for the safety of the patients. All task force members in their practice consider severe exacerbations of asthma as a significant worsening of the disease that require OCS treatment for at least 5 days. In the ERS/ATS task force report of 2009, a 3-day course of OCS was the recommended definition for clinical trials. This small difference was supported by all task force members as it may differentiate from patients with episodes of loss of control requiring short courses ( e.g. 1–2 days) of OCS and from temporary increase of maintenance treatment to improve the control of their disease. These patients may have an accumulated use of OCS over time equivalent to someone with repeated exacerbations but will not be reported as such. Whether 3 or 5 days of OCS is more accurate for discriminating a mild from a severe exacerbation will probably not be addressable in terms of evidence. 1) Herein we report an expert-based opinion that definitely does not intend to change the definition used in trials in order to keep them comparable; and 2) as the harmfulness of cumulative doses of corticosteroids is obvious above 0.5 g per year [ 14 ], a 5-day-based definition would make better fit this OCS-associated risk with the threshold of two exacerbations. Although variable among countries and systems, emergency visit or hospitalisation, the task force members base hospitalisation or initiation of treatment with OCS on the Global Initiative for Asthma (GINA) or British Thoracic Society recommendations to improve standardisation. It seems that it would be important to develop, test and use a composite score that takes into consideration the patient's previous health status, the presence of comorbidities, history of severe or near fatal exacerbations, adherence to treatment, psychosocial status, level of control and, of course, response to treatment (the latter is already factored into asthma exacerbation management guidelines), rather than just clinical severity at presentation and PEF or spirometry values.

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Examples of definitions of severe exacerbation in asthma patients used in the literature

• Triggers and risk factors

Assessment of risk: what is cause and what is effect?

The prevention of exacerbations is probably the most important aim for patients with asthma and healthcare professionals. In order to achieve this aim, it is important to plan the re-assessment of asthma patients and treatment adjustments because of the immediate risks ( i.e. acute respiratory failure, death) and future risks (recurrence of exacerbations, decline in lung function, and side-effects of treatments) [ 1 ]. Routine management strategies assess asthma control based on clinical symptoms, history of exacerbations and pulmonary function testing. In addition, in experienced centres, strategies guided by airway hyperresponsiveness or sputum eosinophilia may provide benefit for preventing future exacerbations [ 16 , 23 ]. In contrast, the use of fractional exhaled nitric oxide ( F ENO ) as a surrogate marker in asthma management is still inconclusive [ 24 – 26 ] except during pregnancy [ 27 ]. A recent meta-analysis found more supportive results deserving further evaluations [ 28 ].

Since a previous exacerbation has been shown to be an important risk factor for future exacerbations (even though this concept has been challenged) [ 29 ], the “frequent exacerbator” likely represents an important clinical phenotype; and asthma treatment should aim to modify what might look like an irreversible cycle [ 30 ]. For this purpose, multiple initiatives have investigated and weighed the importance of individual traits in predicting recurrent exacerbations. Many other characteristics and conditions have also been reported, such as amount of asthma medication, comorbidities including obesity, occupational stress [ 31 ], sensitisation, indoor and outdoor pollution, small airway dysfunction [ 32 ], loss of lung elastic recoil [ 33 ], and psychological factors [ 29 , 34 – 44 ]. Retrospective studies have shown that repeated assessment of composite scores of control, such as the Asthma Control Test or Asthma Control Questionnaire, and other tools, such as eHealth and mHealth [ 45 ], may predict severe exacerbations [ 46 ]. However, whether self-monitoring of asthma control score questionnaires at home can be useful to predict (and consequently, help to prevent) exacerbations in a real-life setting needs to be further investigated [ 47 – 49 ]. An index of fluctuation of PEF measurements at home was able to predict exacerbations [ 50 ]. Lastly, although a hospital admission provides proof of a severe exacerbation (see definition), the decision to hospitalise a patient with asthma also depends on the clinical course during management at the emergency department [ 2 , 51 , 52 ], and on additional factors, such as age, inflammatory phenotype, presence of comorbidities [ 53 , 54 ] and familial and social conditions [ 2 , 51 , 52 ].

Modifiable versus non-modifiable factors and mathematical models

Until recently, modifiable risk factors for exacerbations were mostly seen as behavioural issues or environmental triggers [ 55 – 58 ]. This included patients' beliefs (or parents' beliefs in the case of children) and expectations, poor inhalation technique and/or treatment adherence, (active or passive) smoking and allergen exposure (such as in-house pets, for example). More recently, the key role of viruses has been acknowledged, and viral triggers are now perceived as potentially modifiable factors. However, no therapeutic strategies have yet been able to successfully interfere with rhinovirus carriage and bouts of infections in children and adults; this is an important area of ongoing research. Accordingly, viral infection and impaired host responses to rhinovirus can be modelled to predict the potential of new antiviral drugs [ 53 , 59 – 61 ]. The synergistic action of allergen exposure ( e.g. seasonal pollens, house dust mite) and viruses may indicate a place for combining strategies targeting each factor alone or in association [ 38 , 55 , 62 ].

High blood eosinophil count, reflecting type 2 (T2) inflammation, is well-recognised as a significant risk factor for asthma exacerbations [ 63 ], with a consistent dose-ranging effect reproduced in different large-scale studies [ 64 , 65 ]. The relative weight of elevated blood eosinophilia with any other predictor of future exacerbation is largely unknown, but is influenced by the level of asthma control, asthma severity, asthma phenotype ( e.g. age at onset of asthma), lung function and history of exacerbations. Validated biomarkers reflecting non-T2 asthma phenotype(s) remain an urgent unmet need [ 66 ]. The recognition of T2-related traits makes a patient with uncontrolled severe asthma eligible for biological therapies targeting key T2 disease-drivers, such as eosinophils, interleukin (IL)-4, IL-13 and/or IgE [ 67 ]. Elevated blood eosinophil count is associated with an increased exacerbation risk and to date this is the most relevant phenotyping marker. The reduction in exacerbation rates provided by anti-IgE-, -TSLP (thymic stromal lymphopoietin), -IL-5 and -IL-4/IL-13 antibody therapy supports the concept that T2-associated asthma is associated with an increased risk of exacerbations [ 68 , 69 ], even though it is not the only one.

Asthma patients may follow many different trajectories [ 56 ]. These trajectories can be described under three main categories and sustain the concept of asthma severity (persistently severe, intermittently severe, never severe). Presently, exacerbations represent one of the key outcomes in asthma with the greatest asthma-related risks as defined by GINA [ 1 ] and hence, the development of innovative drugs and effective treatment modalities remains a priority. Exacerbations are episodes of acute respiratory distress; a situation that causes major stress for the patient themselves, their relatives and even for the healthcare providers. They represent an important economic burden both in terms of healthcare use and professional absenteeism. They are also associated with long-term risks (relapses, side-effects of treatments dominated by systemic steroids, lung function decline) [ 1 , 9 , 70 ]. Some single nucleotide polymorphisms and other gene modifiers summarised in figure 1 could be associated with such long-term risks [ 62 , 71 – 82 ]. It would appear worthwhile exploring the epigenetic modifications in well-characterised asthma populations, particularly in late onset disease.

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Potential severe asthma trajectories and the importance of risk factors and genetic variants (such as single nucleotide polymorphisms). This figure presents a summary of the literature and is not intended to be exhaustive.

Risk factors and epidemiology, pheno/geno/endotypes

Since severity of asthma is presently defined by treatment requirement, which partly relies on previous exacerbation rates [ 3 ], the frequency of exacerbations is associated with severity. However, exacerbations are not restricted to patients with the severe form of asthma.

Near-fatal asthma episodes can occur in patients even with so-called “mild asthma”, implying that “mild asthma” (GINA step 1 and 2) does not necessarily mean “low risk asthma”. Most of the time, these patients are not receiving any anti-inflammatory treatment at the time of the event and their asthma can be well-controlled when it is correctly managed and treated [ 2 , 35 ]. Near-fatal episodes represent a minority of exacerbations seen in the emergency department [ 2 ]. Interestingly, a hyperbolic curve relating inhaled corticosteroid (ICS) prescription refilling and asthma mortality is highly suggestive of a strong death-preventing effect of ICS use [ 83 ]. Actually, asthma deaths due to exacerbations have decreased over time in westernised countries. However, their incidence was still estimated to be more than 900 in the UK in the latest National Review of Asthma Deaths, and at least half of these dramatic cases were considered preventable [ 6 , 84 ].

Risk factors and clinical characteristics could be identified and robustly confirmed in different countries. These criteria should be known to all healthcare providers involved in the management of asthma and are shown in table 2 .

Risk factors for various outcomes in asthma exacerbations

Better characterisation of disease mechanisms is required in those patients with an incomplete response to ICS (across GINA steps) [ 70 ]. Defining clinical phenotypes and mechanistic endotypes is a useful concept that has been developed to better manage these patients [ 85 ]. In the SARP-3 cohorts, five factors were positively associated with exacerbation frequency: chronic sinusitis, gastro-oesophageal reflux, blood eosinophils, body mass index and bronchodilator responsiveness. Clusters in primary care identified early onset and obesity as risk factors for exacerbations. A cluster of obese female asthma patients with recurrent exacerbations has been described in both the SARP and UBIOPRED cohorts [ 86 , 87 ]. Furthermore, a large-scale study on children confirmed that obesity is linked with a shorter period of time between exacerbations [ 88 ]. Symptoms such as cough and wheeze are correlated with uncontrolled asthma, but are poorly associated with exacerbations [ 89 ]. Interestingly, new inflammatory patterns of exacerbations are currently described with the integration of the microbiome and T1-related cytokines [ 90 ]. A gene signature derived from sputum gene transcriptomics containing Charcot-Leyden crystal galectin (CLC); carboxypeptidase 3 (CPA3); deoxyribonuclease 1-like 3 (DNASE1L3); alkaline phosphatase, liver/bone/kidney (ALPL); CXCR2; and IL1β (a mixture of eosinophil and mast cell product with neutrophil-associated cytokines) can predict future exacerbation phenotypes of asthma, with the greatest biomarker performance compared to F ENO values and sputum eosinophil counts in identifying those who would experience frequent severe exacerbations [ 91 ].

It should be kept in mind that very high blood eosinophil counts ( e.g. more than a thousand per mm 3 ) are sometimes associated with other conditions such as eosinophilic granulomatous with polyangiitis or allergic bronchopulmonary aspergillosis, which overlap with severe asthma. These specific conditions are prone to very frequent exacerbations. They are sometimes difficult to discriminate from severe asthma when all the diagnostic criteria are not fulfilled [ 92 ].

Typology: gender and psychosocial factors, perception, compliance/adherence

Poor treatment adherence is a major trigger for loss of control at the population level, and this is a common finding also for onset of exacerbations [ 102 ]. Although ICS treatment is able to decrease the exacerbation rate at all dose ranges [ 103 ], it seems that an adherence of at least 75% of the prescribed dose (hazard ratio 0.61, 95% CI 0.41–0.90) is required to achieve this goal [ 103 ]. Of note, 24% of exacerbations can be attributed to poor adherence, which is often unintentional due to poor inhalation technique. Moreover, running out of inhaler was frequently reported in asthma patients attending the emergency department [ 104 ]. The use of multiple devices, especially when different principles are mixed, such as dry powder inhalers and metered dose inhalers (MDIs), is also a risk [ 105 ]. Non-consented switching of inhalers has also been shown to be a significant risk factor for exacerbation; these apparent cost-sparing measures in the short-term are thus subsequently countered by increased healthcare utilisation [ 106 ]. Alexithymia [ 107 ], specific personality traits [ 108 ], and poor perception of symptoms may lead to a delayed request for help [ 95 – 100 ]. Female gender [ 109 , 110 ], ethnicity [ 111 , 112 ] and patient beliefs [ 113 ] could also be identified as risk factors for exacerbation. The prevalence of psychological dysfunction, including anxiety and depression, is increased in patients with asthma and has been shown to be related to severity of disease [ 114 ]. Anxiety and depression are also strong predictors for poor asthma control [ 115 ].

Poor adherence is well-documented for ICS, but new injectable biological therapies also appear susceptible to this, particularly when self-administered [ 116 ]. On the other hand, self-administration is likely to improve access to treatment and to reduce the burden of the disease [ 117 ].

Several drawbacks could be raised against therapeutic educational programmes, but at present many simple and efficient solutions extensively reviewed elsewhere can work [ 70 , 102 ]. The benefits of written or web-based action plans are worthy of investigation [ 118 ]. Furthermore, e-Health solutions such as electronic reminder messages and, more recently, connected (to a computer or a smartphone) inhaler devices can be implemented and have been shown to be effective [ 119 , 120 ], but as they are usually only geared towards the use of one single inhaler per patient and no other medication it is likely of limited value for patients requiring multiple medications. However, these interventions should be prospectively evaluated for their ability to decrease exacerbation rates over time and whether they are really easing patients' lives. Stronger partnerships between patients and healthcare professionals are likely to improve adherence and new self-adherence programmes should be developed and tested for their effect on preventing (severe) exacerbations.

Although there is no perfect tool for associating a severe asthma exacerbation with poor adherence, a minimal adherence checklist is proposed in GINA and the task force decided to echo it presently ( table 3 ). Dose-counter displaying devices are preferred options according to a European Lung Foundation (ELF) open discussion organised for the present task force.

Factors affecting adherence in clinical practice, according to the Global Initiative for Asthma [1]

Virus/allergens

A synergy exists between respiratory viral infections and allergen exposure inducing asthma and causing exacerbations in susceptible, sensitised asthmatics [ 38 , 55 , 62 ]. Additionally, interaction between viral lower respiratory tract infections (LRTIs) and atopic sensitisation has been recognised as a major risk factor contributing to asthma development and exacerbations [ 62 , 121 ]. Birth cohort studies provide strong evidence for a synergistic effect of viral LRTIs and atopic sensitisation on risk of asthma inception, particularly in predisposed children [ 122 , 123 ]. Several studies in both sensitised children [ 55 , 124 ] and adults [ 16 , 38 ] found a strong association between the levels of specific IgE to inhaled allergens and viral LRTIs in increasing the risk of severe asthma exacerbations requiring hospital admission.

The synergy between allergen sensitisation and viral LRTIs has been indirectly confirmed in a study in asthmatic children, showing that pretreatment with omalizumab decreases asthma exacerbations in the fall/autumn, which are likely (rhino-) virus-induced [ 125 ]. Recent evidence demonstrates that omalizumab restores deficient anti-viral immunity in children with asthma, and that exacerbation reduction with omalizumab was greatest in those with greatest restoration of anti-viral immunity [ 125 ]. Rhinoviruses (RV), especially RV-A and RV-C groups, are the most frequent viruses detected during an asthma exacerbation, including severe asthma exacerbations with near-fatal and fatal asthma, and allergic asthma patients usually experience more severe and prolonged LRTI symptoms with RV infection compared to non-atopic healthy controls [ 38 , 55 , 126 – 128 ]. Interestingly, CDHR3 polymorphism is a risk factor for RV-induced severe asthma exacerbations in children [ 71 ], possibly because it has recently been shown to be an RV-C receptor [ 129 ]. Another study showed that documenting a viral infection in the emergency department was a strong predictor for emergency department re-attendance in children [ 130 ]. Impaired interferon responses to RV infection are associated with asthma in both adults and children [ 105 , 106 ], and are associated with increased RV-induced asthma exacerbation severity [ 131 ] Although appealing, the development of a RV vaccine appears highly challenging [ 132 ]. However, a proof of concept study on inhaled interferon-β as a therapeutic intervention in virus-induced asthma exacerbations only showed benefit in a subgroup of people with moderate/severe asthma [ 133 ], implying that further research is needed to investigate the concept of interferon supplementation in asthmatics at exacerbation onset.

Environmental factors: indoor/outdoor air pollution and occupational factors

Outdoor air pollution is an established risk factor for asthma exacerbations, although the magnitude of effect remains difficult to assess precisely [ 101 ]. Diesel exhaust particles and peaks of ambient air pollution, (reflected by, amongst others, high levels of nitrogen dioxide and ozone) were shown as concomitant factors to emergency department attendance in asthmatics but also could be epidemiologically related to asthma exacerbations and deaths [ 97 ]. Work-related exacerbations are probably underestimated, whereas many different non-specific irritants could be identified, such as mineral dusts, gas and fumes, etc . [ 134 ].

Indoor air pollution comprises second-hand tobacco smoke exposure, which is of special interest in children, and other less well-known contributors, such as volatile organic compounds [ 135 ]. Open fireplaces, sick building syndrome, cleaning supplies and household products, and inadequate ventilation are also to be integrated into potential sources of indoor air pollution. We propose to test whether facilitating access to air quality data records may prevent asthma exacerbations. The ELF, while reviewing the present manuscript, supports the use of portable air quality sensors, but more research is needed to identify what substances should be monitored and how best to do this.

Occupational sensitisers and triggers have been causes for concern for many years and efforts have been taken to limit their impact. All task force members in their practice consider it worthwhile facilitating access to free and independent experts in occupational medicine, as well as using F ENO , spirometry, and potentially other relevant diagnostic tests ( e.g. induced sputum) at work, especially considering their relatively low direct and indirect costs. More research is needed on occupational triggers and their effect on severe asthma exacerbations. Patients also raised the need to support asthma patients when choosing careers to avoid known and dangerous sensitisers and triggers.

Drugs and irritants/excessive use of β 2 -agonists

Whether drugs known to affect airway smooth muscle tone (such as β-blockers) are able to trigger an asthma exacerbation is unclear. Non-steroidal anti-inflammatory drugs and aspirin intake in susceptible patients induces asthma exacerbations, and low-dose induction of tolerance must be investigated to assess their benefit in preventing exacerbations.

Excessive use of short-acting β 2 -agonists (SABAs) in the absence of ICS use has long been linked to hospitalisations and asthma deaths, best exemplified by asthma death epidemics related to high doses of fenoterol reported in New Zealand and other countries [ 136 ]. Also, regular use of long-acting β 2 -agonists (LABAs) in the absence of ICS has been shown to increase significantly the risk of asthma exacerbations and asthma deaths potentially through a “masking” effect [ 137 – 139 ]. Not only overuse, but also regular use, of SABA (without ICS [ 140 ]) has also been associated with paradoxical asthma worsening [ 52 , 141 ]. The mechanisms involved are not fully understood, but may relate to induction of inflammatory mediators in bronchial epithelial cells by β 2 -agonists (both SABA and LABA), when administered in the absence of ICS [ 142 ], and/or by a tachyphylaxis phenomenon, but this is still to be demonstrated in vivo [ 143 ]. Because several short- and long-acting β 2 -agonists are now available, their potential side-effects should be assessed in detail and reported, especially as paradoxical triggers for loss of control and exacerbations. The task force members limit these issues by systematic concomitant ICS use and reassess the patients repeatedly. Most task force members avoid frequent and inappropriate use of repeated or regular high doses of SABA irrespective of the manner of administration (inhaled: pressurised MDI (pMDI), dry powder inhaler or nebulisation) without medical supervision.

• Acute management

Treatment of severe asthma exacerbations

Despite optimum maintenance therapy and appropriate prevention strategies, severe exacerbations occur, even in patients with mild disease or well-controlled asthma [ 1 , 144 ]. Therefore, proper assessment and adequate intervention are crucial to stabilise asthma and alleviate symptoms. Although in recent years there has been ample research into the treatment of stable asthma and several new drugs and formulations have been marketed, so far a limited number of treatments are available for asthma exacerbations while limited evidence exists in support of their use [ 145 ].

For patients presenting with acute asthma to primary care or the emergency department, the task force members consider that a proper assessment of exacerbation severity is determined based on history, physical examination and objective measurements of lung function and oxygen saturation (please refer to upper section of figure 2 ) [ 146 ]. Arterial blood gas measurements and chest radiography are not included in the guidelines dedicated to the initial assessment, nevertheless they are performed by all the task force members for patients with severe exacerbations and for those who do not respond to initial treatment or are deteriorating [ 147 – 149 ].

Assessment of exacerbation severity based physical signs and objective measurements. PEF: peak expiratory flow; ICU: intensive care unit; SABA: short-acting β 2 -agonist; ICS: inhaled corticosteroid; FEV 1 : forced expiratory volume in 1 s. Reproduced from the Global Initiative for Asthma Report with permission from the publisher [ 1 ].

Information from patients' history can identify those who are at increased risk of worst outcome and asthma-related death, and prompt arrangements to be made for more frequent evaluation and aggressive treatment ( table 2 ).

Treatment is usually started immediately and simultaneously with the initial evaluation of the patient. The following treatments are usually administered concurrently to achieve the most rapid resolution of the exacerbation and prevent patient deterioration.

Oxygen is usually delivered by nasal cannula or Venturi mask in order to achieve arterial oxygen saturation of 93–98%. In severe exacerbations, high concentration of oxygen increases the risk of hypercapnia while controlled low flow oxygen therapy is associated with better outcomes [ 150 – 152 ].

Short-acting β 2 -agonists

SABAs intend to resolve bronchospasm and to relieve acute symptoms of asthma, and are usually initially administered every 15–20 min for the first hour during an acute asthma exacerbation. Comparison of pMDI-spacer and nebuliser has shown increased efficiency of SABA delivery via pMDI-spacer and equivalent clinical outcomes [ 153 , 154 ]. Data are conflicting whether continuous nebulisation with a SABA is superior to intermittent nebulisation [ 155 , 156 ]. In severe asthma exacerbations, continuous nebulisation may be preferred, based on evidence of reduced admissions and improved pulmonary function [ 155 , 157 ]. There is no evidence to support the routine use of intravenous β 2 -agonists in patients with severe asthma exacerbations [ 158 ].

Ipratropium bromide

Adding ipratropium bromide to SABA decreases rates of hospitalisations and shortens emergency department stays for patients with severe asthma exacerbations [ 159 – 161 ]. Some evidence shows that the use of combination ipratropium/β-agonist therapy in acute asthmatic exacerbations provides benefit without increased risk of adverse events [ 161 ].

Corticosteroids

Early administration of systemic corticosteroids for the treatment of asthma exacerbations is considered a standard of care and is recommended worldwide to be given to the patient within 1 h of presentation [ 162 , 163 ]. A systematic review showed that the use of systemic corticosteroids reduces the rate of hospital admission in emergency department settings, especially in patients with severe asthma and those not currently receiving corticosteroids [ 164 ].

The optimal dose for systemic corticosteroids in asthma exacerbations remains to be established. Doses above 2 mg·kg −1 or 60–80 mg·day −1 do not add benefit to improving lung function, rates of hospital admission or length of hospital stay [ 162 , 165 ]. Furthermore, no differences are found between oral and intravenous administration of comparable corticosteroid doses [ 166 , 167 ]. Thus, daily doses of OCS equivalent to 50 mg prednisolone as a single morning dose, or 200 mg hydrocortisone in divided doses, are adequate for most patients [ 1 ]. A short course of 5 days OCS after emergency department treatment of acute asthma exacerbations has been shown to reduce the rate of relapse [ 1 , 164 ]. Courses longer than 5 days or a dose tapering did not provide additional benefit, while increasing side-effects [ 168 , 169 ].

The role of ICS in the management of asthma in the emergency department remain unclear and their use in severe asthma exacerbations is not evenly adopted [ 170 ].

Other treatments

None of the task force members use intravenous aminophylline and theophylline in the management of asthma exacerbations, in view of their poor efficacy and safety profile [ 1 ]. Intravenous magnesium sulphate (given as a single 2-g infusion over 20 min) has been shown to reduce hospital admissions in severe exacerbations and in patients who fail to respond to initial treatment [ 171 , 172 ]. Evidence does not support a role of antibiotics in asthma exacerbations unless there is strong presumption of lung infection [ 1 , 173 ]. Other associated advice for management (hydration, physiotherapy, avoid exercise, etc .) are poorly evidenced [ 174 ]. It is noteworthy that exercise outside an episode of exacerbation should be largely supported as it was shown to prevent exacerbations and to improve control [ 175 ].

Here we describe the evidence for current therapies available across the severity spectrum of asthma, licensed biologicals and those in phase 3 clinical development.

Current small molecule asthma therapies

Extensive data support the role of ICS in asthma with increasing dose reducing exacerbation frequency [ 1 , 176 , 177 ]. Increasing the ICS dose four-fold at the onset of exacerbation symptoms reduced the need for systemic corticosteroids by 19% [ 178 ]. No randomised controlled trials exist of prednisolone versus placebo as add-on therapy in severe asthma [ 179 ]. Registry data suggested that maintenance oral corticosteroid use was associated with reduced exacerbations among a cohort of patients with severe asthma [ 180 ]. In a small study, high-dose intramuscular triamcinolone reduced hospital admissions and emergency department attendance; however, the long-term side-effect profiles of systemic steroids have to be kept in mind. The task force members use maintenance OCS as a therapeutic strategy for reducing exacerbations as a less preferred option and suggest this practice be supervised in expert referral centres familiar with the management and prevention of OCS side-effects [ 181 ].

Presence of eosinophilic inflammation predicts a good response to corticosteroids in airway disease [ 182 – 184 ]. Tailoring corticosteroid dose to control sputum eosinophilia in asthma has achieved marked reductions in exacerbation rates [ 16 , 18 , 185 ] and the ERS/ATS guideline advocates measurement of eosinophilic inflammation in severe asthma [ 3 ].

Given the superiority of an on-demand ICS-containing regimen in two separate trials performed in patients with mild asthma in reducing the risk of exacerbation [ 186 , 187 ], later confirmed in a real-life setting [ 188 ], the last GINA update promotes this strategy as early as step 1, acknowledging the obvious inflammatory nature of the disease and in particular during episodes of poor control that precedes exacerbation.

The management of asthma using a sputum-guided adjustment of the daily dose of ICS was shown to be efficient in preventing exacerbations in expert centres where induced sputum cytology can be assessed routinely, in patients able to provide an adequate sample within the safety margins of induction [ 16 , 18 ].

Long-acting β 2 -agonists added to ICS

ICS-LABA combination therapy is standard in severe asthma and the addition of a LABA to ICS reduces exacerbation frequency in asthma [ 1 , 176 , 177 ]. The task force echoed recurrent warnings regarding monotherapy with LABA in asthma [ 189 ].

Long-acting muscarinic antagonists added to ICS

Tiotropium, as add-on therapy for asthmatics uncontrolled while treated with ICS and LABA, increased time to first exacerbation by 56 days versus placebo (p=0.03) [ 190 ]. A Cochrane review of long-acting muscarinic antagonist added to ICS versus ICS alone across all severities of asthma showed a reduction in exacerbations requiring oral corticosteroids, and a trend towards reduction in hospital admissions [ 191 ].

Leukotriene receptor antagonists

A systematic review of leukotriene receptor antagonists (LTRAs) identified a significant reduction in exacerbations when used as monotherapy compared to placebo, but no effect on exacerbation rates when used in patients already taking ICS [ 192 ]. Whether LTRAs reduce severe exacerbations in severe asthmatics is unknown.

Theophylline

A study comparing ICS/LABA and theophylline versus ICS/LABA and placebo found a significant reduction in severe exacerbations in the theophylline group in asthma patients who were treatment-naïve [ 193 ]. Whether theophylline affects exacerbation frequency in severe asthma is unknown. Most task force members do not use theophylline as an add-on therapy for preventing exacerbations.

Antimicrobials

In a large clinical trial, thrice-weekly azithromycin in moderate-to-severe asthma resulted in a 41% reduction in severe exacerbations with benefits independent of inflammatory phenotype [ 194 ], in contrast to a previous sub-analysis in severe asthma patients where the benefits were limited to the non-eosinophilic subgroup [ 195 ]. Of note, worldwide, azithromycin is not approved to the best of knowledge in this indication. Anti-fungal agents in fungal-sensitised severe asthma not meeting criteria for allergic bronchopulmonary aspergillosis demonstrated no impact on severe exacerbations [ 196 ].

Immunosuppressants

Data reporting exacerbations was limited in a Cochrane review examining the corticosteroid sparing effect of cyclosporin in severe oral corticosteroid dependent asthma [ 197 ]. A similar review examining the corticosteroid sparing effects of methotrexate in severe asthma did not demonstrate a beneficial effect on exacerbation rates [ 198 ].

Allergen avoidance and immunotherapy

Allergen avoidance advice is standard clinical practice in severe asthma [ 1 , 176 , 177 ], but allergen avoidance has shown controversial benefit [ 199 ], possibly due to difficulty in achieving this effectively. Allergen immunotherapy strategies in asthma report some benefit for reducing symptoms and corticosteroid usage but have not been tested in severe asthma [ 200 ]. It is unknown whether measures such as nocturnal temperature controlled laminar flow will be effective. Reductions in airway inflammation are reported in atopic asthma [ 201 ] and studies in severe asthma are ongoing [ 202 ].

Current biological therapies for asthma

The phase 3 randomised controlled trials for currently available biological therapy in asthma, except for anti-IgE as more established, are summarised in table 4 , including phase 2b studies that were considered pivotal for registration. Studies in less severe asthma with a very low event rate, open-label extensions that confirmed earlier findings and studies that did not report exacerbations were not included.

Pivotal phase 3 randomised clinical trials of licensed biological agents (excluding anti-IgE)

Anti-IgE: omalizumab

A Cochrane review of omalizumab as add-on therapy in moderate-to-severe asthma reported a reduction (OR 0.55, 95% CI 0.42–0.60; 10 studies, 3261 participants) in severe exacerbations [ 203 ]; however, subgroup analysis of severe asthma alone did not demonstrate a clear benefit. Further clinical trials remain ongoing [ 201 ].

Anti-IL-5: mepolizumab and reslizumab

Mepolizumab reduces exacerbation frequency by ∼50% [ 5 , 65 , 204 – 206 ] and reduces the requirement for maintenance oral corticosteroid [ 206 ]. Benefits were observed in severe asthmatics with blood eosinophils >150 cells·µL −1 [ 207 ], with greatest exacerbation frequency reductions seen with increasing eosinophilic inflammation. These beneficial effects were not sustained over the 12 months following treatment withdrawal [ 208 ], while it was the case when treatment was maintained [ 209 ]. This exacerbation rate reduction was also achieved while tapering OCS in long-term OCS users [ 206 ]. Reslizumab demonstrated a reduction in severe exacerbations in severe asthmatics with a baseline blood eosinophil count >400 cells·µL −1 [ 210 ]. Improvements were greatest in those with GINA step 5 disease [ 211 ].

Anti-IL-5R: benralizumab

Benralizumab reduces severe exacerbations [ 64 , 212 , 213 ] in those with a blood eosinophil count >300 cells·µL −1 . A priori sub-analyses using an eosinophil cut-off of 150 cells·µL −1 also demonstrated significant reductions in exacerbation rates [ 214 ], although higher blood eosinophils and more frequent exacerbations predicted greater benefits [ 215 ]. This exacerbation rate reduction was also achieved while tapering OCS in long-term OCS users [ 213 ]. A study of benralizumab administered in the setting of acute asthma exacerbation [ 66 ] reported a positive impact on recovery rates, however further work would be required to define the use of biologicals in this setting.

Bronchial thermoplasty

In 190 subjects who received bronchial thermoplasty (BT) versus 98 who underwent sham procedures, severe exacerbations were reduced by 32% in the 3–12 months post-therapy with an increase in exacerbation events in the peri-procedural period [ 21 ]. This reduction in exacerbations was maintained over a 5 year follow-up period [ 216 ]. BT is currently performed only in trained centres for both managing severe asthma and handling BT.

Emerging biological therapies

Anti-il-4r: dupilumab.

Dupilumab reduced severe exacerbations in all-comers irrespective of their atopic status, with the greatest reduction in those with elevated F ENO and/or eosinophilic inflammation, and reduced OCS requirement for severe asthmatics receiving maintenance OCS [ 68 , 217 , 218 ]. Studies of IL-4 inhibition alone, and more recently of the anti-IL-13 biologicals lebrikizumab [ 219 ] and tralokinumab [ 220 ], have failed to meet their primary end-points of exacerbation reduction, suggesting that inhibition of both IL-4 and -13, as with anti-IL-4R, is necessary to observe sufficient clinical efficacy for this aspect of the disease.

Anti-TSLP: tezepelumab

A recent phase II trial investigated the impact of tezepelumab on exacerbation rates in 584 moderate-to-severe asthmatics, showing a 60–70% reduction in exacerbations in all-comers across dosing regimens [ 221 ]. Effects were observed irrespective of markers of T2 inflammation, although substantial reductions in these measures were noted, suggesting that targeting upstream cytokine pathways may reduce exacerbations across inflammatory profiles.

CRTH2 antagonists, anti-IL-17 and others

ILC2 are now seen as the pivotal cells of T2 airway inflammation. Because they specifically express the PGD2 receptor DP2 or CRTH2, a proof of concept study showed that anti-DP2 treatment could significantly reduce the blood eosinophil count [ 222 ]. Whether this will be sufficient for preventing exacerbations is the aim of a larger ongoing phase 3 trial.

The IL33-ST2 axis is also specifically targeting ILC2 [ 223 ] and pivotal studies are ongoing. In non T2 asthma, the relevance of blocking IL-17 for preventing exacerbations is also currently being tested [ 224 ].

Reduction and ultimately elimination of severe exacerbations in severe asthma remains an important therapeutic target. In addition to corticosteroids and allergen avoidance/immunotherapy, the biologicals targeting T2 immunity and eosinophilic inflammation (anti-IgE, IL-5, IL-4R and TSLP) reduce exacerbations. Whether other therapies that reduce eosinophilic inflammation, such as anti-DP2, will demonstrate a similar efficacy remains to be determined. Beyond T2 inflammation, macrolide antibiotics and bronchial thermoplasty may have a role, but reducing severe exacerbations in non-T2 severe asthma remains an unmet need, although the scale of its importance once T2-mediated disease is adequately treated is uncertain.

• Conclusion and ELF patient perspectives

Preventing severe exacerbations in asthma is very important from the perspective of people with asthma. Too many patients still die from a severe exacerbation, whereas these deaths are likely preventable. In some countries, asthma and respiratory deaths are still increasing, especially in non-severe and moderate asthma [ 84 ]. Why this is happening still needs to be explored but facilitating access to care and medications would probably be of benefit.

In all types of asthma: it is important to remain aware that severe exacerbations don't just happen in patients with the more severe types of asthma.

Exacerbations, and especially recurrent exacerbations, are very debilitating for patients. More research is needed to avoid exacerbations and to break the cycle of recurrent exacerbations. The medications and treatment plans that are available at this time do not seem to be working well enough for all patients.

Adherence: patients and physicians need to work together on improving adherence. Good communication between physician and patient is key. There are many factors that impede adherence for patients. Some straight-forward ways to support patients can be implemented easily, such as having dose-counters on all inhalators. It can be more challenging to address patients developing additional behaviour: for example, those that find it difficult to incorporate different medications into their daily routine, or subsequently, if their routine needs to change again, because of an exacerbation or increased breathlessness. All aspects require continuous positive attention from physicians.

Indoor and outdoor environmental factors: the advice to avoid environmental factors is an additional burden, moreover because it is extremely complex to put into practice for patients. More and better advice needs to be given to patients regarding living conditions, occupational choices, etc .

Working together with patients in improving their asthma care is key. Many patients have good knowledge of their asthma and their reaction to medications. Not all patients have this insight and not all patients are able to manage their asthma on a daily basis. We all need personalised help. E-health can support some patients, but only if these solutions are developed with patients and are sufficiently flexible and personalised.

Research needs and knowledge caps identified throughout this task force are summarised in table 5 , and key points summarised in table 6 .

Research needs and knowledge gaps

Summary of key points

Task force sections and members

• Supplementary material

Supplementary Material

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Supplementary material ERJ-00900-2019.SUPPLEMENT

• Shareable PDF

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Shareable PDF ERJ-00900-2019.Shareable

This document was endorsed by the ERS Executive Committee on 14 August, 2019, and by the European Academy of Allergy and Clinical Immunology.

This article has supplementary material available from erj.ersjournals.com

Conflict of interest: A. Bourdin reports personal and institutional fees for advisory board work from AstraZeneca, Novartis, GSK, Boehringher Ingelheim, Chiesi, Actelion, Pfizer and Teva, outside the submitted work.

Conflict of interest: L. Bjermer has nothing to disclose.

Conflict of interest: C. Brightling reports grants and personal fees for consultancy from GlaxoSmithKline, AstraZeneca/Medimmune, Novartis, Chiesi, Roche/Genentech and Boehringer Inglheim, personal fees for consultancy from Vectura, Theravance, PreP, Gilead, Sanofi/Regeneron, Teva, Gossamer and 4DPharma, grants from Pfizer and Mologic, outside the submitted work.

Conflict of interest: G.G. Brusselle reports personal fees for advisory board work and lectures from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis and Teva, personal fees for advisory board work from Sanofi, outside the submitted work.

Conflict of interest: P. Chanez reports research grants and personal fees for consultancy, advisory board work and lectures from ALK, Almirall, Boehringer Ingelheim, GSK, AstraZeneca, Novartis, TEVA and Chiesi, grants from AMU, outside the submitted work.

Conflict of interest: K.F. Chung has received honoraria for participating in advisory board meetings of GSK, AZ, Novartis, Merck, BI and TEVA regarding treatments for asthma and COPD, and has also been renumerated for speaking engagements.

Conflict of interest: A. Custovic reports personal fees for consultancy from Novartis, Regeneron/Sanofi, Boehringer Ingelheim and Philips, personal fees for lectures from Thermo Fisher Scientific and Novartis, outside the submitted work.

Conflict of interest: Z. Diamant reports personal fees from AstraZeneca and Sanofi-Genzyme, during the conduct of the study; personal fees from Aquilon, ALK, Boehringer Ingelheim, Gilead, Hal Allergy and MSD, outside the submitted work; and in addiction to academic affiliations, also works at a phase I/II unit performing clinical studies for different biotech and pharma companies.

Conflict of interest: S. Diver has nothing to disclose.

Conflict of interest: R. Djukanovic reports receiving fees for lectures at symposia organised by Novartis, AstraZeneca and TEVA, consultation for TEVA and Novartis as member of advisory boards, and participation in a scientific discussion about asthma organised by GlaxoSmithKline; in addition, is a co-founder and current consultant, and has shares in, Synairgen, a University of Southampton spin out company.

Conflict of interest: D. Hamerlijnck has nothing to disclose.

Conflict of interest: I. Horvath reports personal fees from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, GSK, Novartis, CSL-Behring and Roche, outside the submitted work.

Conflict of interest: S.L. Johnston reports personal fees for advisory board work from Therapeutic Frontiers and Virtus Respiratory Research, personal fees for consultancy from Myelo Therapeutics GmbH, Concert Pharmaceuticals, Bayer, Gerson Lehrman Group, resTORbio, Bioforce, Materia Medical Holdings, PrepBio Pharma, Pulmotect, Virion Health and Lallemand Pharma, personal and insititutional fees for consultancy from Synairgen, Novartis, Boehringer Ingelheim and Chiesi; and has received personal fees for the following patents planned, issued or pending: transgenic animal models of HRV with human ICAM-1 sequences (UK patent application number 02 167 29.4, and international patent application number PCT/EP2003/007939); anti-virus therapy for respiratory diseases (UK patent application number GB 0405634.7); interferon-beta for anti-virus therapy for respiratory diseases (international patent application number PCT/GB05/50031); interferon lambda therapy for the treatment of respiratory disease (UK patent application number 6779645.9, granted); induction of cross-reactive cellular response against rhinovirus antigens (European patent number 13305152), outside the submitted work.

Conflict of interest: F. Kanniess reports personal fees for lectures and advisory board work from AstraZeneca, Novartis, Mundipharma and TEVA, outside the submitted work.

Conflict of interest: N. Papadopoulos reports personal fees for advisory board work and lectures from Novartis, Nutricia, HAL, personal fees from Menarini/Faes Farma and Mylan/Meda, personal fees for lectures from Sanofi, Biomay, MSD, ASIT Biotech and Boehringer Ingelheim, personal fees for advisory board work from AstraZeneca and GSK, grants from Gerolymatos International SA and Capricare, outside the submitted work.

Conflict of interest: A. Papi reports grants, personal fees for lectures, advisory board work and consultancy, and travel expenses reimbursement from AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline and Teva, personal fees for advisory board work and consultancy from Sanofi/Regeneron, personal fees for lectures and travel expenses reimbursement from Zambon and Novartis, personal fees for lectures, advisory board work and consultancy, and travel expenses reimbursement from Mundipharma, personal fees for lectures and advisory board work, and travel expenses reimbursement Almirall, grants, personal fees for lectures and travel expenses reimbursement from Menarini, grants from Fondazione Maugeri, grants from Fondazione Chiesi Farmaceutici, outside the submitted work.

Conflict of interest: R.J. Russell has nothing to disclose.

Conflict of interest: D. Ryan reports personal fees for advisory board work from GSK and Trudell Medical, personal fees for advisory board work and lectures from AZ, personal fees for lectures from Mylan and Chiesi, personal fees for consultancy from Optimum Patient Care, outside the submitted work.

Conflict of interest: K. Samitas has nothing to disclose.

Conflict of interest: T. Tonia acts as ERS methodologist.

Conflict of interest: E. Zervas reports personal fees consultancy and lectures from Astra, Bristol-Myers Squibb, Chiesi, GSK, Elpen, Merck, MSD, Novartis, Menarini and Pfizer, non-financial support for travel, accommodation and meeting expenses from Astra, Bristol-Myers Squibb, Galenica, Chiesi, Elpen, Novartis, Menarini and Roche, outside the submitted work.

Conflict of interest: M. Gaga reports grants and personal fees from AZ, grants from BI, Elpen, Novartis and Menarini, personal fees from BMS, MSD, Chiesi and Pharmaten, outside the submitted work.

• Received May 5, 2019.
• Accepted July 17, 2019.
• Copyright ©ERS 2019
• ↵ Global Initiative for Asthma (GINA). 2018 GINA Report: Global Strategy for Asthma Management and Prevention . https://ginasthma.org/2018-gina-report-global-strategy-for-asthma-management-and-prevention/ Date last accessed: 19 Sept 2018 .
• Salmeron S ,
• Elkharrat D , et al.
• Wenzel SE ,
• Brozek JL , et al.
• Chipps BE ,
• Haselkorn T ,
• Paknis B , et al.
• Ortega HG ,
• Pavord ID , et al.
• Andrews R ,
• Buckingham R , et al.
• Bousquet J ,
• Khaltaev N ,
• Cruz A , et al.
• Custovic A ,
• Johnston SL ,
• Pavord I , et al.
• Mantzouranis E ,
• Cruz AA , et al.
• Reddel HK ,
• Taylor DR ,
• Bateman ED , et al.
• Miller MK ,
• Blanc PD , et al.
• Voorham J , et al.
• O'Byrne PM ,
• Pedersen S ,
• Lamm CJ , et al.
• Brightling CE ,
• McKenna S , et al.
• Pauwels RA ,
• Löfdahl CG ,
• Postma DS , et al.
• Jayaram L ,
• Pizzichini MM ,
• Cook RJ , et al.
• Crestani B ,
• Leroyer C , et al.
• Fuhlbrigge A ,
• Apter AJ , et al.
• Laviolette M , et al.
• Murphy VE ,
• Clifton VL ,
• Willems LN ,
• Bel EH , et al.
• Petsky HL ,
• Li A , et al.
• Brassett KP , et al.
• Szefler SJ ,
• Mitchell H ,
• Sorkness CA , et al.
• Taylor DR , et al.
• Kew KM , et al.
• Lapperre TS , et al.
• Miller DP , et al.
• Heikkilä K ,
• Madsen IEH ,
• Nyberg ST , et al.
• Nussbaum E , et al.
• Alvarez GG ,
• Fitzgerald JM
• Schulzer M ,
• Jung D , et al.
• de Groot JC ,
• Amelink M ,
• de Nijs SB , et al.
• Sanderson G , et al.
• Gonzalez-Barcala F-J ,
• Calvo-Alvarez U ,
• Garcia-Sanz M-T , et al.
• Jackson DJ ,
• Mallia P , et al.
• Martinez-Moragón E ,
• Serrano J , et al.
• Kupczyk M ,
• Sterk PJ , et al.
• Tattersfield AE ,
• Postma DS ,
• Barnes PJ , et al.
• Romagnoli M ,
• Caramori G ,
• Braccioni F , et al.
• Honkoop PJ ,
• Simpson A ,
• Bonini M , et al.
• Bateman ED ,
• O'Byrne PM , et al.
• Eriksson G , et al.
• Lv Y , et al.
• Sano H , et al.
• de Jongste J ,
• van der Valk R , et al.
• McFadden ER ,
• Strauss L ,
• Hejal R , et al.
• Turner MO ,
• Noertjojo K ,
• Vedal S , et al.
• Loymans RJB ,
• Termeer EH , et al.
• Denlinger LC ,
• Phillips BR ,
• Ramratnam S , et al.
• Bartley M , et al.
• Bokhour B ,
• Hohman KH , et al.
• Silver EJ ,
• Galvani AP , et al.
• Jamieson KC ,
• Warner SM ,
• Leigh R , et al.
• Clarke DL ,
• Davis NHE ,
• Majithiya JB , et al.
• Gavala ML ,
• Bertics PJ ,
• Rigazio A ,
• Campbell JD , et al.
• Bleecker ER ,
• FitzGerald JM ,
• Chanez P , et al.
• Pavord ID ,
• Howarth P , et al.
• Parker JM ,
• Silverman RA , et al.
• Thomas M , et al.
• Brusselle G , et al.
• Becker A , et al.
• Bønnelykke K ,
• Sleiman P ,
• Nielsen K , et al.
• McGeachie MJ ,
• Tse SM , et al.
• Grotenboer NS ,
• Ketelaar ME ,
• Koppelman GH , et al.
• Torgerson DG ,
• Ampleford EJ ,
• Chiu GY , et al.
• Schuijs MJ ,
• Willart MA ,
• Vergote K , et al.
• Meyers DA ,
• Holloway JW , et al.
• Shrine NRG ,
• Soler Artigas M , et al.
• Moffatt MF ,
• Demenais F , et al.
• Ampleford E , et al.
• Slager RE ,
• Otulana BA ,
• Hawkins GA , et al.
• Roden DM , et al.
• Benayoun S , et al.
• Lötvall J ,
• Bacharier LB , et al.
• Wenzel SE , et al.
• Lefaudeux D ,
• De Meulder B ,
• Loza MJ , et al.
• Bartlett G ,
• Schuster T , et al.
• Morjaria JB ,
• Ghebre MA ,
• Diver S , et al.
• Fricker M ,
• Gibson PG ,
• Powell H , et al.
• Rothenberg ME ,
• Ganesh A , et al.
• Al-Dorzi HM ,
• Al-Shammary HA ,
• Al-Shareef SY , et al.
• Newth CJL ,
• Clark AE , et al.
• Becker JM ,
• Rossini G , et al.
• Basagaña X ,
• Belmonte J , et al.
• Serrano-Pariente J ,
• Rodrigo G ,
• Fiz JA , et al.
• Maggiore D ,
• Chung V , et al.
• Zeiger RS , et al.
• D'Amato G ,
• Liccardi G ,
• D'Amato M , et al.
• Boulet L-P ,
• Vervloet D ,
• Magar Y , et al.
• Williams LK ,
• Peterson EL ,
• Wells K , et al.
• Hasegawa K ,
• Brenner BE ,
• Clark S , et al.
• Usmani OS ,
• Lavorini F ,
• Marshall J , et al.
• Björnsdóttir US ,
• Gizurarson S ,
• Pithon G , et al.
• Chandra D ,
• El-Ekiaby A ,
• Brianas L ,
• Skowronski ME , et al.
• De Simoni A ,
• Fleming L , et al.
• Del Giacco SR ,
• Gambula L , et al.
• Ciprandi G ,
• Schiavetti I ,
• Rindone E , et al.
• Bardin PG ,
• Cea-Calvo L ,
• Carmona L ,
• Calvo-Alén J
• Poureslami I ,
• Lester RT , et al.
• Stewart AW ,
• Harrison J , et al.
• Foster JM ,
• Usherwood T ,
• Smith L , et al.
• Peebles RS ,
• Gangnon RE ,
• Evans MD , et al.
• Kusel MMH ,
• de Klerk NH ,
• Kebadze T , et al.
• Carroll WD ,
• Child F , et al.
• Togias A , et al.
• Marshall C ,
• Smith S , et al.
• Bucchieri F , et al.
• Baraldo S ,
• Contoli M ,
• Bazzan E , et al.
• Bochkov YA ,
• Watters K ,
• Ashraf S , et al.
• Ducharme FM ,
• Chauhan BF , et al.
• Message SD ,
• Laza-Stanca V , et al.
• Glanville N ,
• Johnston SL
• Djukanović R ,
• Harrison T ,
• Johnston SL , et al.
• Henneberger PK ,
• Mirabelli MC ,
• Kogevinas M , et al.
• Jie X , et al.
• Spitzer WO ,
• Ernst P , et al.
• van Schayck CP ,
• Bijl-Hofland ID ,
• Cloosterman SGM , et al.
• Cockcroft DW ,
• Nelson HS ,
• Bleecker ER , et al.
• Drazen JM ,
• Boushey HA , et al.
• Ritchie AI ,
• Singanayagam A ,
• Wiater E , et al.
• Woo JA , et al.
• Marks G , et al.
• Castillo JR ,
• Peters SP ,
• Williams MH
• Carruthers DM ,
• Harrison BD
• Tomlanovich MC ,
• Sarkar DD , et al.
• Lubetsky HW , et al.
• Wijesinghe M ,
• Healy B , et al.
• Rodrigo GJ ,
• Rodriquez Verde M ,
• Peregalli V , et al.
• Newman KB ,
• Hamilton C , et al.
• Camargo CA ,
• Spooner CH ,
• Shrestha M ,
• Gourlay S , et al.
• Travers AH ,
• Jones AP , et al.
• Griffiths B ,
• Ducharme FM
• Rodrigo C ,
• Burschtin O
• Stoodley RG ,
• Ducharme FM , et al.
• Spooner C ,
• Marquette CH ,
• Cardot E , et al.
• Harrison BD ,
• Stokes TC ,
• Hart GJ , et al.
• Sipsey J , et al.
• Munavvar M ,
• Vail A , et al.
• O'Driscoll BR ,
• Wilson M , et al.
• Edmonds ML ,
• Camargo CA , et al.
• Kirtchuk L ,
• Bretzlaff JA ,
• Bourdon C , et al.
• ↵ National Asthma Education and Prevention Program . Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma-Summary Report 2007 . J Allergy Clin Immunol 2007 ; 120 : S94 – S138 . OpenUrl CrossRef PubMed Web of Science
• Charriot J ,
• Volpato M ,
• Sueh C , et al.
• França-Pinto A ,
• Mendes FAR ,
• de Carvalho-Pinto RM , et al.
• ↵ National Heart, Lung, and Blood Institute (NHLBI). Guidelines for the Diagnosis and Management of Asthma (EPR-3). Bethesda, National Heart, Lung, and Blood Institute (NHLBI), 2007. Available from www.nhlbi.nih.gov/health-topics/guidelines-for-diagnosis-management-of-asthma
• ↵ British Thoracic Society. BTS/SIGN British Guideline on the Management of Asthma . London, British Thoracic Society, 2016. Available from www.brit-thoracic.org.uk/standards-of-care/guidelines/btssign-british-guideline-on-the-management-of-asthma/
• McKeever T ,
• Mortimer K ,
• Wilson A , et al.
• Effenberger T ,
• Trautner C , et al.
• Sweeney J ,
• Menzies-Gow A , et al.
• Mancinelli L ,
• Navarro L ,
• Woltmann G , et al.
• Monteiro W ,
• Ward R , et al.
• Pratter MR ,
• Boulet LP , et al.
• Chlumský J ,
• Terl M , et al.
• Beasley R ,
• Holliday M ,
• Reddel HK , et al.
• ↵ National Association for Medical Direction of Respiratory Care (NAMDRC). FDA Removes Boxed Warning from Long-Acting Beta Agonists (LABAs) and Inhaled Corticosteroids (ICS) www.namdrc.org/posts/fda-removes-boxed-warning-long-acting-beta-agonists-labas-and-inhaled-corticosteroids-ics Date last updated: 04 Jan 2018. Date last accessed: 19 Oct 2018.
• Kerstjens HAM ,
• Dahl R , et al.
• Anderson DE ,
• Miligkos M ,
• Bannuru RR ,
• Alkofide H , et al.
• Liu M , et al.
• Upham JW , et al.
• Brusselle GG ,
• Vanderstichele C ,
• Jordens P , et al.
• Agbetile J ,
• Fairs A , et al.
• Cullinan P ,
• Woodcock A ,
• Forster L ,
• Matthews E , et al.
• Normansell R ,
• Bridgman A-L
• Chauhan AJ ,
• Milan SJ , et al.
• Hargadon B , et al.
• Bradford ES ,
• Albers FC , et al.
• Thompson PJ , et al.
• Yancey SW ,
• Mayer B , et al.
• Singapuri A , et al.
• Domingo C ,
• Zangrilli J ,
• Wechsler ME , et al.
• Brusselle G ,
• Weiss S , et al.
• Nair P , et al.
• Rabe KF , et al.
• Goldman M ,
• Zangrilli JG , et al.
• Wechsler ME ,
• Laviolette M ,
• Rubin AS , et al.
• Pearlman D , et al.
• Corren J , et al.
• Hanania NA ,
• Korenblat P ,
• Chapman KR , et al.
• Russell RJ ,
• FitzGerald JM , et al.
• Parnes JR ,
• Wang L , et al.
• ↵ Efficacy and Safety Study of GSK3772847 in Subjects With Moderately Severe Asthma. ClinicalTrials.gov registry: NCT03207243 . https://clinicaltrials.gov/ct2/show/NCT03207243 Date last updated: 18 June 2019. Date last accessed: 21 Sept 2018.
• ↵ Study to Assess the Efficacy and Safety of CJM112 in Patients With Inadequately Controlled Severe Asthma. ClinicalTrials.gov registry: NCT03299686 . https://clinicaltrials.gov/ct2/show/NCT03299686 Date last updated: 23 Jan 2019. Date last accessed: 21 Sept 2018.

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Related Articles

• Open access
• Published: 06 September 2024

Novel insights into the pleiotropic health effects of growth differentiation factor 11 gained from genome-wide association studies in population biobanks

• Jessica Strosahl 1 ,
• Kaixiong Ye 2 , 3 &
• Robert Pazdro   ORCID: orcid.org/0000-0001-9976-4817 1  

BMC Genomics volume  25 , Article number:  837 ( 2024 ) Cite this article

Metrics details

Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor-β (TGF-β) superfamily that has gained considerable attention over the last decade for its observed ability to reverse age-related deterioration of multiple tissues, including the heart. Yet as many researchers have struggled to confirm the cardioprotective and anti-aging effects of GDF11, the topic has grown increasingly controversial, and the field has reached an impasse. We postulated that a clearer understanding of GDF11 could be gained by investigating its health effects at the population level.

Methods and results

We employed a comprehensive strategy to interrogate results from genome-wide association studies in population Biobanks. Interestingly, phenome-wide association studies (PheWAS) of GDF11 tissue-specific cis -eQTLs revealed associations with asthma, immune function, lung function, and thyroid phenotypes. Furthermore, PheWAS of GDF11 genetic variants confirmed these results, revealing similar associations with asthma, immune function, lung function, and thyroid health. To complement these findings, we mined results from transcriptome-wide association studies, which uncovered associations between predicted tissue-specific GDF11 expression and the same health effects identified from PheWAS analyses.

Conclusions

In this study, we report novel relationships between GDF11 and disease, namely asthma and hypothyroidism, in contrast to its formerly assumed role as a rejuvenating factor in basic aging and cardiovascular health. We propose that these associations are mediated through the involvement of GDF11 in inflammatory signaling pathways. Taken together, these findings provide new insights into the health effects of GDF11 at the population level and warrant future studies investigating the role of GDF11 in these specific health conditions.

Peer Review reports

Introduction

Growth Differentiation Factor 11 (GDF11) is a circulating member of the transforming growth factor β (TGF-β) superfamily that has essential roles in mammalian development. Genetic knockout studies have revealed the far-reaching effects of GDF11 on the developing embryo. Most dramatically, global, constitutive deletion of the Gdf11 gene in mice caused early mortality, with Gdf11 −/− mice dying within 24 h after birth [ 1 , 2 ]. Those mice also exhibited anterior homeotic transformations of the axial skeleton [ 1 , 2 ], an effect mediated by Smad signaling pathways [ 3 , 4 , 5 ]. Other studies showed that Gdf11 −/− mice exhibit renal agenesis, cleft palate [ 6 ] and greater numbers of pancreatic NGN3 + islet progenitor cells [ 7 , 8 ], retinal ganglion cells [ 9 ], and olfactory epithelium progenitor cells [ 10 ], resulting from the loss of negative feedback of Gdf11 on progenitor cell number. In adult mice and humans, GDF11 has been implicated in cell differentiation and tissue repair processes, including erythropoiesis [ 11 , 12 , 13 ], angiogenesis [ 14 , 15 , 16 ], bone homeostasis [ 17 , 18 ] and myogenesis [ 19 , 20 ]. In humans, individuals with heterozygous loss-of-function mutations in the GDF11 gene present severe craniofacial and vertebral abnormalities, in addition to other multisystemic phenotypes such as visual and hearing disorders, cardiac abnormalities, and connective tissue dysfunction [ 21 ].

Beyond its defined roles in development, research over the past several years has indicated that GDF11 may have a powerful role in rejuvenating aged tissues, leading to a surge of interest in – and controversies surrounding – this factor. In a landmark study using heterochronic parabiosis, Loffredo et al . discovered that blood from young mice reversed age-related cardiac hypertrophy, and ultimately, GDF11 was identified as the blood-borne factor behind this effect [ 22 ]. According to the study, systemic GDF11 levels decreased with age, and treating old mice with recombinant GDF11 reversed histopathological and molecular markers of cardiac hypertrophy. Similar findings were recapitulated in other tissues, including skeletal muscle [ 23 ], brain [ 24 , 25 , 26 ], and skin [ 27 , 28 , 29 ]; meanwhile, other studies in mice and humans reported conflicting findings [ 30 , 31 , 32 , 33 , 34 , 35 , 36 ], claiming no effect of GDF11 on cardiac structure or function [ 30 ] or even suggesting that it is a risk factor for comorbidity and frailty in older adults with cardiovascular disease [ 31 ]. These contradictions were attributed to multiple issues – most prominent among them was the inability of various antibody-based assays to distinguish between GDF11 and its homolog, myostatin (MSTN) [ 22 , 33 , 37 ], which share 90% amino acid sequence identity in their mature domains [ 38 ], leading to confusion around the independent cardiac impact of each protein. But addressing these issues has not fully resolved the discrepancies in the field, as more recent studies have still presented contradictory results. Several studies reported adverse effects of GDF11 on cardiovascular and overall health [ 39 , 40 ], demonstrating that GDF11 can induce cardiac dysfunction and pathologic atrophy [ 39 ] and even cause severe cachexia and death at high doses [ 40 ]. Yet most studies still support a cardioprotective role for GDF11, showing that it ameliorates pathological remodeling [ 41 , 42 ], mitigates ischemia–reperfusion injury [ 43 , 44 , 45 ], improves outcomes in myocardial infarction [ 46 , 47 ], and is associated with lower risk of cardiovascular events and death [ 37 ]. Despite a greater understanding of the factors contributing to the discrepancies across GDF11 studies, the precise health effects of this circulating protein remain unresolved.

We posited that a new understanding of GDF11 and the heart could be gained by bridging the work previously done in inbred mouse strains and studies of human participants; for this purpose, we selected an outbred mouse population [ 48 , 49 , 50 ] and identified a suggestive peak underlying natural variation in serum GDF11 on murine chromosome 3 [ 51 ]. The peak lies in close proximity to the protein-coding gene  Hes Related Family BHLH Transcription Factor with YRPW Motif 1 ( Hey1 ), a transcriptional repressor involved in the regulation of cardiac atrioventricular canal and vasculature development through Notch-dependent signaling pathways [ 52 , 53 , 54 , 55 ]. Moreover, genetic mapping of serum MSTN levels revealed a significant locus on murine chromosome 3 near the protein-coding gene Forkhead Box O1  ( FoxO1) . Surprisingly, statistical analyses only revealed weak, inconsistent relationships between serum GDF11 and cardiac health, whereas MSTN exhibited significant negative associations with heart weight, heart weight standardized to tibial length, and left ventricular heart wall thickness [ 51 ]. These results did not support an anti-hypertrophic effect for GDF11 but instead added to the large body of evidence suggesting that GDF11 is not a major predictor of cardiovascular health. At this point, a new approach is needed to resolve the true health effects of GDF11 in adulthood and aging.

In the present study, we sought to define the unique health effects of GDF11 at the population level – by interrogating the impact of GDF11 variants on health outcomes using published GWAS results and biobank data from large cohorts, including the UK Biobank – and contrasting the results against those from MSTN. Here, we employed a comprehensive set of analyses that utilizes the deep genetic and phenotypic data housed in public databases. We began by identifying tissue-specific cis -eQTLs [ 56 , 57 , 58 , 59 ], taking into account the wide range of tissues with detectable GDF11 expression in humans [ 60 , 61 ] and mice [ 62 , 63 ]. We then leveraged data from phenome-wide association studies (PheWAS) to identify pleiotropic effects, where a single locus affects multiple distinct phenotypes [ 64 , 65 , 66 ]. Finally, to evaluate the connection between the tissue-specific expression of GDF11 and human disease, we explored integrative platforms housing transcriptome-wide association study (TWAS) results and functional genomics data [ 67 , 68 , 69 , 70 ]. Analytical processes were performed in parallel for both GDF11 and MSTN, and we report the unique connections between traits associated with GDF11 variants and its tissue-specific expression level that expand our knowledge of the health impacts of this gene.

UK Biobank is a globally accessible, large-scale longitudinal population cohort containing genetic and disease information from over 500,000 British individuals [ 71 ]. Participants ranging from 40 to 69 years of age were recruited between the years 2006 and 2010 [ 71 ]. The North West Multi-Centre Research Ethics Committee (11/NW/ 0382) approved the UK Biobank project. Informed consent was obtained from each participant prior to collection of biological and anthropometric measurements, lifestyle indicators, blood and urine biomarkers, and information from their medical records [ 71 ].

The Genotype-Tissue Expression (GTEx) project collected 15,201 RNA-sequencing samples from 54 tissues of 838 postmortem donors. Biospecimen Source Sites (BSS) were required to submit a GTEx research protocol and undergo IRB review or forwent further review on account of deceased donors not constituting as human subjects [ 72 , 73 ]. However, GTEx required explicit next-of-kin or legal representative authorization for study participation, given the public availability of the data [ 72 ]. Specific training regulating how BSS obtained consent can be found at http://gtextraining.org/ . Only de-identified data according to HIPPAA policy is distributed to GTEx project collaborators [ 72 ].

Single-tissue expression-quantitative trait locus analysis

We utilized the GTEx portal to identify variants that were significantly associated with GDF11 and MSTN expression levels. Specifically, we searched for cis -eQTLs of GDF11 and MSTN across tissues. The GTEx project is an open-access database with data including gene expression, QTLs, and histology images from 54 non-diseased tissue sites across nearly 1000 individuals [ 74 , 75 ]. Briefly, quality control (QC) was performed as follows: RNA-seq expression outliers were excluded based on previously described methods [ 76 ], read counts for samples were normalized and log-transformed with an offset of 1, and the read count matrix was hierarchically clustered [ 72 ]. In addition, samples with < 10 million mapped reads were removed, and if replicate samples were present, the replicate with the greatest number of reads was selected [ 72 ]. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 11/08/2022.

Transcriptome-wide association study

We used TWAS results from the TWAS Hub to identify traits associated with the tissue-specific expression of GDF11 and MSTN , as well as their putative genetic regulators, HEY1 and FOXO1 , respectively. TWAS leverage gene expression measurements with summary statistics from large-scale GWAS to identify significant expression-trait associations [ 67 ]. GWAS and functional data for hundreds of traits and over 100,000 expression models were integrated within TWAS Hub [ 67 , 77 ]. Summary association statistics came from 30 large-scale GWAS studies, and SNPs with minor allele frequencies of less than 1% were removed [ 70 ]. RNA sequencing data originated from CommonMind Consortium (brain, n  = 613) [ 78 ], GTEx (41 tissues) [ 60 ], and the Metabolic Syndrome in Men study (adipose, N  = 563) [ 79 , 80 ], and expression microarray data from the Young Finns Study (blood, N  = 1,264) [ 81 , 82 ] and the Netherlands Twins Registry ( N  = 1,247) [ 70 , 76 ]. Associations were considered significant if they reached the tissue-specific threshold determined by Bonferroni correction at an experimental α of 0.05, as a conservative measure.

The PhenomeXcan database was used to supplement results from the TWAS hub. PhenomeXcan is a gene-based program which houses 22,255 gene associations and 4,091 traits with transcriptome regulation data from 49 tissues in GTEx v8 using an adaptation of the PrediXcan method [ 83 , 84 , 85 ]. Colocalization analysis was performed via fastENLOC, a novel Bayesian hierarchical colocalization method [ 83 , 84 ]. We utilized the ‘PhenomeXcan_SingleTissue' function, including 4,091 traits and 49 tissues. We only included associations that met the significance threshold p  < 1e-08.

Variant-centric analysis

To investigate associations between health outcomes and variants of GDF11 , HEY1 , MSTN , and FOXO1 , we employed the Open Target Genetics, PhenoScanner, GeneATLAS, and GWAS Catalog databases. Open Target Genetics is an open-access integrative database that combines human GWAS and functional genomics data to allow researchers to conduct systematic identification and prioritization of plausible causal variants and genes [ 86 , 87 , 88 ]. GWAS with and without summary statistics were sourced from the NHGRI-EBI GWAS Catalog summary statistics repository (number of studies = 300; only included associations with p  ≤ 5 e  − 8 and removed redundant associations via distance-based clustering ± 500 kb) [ 89 ]. GWAS with full summary statistics were sourced from two GWAS analyses using UK Biobank data: the SAIGE study of binary phenotypes (number of studies = 2,139) [ 90 ], and the Neale Lab study (number of studies = 1,283) [ 91 ]. Full GWAS summary statistics were only included from those studies of predominantly European ancestries due to limited reference genotypes from other populations [ 87 , 89 ]. Additionally, 92 tissue- and cell-type-specific molecular QTL (molQTL) datasets were integrated from GTEx [ 60 ], eQTLGen [ 92 ], the eQTL Catalogue, and pQTLs [ 93 ], and systematic disease-molecular trait colocalization tests were performed [ 87 ]. Variants are sorted by their locus to gene (L2G) pipeline score on a scale from 0–1 based on evidence including molecular phenotype quantitative trait loci data, chromatin interaction data, in silico functional predictions, and distance from the canonical transcript start site [ 86 , 87 ]. Associations from all studies were only included if p  ≤ 5e − 8 [ 86 , 87 ].

PhenoScanner is a database that contains over 65 billion association results, including eQTL, pQTL, methylation QTL (mQTL), and upwards of 150 million genetic variants to enable researchers to conduct “phenome-wide scans” [ 94 , 95 , 96 ]. Variants with minor allele frequencies < 0.5%, multiallelic variants, and large indels (⁠ ≥ 5 bases) were removed from analyses [ 94 , 95 ]. Variants were positionally annotated utilizing the Variant Effect Predictor, and traits were mapped to Experimental Factor Ontology Terms [ 94 , 95 ]. The significance cut-off p  < 1e–5 was used for all genes, genomic regions, and phenotypes [ 94 , 95 ].

GeneATLAS utilizes the UK Biobank cohort ( N  = 452,264) of British individuals to systematically catalog associations between 778 traits and over 30 million variants [ 97 , 98 ]. The associations were computed by use of Mixed Linear Models in a large supercomputer using the DISSECT software (freely available at  https://www.dissect.ed.ac.uk  under GNU Lesser General Public License v3). We utilized the GeneATLAS “region PheWAS” function to extract PheWAS associations located ± 1000 kb of our genes of interest, and significance was determined at p  ≤ 1e-8. Additionally, we searched the GWAS Catalog for significant associations with the genes of interest. We only included associations that met the significance threshold p  ≤ 5e − 8.

Tissue-specific cis -eQTLs for GDF11 are associated with asthma, immune function, lung function, and thyroid phenotypes

To comprehensively define the health effects of GDF11 variation, we started by identifying variants that (1) lie in close proximity to the GDF11 gene and (2) are associated with its expression levels in at least one tissue. We compiled a total of 110 variants located from within ± 1 Mb of the transcription start site (TSS). Those cis -eQTLs spanned the genomic region of chr12:54,899,536–56,468,936 base pairs (bp; Supplementary Table S1), and a visual depiction of all cis -eQTLs associated with GDF11 expression is shown in Fig.  1 A, which highlights a tissue-specific association pattern (Fig.  1 B). From there, we narrowed the list of cis -eQTLs for further examination by selecting the most significant variant for each tissue as a representative of the haplotype block. Notably, the most significant GDF11 cis -eQTL, rs117385153, was associated with GDF11 expression in thyroid tissue ( p  = 6.30E-07; Table  1 ). A visual of all genes located in the GDF11 cis -window can be found in the Supplementary file (Supplementary Fig. S1).

Genetic variants significantly associated with GDF11 expression as detected in the GTEx project. A GDF11 cis -eQTLs (± 1 Mb of the transcription start site) separated by tissue. Specific tissues are denoted by colors. The most significant eQTL in each tissue is denoted by a black square. B Linkage disequilibrium (LD) blocks for GDF11 cis -eQTLs from the GTEx project. The LD heatmap reports pairwise LD values (R 2 ) of the QTL variants. The corresponding eQTL normalized effect size (NES) bar chart heatmaps are located above the LD heatmap. Row labels (to the left of each chart) denote the tissue type and number of samples. The y-axis (to the right of each chart) is the -log 10 ( p -value). Tissue abbreviations: ARTAORT = Artery – Aorta; BRNCHA = Brain – Cerebellum; MSCLSK = Muscle – Skeletal; SKINNS = Skin – Not Sun Exposed (Suprapubic); WHLBLD = Whole Blood. TSS = transcription start site; TES = transcription end site

Next, we aimed to identify the health effects of the most significant GDF11 cis- eQTL in each tissue. We began by performing a PheWAS in PhenoScanner for rs117385153, the most significant variant in thyroid tissue, and the results pointed to associations with “self-reported pulmonary fibrosis” ( p  = 2.76E-05) and “cause of death: asthma, unspecified” ( p  = 6.54E-05). Then, we performed a PheWAS for the cis- eQTLs with the highest statistical significance from other tissues. The most significant cis- eQTL in skeletal muscle tissue was rs7297175 ( p  = 6.8E-6), and PheWAS results for this SNP revealed associations with 11 traits related to asthma, immune function, lung function, and thyroid health (Table  1 ). We identified rs7312770 as the most significant cis- eQTL in unexposed suprapubic skin ( p  = 3.9E-5), and PheWAS analysis of this SNP indicated associations with 13 traits related to asthma, immune function, lung function, and thyroid health (Table  1 ). More information on sample data and procedures in unexposed suprapubic skin can be found in Supplementary Table S2. Both rs7297175 and rs7312770 exhibited the most significant association with the entry “no blood clot, bronchitis, emphysema, asthma, rhinitis, eczema or allergy diagnosed by a doctor." Lastly, the most significant cis -eQTLs in the cerebellum, testis, aorta, and whole blood were rs3138140 ( p  = 1.5E-5), rs879920435 (p  = 1.5E-5), rs59980219 ( p  = 3.6E-5), and rs76779798 ( p  = 4.1E-5), respectively. PheWAS of these cis -eQTLs did not return any significant associations in PhenoScanner.

To contrast the health impacts of GDF11 against those of its homolog, MSTN , we searched for all MSTN cis -eQTLs in the GTEx portal and identified 771 significant variants (Supplementary Table S3). A visual depiction of all variants associated with MSTN expression can be found in Supplementary Fig. S2A. We observed a similar tissue-specific association pattern among MSTN cis -eQTLs as we previously did for those associated with GDF11 (Supplementary Fig. S2B). In contrast to GDF11 , PheWAS of the most significant MSTN cis -eQTL in each tissue did not reveal consistent associations with any particular health conditions (Supplementary Table S4). As a result, we were unable to find any overlap between GDF11 and MSTN cis -eQTL PheWAS data.

Importantly, we included a positive control in the form of a benchmark gene to evaluate the reliability of our inquiry. We used a SNP (rs174546), whose PheWAS results have been previously reported [ 99 ]. We confirmed that our PheWAS of this SNP reproduced all the previously reported associations (Supplementary Table S5).

GDF11 variants demonstrate links to asthma, immune function, lung function, and thyroid health

The Open Targets Genetics Portal integrates GWAS and functional genomics data to allow for variant-centric analysis across thousands of traits. Variants were assigned to genes based on predicted functional effects, distance from the transcript start site, molecular phenotype quantitative trait loci experiments, and chromatin interaction experiments [ 86 , 87 ]. To further analyze the health effects of GDF11 variants, we employed the Open Targets Genetics Portal and identified 297 associations with GDF11 variants (Supplementary Table S6). We sorted the total number of associations by disease category to identify the most prevalent health impact of GDF11 variation (Fig.  2 A). Associations related to a specific disease were grouped together. For example, asthma and eosinophil counts were grouped with respiratory health, allergies, and immunity, and hypothyroidism was grouped with thyroid traits. Associations that did not easily fit a disease classification were placed in the “other” category.

Traits associated with variants and predicted tissue-specific expression of GDF11 and MSTN in Open Targets Genetics and the TWAS Hub. Traits were sorted by disease category to identify the most prevalent associations in each database. Disease categories are denoted by colors in the legend. Traits that did not fit a category were placed into the “other” category

Among the associations we identified with GDF11 variants, the largest portion (26.94%) were traits related to respiratory health, allergies, and immunity. The association with the highest statistical significance in this category was observed between rs705702 and “eosinophil counts” ( p  = 1.6E-41; Table  2 ), whereas the most significant association overall was between rs61134397 and “refractive error” ( p  = 6.0e-174). Asthma emerged as the most prevalent trait, accounting for 32.86% of all respiratory health, allergies, and immunity associations. Intriguingly, we found another GDF11 variant, rs1689510, exhibited significant associations with asthma, immune function, and lung function across multiple studies (Table  2 ). To further investigate this SNP, we searched for all associations with rs1689510 in the Open Targets Genetics Portal and presented those data in Fig.  3 . The most statistically significant association with rs1689510 was “type 1 diabetes” ( p  = 5.0e-61), followed by “eosinophil percentage of white cells” ( p  = 8.9e-39). rs1689510 was also associated with “asthma” ( p  = 2.7e-23), and “hypothyroidism or myxedema” ( p  = 3.9e-16) (Supplementary Table S7).

PheWAS results from Open Target Genetics reveal associations between the SNP rs1689510 and asthma, immune function, lung function, and hypothyroidism. The x-axis represents categories of disease traits, and the y-axis represents the -log 10 ( p -value) of each association. The red significance line represents p  = 1e-5. Associations that met the threshold p  < 1e-14 are labeled in the figure. Results are sourced from FinnGen, UK Biobank, and GWAS Catalog

To complement discoveries made with Open Targets Genetics, we employed PhenoScanner to screen for associations with GDF11 variants. We identified 34 total associations with GDF11 variants, and the most significant association overall was between rs61134397 and “cause of death: pharynx, unspecified” ( p  = 1.763e-21; Supplementary Table S8). The most significant respiratory association was between rs139996303 and “self-reported respiratory infection” ( p  = 5.46E-06; Supplementary Table S8). The investigation also revealed two GDF11 variants associated with “self-reported pulmonary fibrosis”: rs12304296 and rs7297523 ( p  = 8.69E-06 and p  = 8.99E-06, respectively; Supplementary Table S8). Additionally, we searched for associations with GDF11 variants in GeneATLAS and identified associations with respiratory disease, asthma, and hypothyroidism, validating our previous findings (Supplementary Table S9).

Once again, we sought to contrast the health effects of GDF11 and MSTN variants, so we conducted a reciprocal analysis of MSTN in the Open Target Genetics Portal and identified 72 significant health associations (Supplementary Table S10). The results indicated that the largest number of associations with MSTN variants were red blood cell traits (43.06%), and the most significant association overall was between rs291444 and “serum levels of protein HIBCH” ( p  = 2.0e-258; Supplementary Table S10). The search did not reveal a robust relationship between MSTN variants and respiratory health, allergies, and immunity that was found for GDF11 (Fig.  2 B). Lastly, we investigated the health effects of MSTN variants in PhenoScanner and GeneATLAS but did not identify consistent associations with a particular disease category (Supplementary Tables S11 and S12).

Predicted GDF11 expression is associated with asthma, immune function, lung function, and thyroid health

TWAS Hub is an open-access database that contains genomics data on hundreds of traits and over 100,000 expression models [ 67 ]. We identified 91 associations between tissue-specific GDF11 expression and health outcomes (Fig.  2 C; Supplementary Table S13). Predictive models for the expression of GDF11 were only available for one tissue, unexposed suprapubic skin . Associations between GDF11 expression in the skin and various health conditions were compiled and sorted into disease categories; 18.18% were traits related to respiratory health, allergies, and immunity. "Blood eosinophil count" demonstrated the highest statistical significance within this category ( p  = 4.79E-07, Z-score = -4.9; Table  3 ), whereas the most significant association with GDF11 expression overall was “smoking status” ( p  = 1.70e-07, Z-score = 5.1). Other traits associated with GDF11 expression in this category included “respiratory disease” ( p  = 1.30E-06, Z-score = -4.7), “self-reported asthma” ( p  = 3.17E-05, Z-score = -4.0), and “lung FEV1/FVC ratio” ( p  = 4.81E-05, Z-score = 3.9). Furthermore, the search revealed thyroid traits associated with GDF11 expression, such as “self-reported hypothyroidism” ( p  = 8.54E-06, Z-score = -4.3) and “hypothyroidism/myxodema” ( p  = 2.07E-05, Z-score = -4.1). All associations remained significant after a tissue-specific Bonferroni correction at an experiment-wide α of 0.05 was applied. In tandem, we mined MSTN TWAS results in the TWAS hub and identified 50 significant associations. Predictive models for MSTN expression were only available for one tissue, hypothalamus. The most significant association with MSTN expression in the hypothalamus was “diastolic blood pressure, automated reading” ( p  = 2.60e-12, Z-score = -6.9; Supplementary Table S14), and the disease category most frequently associated with MSTN expression was cardiovascular health (20.00%; Fig.  2 D).

HEY1 , a candidate genetic regulator of GDF11 expression, is associated with respiratory, immune function, and thyroid health

In the next step of evaluating the respective effects of GDF11 and MSTN , we contrasted their putative genetic regulators, HEY1 and FOXO1, respectively, which we identified previously. We utilized the GTEx dataset (Supplementary Fig. S3) to contrast GDF11 and HEY1 expression across many tissues. GDF11 appeared to exhibit a similar expression pattern as HEY1 across tissues. These results indicated low MSTN expression levels across tissues relative to other genes in the query, and MSTN and FOXO1 did not appear to follow similar expression profiles across tissues. Moreover, bulk tissue expression data from the GTEx project revealed distinct expression profiles between GDF11 and MSTN . These expression data indicated the highest level of GDF11 expression in various areas of the brain, including the cervical spinal cord, cerebellum, hypothalamus, amygdala, and spleen (Fig.  4 ). GDF11 ’s expression profile provided further evidence to support the health associations we uncovered; GDF11 showed high levels of expression in the lungs and thyroid, with median bulk tissue expression levels of approximately 7 and 8 TPM, respectively. In contrast, MSTN exhibited the highest expression in cultured fibroblasts and skeletal muscle but had relatively low levels of expression across tissues compared to GDF11 (Supplementary Fig. S4).

Bulk tissue gene expression for GDF11 from the GTEx dataset. The x-axis represents separate tissues, and the y-axis represents expression values. Expression values are shown in TPM (transcripts per million), calculated from a gene model with isoforms collapsed to a single gene

Lastly, we sought to define the extent to which health effects of GDF11 overlapped with those of its own potential genetic regulator, HEY1 . We conducted a PheWAS analysis of HEY1 in GeneATLAS and identified a total of 27 health associations (Supplementary Table S15) . Interestingly, PheWAS results revealed associations between HEY1 variants and respiratory and immune function traits (Table  4 ). The association with the highest statistical significance was between rs3888020 and “lymphocyte count” ( p  = 2.43E-18). Two other HEY1 variants, rs4739738 and rs13263709, were associated with “asthma” ( p  = 6.40E-15 and p  = 5.06E-12, respectively). Furthermore, we searched PhenomeXcan for TWAS results and identified associations between tissue-specific HEY1 expression and respiratory and thyroid phenotypes (Table  5 ). The strongest respiratory-related association with HEY1 expression across all tissues with available data was “diagnoses—main ICD10: J39 Other diseases of upper respiratory tract” ( p  = 2.35E-4) and was identified in the minor salivary gland tissue. Thyroid traits associated with HEY1 expression in PhenomeXcan included “non-cancer illness code, self-reported: thyroid problem (not cancer)” identified in the minor salivary gland ( p  = 9.06E-3) and hypothalamus ( p  = 1.53E-2), and “hypothyroidism (congenital or acquired)” identified in the testis ( p  = 9.89E-3). All associations with tissue-specific HEY1 expression identified in PhenomeXcan can be found in Supplementary Table S16. Using the GWAS Catalog, we uncovered associations between HEY1 variants and various health outcomes, including educational attainment and colorectal cancer survival, though none of which overlapped with respiratory, lung function, immune function, or thyroid traits (Supplementary Table S17). Of note, we investigated the other HEY family genes and the results were consistent with those for HEY1 (Supplementary Table S18).

Finally, to be as comprehensive as possible, we searched for overlap between MSTN and its potential genetic regulator, FOXO1 , and identified shared associations between these genes in several databases (Supplementary Tables S19-S22). A flow chart depicting the study design and overarching results for each gene included in this study can be found in Fig.  5 .

Overarching study design and results flow chart for GDF11 , MSTN , HEY1 , and FOXO1 . Each step of the study design and corresponding databases are depicted to the left of the vertical black line. Overarching results for each gene identified from each step are depicted to the right of the vertical black line

In the present study, we sought to define the unique health effects of GDF11 at the population level, versus that of its homolog MSTN, using repositories of published GWAS results in population biobanks. Prior studies had demonstrated roles for GDF11 in rejuvenating the aged heart [ 22 , 100 ], brain [ 24 , 25 , 26 ], and skeletal muscle [ 23 ], so we predicted that GDF11 variants would be associated with cardiovascular, cognitive, and muscular diseases and phenotypes. Yet our results revealed consistent relationships between GDF11 and respiratory, immune function, and thyroid health instead. PheWAS of GDF11 cis -eQTLs revealed associations with asthma, lung function, immune function, and thyroid health, and PheWAS of broader GDF11 variants and TWAS of its predicted tissue-specific expression confirmed those findings. Through our comprehensive approach, we documented novel associations with GDF11 , expanding our knowledge of the pleiotropic health effects of this gene.

Our analysis revealed that GDF11 variants and its predicted tissue-specific expression levels were consistently associated with asthma across multiple databases. Asthma is a chronic inflammatory lung disease characterized by airflow obstruction in which airway smooth muscle constricts due to a variety of triggers, such as allergens, tobacco smoke, air pollution, and infections [ 101 , 102 ]. Asthma affects over 300 million individuals worldwide and claimed over 455,000 deaths in 2019, according to the Global Burden of Disease study [ 103 , 104 ]. Asthma, like many other chronic conditions, is polygenic – driven by complex interactions among many genes and variants. Human GWAS consistently implicate the 17q21 locus with asthma, and variants of four genes within this locus have been linked to the development of the disease [ 105 ]. Mutations in these genes, including ORMDL3 , GSDMB , ZPBP2 , and IKZF3 , result in reduced protein folding in the endoplasmic reticulum leading to an overall pro-inflammatory effect in asthma patients [ 106 ]. However, as with other complex genetic diseases, much of its heritability remains undefined [ 106 ]. In addition to the presence of asthma, in our study, GDF11 variants and transcript levels were also associated with blood eosinophil counts. These data are supportive of a potential relationship between GDF11 and asthma due to the major role eosinophils play in asthma pathogenesis. In T2 high asthma, distinguished by eosinophilic inflammation in the airways [ 107 ], eosinophils are recruited to the inflammatory site and release inflammatory mediators such as cytokines and chemokines [ 108 ]. Furthermore, sputum and blood eosinophil counts have been used as clinical biomarkers for disease exacerbation [ 109 , 110 , 111 ]. In this study, we identified high GDF11 expression levels in the spleen, consistent with findings from past studies [ 112 , 113 ]. The spleen has a broad range of immunological functions and contains several types of resident immune cells, including T and B cells, dendritic cells, and macrophages [ 114 , 115 , 116 ]. These results suggest GDF11 may influence the development or progression of asthma through its relationship with the immune system. Future research will expand our understanding of asthma genetics, including the relationship between GDF11 , asthma, and the immune system.

Furthermore, our results pointed to a relationship between GDF11 and thyroid phenotypes, particularly hypothyroidism. Hypothyroidism is a chronic disease characterized by a deficiency in thyroxine (T4) and triiodothyronine (T3) [ 117 ], with an estimated worldwide prevalence of 5% [ 118 ]. While environmental iodine deficiency is the most common cause of hypothyroidism globally, autoimmune thyroiditis (Hashimoto’s disease) is the leading cause of primary hypothyroidism in regions of iodine sufficiency [ 119 ]. Hypothyroidism results from pathological processes within the thyroid gland (primary hypothyroidism) but can also develop from hypothalamus or pituitary disorders (central hypothyroidism) or disorders of the peripheries [ 119 , 120 ]. The genetic basis of hypothyroidism has yet to be well-defined [ 119 ], although GWAS have identified common loci associated with thyroid hormone regulation [ 121 , 122 , 123 ]. Interestingly, a recent study by Añón-Hidalgo et al. identified a positive association between GDF11 and TSH levels in humans [ 124 ], supporting the relationship we found between GDF11 and hypothyroidism. Importantly, the top cis- eQTL of GDF11 , rs117385153, was identified in the thyroid tissue, and bulk tissue expression from the GTEx dataset supports this finding, revealing moderate GDF11 expression levels in the thyroid tissue. Collectively, these data highlight a consistency between the genetic regulation of GDF11 and its associations with hypothyroidism, supporting the potential role of GDF11 in the development or progression of thyroid disease.

We propose that the associations identified within this study, linking GDF11 variants and transcript levels to respiratory and thyroid phenotypes—specifically asthma and hypothyroidism—are mediated through the involvement of GDF11 in inflammatory signaling pathways. The relationship between GDF11 and inflammation has been reported in prior studies, particularly by its attenuation of inflammatory factor expression by impeding nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) and JNK signaling pathways through TGF-β/Smad2/3 activation [ 27 , 124 , 125 , 126 , 127 , 128 ]. Through its anti-inflammatory actions, GDF11 has been shown to be beneficial by relieving acute lung injury [ 127 ], the development of inflammatory arthritis [ 125 ], endothelial injury and atherosclerotic lesion formation [ 126 ], and aging of the skin [ 27 ]. Moreover, prior studies in humans with chronic obstructive pulmonary disease (COPD) report decreases in circulating GDF11 levels [ 128 , 129 ] and reduced GDF11 expression in the serum and cells of these patients [ 130 ]. Asthma and hypothyroidism are complex, chronic conditions whose pathogeneses and progression are largely dictated by inflammation [ 131 , 132 , 133 ]. Both conditions are often diagnosed in individuals with autoimmune disorders, such as Type 1 diabetes [ 117 , 134 ]. Asthma and thyroid diseases have been correlated with each other in several studies [ 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 ], but the research is mostly limited to association data. These reports include case studies that identify patients afflicted by both diseases [ 143 , 142 ], epidemiological evidence from the Oxford Record Linkage Study (ORLS) supporting a possible association between the two conditions [ 137 ], and a population-based cohort study suggesting maternal hypothyroidism may increase the risk of childhood asthma [ 144 ]. Several studies report associations between hypothyroidism and milder asthma symptoms [ 140 , 145 , 146 ], potentially due to reduced thyroid hormone levels which cause decreased oxygen consumption [ 147 ]. We posit that GDF11 influences respiratory and thyroid health, particularly asthma and hypothyroidism, through its anti-inflammatory effects. To our knowledge, no group has reported a connection between GDF11 , asthma, and hypothyroidism simultaneously, warranting future research on the potential role of GDF11 in the pathogenesis of these conditions.

One SNP identified in Open Target Genetics, rs1689510, was found to be associated with asthma, immune function, lung function, and thyroid traits across multiple studies. PheWAS results from FinnGen, UK Biobank, and GWAS Catalog for this SNP indicate significant associations with type 1 diabetes, asthma, immune function, and hypothyroidism. These findings highlight a major advantage of PheWAS – the ability to identify a single locus that affects multiple distinct phenotypes – and provide pleiotropic variants to inform the next steps in this research. For instance, mechanistic investigations are now needed to test and validate rs1689510 as a key player in asthma pathogenesis. rs1689510 is located 259,862 bp away from GDF11’s canonical transcription start site (TSS), and upon further investigation, we identified this variant as a cis- eQTL of GDF11 in the eQTL Gen database [ 92 ]. The nearest gene to rs1689510 is IKAROS family zinc finger 4 ( IKZF4; 4,675 bp to canonical TSS), which encodes a protein that binds to the 5'GGGAATRCC-3' Ikaros-binding sequence and serves as a transcriptional repressor [ 148 ]. Results from the GTEx portal indicate that rs1689510 is a cis -eQTL of IKZF4 in adipose tissue ( p  = 6.6E-08), lymphocytes ( p  = 1.2E-06), and unexposed suprapubic skin ( p  = 3.7E-05). Intriguingly, IKZF4 has been shown to be necessary for the inhibitory role of T-regulatory cells [ 149 , 150 ], suggesting rs1689510 may regulate the predicted expression levels of several genes involved in immune function, including IKZF4 and GDF11 . Overall, these results encourage future studies on the role rs1689510 plays in the immune system and disease progression and development, particularly asthma.

In our prior rodent work, we provided evidence of members of the hairy and enhancer of split-related (HESR) family of basic helix-loop-helix (bHLH) transcriptional repressors [ 151 ], specifically Hey1 , as genetic regulators of GDF11 [ 51 ]. In the present study, gene expression results from the GTEx dataset indicate similar expression patterns for GDF11 and HEY1 across tissues . These relationships remain, although less consistently, between GDF11 and other HEY family genes. These human expression data mirror those of mice, wherein Gdf11 and Hey family genes are positively correlated with each other [ 152 ]. Moreover, we noted general associations between HEY1 variants and its predicted tissue-specific expression levels with respiratory and thyroid conditions, as we did for GDF11. These results are consistent with HEY1 as a potential genetic regulator of GDF11, specifically in the context of inflammatory disease. We also investigated the homolog of GDF11 , MSTN, to parse out their distinct biological roles. Results mirror MSTN’s known role in the heart [ 153 , 154 , 155 , 156 ], as many associations were related to cardiovascular health. However, MSTN did not share the same robust relationship with respiratory, lung function, immune function, and thyroid traits as GDF11 did. This suggests that GDF11 has a separate, distinct role in the development of inflammatory diseases that is not shared with MSTN . Future work should continue to delineate the shared and distinct functions of these homologs.

It must be noted that there are several limitations to our study. First, we applied Bonferroni correction on many transcriptome-wide associations to establish a conservative significance threshold, but not all of our variables were truly independent [ 157 ]. TWAS results were based on genetically predicted gene expression, not direct measurements of gene expression – TWAS signals rely on the predictive power of the genetic model to compute gene expression and GWAS to source variant-level trait associations. Furthermore, our stratified approach used multiple databases to gather evidence; however, these databases were not completely independent from one another. Some of the consistent observations we identified between databases were due to the same underlying GWAS results housed in several platforms. Importantly, these databases primarily include British individuals, which affords them limited ancestral diversity. It is imperative that future studies investigate these genotype–phenotype relationships in populations with greater genetic diversity. Lastly, due to incomplete linkage disequilibrium (LD) between SNPs and the availability of SNPs in the databases used in this study, we did observe trait associations for some SNPs within LD blocks, but not others. In the interest of communicating the novel relationships identified between GDF11 and health, we included all reported significant associations to be comprehensive.

In this study, we provide evidence of GDF11 in the involvement of inflammatory diseases, namely asthma and hypothyroidism. PheWAS revealed robust associations between GDF11 cis -eQTLs and asthma, immune function, lung function, and thyroid health. Associations identified from PheWAS on GDF11 variants and TWAS on predicted GDF11 tissue-specific expression confirmed our findings. Secondarily, we found similar health associations with HEY1 as we did with GDF11 , supporting our previous work which identified HEY1 as a candidate genetic regulator of GDF11 in the DO mouse stock. Moreover, gene expression data strengthen our hypotheses that GDF11 is involved in respiratory and thyroid disease pathogenesis and that HEY1 regulates GDF11 . Through these efforts, we report novel relationships between GDF11 and disease, suggesting GDF11 may exert its effects by acting on inflammatory pathways, in contrast to its formerly assumed role as a rejuvenating factor in basic aging. These data provide novel insights into the health impacts of GDF11 and lend further support for future mechanistic studies to illuminate the precise role of GDF11 in inflammatory disease pathogenesis.

Availability of data and materials

All data analyzed during this study are included in this published article and its supplementary information files. All data was downloaded from open-access databases, and details with links can be found in references [ 79 , 80 , 89 , 92 , 100 , 102 ].

Abbreviations

Diversity Outbred

Forkhead Box O1

• Growth differentiation factor 11

Hes Related Family BHLH Transcription Factor with YRPW Motif 1

Phenome-wide association study

Single nucleotide polymorphism

Transforming growth factor-β

McPherron AC, Huynh TV, Lee SJ. Redundancy of myostatin and growth/differentiation factor 11 function. BMC Dev Biol. 2009;9:24.

Article   PubMed   PubMed Central   Google Scholar  

McPherron A, Lawler A, Lee SJ. Regulation of anterior/posterior patterning of the axial skeleton by growth/differentiation factor 11. Nat Genet. 1999;22:260–4.

Article   CAS   PubMed   Google Scholar  

Andersson O, Reissmann E, Ibanez CF. Growth differentiation factor 11 signals through the transforming growth factor-β receptor ALK5 to regionalize the anterior–posterior axis. EMBO Rep. 2006;7(8):831–7.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Oh SP, et al. Activin type IIA and IIB receptors mediate Gdf11 signaling in axial vertebral patterning. Genes Dev. 2002;16(21):2749–54.

Zhang Y, et al. Role of growth differentiation factor 11 in development, physiology and disease. Oncotarget. 2017;8(46):81604–16.

Esquela AF, Lee S-J. Regulation of metanephric kidney development by growth/differentiation factor 11. Dev Biol. 2003;257(2):356–70.

Harmon EB, et al. GDF11 modulates NGN3+ islet progenitor cell number and promotes β-cell differentiation in pancreas development. Development. 2004;131(24):6163–74.

Dichmann DS, Yassin H, Serup P. Analysis of pancreatic endocrine development in GDF11-deficient mice. Dev Dyn. 2006;235(11):3016–25.

Kim J, et al. GDF11 controls the timing of progenitor cell competence in developing retina. Science. 2005;308(5730):1927–30.

Wu H-H, et al. Autoregulation of neurogenesis by GDF11. Neuron. 2003;37(2):197–207.

Rochette L, et al. Growth and differentiation factor 11 (GDF11): functions in the regulation of erythropoiesis and cardiac regeneration. Pharmacol Ther. 2015;156:26–33.

Dussiot M, et al. An activin receptor IIA ligand trap corrects ineffective erythropoiesis in β-thalassemia. Nat Med. 2014;20(4):398–407.

Suragani RN, et al. Transforming growth factor-β superfamily ligand trap ACE-536 corrects anemia by promoting late-stage erythropoiesis. Nat Med. 2014;20(4):408–14.

Liu Z, et al. Long-term intermittent fasting improves neurological function by promoting angiogenesis after cerebral ischemia via growth differentiation factor 11 signaling activation. PLoS ONE. 2023;18(3):e0282338.

Yu X, et al. Growth Differentiation Factor 11 Promotes Abnormal Proliferation and Angiogenesis of Pulmonary Artery Endothelial Cells. Hypertension. 2018;71(4):729–41.

Lu L, et al. Growth Differentiation Factor 11 Promotes Neurovascular Recovery After Stroke in Mice. Front Cell Neurosci. 2018;12:205.

Chen Y, et al. Relationship of serum GDF11 levels with bone mineral density and bone turnover markers in postmenopausal Chinese women. Bone Research. 2016;4(1):1–5.

Article   Google Scholar  

Zhang Y, et al. Growth differentiation factor 11 is a protective factor for osteoblastogenesis by targeting PPARgamma. Gene. 2015;557(2):209–14.

Jeanplong F, et al. Growth and differentiation factor-11 is developmentally regulated in skeletal muscle and inhibits myoblast differentiation. Open J Mol Integr Physiol. 2012;2:127–38.

Egerman MA, et al. GDF11 increases with age and inhibits skeletal muscle regeneration. Cell Metab. 2015;22(1):164–74.

Ravenscroft TA, et al. Heterozygous loss-of-function variants significantly expand the phenotypes associated with loss of GDF11. Genet Med. 2021;23(10):1889–900.

Poggioli T, et al. Circulating growth differentiation factor 11/8 levels decline with age. Circ Res. 2016;118(1):29–37.

Sinha M, et al. Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. Science. 2014;344(6184):649–52.

Katsimpardi L, et al. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science. 2014;344(6184):630–4.

Shi Y, Liu J-P. Gdf11 facilitates temporal progression of neurogenesis in the developing spinal cord. J Neurosci. 2011;31(3):883–93.

Vanbekbergen N, Hendrickx M, Leyns L. Growth differentiation factor 11 is an encephalic regionalizing factor in neural differentiated mouse embryonic stem cells. BMC Res Notes. 2014;7(1):1–7.

Article   CAS   Google Scholar  

Rochette L, et al. Anti-aging effects of GDF11 on skin. Int J Mol Sci. 2020;21(7):2598.

Tito A, et al. The growth differentiation factor 11 is involved in skin fibroblast ageing and is induced by a preparation of peptides and sugars derived from plant cell cultures. Mol Biotechnol. 2019;61(3):209–20.

Kim Y-J, et al. Conditioned media from human umbilical cord blood-derived mesenchymal stem cells stimulate rejuvenation function in human skin. Biochemistry and biophysics reports. 2018;16:96–102.

Smith SC, et al. GDF11 does not rescue aging-related pathological hypertrophy. Circ Res. 2015;117(11):926–32.

Schafer MJ, et al. Quantification of GDF11 and myostatin in human aging and cardiovascular disease. Cell Metab. 2016;23(6):1207–15.

Glass DJ. Elevated GDF11 is a risk factor for age-related frailty and disease in humans. Cell Metab. 2016;24(1):7–8.

Egerman MA, Glass DJ. The role of GDF11 in aging and skeletal muscle, cardiac and bone homeostasis. Crit Rev Biochem Mol Biol. 2019;54(2):174–83.

Article   PubMed   Google Scholar  

Rodgers BD. The Immateriality of circulating GDF11. Circ Res. 2016;118(10):1472–4.

Rodgers BD, Eldridge JA. Reduced Circulating GDF11 Is Unlikely Responsible for Age-Dependent Changes in Mouse Heart, Muscle, and Brain. Endocrinology. 2015;156(11):3885–8.

Zhou Y, et al. GDF11 treatment attenuates the recovery of skeletal muscle function after injury in older rats. AAPS J. 2017;19(2):431–7.

Olson KA, et al. Association of growth differentiation factor 11/8, putative anti-ageing factor, with cardiovascular outcomes and overall mortality in humans: analysis of the Heart and Soul and HUNT3 cohorts. Eur Heart J. 2015;36(48):3426–34.

Nakashima M, Akamine TTA, Joyner A. Expression of growth/differentiation factor 11, a new member of the BMP/TGFbeta superfamily during mouse embryogenesis. Mech Dev. 1999;80(2):185–9.

Roh, J.D., et al., Activin type II receptor signaling in cardiac aging and heart failure. Sci Transl Med, 2019. 11(482).

Harper SC, et al. Decreases pressure overload-induced hypertrophy, but can cause severe cachexia and premature death. Circ Res. 2018;123(11):1220–31.

Garrido-Moreno V, et al. GDF-11 prevents cardiomyocyte hypertrophy by maintaining the sarcoplasmic reticulum-mitochondria communication. Pharmacol Res. 2019;146:104273.

Zhu HZ, et al. GDF11 Alleviates Pathological Myocardial Remodeling in Diabetic Cardiomyopathy Through SIRT1-Dependent Regulation of Oxidative Stress and Apoptosis. Front Cell Dev Biol. 2021;9: 686848.

Su HH, et al. Exogenous GDF11 attenuates non-canonical TGF-beta signaling to protect the heart from acute myocardial ischemia-reperfusion injury. Basic Res Cardiol. 2019;114(3):20.

Chen L, et al. Growth differentiation factor 11 attenuates cardiac ischemia reperfusion injury via enhancing mitochondrial biogenesis and telomerase activity. Cell Death Dis. 2021;12(7):665.

Bin Z, et al. GDF11 ameliorated myocardial ischemia reperfusion injury by antioxidant stress and up-regulating autophagy in STZ-induced type 1 diabetic rats. Acta Cir Bras. 2020;34(11):e201901106.

Zhao Y, et al. GDF11 enhances therapeutic efficacy of mesenchymal stem cells for myocardial infarction via YME1L-mediated OPA1 processing. Stem Cells Transl Med. 2020;9(10):1257–71.

Li Z, et al. GDF11 inhibits cardiomyocyte pyroptosis and exerts cardioprotection in acute myocardial infarction mice by upregulation of transcription factor HOXA3. Cell Death Dis. 2020;11(10):917.

Schmidt CW. Diversity outbred: a new generation of mouse model. Environ Health Perspect. 2015;123(3):A64–7.

Churchill GA, et al. The diversity outbred mouse population. Mamm Genome. 2012;23:713–8.

Gatti DM, et al. Quantitative trait locus mapping methods for diversity outbred mice. G3 (Bethesda). 2014;4(9):1623–33.

Starcher AE, et al. A systems approach using Diversity Outbred mice distinguishes the cardiovascular effects and genetics of circulating GDF11 from those of its homolog, myostatin. G3 (Bethesda), 2021. 11(11).

Rutenberg JB, et al. Developmental patterning of the cardiac atrioventricular canal by Notch and Hairy-related transcription factors. Development. 2006;133(21):4381–90.

Fischer A, et al. Combined loss of Hey1 and HeyL causes congenital heart defects because of impaired epithelial to mesenchymal transition. Circ Res. 2007;100(6):856–63.

Fischer A, et al. The Notch target genes Hey1 and Hey2 are required for embryonic vascular development. Genes Dev. 2004;18(8):901–11.

Watanabe Y, et al. Importance of endothelial Hey1 expression for thoracic great vessel development and its distal enhancer for notch-dependent endothelial transcription. J Biol Chem. 2020;295(51):17632–45.

Albert FW, Kruglyak L. The role of regulatory variation in complex traits and disease. Nat Rev Genet. 2015;16(4):197–212.

Skelly DA, Ronald J, Akey JM. Inherited variation in gene expression. Annu Rev Genomics Hum Genet. 2009;10:313–32.

Qu W, et al. Identification of splicing Quantitative Trait Loci (sQTL) in drosophila melanogaster with developmental lead (Pb(2+)) exposure. Front Genet. 2017;8:145–145.

van der Wijst M, et al. The single-cell eQTLGen consortium eLife. 2020;9:e52155.

Google Scholar  

Consortium, G.T. The Genotype-Tissue Expression (GTEx) project. Nat Genet. 2013;45(6):580–5.

Madeira F, et al. Search and sequence analysis tools services from EMBL-EBI in 2022. Nucleic Acids Res. 2022;50(W1):W276-9.

Blake JA, et al. Mouse Genome Database (MGD): Knowledgebase for mouse-human comparative biology. Nucleic Acids Res. 2021;49(D1):D981-d987.

Baldarelli RM, et al. The mouse Gene Expression Database (GXD): 2021 update. Nucleic Acids Res. 2021;49(D1):D924–31.

Robinson JR, et al. Genome-wide and phenome-wide approaches to understand variable drug actions in electronic health records. Clin Transl Sci. 2018;11(2):112–22.

Stearns FW. One hundred years of pleiotropy: a retrospective. Genetics. 2010;186(3):767–73.

Diogo D, et al. Phenome-wide association studies across large population cohorts support drug target validation. Nat Commun. 2018;9(1):4285.

Gusev A, et al. Integrative approaches for large-scale transcriptome-wide association studies. Nat Genet. 2016;48(3):245–52.

Bhattacharya A, et al. A framework for transcriptome-wide association studies in breast cancer in diverse study populations. Genome Biol. 2020;21(1):42.

Gamazon ER, et al. A gene-based association method for mapping traits using reference transcriptome data. Nat Genet. 2015;47(9):1091–8.

Mancuso N, et al. Integrating gene expression with summary association statistics to identify genes associated with 30 complex traits. Am J Hum Genet. 2017;100(3):473–87.

Bycroft C, et al. The UK Biobank resource with deep phenotyping and genomic data. Nature. 2018;562(7726):203–9.

Carithers LJ, et al. A Novel Approach to High-Quality Postmortem Tissue Procurement: The GTEx Project. Biopreservation and biobanking. 2015;13(5):311–9.

Siminoff LA, et al. Consent to a Postmortem tissue procurement study: distinguishing family decision makers’ knowledge of the genotype-tissue expression project. Biopreserv Biobank. 2018;16(3):200–6.

Consortium, G.T., et al. Genetic effects on gene expression across human tissues. Nature. 2017;550(7675):204–13.

The Genotype-Tissue Expression (GTEx) Project; Available from: https://www.gtexportal.org/home/ . Cited 2022 Nov 8.

Wright FA, et al. Heritability and genomics of gene expression in peripheral blood. Nat Genet. 2014;46(5):430–7.

TWAS Hub. Available from: http://twas-hub.org/ . Cited 2022 Nov 8.

Fromer M, et al. Gene expression elucidates functional impact of polygenic risk for schizophrenia. Nat Neurosci. 2016;19(11):1442–53.

Stancáková A, et al. Hyperglycemia and a common variant of GCKR are associated with the levels of eight amino acids in 9,369 Finnish men. Diabetes. 2012;61(7):1895–902.

Stancáková A, et al. Changes in insulin sensitivity and insulin release in relation to glycemia and glucose tolerance in 6,414 Finnish men. Diabetes. 2009;58(5):1212–21.

Raitakari OT, et al. Cohort profile: the cardiovascular risk in Young Finns Study. Int J Epidemiol. 2008;37(6):1220–6.

Nuotio J, et al. Cardiovascular risk factors in 2011 and secular trends since 2007: the Cardiovascular Risk in Young Finns Study. Scand J Public Health. 2014;42(7):563–71.

Pividori M, et al. PhenomeXcan: Mapping the genome to the phenome through the transcriptome. BioRxiv. 2020;6(37):eaba2083.

Barbeira AN, et al. Exploiting the GTEx resources to decipher the mechanisms at GWAS loci. Genome Biol. 2021;22(1):49.

PhenomeXcan. Available from: http://apps.hakyimlab.org/phenomexcan/ . Cited 2022 Nov 8.

Ghoussaini M, et al. Open Targets Genetics: systematic identification of trait-associated genes using large-scale genetics and functional genomics. Nucleic Acids Res. 2021;49(D1):D1311–20.

Mountjoy E, et al. An open approach to systematically prioritize causal variants and genes at all published human GWAS trait-associated loci. Nat Genet. 2021;53(11):1527–33.

Open Targets Genetics. Available from: https://genetics.opentargets.org/ . Cited 2022 Nov 8.

Buniello A, et al. The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019. Nucleic Acids Res. 2019;47(D1):D1005-d1012.

Zhou W, et al. Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies. Nat Genet. 2018;50(9):1335–41.

Lab N. UK Biobank bulk summary statistics. 2018.

Võsa U, et al. Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression. Nat Genet. 2021;53(9):1300-10.

Sun BB, et al. Genomic atlas of the human plasma proteome. Nature. 2018;558(7708):73–9.

Kamat MA, et al. PhenoScanner V2: an expanded tool for searching human genotype-phenotype associations. Bioinformatics. 2019;35(22):4851–3.

Staley JR, et al. PhenoScanner: a database of human genotype-phenotype associations. Bioinformatics. 2016;32(20):3207–9.

PhenoScanner. Available from: http://www.phenoscanner.medschl.cam.ac.uk/ . Cited 2022 Nov 8.

Canela-Xandri O, Rawlik K, Tenesa A. An atlas of genetic associations in UK Biobank. Nat Genet. 2018;50(11):1593–9.

Gene ATLAS. Available from: http://geneatlas.roslin.ed.ac.uk/ . Cited 2022 Nov 8.

Yang S, Ye K. Recent advances in understanding the adaptive evolution of metabolic genes and traits. Curr Opin Clin Nutr Metab Care. 2021;24(4):308–14.

Du G-Q, et al. Targeted myocardial delivery of GDF11 gene rejuvenates the aged mouse heart and enhances myocardial regeneration after ischemia–reperfusion injury. Basic Res Cardiol. 2017;112:1–14.

Holgate ST. Asthma: a simple concept but in reality a complex disease. Eur J Clin Invest. 2011;41(12):1339–52.

Win PH, Hussain I. Asthma Triggers: What Really Matters? Clinical Asthma. 2008:149-56.

Frossing L, et al. The prevalence of subtypes of type 2 inflammation in an unselected population of patients with severe asthma. J Allergy Clin Immunol Pract. 2021;9(3):1267–75.

Vos T, et al. Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020;396(10258):1204–22.

Mims JW. Asthma: definitions and pathophysiology. Int Forum Allergy Rhinol. 2015;5(Suppl 1):S2-6.

PubMed   Google Scholar  

Bunyavanich S, Schadt EE. Systems biology of asthma and allergic diseases: a multiscale approach. J Allergy Clin Immunol. 2015;135(1):31–42.

Fahy JV. Type 2 inflammation in asthma - present in most, absent in many. Nat Rev Immunol. 2015;15:57–65.

Kuruvilla ME, Lee FE, Lee GB. Understanding asthma phenotypes, endotypes, and mechanisms of disease. Clin Rev Allergy Immunol. 2019;56(2):219–33.

Denlinger LC, et al. Inflammatory and comorbid features of patients with severe asthma and frequent exacerbations. Am J Respir Crit Care Med. 2017;195(3):302–13.

Price DB, et al. Blood eosinophil count and prospective annual asthma disease burden: a UK cohort study. Lancet Respir Med. 2015;3(11):849–58.

Green RH, et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. The Lancet. 2002;360(9347):1715–21.

Loffredo FS, et al. Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell. 2013;153(4):828–39.

McPherron AC. Metabolic functions of myostatin and GDF11. Immunology Endocr Metab AgentsMed Chem (Formerly Current Medicinal Chemistry-Immunology Endocrine and Metabolic Agents). 2010;10(4):217–31.

Bronte V, Pittet MJ. The spleen in local and systemic regulation of immunity. Immunity. 2013;39(5):806–18.

Travers J, Rothenberg M. Eosinophils in mucosal immune responses. Mucosal Immunol. 2015;8(3):464–75.

Lewis, S.M., A. Williams, and S.C. Eisenbarth, Structure and function of the immune system in the spleen. Sci Immunol, 2019. 4(33).

Chaker L, et al. Hypothyroidism. The Lancet. 2017;390(10101):1550–62.

Chiovato L, Magri F, Carlé A. Hypothyroidism in context: where we’ve been and where we’re going. Adv Ther. 2019;36(Suppl 2):47–58.

Taylor PN, et al. Global epidemiology of hyperthyroidism and hypothyroidism. Nat Rev Endocrinol. 2018;14(5):301–16.

Persani L. Clinical review: Central hypothyroidism: pathogenic, diagnostic, and therapeutic challenges. J Clin Endocrinol Metab. 2012;97(9):3068–78.

Porcu E, et al. A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function. PLoS Genet. 2013;9(2):e1003266.

Teumer A, et al. Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation. Nat Commun. 2018;9(1):4455.

Taylor PN, et al. Whole-genome sequence-based analysis of thyroid function. Nat Commun. 2015;6:5681.

Añón-Hidalgo J, et al. Circulating concentrations of GDF11 are positively associated with TSH levels in humans. J Clin Med. 2019;8(6):878.

Li W, et al. GDF11 antagonizes TNF-α-induced inflammation and protects against the development of inflammatory arthritis in mice. Faseb j. 2019;33(3):3317–29.

Mei W, et al. GDF11 protects against endothelial injury and reduces atherosclerotic lesion formation in apolipoprotein E-null mice. Mol Ther. 2016;24(11):1926–38.

Xu HB, et al. Growth differentiation factor 11 relieves acute lung injury in mice by inhibiting inflammation and apoptosis. Eur Rev Med Pharmacol Sci. 2020;24(12):6908–18.

Onodera K, et al. Decrease in an anti-ageing factor, growth differentiation factor 11, in chronic obstructive pulmonary disease. Thorax. 2017;72(10):893–904.

Tanaka R, et al. Physical inactivity is associated with decreased growth differentiation factor 11 in chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2018;13:1333–42.

Tang F, Ling C, Liu J. Reduced expression of growth differentiation factor 11 promoted the progression of chronic obstructive pulmonary disease by activating the AKT signaling pathway. Biomed Pharmacother. 2018;103:691–8.

Ishmael FT. The inflammatory response in the pathogenesis of asthma. J Am Osteopath Assoc. 2011;111(11 Suppl 7):S11–7.

Murdoch JR, Lloyd CM. Chronic inflammation and asthma. Mutat Res. 2010;690(1–2):24–39.

Mancini A, et al. Thyroid hormones, oxidative stress, and inflammation. Mediators Inflamm. 2016;2016:6757154–6757154.

Tedeschi A, Asero R. Asthma and autoimmunity: a complex but intriguing relation. Expert Rev Clin Immunol. 2008;4(6):767–76.

Manzolli S, et al. Allergic airway inflammation in hypothyroid rats. J Allergy Clin Immunol. 1999;104(3 Pt 1):595–600.

Sato A, et al. A possible role of immunoglobulin E in patients with hyperthyroid graves’ disease. J Clin Endocrinol Metab. 1999;84(10):3602–5.

CAS   PubMed   Google Scholar  

Goldacre M, et al. Use of large medical databases to study associations between diseases. QJM. 2000;93(10):669–75.

Hoffman DA, McConahey WM. Thyrotoxicosis and asthma. Lancet. 1982;1(8275):808.

Ursu HI, et al. Graves’-Basedow’s disease–asthma association. Presentation of five cases. Rom J Endocrinol. 1993;31(1–2):89–94.

Bingyan Z, Dong W. Impact of thyroid hormones on asthma in older adults. J Int Med Res. 2019;47(9):4114–25.

Qashqary M, et al. Prevalence of suspected cases of hyperthyroidism in Jeddah by using wayne’s scoring index. Cureus. 2020;12(11):e11538–e11538.

PubMed   PubMed Central   Google Scholar  

Oppedal RJ, Khan DA, Brown ES. Hypothyroidism in patients with asthma and major depressive disorder. Primary care companion to the Journal of clinical psychiatry. 2007;9(6):467–8.

Thorsteinsson BA, Kirkegaard C. Iodine-induced hypothyroidism and bronchial asthma. Lancet. 1979;310(8032):294.

Liu X, et al. Maternal hypothyroidism in the perinatal period and childhood asthma in the offspring. Allergy. 2018;73(4):932–9.

Harrison RN, Tattersfield AE. Airway response to inhaled salbutamol in hyperthyroid and hypothyroid patients before and after treatment. Thorax. 1984;39:34–9.

Fedrick J, Baldwin JA. Thyroid disease and asthma. Br Med J. 1977;2(6101):1539.

Weare-Regales N, et al. Hormonal effects on asthma, rhinitis, and eczema. J Allergy Clin Immunol Pract. 2022;10(8):2066–73.

Consortium, T.U. UniProt: the Universal Protein Knowledgebase in 2023. Nucleic Acids Res. 2022;51(D1):D523–31.

Gokhale AS, et al. Selective deletion of Eos (Ikzf4) in T-regulatory cells leads to loss of suppressive function and development of systemic autoimmunity. J Autoimmun. 2019;105:102300.

Stéphan P, et al. Transcriptional Control of Regulatory T Cells in Cancer: Toward Therapeutic Targeting? Cancers (Basel). 2020;12(11):3194.

Weber D, et al. Mechanisms of epigenetic and cell-type specific regulation of Hey target genes in ES cells and cardiomyocytes. J Mol Cell Cardiol. 2015;79:79–88.

Gene Expression Database (GXD). Available from: http://www.informatics.jax.org . Cited 2022 Aug 22

Lee S-J, McPherron AC. Myostatin and the control of skeletal muscle mass: commentary. Curr Opin Genet Dev. 1999;9(5):604–7.

Biesemann N, et al. Myostatin regulates energy homeostasis in the heart and prevents heart failure. Circ Res. 2014;115(2):296–310.

McKoy G, et al. Developmental expression of myostatin in cardiomyocytes and its effect on foetal and neonatal rat cardiomyocyte proliferation. Cardiovasc Res. 2007;74(2):304–12.

Morissette MR, et al. Myostatin regulates cardiomyocyte growth through modulation of Akt signaling. Circ Res. 2006;99(1):15–24.

Hebbring SJ. The challenges, advantages and future of phenome-wide association studies. Immunology. 2014;141(2):157–65.

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Acknowledgements

The authors wish to acknowledge Abigail DeBacker for her contributions to this work.

This work was supported by National Institutes of Health grant GM121551 (R.P.).

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Jessica Strosahl & Robert Pazdro

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Kaixiong Ye

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K.Y. guided the study design; J.S. collected and analyzed the data; R.P. supervised the project. All authors participated in writing the manuscript; all authors approved the final manuscript.

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Strosahl, J., Ye, K. & Pazdro, R. Novel insights into the pleiotropic health effects of growth differentiation factor 11 gained from genome-wide association studies in population biobanks. BMC Genomics 25 , 837 (2024). https://doi.org/10.1186/s12864-024-10710-7

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New-onset obstructive airway disease following COVID-19: a multicenter retrospective cohort study

• Min-Hsiang Chuang 1 ,
• Wei Hsu 2 ,
• Ya-Wen Tsai 3 , 4 ,
• Wan-Hsuan Hsu 2 ,
• Jheng-Yan Wu 5 ,
• Ting-Hui Liu 6 ,
• Po-Yu Huang 2 &
• Chih-Cheng Lai 7 , 8  

BMC Medicine volume  22 , Article number:  360 ( 2024 ) Cite this article

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The study assessed the association between COVID-19 and new-onset obstructive airway diseases, including asthma, chronic obstructive pulmonary disease, and bronchiectasis among vaccinated individuals recovering from COVID-19 during the Omicron wave.

This multicenter retrospective cohort study comprised 549,606 individuals from the U.S. Collaborative Network of TriNetX database, from January 8, 2022, to January 17, 2024. The hazard of new-onset obstructive airway diseases between COVID-19 and no-COVID-19 groups were compared following propensity score matching using the Kaplan–Meier method and Cox proportional hazards model.

After propensity score matching, each group contained 274,803 participants. Patients with COVID-19 exhibited a higher risk of developing new-onset asthma than that of individuals without COVID-19 (adjusted hazard ratio (aHR), 1.27; 95% CI, 1.22–1.33; p  < 0.001). Stratified analyses by age, SARS-CoV-2 variant, vaccination status, and infection status consistently supported this association. Non-hospitalized individuals with COVID-19 demonstrated a higher risk of new-onset asthma (aHR, 1.27; 95% CI, 1.22–1.33; p  < 0.001); however, no significant differences were observed in hospitalized and critically ill groups. The study also identified an increased risk of subsequent bronchiectasis following COVID-19 (aHR, 1.30; 95% CI, 1.13–1.50; p  < 0.001). In contrast, there was no significant difference in the hazard of chronic obstructive pulmonary disease between the groups (aHR, 1.00; 95% CI, 0.95–1.06; p  = 0.994).

This study offers convincing evidence of the association between COVID-19 and the subsequent onset of asthma and bronchiectasis. It underscores the need for a multidisciplinary approach to post-COVID-19 care, with a particular focus on respiratory health.

Peer Review reports

Over the past 3 years, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected more than 773 million individuals globally [ 1 ]. Despite coronavirus disease (COVID-19) being responsible for over seven million fatalities, the case fatality rate stood at a mere 0.9% [ 1 ], suggesting that more than 99% of patients with COVID-19 have survived the acute phase of SARS-CoV-2 infection. Nevertheless, a significant number of COVID-19 survivors develop post-COVID-19 conditions, also termed long COVID, which present a grave threat to global health [ 2 , 3 , 4 ]. Reports have documented a broad range of persistent symptoms linked to post-COVID-19 conditions, impacting the cardiovascular and pulmonary systems, gastrointestinal tract, neurocognitive functions, psychological well-being, and musculoskeletal system [ 3 , 4 , 5 , 6 , 7 ].

The respiratory system is frequently involved in post-COVID-19 conditions, as demonstrated by clinical and radiologic findings, along with pulmonary function tests [ 8 , 9 ]. Predominantly, studies have concentrated on the restrictive ventilatory defect, which is marked by lung fibrosis, a diminished diffusion capacity of the lung for carbon monoxide, and reduced lung volume [ 8 , 9 , 10 , 11 ]. In addition, residual abnormalities on computed tomography for patients with COVID-19 are not uncommon. One meta-analysis showed that fibrotic-like changes had the highest event rates of 0.44 and 0.38 during both short-term (1–6 months) and long-term (12–24 months) follow-up periods [ 12 ]. Moreover, patients with severe COVID-19 exhibited significantly higher rates of various abnormalities, including bronchiectasis, fibrotic-like changes, and reticulation, at long-term follow-ups compared to those in the non-severe subgroup [ 12 ]. Conversely, although prior research has identified a link between respiratory virus infections and the subsequent onset of asthma [ 13 , 14 , 15 ], the evaluation of obstructive airway disease risk following COVID-19 has been limited [ 16 , 17 , 18 ].

Kim et al. using the Korean National Health Insurance claim-based database demonstrated that COVID-19 could be associated with a higher risk of new-onset asthma (adjusted hazard ratio (aHR), 2.14; 95% CI, 1.88–2.45) [ 16 ]. However, the study was conducted between 2020 and June 30, 2021, in South Korea and focused specifically on asthma. Their findings were thus limited to the Asian population and the non-Omicron wave. Since then, the virulence, epidemiology, and disease severity of the currently prevalent Omicron variant have changed significantly from those of the early strains [ 19 , 20 ]. An updated investigation among non-Asian populations is also needed to provide a broader understanding of the association between COVID-19 and obstructive airway diseases. Therefore, we conducted this study using the TriNetX network to assess the association between COVID-19 and new-onset obstructive airway diseases, particularly asthma, following COVID-19 during the Omicron wave.

Characteristics of study subjects

Among the vaccinated individuals without pre-existing asthma, COPD, or bronchiectasis, the study included 274,820 enrollees in the COVID-19 group and 2,214,332 in the no-COVID-19 group (Fig.  1 ). Prior to PSM, the average age of patients with COVID-19 was 55.5 years, compared to 54.8 years for those without. The COVID-19 group was 57.4% female, while the no-COVID-19 group was 58.9% female; 64% of the COVID-19 group and 67.5% of the no-COVID-19 group were Caucasians. Age, sex, and race did not differ significantly between the groups (all standardized differences < 0.1). However, the COVID-19 group showed a higher prevalence of comorbidities, including DM, dyslipidemia, hypertension, ischemic heart disease, heart failure, cerebrovascular disease, CKD, neoplasm, anemia, and systemic connective tissue disease, as well as allergic rhinitis, compared to their counterparts (Table  1 ). Additionally, a greater percentage of the COVID-19 group had histories of tobacco use/nicotine dependence, a BMI of ≥ 30 kg/m 2 , and socioeconomic status (SES)- or psychosocial-related health hazards. Regarding medication, a higher proportion of the COVID-19 group had received systemic glucocorticoids, antihistamines, beta-blockers, aspirin, and NSAIDs within 1 year preceding the index date (Table  1 ).

Flowchart of cohort construction. BMI body mass index, COVID-19 coronavirus disease 2019, FEV1 forced expiratory volume in the first second, FVC forced vital capacity, HCO healthcare organization, COPD chronic obstructive pulmonary disease

After PSM, each group consisted of 274,803 patients. Characteristics for all the considered covariates, including demographics, comorbidities, and medications, were balanced between the two groups with standardized differences < 0.1 (Table  1 ). The group with COVID-19 was designated as the study group, whereas the group without COVID-19 was designated as the control group.

Primary outcome

During the follow-up period, 4216 new asthma cases were diagnosed in the study group, compared with 3352 in the control group. The study group had a significantly higher risk of developing new-onset asthma than the control group (aHR, 1.27; 95% CI, 1.22–1.33; p  < 0.001; see Table  2 ). Additionally, Kaplan–Meier analysis showed a lower probability of event-free survival for the study group relative to the control group (log-rank p  < 0.001; see Fig.  2 ).

Kaplan–Meier curves of event-free survival for new-onset asthma (log-rank test p  < 0.001)

Stratified analyses by age group, SARS-CoV-2 variant, vaccine status, and infection status consistently demonstrated similar trends. Patients with COVID-19 exhibited a higher risk of new-onset asthma, as illustrated in Fig.  3 . Notably, there were no significant differences in effect size estimates across the analyses, except for those based on disease severity ( p for interaction = 0.011). A significantly higher risk of new-onset asthma was observed only in non-hospitalized patients with COVID-19, whereas no significant differences were observed between hospitalized and critically ill groups (Fig.  3 ).

Subgroup analysis of new-onset asthma between COVID-19 and no-COVID-19 groups

Secondary outcomes

We also identified that patients with COVID-19 had a higher risk of bronchiectasis (aHR, 1.30; 95% CI, 1.13–1.50, p  < 0.001, Table  2 ). There was a trend towards an increased risk of bronchiectasis in patients with critical COVID-19 compared to those not hospitalized, but no statistically significant between-subgroup heterogeneity was observed for bronchiectasis as evidenced by the interaction tests (all p values for interaction > 0.05) and the largely overlapping confidence intervals (Fig.  4 ). On the other hand, there was no significant difference in the incidence of COPD between the groups (aHR, 1.00; 95% CI, 0.95–1.06, p  = 0.994, Table  2 ).

Subgroup analysis of new-onset bronchiectasis between COVID-19 and no-COVID-19 groups

Sensitivity analysis

Our sensitivity analysis using different cutoff landmarks (2, 3, and 6 months after the index date) to define new-onset obstructive airway diseases and the start of follow-up, showed consistent results. These results suggested that COVID-19 is associated with an increased risk of new-onset asthma and bronchiectasis, but not COPD (Additional file 1: Table S4).

Regarding the negative and positive control outcomes, we observed a positive association between COVID-19 and symptoms characteristic of the post-COVID-19 condition, as expected, compared to the no-COVID-19 group. No significant associations were observed with the negative control outcomes, as depicted in Additional file 1: Fig. S1.

This large-scale study evaluated the respiratory sequelae of COVID-19, including asthma, COPD, and bronchiectasis. We found a potential link between COVID-19 and an increased risk of new-onset asthma. Specifically, patients with COVID-19 had a 27% higher risk of developing asthma during the follow-up period compared to those without COVID-19. Further analyses, stratified by age, SARS-CoV-2 variant, vaccination status, and infection status, as well as sensitivity analyses using different landmarks, consistently supported these findings. In summary, our study presents compelling evidence regarding the association between COVID-19 and the subsequent development of asthma, highlighting the potential long-term respiratory impacts of SARS-CoV-2 infection and enhancing our knowledge of the disease’s progression beyond the acute phase.

Stratified analysis by disease severity revealed an intriguing nuance. Although the overall risk of new-onset asthma was significantly higher in the COVID-19 group, this association was particularly pronounced in non-hospitalized individuals. The absence of a significant difference in hospitalized and critically ill groups might be partly due to a smaller patient count in these categories. Progression to viral pneumonia could indicate more severe inflammation of the lower airway and could be associated with the risk of subsequent obstructive airway diseases, but its occurrence, the chronological relationship with SARS-CoV-2 infection, and the etiologies could not be ascertained in the current database, thereby precluding further analysis on this variable. However, the interaction test suggested a significant difference, indicating a complex relationship between COVID-19 disease severity and the risk of obstructive airway diseases that warrants further exploration.

Our findings are consistent with those reported by Kim et al., who used the Korean National Health Insurance claim-based database. They found that 1.6% of the COVID-19 cohort and 0.7% of the matched cohort developed new-onset asthma, with an aHR of 2.14 (95% CI, 1.88–2.45) [ 16 ]. However, unlike the Korean study [ 16 ] conducted during 2020–2021, our analyses were based on data collected after 2022 and feature a more ethnically diverse population from the TriNetX platform. Consequently, our results provided updated insights during the Omicron wave and are likely to be more generalizable and relevant to the current context.

Respiratory tract viral infections, including respiratory syncytial virus and measles, have been identified as potential causes of bronchiectasis [ 21 ], but the link between SARS-CoV-2 and post-infectious bronchiectasis is not well established. Although a meta-analysis by Guinto et al. [ 22 ] reported a 16.8% prevalence of bronchiectasis (95% CI, 9.10–26.1%) based on imaging studies during post-COVID-19 follow-up, our study is the first to demonstrate an increased risk of subsequent bronchiectasis following COVID-19, with an aHR of 1.30 (95% CI, 1.13–1.50). These findings suggest that bronchiectasis may be a respiratory sequela of COVID-19. Respiratory viruses were found more frequently in bronchiectasis exacerbations and the proposed mechanisms included disturbances in host-defense responses, heightened inflammation, and changes in bacterial virulence [ 23 ], which could be involved in the vicious cycle model of development and progression of bronchiectasis, for which the primary insult is often unknown [ 24 ]. Our findings accordingly supported that clinicians should be vigilant for this potential complication after COVID-19.

The current study aligns with previous research [ 16 , 22 ] highlighting the respiratory system’s vulnerability to post-COVID-19 conditions. Notably, the increased incidence of new-onset asthma and bronchiectasis observed in the study group suggests a potential link between SARS-CoV-2 infection and the development of obstructive airway diseases. This represents a contradiction with the results of previous studies [ 25 , 26 ] which primarily focused on restrictive ventilatory defects associated with lung fibrosis. However, further investigation is crucial to validate these findings and elucidate the potential mechanisms involved.

This study boasts several strengths. First, the analyses utilized the TriNetX platform, a sizable database, which facilitated the inclusion of a substantial patient cohort. Second, we conducted numerous stratification analyses and sensitivity tests, with the majority yielding consistent results. Third, although patients with COVID-19 exhibited a higher prevalence of comorbidities such as diabetes mellitus, cardiovascular diseases, and systemic connective tissue disorders—conditions potentially elevating the risk of obstructive airway diseases—these factors were meticulously adjusted in relation to study outcomes. The application of PSM effectively equalized baseline characteristics between the COVID-19 and control groups, thus bolstering the study’s internal validity.

Despite the study’s strengths, we must acknowledge certain limitations. The reliance on electronic health records and administrative data raises the possibility of misclassification and underreporting. Furthermore, the study does not investigate potential mechanisms behind the observed associations, which leaves a gap for future research to clarify the pathophysiological connections between SARS-CoV-2 infection and obstructive airway diseases. Long-term patient follow-up is also essential to comprehend the persistence and progression of these respiratory conditions over time. Meanwhile, FEV 1 and disease staging data for asthma or COPD were not documented for most patients in the TriNetX database, thereby introducing potential information bias and precluding further analysis on these variables. Finally, the possibility of residual confounding could not be fully eliminated though we had accounted for numerous clinically significant confounders in our analyses.

Conclusions

This study provides essential insights into the long-term respiratory consequences of COVID-19, highlighting the need for continued monitoring and care for individuals recovering from SARS-CoV-2 infection. The associations found with new-onset asthma and bronchiectasis underscore the importance of a multidisciplinary approach to post-COVID-19 care, with a particular focus on respiratory issues. Further research is necessary to investigate the underlying mechanisms and to develop therapeutic strategies to mitigate the effects of SARS-CoV-2 on the respiratory system.

Data source

The present study utilized data from the US Collaborative Network of the TriNetX database, which gathered de-identified patient-level information from electronic health records. A health care organization (HCO) typically referred to an academic healthcare center that compiled data from its associated facilities, including the main and satellite hospitals, and outpatient clinics. The collected data encompassed patient demographics, clinical diagnoses (coded using ICD-10-CM), medical procedures (categorized according to ICD-10-PCS or Current Procedural Terminology), medications (coded based on the Veterans Affairs Drug Classification System and RxNorm medication codes), laboratory tests (organized with Logical Observation Identifiers Names and Codes), and records of healthcare utilization. The US Collaborative Network contained data from over 100 million patients across 61 HCOs in the United States. Analysis of patient-level data was conducted on the TriNetX platform, and the results were provided to researchers in a summarized format. The TriNetX database performs intensive data preprocessing procedures to minimize missing values and maps the data to a consistent framework. Details regarding the database can be found online [ 21 ].

The current study’s use of the TriNetX database received ethical approval from the Chi-Mei Hospital’s Institutional Review Board (no: 11202–002). We conducted the study in accordance with the Declaration of Helsinki and reported our findings following the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.

Study population

Participants of this study were ≥ 18-year-olds and visited HCOs ≥ 3 times after January 8, 2022. This date coincides with the emergence of the Omicron variant as the predominant strain in the United States [ 26 ], ensuring that the data for our analysis were collected within a comparable timeframe. We limited our inclusion to those vaccinated against COVID-19 to reflect the high vaccination rates among U.S. adults, which had surpassed 90% in U.S. adults [ 27 ], and to minimize biases related to health-seeking behavior using vaccination status as a proxy. To avoid misinterpretation, we excluded individuals with pre-existing diagnoses of asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis, or forced expiration in the first second (FEV1)/forced vital capacity (FVC) < 70% before the index date. The index date was defined as the date of COVID-19 diagnosis for the COVID-19 group and the date of the first visit to HCOs during the inclusion period for the no-COVID-19 group.

The enrollees were further divided into those diagnosed with COVID-19 (the COVID-19 group) during the study timeframe and those who never had COVID-19 (the no-COVID-19 group). One-to-one propensity score matching (PSM) was conducted, involving 34 variables, including demographics, comorbidities, and medication usage, to balance the two groups. Both groups were followed for a maximum of 2 years or until the date of data analysis on January 17, 2024. Details regarding the codes used to identify demographics, diagnoses, procedures, and medications are provided in Additional file 1: Table S2.

In the current analysis, we considered the following variables to balance baseline characteristics between the COVID-19 and non-COVID-19 groups: age, sex, race, diabetes mellitus (DM), dyslipidemia, cardiovascular diseases (hypertension, ischemic heart diseases, heart failure, peripheral vascular disease, cerebrovascular diseases), dementia, chronic kidney disease (CKD), hepatitis, cirrhosis, autoimmune diseases (systemic connective tissue disorders, rheumatoid arthritis), anemia, neoplasms, human immunodeficiency virus (HIV) disease, atopic dermatitis, allergic rhinitis, tobacco use/nicotine dependence, alcohol-related disorders, potential health hazards related to socioeconomic and psychosocial circumstances, and BMI (≥ 30 kg/m 2 ). We also included medications that could alter allergic or inflammatory responses or are potentially associated with bronchospasm (glucocorticoids, antihistamines, beta-adrenergic blockers, aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs)). The codes used to define the covariates are provided in Additional file 1: Table S3.

Prespecified outcomes

The primary outcome of this study was the hazard of new-onset asthma during the follow-up period, which commenced 4 months after the index date to preclude the confounding effects of post-viral bronchial hyperreactivity syndrome. Secondary outcomes encompassed the hazard of bronchiectasis and COPD within the same follow-up timeframe. To ascertain the specificity of our results, we incorporated negative control outcomes, including traumatic intracranial injury, skin cancer, schizophrenia, and cataract. Conversely, the positive control outcome was the post-COVID-19 condition, characterized by a collection of symptoms such as fatigue, headache, dizziness, myalgia, sleep disturbance, emotional distress, cognitive impairment, palpitation, shortness of breath, and changes in bowel habits [ 28 ]. Additional file 1: Table S4 contains the definitions and codes pertinent to these outcomes.

Statistical analysis

Baseline characteristics for the COVID-19 and no-COVID-19 groups are presented as means with standard deviations (SD) or as counts and percentages. We compared categorical variables using the χ 2 test and assessed continuous variables with the independent two-sample t -test. We conducted one-to-one PSM using the greedy nearest neighbor algorithm with a caliper of 0.1 pooled standardized differences to balance baseline characteristics. Variables were considered adequately matched post-PSM if the standardized difference between groups was less than 0.1. We computed survival probabilities using the Kaplan–Meier method and calculated adjusted hazard ratios (aHR) for the outcomes using the Cox proportional hazards model, including corresponding 95% confidence intervals (CI) and p -values. We tested the proportional hazards assumption with the generalized Schoenfeld residuals method. Outcome variables were categorized as present or absent; thus, missingness was not applicable. We excluded cases lost to follow-up to reduce potential biases or inaccuracies from incomplete data.

We conducted sensitivity analyses using different cutoff landmarks (2, 3, and 6 months post-index date) to initiate follow-up and define new-onset asthma. To investigate potential differences in effect sizes among clinically relevant subgroups, we performed pre-specified subgroup analyses based on age (≥ 18 to < 40, ≥ 40 to < 65, or ≥ 65 years), variants (BA.1.1, BA.2, BA.2.12.1, BA.5, or XBB, corresponding to periods when a variant predominated in the U.S. [ 27 ]), booster vaccination status, COVID-19 severity (not admitted, hospitalized, or critical, the latter defined by the need for endotracheal intubation, mechanical ventilation, extracorporeal membrane oxygenation, or intensive care unit admission), and infection status (primary infection or reinfection). All tests were two-sided with a significance threshold of 0.05. Statistical analyses were performed using TriNetX analytics tools and R (version 4.2.2; R Foundation for Statistical Computing, Vienna, Austria).

Availability of data and materials

All data generated or analyzed during this study are included in this published article and will be available upon request to CCL.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

Adjusted hazard ratio

Body mass index

Confidence interval

Chronic obstructive pulmonary disease

Coronavirus disease 2019

Chronic kidney disease

Diabetes mellitus

Forced expiration in the first second.

Forced vital capacity

Health care organization

Human immunodeficiency virus

International Classification of Diseases, Tenth Revision, Clinical Modification

International Classification of Diseases, Tenth Revision, Procedure Coding System

Non-steroidal anti-inflammatory drugs

Propensity score matching

Severe acute respiratory syndrome coronavirus 2

Standard deviation

World Health Organization. Who COVID-19 dashboard. Available at: https://data.who.int/dashboards/covid19/cases?n=c Accessed January 18, 2024.

Frallonardo L, Segala FV, Chhaganlal KD, Yelshazly M, Novara R, Cotugno S, et al. Incidence and burden of long covid in Africa: a systematic review and meta-analysis. Sci Rep. 2023;13(1):21482.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Liu TH, Huang PY, Wu JY, Chuang MH, Hsu WH, Tsai YW, et al. Comparison of post-acute sequelae following hospitalization for COVID-19 and influenza. BMC Med. 2023;21(1):480.

Article   PubMed   PubMed Central   Google Scholar  

Kelly JD, Curteis T, Rawal A, Murton M, Clark LJ, Jafry Z, et al. SARS-CoV-2 post-acute sequelae in previously hospitalised patients: systematic literature review and meta-analysis. Eur Respir Rev. 2023;32(169): 220254.

Natarajan A, Shetty A, Delanerolle G, Zeng Y, Zhang Y, Raymont V, et al. A systematic review and meta-analysis of long COVID symptoms. Syst Rev. 2023;12(1):88.

Liu TH, Huang PY, Wu JY, Chuang MH, Hsu WH, Tsai YW, et al. Post-covid-19 condition risk in patients with intellectual and developmental disabilities: a retrospective cohort study involving 36,308 patients. BMC Med. 2023;21(1):505.

Chuang MH, Wu JY, Liu TH, Hsu WH, Tsai YW, Huang PY, et al. Efficacy of nirmatrelvir and ritonavir for post-acute COVID-19 sequelae beyond 3 months of SARS-CoV-2 infection. J Med Virol. 2023;95(4): e28750.

Article   CAS   PubMed   Google Scholar  

Cha MJ, Solomon JJ, Lee JE, Choi H, Chae KJ, Lee KS, et al. Chronic lung injury after COVID-19 pneumonia: clinical, radiologic, and histopathologic perspectives. Radiology. 2024;310(1): e231643.

Article   PubMed   Google Scholar  

Pietruszka-Wałęka E, Rząd M, Żabicka M, Rożyńska R, Miklusz P, Zieniuk-Lesiak E, et al. Impact of symptomatology, clinical and radiological severity of COVID-19 on pulmonary function test results and functional capacity during follow-up among survivors. J Clin Med. 2023;13(1):45.

Eizaguirre S, Sabater G, Belda S, Calderón JC, Pineda V, Comas-Cufí M, et al. Long-term respiratory consequences of COVID-19 related pneumonia: a cohort study. BMC Pulm Med. 2023;23(1):439.

Suppini N, Fira-Mladinescu O, Traila D, Motofelea AC, Marc MS, Manolescu D, et al. Longitudinal analysis of pulmonary function impairment one year post-covid-19: a single-center study. J Pers Med. 2023;13(8):1190.

Babar M, Jamil H, Mehta N, Moutwakil A, Duong TQ. Short- and long-term chest-CT findings after recovery from COVID-19: a systematic review and meta-analysis. Diagnostics (Basel). 2024;14(6):621.

Rantala A, Jaakkola JJ, Jaakkola MS. Respiratory infections precede adult-onset asthma. PLoS ONE. 2011;6(12): e27912.

Jackson DJ, Gangnon RE, Evans MD, Roberg KA, Anderson EL, Pappas TE, et al. Wheezing rhinovirus illnesses in early life predict asthma development in high-risk children. Am J Respir Crit Care Med. 2008;178(7):667–72.

Kusel MM, de Klerk NH, Kebadze T, Vohma V, Holt PG, Johnston SL, et al. Early-life respiratory viral infections, atopic sensitization, and risk of subsequent development of persistent asthma. J Allergy Clin Immunol. 2007;119(5):1105–10.

Kim BG, Lee H, Yeom SW, Jeong CY, Park DW, Park TS, et al. Increased risk of new-onset asthma after COVID-19: a nationwide population-based cohort study. J Allergy Clin Immunol Pract. 2024;12(1):120–32.e5.

Lee H, Kim BG, Chung SJ, Park DW, Park TS, Moon JY, et al. New-onset asthma following COVID-19 in adults. J Allergy Clin Immunol Pract. 2023;11(7):2228–31.

Cherrez-Ojeda I, Osorio MF, Robles-Velasco K, Calderón JC, Cortés-Télles A, Zambrano J, et al. Small airway disease in post-acute COVID -19 syndrome, a non-conventional approach in three years follow-up of a patient with long covid: a case report. J Med Case Rep. 2023;17(1):386.

Dhama K, Nainu F, Frediansyah A, Yatoo MI, Mohapatra RK, Chakraborty S, et al. Global emerging omicron variant of SARS-CoV-2: Impacts, challenges and strategies. J Infect Public Health. 2023;16(1):4–14.

Tian D, Sun Y, Xu H, Ye Q. The emergence and epidemic characteristics of the highly mutated SARS-CoV-2 omicron variant. J Med Virol. 2022;94(6):2376–83.

Chalmers JD, Polverino E, Crichton ML, Ringshausen FC, De Soyza A, Vendrell M, et al. Bronchiectasis in europe: data on disease characteristics from the european bronchiectasis registry (embarc). Lancet Respir Med. 2023;11(7):637–49.

Guinto E, Gerayeli FV, Eddy RL, Lee H, Milne S, Sin DD. Post-COVID-19 dyspnoea and pulmonary imaging: a systematic review and meta-analysis. Eur Respir Rev. 2023;32(169): 220253.

Gao YH, Guan WJ, Xu G, Lin ZY, Tang Y, Lin ZM, et al. The role of viral infection in pulmonary exacerbations of bronchiectasis in adults: a prospective study. Chest. 2015;147(6):1635–43.

Chalmers JD, Sethi S. Raising awareness of bronchiectasis in primary care: overview of diagnosis and management strategies in adults. NPJ Prim Care Respir Med. 2017;27(1):18.

Duong-Quy S, Vo-Pham-Minh T, Tran-Xuan Q, Huynh-Anh T, Vo-Van T, Vu-Tran-Thien Q, et al. Post-COVID-19 pulmonary fibrosis: facts-challenges and futures: A narrative review. Pulm Ther. 2023;9(3):295–307.

Stewart I, Jacob J, George PM, Molyneaux PL, Porter JC, Allen RJ, et al. Residual lung abnormalities after COVID-19 hospitalization: interim analysis of the UKILD post-COVID-19 study. Am J Respir Crit Care Med. 2023;207(6):693–703.

Centers for Disease Control and Prevention. COVID data tracker: COVID-19 vaccinations in the United States. Available at: https://covid.cdc.gov/covid-data-tracker/#vaccinations_vacc-people-booster-percent-pop5 . Accessed January 22, 2024.

Nalbandian A, Desai AD, Wan EY. Post-COVID-19 condition. Annu Rev Med. 2023;74:55–64.

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Acknowledgements

We express our gratitude to Chung-Han Ho for his consultation on statistical analysis.

No specific funding was received from any bodies in the public, commercial, or not-for-profit sectors to carry out the work described in this article.

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Min-Hsiang Chuang

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Ya-Wen Tsai

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Jheng-Yan Wu

Department of Psychiatry, Chi Mei Medical Center, Tainan, Taiwan

Ting-Hui Liu

Department of Intensive Care Medicine, Chi Mei Medical Center, Tainan, Taiwan

Chih-Cheng Lai

School of Medicine, College of Medicine, National Sun Yat-Sen University, Kaohsiung, Taiwan

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MHC conceptualized, designed the study performed the data analysis and drafted the manuscript. WH, YWT, WHH, JYW, THL and PYH assisted data correction and created figures. MHC, and CCL contributed to project design and edited the manuscript. MHC and CCL was responsible for the data interpretation. MHC and CCL finalized the manuscript. All authors approved the final version of the manuscript.

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Correspondence to Chih-Cheng Lai .

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Supplementary Information

12916_2024_3589_moesm1_esm.docx.

Additional file 1: Table S1. Sensitivity analysis for primary and secondary outcomes with different cutoff landmarks to define new-onset obstructive airway diseases and the start of follow-up. Table S2. Demographic, diagnostic, procedural, medication, visit, and laboratory codes used in the definition of the cohort. Table S3. Demographic, diagnostic, laboratory, and medication codes used in the definition of covariates. Table S4. Diagnostic codes used in the definition of outcomes. FigS1. Results for negative and positive control outcomes.

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Chuang, MH., Hsu, W., Tsai, YW. et al. New-onset obstructive airway disease following COVID-19: a multicenter retrospective cohort study. BMC Med 22 , 360 (2024). https://doi.org/10.1186/s12916-024-03589-4

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Acute Severe Asthma in Adolescent and Adult Patients: Current Perspectives on Assessment and Management

Eirini kostakou.

1 ICU, 1st Department of Pulmonary Medicine, “Sotiria” Hospital, Athens School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece

Evangelos Kaniaris

Effrosyni filiou, ioannis vasileiadis, paraskevi katsaounou.

2 1st ICU, Evangelismos Hospital, Athens School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece

Eleni Tzortzaki

3 Respiratory Outpatient Clinic, 71305 Heraklion, Greece

Nikolaos Koulouris

Antonia koutsoukou, nikoletta rovina.

Asthma is a chronic airway inflammatory disease that is associated with variable expiratory flow, variable respiratory symptoms, and exacerbations which sometimes require hospitalization or may be fatal. It is not only patients with severe and poorly controlled asthma that are at risk for an acute severe exacerbation, but this has also been observed in patients with otherwise mild or moderate asthma. This review discusses current aspects on the pathogenesis and pathophysiology of acute severe asthma exacerbations and provides the current perspectives on the management of acute severe asthma attacks in the emergency department and the intensive care unit.

1. Introduction

Asthma is a chronic inflammatory disorder of the airways, a common and potentially serious chronic disease that is associated with variable expiratory flow, airway wall thickening, respiratory symptoms, and exacerbations (flare-ups), which sometimes require hospitalization and may be fatal [ 1 ]. In reference to asthma, an exacerbation is defined as an event characterized by change from the patient’s previous status, including a progressive increase in relevant symptoms and a decrease in respiratory function. The latter can be quantified by respiratory function measurements such as peak expiratory flow (PEF), and forced expiratory volume in 1 s (FEV 1 ), which when compared with the patient’s previous or predicted values, reflect the deterioration in expiratory airflow, the prominent pathophysiological effect of an asthma attack.

The most common causes of these exacerbations are exposure to external agents, such as indoor and outdoor allergens [ 2 , 3 , 4 ], air pollutants [ 5 ], and respiratory tract infections (primarily viral mainly human rhinovirus (HRV) [ 6 , 7 ]. The mechanisms by which these environmental stimuli and viruses initiate asthma or cause worsening of the disease are under research.

Asthma exacerbations may also be triggered by exercise [ 8 ], weather changes [ 9 ], foods [ 10 , 11 ], additives, drugs [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ], and extreme emotional expressions [ 15 , 16 ]. The physiological hallmarks of asthma are airway inflammation, airway remodeling and bronchial hyperresponsiveness (BHR) [ 17 ]. Exposure to the above-mentioned external stimuli and specifically to inhaled allergens is capable of inducing an inflammatory response in sensitized individuals and as a result to lead to exacerbations [ 18 , 19 ]. A hypothesis explaining this fact is that the inflammatory response resulting from inhaled allergen may drive BHR directly, or induce structural changes in the airway leading to persistent BHR [ 17 , 20 ]. Experimental mouse models of asthma have shown that allergen exposure protocols induce immune-mediated airway inflammation defined by: elevated levels of asthma biomarkers (IgE, the T-helper cell 2 (Th2) cytokines, interleukins (IL)-4, -5 and -13, and eosinophils), induction of airway remodeling (increases in airway smooth muscle, collagen deposition and goblet cell hyperplasia), and BHR that is sustained after the resolution of eosinophilic inflammation [ 21 , 22 , 23 ].

Other factors that may cause exacerbations are rhinitis [ 24 ] or sinusitis [ 25 ], polyposis [ 26 ], gastroesophageal reflux [ 27 ], menstruation [ 28 , 29 ], or even pregnancy [ 30 , 31 ]. They can happen either to patients with known asthma of any level of severity, or less frequently as a first presentation. Exacerbations vary in severity, as well as in response to therapy. This has led to an effort of categorize the severity of these exacerbations. The most frequently proposed categories include elements of the clinical presentation of the asthma patient, as well as a measurement of their respiratory function at the time of the exacerbation. It is of paramount importance for the clinician to distinguish the severe exacerbations, because these are the ones that correlate with worse consequences.

2. Definition of Acute Severe Asthma

The Global Initiative for Asthma guidelines refers to a severe asthma exacerbation describing a patient who talks in words, leans forward, is agitated, uses accessory respiratory muscles, has a respiratory rate > 30/min, heart rate > 120/min, O 2 saturation on air < 90% and PEF ≤ 50% of their best or predicted value [ 1 ]. According to the 2014 British Guidelines for Asthma, acute severe asthma is defined as the asthma exacerbation that presents with any of the following: PEF 33–50% best or predicted, respiratory rate ≥ 25/min, heart rate ≥ 110/min and inability to complete sentences in one breath [ 32 ]. The ATS/ERS task force defines a severe asthma exacerbation by the fact that they require urgent action in order to prevent a serious outcome, such as hospitalization or death from asthma [ 33 ]. This task force recommends that the definition of a severe asthma exacerbation for clinical trials should include at least one of the following: (a) use of systemic corticosteroids (tablets, suspension, or injection), or an increase from a stable maintenance dose, for at least three days; and (b) a hospitalization or emergency department visit because of asthma, requiring systemic corticosteroids. Although these definitions are not identical, the point remains that identifying this condition is important as it is correlated with worse outcomes and greater risk of needing mechanical ventilation.

There are other entities similar but not identical to that of acute severe asthma that also require precise definitions. Kenyon et al. proposed the term Critical Asthma Syndromes (CAS) to identify any child or adult who is at risk of fatal asthma [ 34 ]. This term includes acute severe asthma, refractory asthma, status asthmaticus, and near fatal asthma, all of them conditions that can lead to respiratory exhaustion and arrest. Refractory asthma is, according to a definition set by the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) consortium in 2011, patients with asthma in whom after excluding any alternative diagnoses, after treating comorbidities and removing trigger factors cannot maintain good asthma control, despite high-intensity treatment and confirmed compliance with treatment. These patients have frequent severe exacerbations (≥2 per year), or can only be well when receiving systemic corticosteroids [ 35 ]. Near fatal asthma (NFA) is defined as an asthma exacerbation resulting in respiratory arrest requiring mechanical ventilation or a pCO 2 ≥ 45 mm Hg. Some writers tend to recognize status asthmaticus and acute severe asthma as the same condition and define it mainly by its response to treatment, thus referring to it as an exacerbation that does not respond to repeated courses of β2-agonist therapy [ 36 ].

3. Epidemiology

According to the Global Asthma Report, approximately 334 million people in the world suffer from asthma, thus being the most prevalent chronic respiratory disease, with chronic obstructive pulmonary disease (COPD) affecting only half of the aforementioned number of people [ 37 ]. However, according to Eurostat [ 38 ], in most European countries age standardized asthma admission rates declined from 2001–2005 to 2011–2015, with an over two-fold reduction in some countries. ( Figure 1 ) The latest World Health Organization (WHO) estimates, released in December 2016, present that there were 383,000 deaths due to asthma in 2015. There has been a decrease of almost 26% in the asthma deaths, when comparing 2015 to 1990 [ 37 ]. However, international mortality statistics for asthma are limited to those countries reporting detailed causes of death. Figure 2 depicts the age-standardized mortality rates for asthma among countries reporting asthma separately in two recent five-year periods (2001–2005 and 2011–2015) [ 38 ].

Age-standardized admission rates for asthma (all ages) in 30 European countries in two time periods: 2001–2005 and 2011–2015. Source: Eurostat updated from ec.europa.eu/Eurostat/web/health/health-care/data/database (version dated November 2017).

Age-standardized mortality rates for asthma (all ages) by country in two time periods: 2001–2005 and 2011–2015. Source: Eurostat updated from ec.europa.eu/Eurostat/web/health/health-care/data/database (version dated November 2017).

Although asthma is a disease not only of low- and lower-middle-income countries, most asthma-related deaths occur in those areas [ 38 ]. There is an established connection between asthma deaths and the Socio-Demographic Index (SDI), but interestingly not with SDI and asthma prevalence. A recent study in Brazil demonstrated that urbanization has affected public health, resulting in higher asthma related morbidity and mortality, despite the fact that the urbanized population now has improved access to the health system [ 39 ]. There are no accurate figures describing the rate of acute severe asthma, but there are sufficient data regarding the asthma related hospitalizations and asthma related mortality. Recent studies estimate the risk of death of the patients who are hospitalized as a result of asthma exacerbation as less than 0.5% [ 40 , 41 ]. That risk is greater when the patient requires intubation and mechanical ventilation, which underlines the importance of identifying and promptly treating acute severe asthma. Four percent of asthma related hospitalizations result in mechanical ventilation. There is a substantial economic burden associated with asthma hospitalizations, and it has been demonstrated that in the US in 2012 the overall cost was more than 2 billion dollars, which is a significant percentage (more than 1/3) of the annual asthma related expenditure [ 41 ]. Middle aged women are more likely to get hospitalized with asthma related morbidities [ 41 ].

With regards to the identified phenotypes of asthma, data from a recent cluster analysis from Japan revealed a wide heterogeneity among asthma patients who presented and were admitted with severe and life-threatening asthma in 17 institutions across the country [ 42 ]. Another recent group-based trajectory analysis on patients with problematic and uncontrolled asthma, showed that near fatal events were noted in all groups, but were more frequent in patients with persistent frequent exacerbations [ 43 ]. It is not only patients with severe and poorly controlled asthma who are at risk for having an acute severe asthma exacerbation, but this has been observed as well in patients with otherwise mild or moderate asthma. The current literature describes two distinct clinico-pathophysiological entities of acute severe asthma attacks that present at the emergency department: the slow onset, late arrival and the sudden onset fatal asthma. It has been estimated that the majority (80–85%) of asthma-related fatalities belong to the slow onset group. These patients may have symptoms and uncontrolled disease for several days prior to the presentation with acute severe asthma. Sudden onset has been defined as severe airflow obstruction established after 1–3 h of symptom presentation. Barr et al. reported that patients presenting with sudden onset asthma, were more likely to have been exposed to an exacerbation trigger such as a respiratory allergen, exercise and psychosocial stress and less often respiratory infection and had greater improvement when compared with the slow onset cohort [ 44 ]. A retrospective cohort study in the United States demonstrated evidence that the sudden-onset patients were older, were more likely to present during the night and early morning hours at the emergency department, more often required intubation and mechanical ventilation, and had higher rate of ICU admission, but, on the other hand, had shorter hospital stay [ 45 ]. In this study the sudden onset cohort was only 6% of 1260 patients in 30 hospitals.

4. Risk Factors for Asthma Exacerbations

Many factors have been studied regarding their correlation with acute severe asthma and asthma related death ( Table 1 ). In adults, asthma exacerbations are more often in females [ 46 , 47 ]. This is difficult to be explained since female asthmatics have lower levels of total serum IgE [ 48 ] and the incidence of atopy is actually lower in comparison to males [ 49 ]. A possible explanation could have to do with the connection between asthma worsening and the menses, which is a recognized contributing factor of asthma worsening [ 50 ]. Furthermore, pregnancy in asthmatic women is a condition that requires special considerations, considering the effect of the disease, as well as the medication on the mother and the fetus. Pregnancy is not always correlated with worse asthma control, although there seems to be a correlation between asthma severity and morbidities and exacerbations during pregnancy [ 51 ]. There has been reported a cluster of obese females with late-onset corticosteroid asthma with frequent exacerbations although they preserve a relatively good baseline lung function [ 52 ].

Risk factors for fatal asthma exacerbations.

SABA, short acting beta agonist. Adapted from Global Initiative for Asthma (GINA) guidelines 2018 [ 1 ].

Obesity per se has also been correlated with worse asthma control, as well as more frequent and severe exacerbations. This correlation is strengthened by the apparent effect of weight loss and bariatric surgery on better control and less exacerbations and hospitalizations [ 53 ].

Ethnicity and socioeconomic status [ 54 , 55 ] are robust determinants of asthma exacerbation rates. African Americans have 4.2- and 2.8-fold higher rates of emergency room visits and hospitalizations for asthma exacerbation, respectively, compared to Caucasians, followed by Hispanics [ 39 ]. A possible explanation for these differences could be the poorer adherence to treatment [ 56 ] and the poorer quality of healthcare in ethnic minorities [ 57 ]. A significant genetic component might also contribute, since an increased risk of exacerbations has been documented in males with African ancestry [ 58 ].

Severe exacerbations may occur in patients with mild or well controlled asthma [ 59 , 60 ]. However, poor asthma control is an independent risk factor for future acute exacerbations [ 61 , 62 , 63 , 64 , 65 ]. A history of a recent exacerbation is the strongest predictor of future exacerbations in children and adults with asthma [ 66 , 67 , 68 , 69 ]. A small percentage of asthmatics exhibit severe disease exacerbations, despite the fact that they are already under treatment with high doses of inhaled and/or systemic corticosteroids [ 70 , 71 ]. These patients suffering from severe asthma (SA) that is poorly controlled and in some cases life-threatening [ 34 , 35 ], although comprising a small percentage of the total asthma population (5–10%), they denote 50% of total healthcare costs, rendering SA a substantial health and socio-economic burden [ 36 , 37 ].

Finally, poor perception of airflow limitation may affect patients with a history of near-fatal asthma and appears to be more common in males [ 72 , 73 ]. On the other hand, regular or overuse of short acting beta agonists (SABA) causes down regulation of beta receptors and leads to lack of response, leading in turn to overuse [ 74 ]. Overuse may also be habitual. Dispensing ≥3 SABA canisters/year (average 1.5 puffs/day or more) is associated with increased risk of emergency department visits or hospitalizations no matter what the severity of asthma is [ 75 ], while dispensing ≥12 canisters/year (1/month) increases the risk of death [ 76 ]. Incorrect inhaler technique (seen in up to 80% of asthma patients) [ 77 ], as well as suboptimal adherence to treatment (seen in up to 75% of patients) are important modifiable factors contributing to symptoms and exacerbations [ 77 ].

There has been a lot of interest regarding the effect of psychological factors on the risk for fatal or near fatal asthma, this however has not been established, as shown in a 2007 systematic review by Alvarez et al. [ 78 ]. Anxiety, depression and socio-economic problems are very common in patients with difficult to treat asthma and contribute to poor symptom control, poor adherence to treatment and impaired quality of life [ 79 ].

Obesity and other comorbidities other than the psychiatric conditions already mentioned that contribute to persistent symptoms, exacerbations and poor quality of life include chronic rhinosinusistis [ 80 ], inducible laryngeal obstruction (often referred as vocal cord dysfunction, VCD), gastroesophageal regurgitation disorder (GERD), chronic obstructive pulmonary disease (COPD), obstructive sleep apnea, bronchiectasis, cardiac disease, and kyphosis due to osteoporosis (followed by corticosteroid overuse) [ 80 ].

5. Factors that Trigger Asthma Exacerbations

Severe exacerbations usually occur in response to a variety of external agents (e.g., respiratory pathogens, allergens, air pollutants, smoke, and cold or dry air).

5.1. Respiratory Pathogens

Viral respiratory infections are the most common triggers for a severe asthma exacerbation, comprising up to 76–80% of the causes of an acute asthma exacerbation in adults [ 81 ]. Human rhinovirus (RV) (types A and C), influenza virus (types A and B), para-influenza virus, and respiratory syncytial virus (RSV) are frequent causes of an acute exacerbation and hospitalization [ 56 , 82 ]. Coronaviruses, meta-pneumoviruses, bocaviruses, and adenoviruses may also trigger a severe acute exacerbation, however to a lesser extent [ 57 ]. During the 2009 H1N1 influenza A pandemic, mortality and admissions to the ICU with H1N1 infections were frequently associated with asthma [ 82 , 83 ]. In contrast to other respiratory viruses (i.e., RSV and Influenza Virus), RV does not exert a definite cytopathic effect [ 84 ]; instead, it compromises the function of the epithelial barrier through the release of reactive oxygen species during viral replication [ 85 ]. During this process, the induction of immune and adaptive immune response activates the synthesis and early secretion of IFNs and other pro-inflammatory cytokines (i.e., IL-10, IL-6, IL-8, RANTES, and ENA-78) [ 86 ], which play a significant role in the protective mechanisms against viral infection [ 87 , 88 ]. There is evidence that in asthmatic patients there is dysregulated immune response against RV [ 89 ]. Several studies have demonstrated the implication of interferons in the susceptibility to asthma exacerbations in children and adults in the context of a viral respiratory infection. Miller et al. [ 90 ] showed that RV was related to asthma exacerbation with the implication of IFN III. Similarly, Jones et al. [ 91 ] documented an increased susceptibility to severe respiratory viral infections during the first years of life through dysregulated type III IFN responses, while recent studies [ 92 , 93 ] document a varying susceptibility to asthma exacerbations depending on the type and level of expression of cytokines and IFNs upon viral infection. Finally, Fedele et al. [ 94 ] documented that RV infection more frequently induces a Th2-mediated immune response than RSV infection, justifying the higher incidence of asthma prevalence after RV infections.

Bacterial infections may also trigger acute exacerbations, usually on the basis of impaired anti-bacterial defense after a viral respiratory infection [ 95 ]. There are bidirectional interactions between viruses and bacteria that seem to have an impact on the severity of asthma as well as the likelihood of an acute exacerbation. Viral infections facilitate the disruption of airway epithelial layers and the expression of airway receptors that bacteria use in order to invade [ 96 ]. Furthermore, in the presence of co-infection, an increased release of inflammatory cytokines and mediators is induced, heightening the burden of inflammation and predisposing to a higher risk of exacerbations [ 97 ]. Specifically, co-infections of respiratory viruses and Moraxella catarrhalis , Hemophilus influenza , and/or Streptococcus pneumonia have a greater impact on the risk for more severe acute asthma exacerbations [ 97 ]. The clarification of the mechanisms implicate the case of co-infections on inter-relationship for providing evidence for potential novel therapeutic targets that may prevent acute asthma exacerbations.

5.2. Allergen Sensitization and Viral Infections

Evidence support the theory that allergic sensitization increases the susceptibility for viral infections and probably their ability to provoke further inflammation [ 98 ].

For example, it has been shown that the combination of RV infection and direct exposure to allergens cause epithelial cell production of IL-25 and IL-33 in the airways, mediators involved in Th2 type inflammation and remodeling [ 99 , 100 ]. Moreover, in a murine model of asthma RV infection acquired in early life stages in mice induced an IL-13- and IL-25-mediated Th2 immune response with parallel suppression of IFN-γ, IL-12, and TNF-α [ 101 ], with detrimental changes in airway homeostasis, consisting of innate lymphoid cell expansion, mucous hypersecretion, and airway responsiveness. Furthermore, recurrent RV infections stimulate airway remodeling by upregulating molecules such as VEGF and TGF-β, as well as chemoattractants for airway smooth muscles (i.e., CCL5, CXCL8, and CXCL10) [ 102 , 103 ].

Other data show that the occupancy of the IgE membrane receptors inhibits antiviral induction of interferon-a from plasmacytoid dendritic cells leading to subsequent increased susceptibility to viral infections and asthma exacerbations. It is noteworthy that an inverse correlation between interferon levels and airway eosinophilia, IL-4 levels, and total serum IgE was observed [ 104 ].

5.3. Allergen Exposure, Tobacco Smoke, and Environmental Pollutants

Indoor or outdoor exposure to allergens may lead to poor asthma control and severe asthma exacerbations in sensitized patients [ 105 , 106 , 107 , 108 , 109 ]. Allergens activate mast cells to release histamine, prostaglandin D2, and cysteinyl leukotrienes. These induce inflammatory responses, airway smooth muscle constriction, increased microvascular permeability, and mucus secretion, diminishing at the same time the innate immune responses and subsequently increasing the susceptibility to viral infections [ 106 , 107 ]. Of great importance is the mold sensitization, which has been associated with the phenotype of severe asthma and with severe asthma attacks. High airborne concentrations of mold have been associated with increased emergency visits for asthma exacerbations [ 108 ]. Specifically, Alternaria is associated with highly increased risk (almost 200-fold) of severe exacerbations and need for ICU admittance in both children and adults [ 109 ]. Furthermore, cockroach and mouse antigens are associated with early wheeze and atopy in an inner-city birth cohort [ 110 ].

Exposure to multiple allergens has been documented as being a common feature in several studies of indoor exposure [ 111 , 112 ]. Salo et al. [ 112 ] showed that more than 50% of subjects were sensitized at least to six detectable allergens, while 45% were sensitized at least to three allergens. In a study from China, Kim et al. [ 111 ] showed sensitization to one or more allergens in almost 50% of the subjects with most common sensitizers being shellfish, dust mites, and cockroaches. However, less than 1% of these subjects had clinically important food allergy or asthma.

Indoor exposure to endotoxin and pollutants (such as particulate matter and nitrogen dioxide) has also been found to increase the risk of severe exacerbations in children with asthma and the use of particulate filters seem effective in reducing exposure levels and therefore, asthma control [ 113 , 114 ]. Differences in allergic sensitizations by race and genetic ancestry have also been documented [ 115 ], and along with the location of residence seem to be more important predictors of allergic sensitization than genetic ancestry. This fact points out the hypothesis that disparities in allergic sensitization by race may be observed as an effect of environmental rather than genetic factors.

Tobacco smoke remains one of the most significant triggers of disease, despite increased public awareness of the detrimental effects of smoking. Asthma patients who smoke have more frequent emergency department visits and hospitalizations for an exacerbation than asthma patients who do not smoke [ 116 ]. Several studies of patients with allergic rhinitis have shown the significant effect of smoking on the development of asthma. Polosa et al. [ 117 ] showed that in a 10-year period smoking had a dose-related effect on the development of asthma in allergic rhinitic patients resulting in an odds ratio of 2.05 for incident asthma for smoking 10 pack-years, and 3.7 and 5.05 for 11–20 and >20 pack-years, respectively.

Second-hand smoke is also associated with deteriorated lung function, poor treatment response, and frequent emergency department visits for asthma [ 118 , 119 , 120 ]. The measurement and monitoring of cotinine levels in serum, urine, and saliva have become a useful tool in determining passive smoke exposure as well as in evaluating uncontrolled asthma. Hassanzad et al. demonstrated that higher cotinine levels were associated with a higher risk for severe asthma. [ 121 ]. Increasing interest has also raised on the potential hazards of third-hand smoke (THS) in children. THS is residual nicotine and other chemical pollutants remaining in the indoor environment and on household surfaces for weeks to months after active tobacco smoking has stopped. It seems that young children may be more susceptible to the adverse effects of THS exposure since they crawl and tend to ingest several items from the surrounding [ 122 ]. However, more research is needed to assess the real extent of the hazards arising from THS.

Environmental pollutants, such as particulate matter, ozone, sulfur dioxide, nitrogen dioxide, and diesel exhaust, may act synergistically with viral infections to cause asthma exacerbations [ 123 ] The effects of air pollution on severe asthma exacerbations may be affected by other exposures, such as stress, vitamin D insufficiency, and seasonality [ 4 , 5 ]. This was demonstrated in a study of children aged 0–18 years in California, where particulate matter (size, 2.5 mm; PM 2.5 ) and ozone were associated with severe asthma exacerbations in the warm season, while in the cool season exacerbations were associated with articulate matter of PM 2.5 , carbon monoxide, and NOx (NO 1 NO 2 ) [ 124 , 125 ].

6. Genetic Associations with Asthma Exacerbations

Genome-wide association studies of asthma in children and adults have identified polymorphisms for IL33, IL1RL1/IL18R1, HLA-DQ, SMAD3, and IL2RB9 and the locus on chromosome 17q21 including the genes ZPBP2, GSDMB, and ORMDL3 that are implicated in epithelial barrier function and innate and adaptive immune responses in asthma [ 126 , 127 ]. Genetic variants in the class I major histocompatibility complex-restricted T cell-associated molecule gene (CRTAM) was associated with an increased rate of asthma exacerbations in children with low circulating vitamin D levels [ 128 ]. One of the most well replicated genetic regions affecting asthma risk is the 17q12–21 locus, which includes ORMDL3 and GSDMB. The TT allele at rs7216389 is associated with an odds ratio of 1.6 of having an asthma exacerbation when compared with the CC allele [ 129 ].

Furthermore, polymorphisms for FCER2 have been associated with decreased FCER2 gene expression, increased serum IgE levels and risk of severe exacerbations [ 130 ]. Association was also found between variants in chitinase 3-like 1 (CHI3L1; YKL-40) and asthma exacerbations and hospitalizations [ 131 , 132 ]. Specifically, studies in murine models of asthma implicate YKL-40 in IgE induction, antigen sensitization, dendritic cell accumulation and activation, and alternative macrophage activation [ 133 ], while purified YKL-40 induces interleukin-8 secretion in bronchial epithelial cells [ 134 ].

7. Pathogenesis-Immunobiology

Asthma is a heterogeneous condition with complex observable characteristics (phenotype) and their underlying mechanisms (endotype), resulting from complex host–environment interactions ( Figure 3 ). Usually, inflammatory cells are present and activated in the airways of severe asthmatics and persist despite treatment, but their relevance to lack of control and disease severity is largely unknown. These cells include not only eosinophils and neutrophils, but also T-lymphocytes, mast cells, macrophages and airway structural cells which are also crucially involved in the inflammatory reaction and remodeling in asthma. Although it is well accepted that asthma is characterized by eosinophilic infiltration, inflammatory phenotypes of severe asthma can be characterized by persistence of eosinophilic or neutrophilic infiltration, as well as by absence of inflammatory infiltration (paucigranulocytic) [ 135 , 136 ]. Depending on the type of immune cell responses implicated in disease pathogenesis, asthma endotypes are categorized as type 2 asthma, characterized predominantly by T helper type 2 (Th2) cell-mediated inflammation and non-type 2 asthma, associated with Th1 and/or Th17 cell inflammation [ 137 , 138 ]. Eosinophilic, Th2 airway inflammation is present in around 50% of adults with asthma, and is estimated to be higher in the absence of corticosteroids [ 139 ].

Pathogenesis of acute exacerbations in asthma.

Th2 mediated airway inflammation plays a central role in the pathophysiology of allergic eosinophilic asthma. The allergic sensitization of dendritic cells (DCs) in the presence of thymic stromal lymphopoietin (TSLP), induces Th2 lymphocytes to produce cytokines such as interleukins IL-4, IL-5, and IL-13 [ 140 ]. Chemokines such as eotaxin 1, 2, 3 (CCL11, CCL24 and CCL26, respectively) induce through their receptors (chemokine receptor 3, CCR3) [ 141 ] and other chemoattractant agents, such as mast cell derived prostaglandin D2 (PGD2) eosinophil recruitment in the mucosa. Furthermore, IL-4 and IL-13 activate B lymphocytes to produce allergen specific IgE, which binds to the high affinity mast cell receptors, leading to their activation [ 140 ].

In non-allergic eosinophilic asthma, airway epithelial damage caused by pollution and pathogens leads to IL-5 and IL-13 production by innate lymphoid cells (ILC2s), in response to PGD2, TSLP, IL-25 and IL-33 [ 142 ]. ILC2s and Th2 cells are a significant source of type 2 cytokines and play a role in eosinophilic inflammatory response, allergy and remodeling in asthma [ 143 , 144 ]. Increased circulating and sputum IL-5 and IL-13-producing ILC2s were detected in severe asthma compared to mild asthma patients [ 145 ]. Furthermore, increased numbers of IL-5 + and IL-13 + ILC2s were found in sputum after allergen challenge in asthma patients [ 146 ]. IL-13-expressing ILC2 and Th2 cells are also responsible for bronchial epithelial tight junction barrier leakiness in asthma patients [ 147 , 148 ].

Chronic inflammation that characterizes severe asthma leads to tissue remodeling, fixed airway obstruction, and no response to bronchodilatory treatment [ 149 ]. It seems that chronic persistent inflammation and the release of a plethora of cytokines (IL-5, IL-9, IL-13, osteopontin, and activin-A9), chemokines (CCR3 dependent) and growth factors (TGF-β1 and VEGF) from inflammatory and epithelial cells play a central role in the establishment of airway remodeling [ 150 ].

Physiologically, airway inflammation is counteracted by inhibitory molecules and suppressor cells including CD4 + regulatory T cells (Tregs) [ 151 , 152 ] which becomes visible upon Treg depletion which causes spontaneous asthma-like airway pathology [ 153 ]. Patients suffering from allergic asthma have reduced numbers of Tregs that furthermore show impaired suppressive capacity [ 154 , 155 , 156 , 157 ]. Some currently applied therapies aim at enhancing Treg cell number and function [ 154 , 158 ], whereas adoptive transfer of Tregs can suppress both the priming and the effector phase of allergic airway inflammation in experimental models of murine asthma [ 159 , 160 , 161 ].

Mixed eosinophilic and neutrophilic inflammation of the airways are commonly found in severe asthma [ 162 ] and this mixed inflammatory pattern can be a biomarker of the most severe types of the disease [ 163 ]. Elevated sputum neutrophil counts were found to be associated with more severe asthma phenotypes and with poor response to treatment with steroids in a cluster analysis from the Severe Asthma Research Program (SARP) [ 164 ]. Airway neutrophilia has been associated with persistent airflow obstruction in patients with refractory asthma and a progressive loss of lung function [ 165 ] Furthermore, it is associated with higher bronchial hyperresponsiveness independent of eosinophilia [ 166 ].

It is suggested that increased neutrophil counts in peripheral blood and sputum could be secondary to the treatment with corticosteroids, since the anti-apoptotic effect of corticosteroids on neutrophils is well established [ 167 ]. However, neutrophilic inflammation may be observed regardless of corticosteroid treatment in patients with refractory asthma or in patients experiencing acute severe exacerbations [ 168 , 169 , 170 ].

Neutrophil recruitment and activation into the airways have been associated with stimulation of toll-like receptors (TLR) signaling and activation of innate immunity, causing a shift toward Th1 and Th17 responses. This process leads to increased production of interleukin (IL)-8, IL-17A, neutrophil elastase, and matrix metalloproteinase 9 [ 171 ]. Neutrophils are triggered by IL-8 to produce enzymes and other factors that contribute to eosinophil activity [ 171 ]. Evidence suggests that neutrophil subsets may mediate differential effects on immune surveillance and microbial killing. A variety of epithelial insults (ozone, bacteria, and viruses) induce secretion of chemokines and cytokines that promote neutrophil trafficking. Neutrophils primarily traffic to inflamed sites and then secrete granular enzymes, reactive oxygen species, and proteins to eliminate invading bacteria, fungal elements, and viruses. Undoubtedly, neutrophils play pivotal roles in innate immunity [ 172 ]. During asthma exacerbations, the presence of chemokines and cytokines (IL-8 and IL-17A) prolongs neutrophils’ lifespan thus enabling them to migrate from tissue to the systemic circulation or to lymph nodes to modulate adaptive immune responses, Figure 4 . The combined functions of these cytokines and activated enzymes promote airway structures to contribute to the lower FEV 1 , remodeling and fixed airway obstruction seen in adult patients with severe neutrophilic asthma [ 173 ].

The role of the neutrophil in modulating local inflammatory responses.

8. Biomarkers Correlating with Risk of Asthma Exacerbations

The better understanding of the pathophysiology of asthma has led to the recognition of biomarkers with a potential to predict severe exacerbations. Among T2-high asthma biomarkers sputum and blood eosinophil count, serum IgE, serum periostin levels, and levels of nitric oxide in exhaled breath (FeNO) seem to associate with the severity of asthma and the rate and severity of exacerbations.

Sputum eosinophils have been correlated with increased asthma severity and airway responsiveness. Increased sputum eosinophil counts have been used as a measure of better response to corticosteroid treatment, in terms of reducing exacerbations. In the systematic review by Petsky et al. [ 174 ] it was demonstrated that asthma treatment guided by sputum eosinophil counts led to a significant reduction in the exacerbation rate. In children, elevated blood eosinophil count is associated with persistent asthma symptoms, and responsiveness to treatment can be predicted by the number of eosinophils without having set though a validated cut-off point [ 175 ]

Baseline blood eosinophil count is being used as a biomarker that predicts the clinical efficacy of anti-IL5 therapy in patients with severe eosinophilic asthma with a history of exacerbations [ 176 , 177 , 178 ], with eosinophil cut-offs set to ≥150 to ≥300 cells/μL [ 179 ] in mepolizumab trials. It has been demonstrated, however, that higher eosinophil counts than these cut-offs are associated with poor asthma control and more severe exacerbations [ 180 ]. In the study of Zieger et al. [ 181 ], a blood eosinophil count > 400 cells/μL was found to be an independent risk factor for exacerbations, emergency department visits or hospitalizations for asthma. Although blood eosinophil count levels predict the rate of exacerbations, this is not the case with sputum eosinophil count [ 179 , 182 ].

Total serum IgE level is a biomarker used in severe allergic asthma for the treatment with anti-IgE antibody (omalizumab). In association with elevated levels of fractional exhaled nitric oxide (FENO) (>19.5 parts per billion) and blood eosinophil count (>260/μL), it significantly predicts which patients with severe allergic asthma will respond to omalizumab, reducing the exacerbation rate [ 183 ].

The production of nitric oxide in the airways indicates Th2 type inflammation [ 184 , 185 ] and FeNO is a noninvasive biomarker of eosinophilic airway inflammation. There are contradictory data on whether FeNO has the ability to classify asthma severity [ 186 , 187 , 188 ]. Studies have shown that FeNO can predict accelerated decline of lung function [ 189 ], asthma relapse after corticosteroid treatment discontinuation [ 184 ], and degree of airway inflammation [ 190 ]. However, its ability to be used as a biomarker to predict exacerbations seems to be limited, even when combined with clinical features [ 191 ]. In the study by van der Valk et al. [ 192 ], repeated measurements of FENO predicted moderate asthma exacerbations (not requiring systemic corticosteroids or hospitalizations) but not severe asthma exacerbations.

Exhaled breath condensate (EBC) has been used in assessing exacerbations. Low EBC pH, various cytokines, chemokines, NO-related products, leukotrienes, and volatile organic compounds, better in combination, have been used as biomarkers associated with clinical characteristics and exacerbations [ 193 ].

Serum periostin is a biomarker of allergic eosinophilic asthma and has been used in the identification of patients who will respond to Th2-directed therapies [ 194 ]. However, limited data suggest that the serum periostin level predicts asthma exacerbations [ 195 ]. Sputum periostin, on the other hand, is associated with persistent airflow limitation, eosinophilic asthma refractory to ICS [ 196 ], while it is a potential marker for airway remodeling, as well [ 197 , 198 ].

There is an increasing need for developing biomarkers that will guide clinicians in the management of asthma, in terms of better and easier phenotyping asthma, predicting exacerbations, and treatment response.

9. Pathophysiology

Acute severe asthma commonly presents with abnormal arterial gas exchange. Arterial hypoxemia is largely attributed to ventilation/perfusion mismatch (V/Q mismatch). Hypercapnia, on the other hand, is not only present due to V/Q mismatch, but also due to respiratory muscle fatigue leading to alveolar hypoventilation. Trying to assess the exact profile of the V/Q mismatch that characterizes acute severe asthma, studies have demonstrated that although in asthma patients there is a wide spectrum of V/Q abnormalities, the most common in acute severe asthma (ASA) patients is having increased blood flow, in the context of high cardiac output, distributed in alveolar spaces with low ventilation and remarkably low V/Q ratios [ 199 ]. The pattern of ventilation-perfusion is bimodal in acute severe asthma, ranging from normally perfused areas to areas of hypoxic pulmonary vasoconstriction.

With regards to the mechanics of the respiratory system, acute asthma exacerbation is characterized by reversible bronchoconstriction and increased airway resistance, followed by low flow rates, premature small airway closure, decreased elastic recoil, pulmonary hyperinflation and increased work of breathing. There is a substantial decrease in the FEV 1 and the PEF of the patients, whereas the residual volume may increase as much as 400% of the normal and the functional residual capacity may even reach double the normal values [ 199 ]. In severe asthma exacerbations, total lung capacity (TLC) is also increasing. These changes in lung volumes help constricted airways remain open. During passive expiration of the lungs, the driving forces of the respiratory system are the elastic forces. The lower the elastic forces are, or the higher the resistive forces, the longer will the time needed to full expiration of the inspired tidal volume be, characteristic that may be quantified by a long expiratory time constant of the respiratory system. Incomplete exhalation of delivered tidal volume makes inspiration begin at a volume at which respiratory system exhibits a positive recoil pressure. The presence of flow at the end of the expiration is due to the presence of positive alveolar pressure at the end of expiration. This process is called dynamic hyperinflation and the positive end-expiratory alveolus pressure associated with higher relaxation volume is called intrinsic (auto) Positive End Expiratory Pressure (PEEP) [ 200 ] ( Figure 5 ). Dynamic hyperinflation depends on the expiratory time constant, expiratory flow limitation, expiratory time, inspiratory muscle activity during exhalation, tidal volume, and external flow resistance [ 201 ]. Although this initially may act in favor of the patient, by reducing the resistive work of breathing, the thorax and lungs increase in volume, length–tension relationships of the respiratory muscles shorten and the strength of contraction eventually diminishes. As the severe exacerbation remains unresponsive, expiratory and accessory muscles become active, the work of breathing increases and fatigue is a serious and potentially fatal possibility, as it further compromises respiratory function and deteriorates respiratory failure. Bronchospasm and increased resistance, mucous and compression of the peripheral airways from auto-PEEP, lead to significant heterogeneity of the lung. Normal lung units coexist with pathological lung units creating a variety of many different time constants across the lung.

Dynamic hyperinflation during exacerbation.

Hemodynamic compromise is another important feature of a severe asthma attack that leads to significant dynamic hyperinflation. The development of positive intrathoracic pressures lead to decrease of the right heart output by decreasing right heart preload (venous return and end–diastolic volume of the right heart) and increasing right heart afterload (vascular pulmonary resistance). The decreased right heart output in parallel with the diastolic dysfunction of the left heart (caused by shifting the intraventricular septum towards the left ventricle) and its incomplete filling, lead to a significant reduction of the arterial systolic pressure in inspiration and the presence of pulsus paradoxus sign [ 202 ] ( Figure 6 ).

Pathophysiological changes due to dynamic hyperinflation.

Thus, due to uncontrolled or difficult to treat dynamic hyperinflation, a patient with asthma can be drowsy, confused or agitated, or may present with paradoxical thoracic-abdominal movement, with absent of wheeze in lung auscultation, bradycardia or with pulsus paradoxus. This patient is near respiratory arrest status and endotracheal intubation. Mechanical ventilation and admission to an ICU may be imminent [ 203 ].

10. Clinical Assessment

Identification of severe asthma exacerbations is of outmost importance, as they are related with worse outcomes and require close observation and aggressive management. A brief interview with the patient is necessary to determine certain features in the patient’s history that need to be looked into closely, because current literature identifies them as factors that increase asthma-related death. Hospital and Intensive Care Unit (ICU) admission, as well as mechanical ventilation due to an asthma exacerbation has been shown to significantly increase the risk for a new episode of near fatal and fatal asthma [ 204 ]. It is also very important to obtain a detailed description of the patient’s medication history. Medications that play a significant role in the prediction of asthma related morbidities and death are inhaled and systematic corticosteroids, as well as the use of beta agonists. In this context, not currently using inhaled corticosteroids (ICS), currently using or having recently discontinued treatment with oral corticosteroids (OCS), as well as documented overuse of short acting β agonists (SABAs) are all factors related with an increased risk for asthma associated morbidity and mortality [ 205 , 206 ]. Elements from the medication history may also conceal clues that may suggest inadequate treatment, or even poor adherence to a prescribed treatment plan. The lack of a written asthma plan and socioeconomic factors are also associated with a greater risk for a severe exacerbation [ 207 ].

Patients suffering from an asthma exacerbation may present with a variety of signs and symptoms [ 208 ] ( Figure 7 ). Dyspnea, chest tightness, cough and wheezing are few of those, but there is wide heterogeneity in the asthmatic patient presentation. Features that characterize acute severe asthma are agitation, drowsiness or signs of confusion, significant breathlessness at rest, with the patient talking in words, tachypnea of more than 30 breaths per minute, use of accessory respiratory muscles, tachycardia of >120 beats per minute and pulsus paradoxus. Moreover, it is crucial to identify signs that indicate an imminent respiratory arrest, such as paradoxical thoraco-abdominal movement, silent chest with absence of wheeze, bradycardia, while the absence of pulsus paradoxus might imply muscle fatigue [ 208 ]. Upon examining the patient with acute severe asthma, apart from recognizing the signs that indicate severity, it is imperative to diagnose any pathology that might attenuate the exacerbation and requires specific treatment. Such entities are pneumothorax and pneumo-mediastinum, and pneumonia. At the same time, the clinician needs to exclude conditions that may mimic the symptoms of an asthma attack, such as cardiogenic pulmonary edema, exacerbation of chronic obstructive disease, airway obstruction caused by a foreign body or an intraluminal mass, pulmonary embolism, hyperventilation syndrome and vocal cord dysfunction [ 209 , 210 , 211 ].

Global Initiative for Asthma (GINA) recommendations for the management of asthma exacerbations in acute care facility. PEF: Peak expiratory flow; FEV 1 : Forced expiratory volume in one second; SABA, short acting beta 2 agonists; ICU, Intensive Care Unit.

Although lung function measurements are less sensitive than the history of symptoms, during an asthma exacerbation, serial PEF and FEV 1 measurements are more objective and reliable indicators of severity and should remain part of the initial assessment of an asthma patient presenting to the emergency department according to current guidelines [ 1 , 2 ]. Regarding PEF, the cut-off value of 50% of the patient’s best or predicted value is within the definition of an acute severe asthma episode, and requires greater attention and action. Moreover, a value of less than 33% of their best or predicted value is an indicator of life-threatening asthma. Serial monitoring of PEF may also assist the decision of either discharging the patient, should this be accompanied with a clinical improvement, or for ICU referral if the values are continuously deteriorating despite initial appropriate treatment. There is certainly a concern regarding the safety of this test in the setting of an acute exacerbation in the emergency department, and it should be performed with caution and continuous observation of the patient.

Further laboratory testing is not necessary for every patient that presents to the emergency department with an exacerbation. Chest radiographs are advised when the clinician needs to exclude conditions such as pneumonia, pneumothorax or atelectasis, but not for all patients. Arterial blood gas analysis should be performed on all patients that are critically ill, and/or are desaturating less than 92% despite treatment [ 212 ]. By performing arterial blood gas analysis, the clinician will be able to assess not only hypoxemia and the trend of PaCO 2 , but also acid base disturbances, such as respiratory acidosis and lactic acidosis which are common on acute severe asthma [ 213 ]. Further investigations may include total white blood cell count, to evaluate the potential of infection, levels of brain natriuretic peptide to exclude the presence of congestive heart failure and electrolyte level measurement.

11. Pharmacological and Non-Pharmacological Management

Most current guidelines regarding asthma exacerbations highlight the necessity of supplying the asthma patient with a written plan of action appropriate for their level of control, which will lead to early recognition and management of their exacerbations [ 1 , 2 ]. It is of outmost importance that the patients become educated on when to seek help, during the event of an acute exacerbation. In primary care and further in the emergency department or the hospital ward, a severe asthma attack needs to be identified within a short time period in order for the correct action to be taken. A severe exacerbation of asthma is a life-threatening medical emergency, thus being crucial to transfer the patient to an acute care facility, once such a condition is identified, ensuring the patient’s safety. During the transfer, it is required to provide controlled oxygen therapy, inhaled SABA, ipratropium bromide, and systemic corticosteroids. In the emergency department the pharmacological therapy of acute severe asthma should consist of SABA, ipratropium bromide, systemic corticosteroids (oral or iv), controlled oxygen therapy, and the clinician should consider the use of iv magnesium sulfate and high dose ICS [ 1 ]. ( Figure 7 , Table 2 )

Pharmacological management of patients with acute severe exacerbation in the emergency department.

iv, intravenous; sc, subcutaneous.

11.1. β2-Adrenergic Receptor Agonists

The cornerstones of acute asthma medication are bronchodilators and especially short acting beta agonists (SABA). It is recommended that in acute severe asthma SABAs are administered repetitively or continuously. These substances activate the β2 adrenoreceptors (β2ARs), which are located mainly on the smooth airway muscle cells, but are also found on other airway cells even on the inflammatory cells. Their very important characteristic is that they have a rapid onset of action, while at the same time being well tolerated, despite high doses. Although the β2 AR agonists are substances known for centuries, the great challenge remains improving their selectivity, in order to benefit from their desired effect, while at the same time reducing their adverse effects. All current asthma guidelines introduce short acting β2 agonists (SABAs), as the first line treatment for acute severe asthma. In the first steps of escalating therapy during an exacerbation, the patient is advised to increase their use “as needed”. That is also the recommendation for the primary care setting, as well as for the emergency department, where repeated inhaled administration of SABA is advised. Studies on the efficacy of nebulizers vs. metered dose inhalers (MDIs) have not proven superiority of nebulized administration. In a recent review, nebulized delivery did not improve hospital admission, length of stay in the emergency department or pulmonary function [ 214 ]. According to GINA 2018, the preferred method of administration is with strong evidence (Evidence A) pMDI with a spacer [ 1 ]. This evidence becomes less strong when referring to severe and near fatal asthma. Although continuous nebulization of SABAs was initially a very promising perspective, several studies and meta-analyses have failed to clearly demonstrate strong evidence on favor of continuous nebulized SABAs for acute asthma. Rodrigo et al. in 2002 performed a systematic review and meta-analysis that showed no difference in respiratory function measured in the first hours of administration or on the rate of hospital admissions [ 215 ]. A Cochrane systematic review on the subject, including few more studies, showed significant difference on both respiratory function and hospital admissions, in favor of the continuous use of SABA, while at the same time demonstrating a good tolerance from the patients who did not present more adverse effects with this method of administration [ 216 ]. The most commonly used SABA is salbutamol or albuterol as named in the United States, which has an onset of action of less than 10 min and duration of approximately 6 h. Lebalbuterol is a recent addition to the choices of SABAs, with its benefit of a lower than salbutamol dose that provides similar effect. There is currently evidence about its efficacy in acute severe asthma as an intermittent regimen, but not as a continuous nebulization strategy [ 217 , 218 ]. Continuous intravenous infusion of β2 agonists has also been proposed as a therapy, especially in patients who did not respond to intensive bronchodilation. There is no evidence to support the use of intravenous β2 agonists [ 219 , 220 ] or the method of continuous, subcutaneous infusions of terbutaline [ 221 ]. Epinephrine has been studied, as a nebulized, subcutaneous, intramuscular and intravenous administration, but, in current guidelines, its use is restricted for acute asthma related with anaphylaxis and angioedema [ 1 , 222 , 223 ].

11.2. Anticholinergics

Anticholinergic agents act as inhibitors of acetylcholine at the muscarinic cholinergic receptor. Therefore, they inhibit parasympathetic nerve impulses and they produce a beneficial effect in acute asthma, by causing airway smooth muscle relaxation. Furthermore, they enhance β2-agonist-induced bronchodilation via intracellular processes and they prolong their bronchodilator effect [ 61 , 224 ]. The anticholinergic agent used primarily is ipratropium bromide due to its selectivity for airway smooth muscle receptors, which reduces the systemic adverse effects. Their use is included in current guidelines for moderate to severe acute and life-threatening asthma, as well as for patients who show poor response to initial SABA therapy [ 1 , 2 ]. It is not recommended to use anticholinergics as a single therapy for acute asthma. It has been demonstrated that the addition of inhaled ipratropium bromide to therapy with SABAs improve hospitalization rates, relapse rates and are associated with lung function improvement [ 62 , 63 , 64 ]. This combination therapy benefit is greater for the patients who present with acute severe asthma and are at a higher risk of hospitalization. There is an increased rate of adverse effects, which are of mild nature, such as mouth dryness and tremor.

11.3. Corticosteroids

Within the asthma setting, it has been well established that inhaled corticosteroids reduce the rates of hospitalization and mortality for patients with asthma [ 65 , 225 ]. In the event of acute exacerbation, there is a different approach of their use. Current recommendations suggest that high dose ICS given within the first hour of the patient’s presentation in the emergency department, reduce the rate of hospital admissions, for patients who are not on systemic corticosteroid therapy [ 1 ]. Recent evidence however seems to be conflicting regarding their performance without the use of systemic corticosteroids, when rate of hospital admissions or changes in lung function has been studied [ 226 , 227 ].

Systemic corticosteroids, due to their significant anti-inflammatory properties, have a fundamental role in the management of acute asthma, and particularly for patients who present with exacerbation while receiving oral corticosteroids (OCS), or have previous history of exacerbation that required use of OCS. They are also recommended for patients who did not respond to initial SABA therapy with a prolonged effect. Apart from their role against asthma associated inflammation, they seem to increase the number and sensitivity of β-adrenergic receptors, and also restrain the migration and function of eosinophils and other inflammatory cells. On the other hand, their lack of bronchodilatory effects prohibits their use for acute asthma as a monotherapy [ 74 ]. A recent multi-center study showed that there is a significant percentage of patients who get admitted to hospital with acute asthma and do not receive systemic corticosteroids, despite the clear suggestion of current guidelines [ 228 ]. With regards to the root of administration, intravenous administration seems to not provide additional efficacy to the use of oral therapy [ 229 , 230 ]. Intramuscular regimens seem to be as effective as oral in reducing the risk for relapse [ 231 ]. The oral route is better tolerated and preferred, because it is quicker and less expensive. Identifying groups of patients where intravenous administration could be more beneficial is a recent field of study, and guidelines support that they should be considered for patients who may be unable to swallow due to breathlessness, or may not absorb efficiently the medication due to gastro-enteral disturbances, such as vomiting [ 1 ]. There is a lack of robust evidence to clarify the superiority of longer or higher dose OCS, thus the literature suggests a 5–7-day regimen of 50 mg prednisolone as a single dose, or 200 mg hydrocortisone in divided doses [ 1 , 2 , 232 ].

11.4. Magnesium Sulfate

Magnesium has been proven to be an important co-factor in enzymatic reactions and changes of its concentrations may result in different response from the smooth muscles. Hypomagnesemia may cause contraction, whereas hypermagnesemia causes relaxation of the smooth muscles and bronchodilation, possibly through inhibition of calcium influx into the muscles.

Recent recommendations include magnesium sulfate, at dose of 2 g infused over 20 min, as a second line intervention for acute severe asthma exacerbation [ 1 , 233 ]. It has been shown to reduce the rate of hospitalization in adults with FEV 1 of 25–30% at presentation and those who are unresponsive to initial treatment, and have persistent hypoxemia, and correlates with improvement in lung function [ 234 , 235 ]. Its infusion has not been correlated with severe adverse events; it is however contra-indicated for patients with renal insufficiency, hypermagnesemia and myasthenia Gravis. Magnesium has also been tried in its nebulized form for asthma exacerbation, with very few data to support it. A recent systematic review, which examined the efficacy and safety of inhaled administration of magnesium, concluded that, although safe, it has not shown significant benefits when compared with the first line inhaled agents, thus it is not routinely recommended [ 236 ]. The current literature is reluctant to fully support the use of magnesium, mainly because of the heterogeneity of the severity of asthma attacks it has been used on in trials, especially in the context of optimized first line treatment with β2-agonists and corticosteroids [ 237 ]. A 2014 randomized controlled trial failed to show any evidence of clear benefit in the use of either intravenous or inhaled magnesium [ 238 ]. Further prospective trials are necessary to provide accurate evidence on this treatment option.

11.5. Methylxanthines

On the ground of their anti-inflammatory properties, methylxanthines (aminophylline and theophylline) used to be included in the primary treatment for acute asthma. Their poor safety profile, which includes significant side effects, in combination with the inability to provide evidence of improved outcomes, such as improved pulmonary function or rate of hospitalization when given for severe acute asthma, has excluded them from current guidelines [ 1 , 239 ]. A more recent review and meta-analysis, however, has supplied some evidence of aminophylline’s efficacy, when combined with other bronchodilators, but more data are needed on this direction [ 240 ].

11.6. Leukotriene Modulators

Although leukotriene receptor antagonists (LTRAs) are included as a controller agent in the asthma management, there are limited data on the efficacy of intravenous or oral antileukotriene drugs in acute asthma. Montelukast and zafirlukast were studied on patients with acute asthma and demonstrated some evidence of lung function improvement [ 241 , 242 ]. A review of the literature, however failed to provide robust evidence of the effectiveness of this medication category on lung function or on the outcomes of the patients [ 243 ].

11.7. Oxygen Supply

Although asthma exacerbations are not usually accompanied with severe hypoxemia, acute severe asthma often presents with arterial PO 2 derangements, due to extensive V / Q mismatch as explained above. Oxygen should be administered via nasal cannula or mask, with a target of arterial oxygen saturation of 93–95%, or to those patients where saturation monitoring is not available [ 1 ]. Although not all guidelines agree on the level of the desirable target saturation, studies have shown that, in severe acute asthma, oxygen therapy with controlled low flow administration, with a target SpO 2 , is correlated with better outcomes than the use of per se high flow 100% oxygen delivery, as it has been shown to correlate with increases in PaCO 2 , as well as with decreased values of PEF [ 244 , 245 ]. There is also some evidence about the use of oxygen driven nebulization with SABAs, because of the pulmonary vasodilation caused by the β2-agonist, which results in increasing perfusion of poorly ventilated areas, thus resulting in deterioration of the V/Q abnormalities [ 246 ].

11.8. Heliox

Heliox is a mixture of helium (70–80%) with oxygen (20–30%). Heliox can be used for severe asthma exacerbations that are unresponsive to standard therapy or in patients having an upper airway obstruction component. Heliox, with density less than air, leads to lower Reynolds number, thus decreasing resistance to airflow under conditions of turbulent flow, as are prominent in the central airways and at the branch points. This effect can potentially decrease the work of breathing and improve ventilation. On the contrary, airflow in smaller airways, which are mainly affected during an asthma exacerbation, will not improve with heliox, as it is typically laminar, depending on gas viscosity rather than density.

Despite the theoretical benefits of heliox, and while a few case series have suggested a beneficial effect in acute asthma, no studies in adults have demonstrated an advantage of heliox above and beyond standard oxygen therapy. In asthma exacerbation either without or with intubation, heliox has not demonstrated consistent benefit [ 247 , 248 ].

Heliox has demonstrated greatest benefit for improving symptoms when used as a nebulizing gas for a beta-2 agonist medication. Benefit is generally seen within minutes after the initiation of therapy [ 247 ]. Another study has shown that using heliox as a carrier gas increase gas delivery up to 50% in a mechanical model for both MDIs and nebulizers [ 249 ]. Given that its effect is based on the percentage of helium, it should not be administrated to patients requiring FiO 2 > 40%.

11.9. Ketamine

Ketamine is well known drug that has been in use since circa 1960. It is a dissociative anesthetic drug that has the potential to have different actions, depending on the dose used. It may work as a potent analgesic and as an anesthetic agent, but may also have secondary effects as a bronchodilator, while at the same time preserving airway reflexes and sympathetic nervous system tone, with no effects on the cardiovascular system. A dose of 1–2 mg/kg dose has been described as an inductive agent in rapid sequence intubation (RSI) of asthma patients [ 250 ]. In doses lower than this it does not have sedative effects, whereas in higher doses it can cause laryngospasm and apnea. Its psychoactive effects make it even less popular for use. In the context of asthma, there are no large randomized trials to examine its effect. There is some evidence of its bronchodilatory effect, especially in mild and moderate asthma exacerbations, and in doses lower than 1 mg/kg, but larger trials would be necessary to establish its role for asthma [ 251 , 252 ].

11.10. Antibiotics

There is no evidence supporting the use of antibiotics per se for severe acute asthma, unless the patient’s history and clinical assessment indicate the presence of infection. In a recent retrospective cohort study, it has been demonstrated that, in patients hospitalized with acute asthma and receiving OCS, antibiotic use was associated with longer hospital length of stay and hospital cost, whereas it held similar risk of treatment failure [ 253 ]. In a previous study in the US, 60% of the patients who were admitted to hospital with asthma exacerbation, received antibiotics, with no clear indication accompanying this decision [ 254 ]. Current guidelines suggest against their use and that they should be considered after optimizing other treatment options and when there is clear evidence of infection [ 1 ].

11.11. Non-Invasive Mechanical Ventilation

Although the benefits of non-invasive mechanical ventilation (NIMV) are well recognized in the acute exacerbation of chronic obstructive pulmonary disease and pulmonary edema, its usage for asthma exacerbation remains controversial. Despite the lack of supporting evidence, NIMV is commonly used in patients with severe asthma exacerbation as a mean to obviate the need for intubation and mechanical ventilation and its detrimental effects.

In the absence of clinical guidelines that recommend the use of NIMV for the management of acute asthma, evidence suggests that a trial of NIMV (for one or two hours) may be beneficial for a low risk group of patients [ 255 ], particularly those unresponsive to medical therapy. Prolonged trials of NIMV are not recommended. Suggested criteria for an NIMV trial include RR > 25 breaths per minute, heart rate > 110 beats per minute, hypoxemia with PaO 2 /FiO 2 ratio greater than 200, hypercapnia with PaCO 2 < 60 mmHg, FEV 1 < 50% less than predicted and use of accessory respiratory muscles. A trial of NIMV should not be undertaken if there is any absolute criterion for endotracheal intubation (respiratory arrest, hemodynamic instability or shock, GSC < 8), excessive respiratory secretions and risk of aspiration, severe agitation and poor patient collaboration and any cause that precludes the right mask fitting (facial surgery) [ 256 ].

In a trial of 30 patients who presented to the emergency department with a severe asthma exacerbation that was not responding to inhaled bronchodilator therapy, NIMV was associated with reduction in the rate of hospitalization and increased lung function. Improvements in respiratory rate and dyspnea appear to be influenced by the amount of pressure support above expiratory positive airway pressure (EPAP) provided. The use of NIMV has been associated with reduction in endotracheal intubation, improvement in oxygenation, decrease in carbon dioxide retention, and improvement in airflow obstruction. Studies are controversial regarding the mortality and ICU length stay [ 86 ]. NIMV can also be used in the asthmatic patients who are at risk for intubation, following extubation [ 257 ].

11.12. Invasive Mechanical Ventilation

The decision to intubate and mechanically ventilate a near-fatal asthma patient is considered a challenging task and should be based primary on a series of clinical evaluations. Major indications for initiation of invasive mechanical ventilation (IMV) are: (1) cardiac arrest; (2) respiratory arrest or bradypnea; (3) respiratory insufficiency with PaO 2 < 60 mmHg on 100% FiO 2 and PaCO 2 > 50 mmHg; (4) physical exhaustion; and (5) compromised level of consciousness. Relative indications for IMV are: (1) hypercapnia PaCO 2 > 50 mmHg or PaCO 2 increased by 5 mmHg per hour; (2) worsening respiratory acidosis;, (3) inability to treat patient appropriately; (4) failure to improve with proper therapy; and (5) clinical signs of deterioration and respiratory fatigue such as tachypnoea of >40 breaths per minute, severe hypoxemic respiratory insufficiency, hemodynamic instability, paradoxical thoracic movement, and silent chest [ 258 ].

The decision to intubate and mechanically ventilate a patient with acute asthma exacerbation is a clinical one and may be made urgently. When the clinician decides that respiratory failure is progressing, and is unlikely to be reversed by further pharmacologic therapy, intubation should be performed as quickly as possible by a skilled intensivist or anesthesiologist, who has extensive experience in intubation and airway management, using rapid sequence intubation (RSI) protocol suitable for asthmatic patients (good preparation, sufficient pre-oxygenation, suitable induction to anesthesia agents suitable for asthma, and placement of the endotracheal tube) [ 259 ]. Regarding the preferred method of intubation, oral endotracheal intubation is preferred, although the literature also includes awake nasotracheal intubation, which may be complicated by the fact that many asthmatic patients also have nasal polyps [ 203 ]. Additionally, oral intubation allows the use of an endotracheal tube of a larger diameter, facilitating secretion removal and bronchoscopy, if needed, while at the same time decreasing inspiratory airway resistance. It should be noted that unlike other conditions in which intubation and mechanical ventilation can solve problems, the dynamic hyperinflation that mechanical ventilation can create or even exacerbate can have devastating consequences for a severe asthmatic patient, such as cardiovascular collapse and/or barotrauma and ventilator induced lung injury. Therefore, there are certain considerations to be made before and during RSI. During RSI in such patients one should anticipate rapid oxygen desaturation despite maximal effort at pre-oxygenation especially in those patients who do not achieve a SpO 2 above 93%, so adequate pre-oxygenation is advised. Bag mask ventilation should be done using small tidal volume and high inspiratory flow rate with a prolonged expiratory phase, attempting with this way to mimic the approach used during mechanical ventilation. Excessive mag mask ventilation should be avoided because of the risk of pneumothorax [ 260 , 261 ]. Manipulation of the airway can cause laryngospasm and worsening of bronchoconstriction, so one could consider the use of atropine to attenuate vagal reflexes [ 203 ]. The literature suggests the bolus use of intravenous ketamine for RSI taking advantage of its bronchodilatory effect, while propofol is also considered a safe approach. Opiates and barbiturates should be avoided due to the risk of histamine release that can exacerbate bronchoconstriction [ 262 ]. If muscle relaxants are needed, non-depolarizing muscle relaxants (except maybe atracurium and mivacurium) and succinylcholine are suitable in asthmatic patients [ 263 ].

11.13. Goals of Mechanical Ventilation

Near fatal asthma is characterized by severe dynamic hyperinflation of the lung with severe respiratory and circulatory consequences. The aim of mechanical ventilation is to maintain adequate oxygenation, to reduce the work of breathing and to prevent and confront further hyperinflation without any circulatory compromise or ventilator induced lung injury [ 264 ]. The intubation and post-intubation period is often complicated with severe cardio-respiratory derangement. Hypotension, the most common post-intubation complication, may be caused due to dynamic hyperinflation and auto-PEEP, and can be aggravated by dehydration, sedatives and neuromuscular blocking agents. Arrhythmias, barotraumas, laryngospasm or even seizures have also characterized the post-intubation period [ 265 , 266 ]. Phenomena such as hypercapnia, hypoxemia and acidemia, as well as ventilatory lung injury and life threatening pneumotrauma (pneumothorax and pneumo-mediastinum), may also complicate the post-intubation period. Reasons for the aforementioned may be the severity and non-responsiveness of the disease, but may also be the result of inadequate sedation or patient–ventilator desynchrony. Wrong and harmful initial ventilator settings may also result in providing too little or too excessive minute ventilation, potentially deteriorating the already very fragile asthmatic patient [ 267 ].

Management of the asthmatic patient post intubation starts with ensuring adequate sedation in order to achieve the desirable patient–ventilator synchronization. Sedation and analgesia will also decrease the metabolic rate, oxygen consumption and carbon dioxide production. Dexmedetominide, propofol and remifentanyl are the appropriate drugs for sedation and analgesia. Their usage has been associated with shorter length of ICU stay, shorter duration of mechanical ventilation and improved long term neurocognitive outcomes when compared to benzodiazepines [ 266 , 268 ]. It is important to use agents that accomplish deep sedation, while at the same time allow rapid awakening, should the patient improve quickly, which is common in the asthma cases ( Table 3 ).

Sedation, analgesia and paralysis in patients with acute severe asthma exacerbation requiring intubation.

Patients with severe asthma with persistently dangerous levels of hypercapnia and arterial hypoxemia, and extreme patient–ventilatory asynchrony may require paralysis in addition to sedation. The preferred paralytic, non-depolarizing agent is cis-atracurium, as it is eliminated by esterase degradation and spontaneous breakdown in the serum. Paralytic agents can be administered either intermittently through bolus injections, or by continuous intravascular infusion. Its duration must be as short as possible, because concomitant use of intravascular corticosteroids and paralytic neuromuscular agents increases the incidence of critical illness myopathy [ 269 , 270 ].

To avoid the hemodynamic effects of dynamic hyperinflation, once the patient is intubated, it is advised to perform a brief discontinuation (60–90 s) from the ventilation (apnea test), a slowly bagged ventilation and to administer fluids (1–2 L or more) and vasopressors. Although there is no clear evidence to support the volume-preset over the pressure-preset modes, the preferred ventilator modes for the asthmatic patient are the volume-limited ones [ 263 ]. Barotrauma seems to occur regardless of the mode of ventilation. Volume-limited modes of ventilation are usually used for near death asthmatic patients at their entrance in the ICU. It is essential to closely monitor the Peak inspiratory and Plateau pressures, to early detect any change in resistance and compliance, and this is easily achievable when using volume modes ( Figure 8 ). Although high inspiratory flow rates of 80 L/min up to 100 L/min and square waveforms shorten inspiratory time and increase expiration time, thus reducing hyperinflation, it has been shown that this may not have a significant impact to the degree of hyperinflation once the minute ventilation has been limited by high peak inspiratory pressure [ 271 ]. Minute ventilation should be set at a level of less than 115 mL/kg/min (less than 10 L/min) with a respiratory rate of 10–12 breaths/min and a prolonged expiratory time by decreasing I:E ratio (1:3 or 1:4 up to 1:5) [ 263 , 266 ]. Tuxen and Lane showed a remarkable increase in hyperinflation when using higher levels of minute ventilation [ 120 ]. The fraction of inspired oxygen (FIO 2 ) should be titrated to maintain the pulse oxygen saturation (SpO 2 ) above 90% (up to 94%) or the arterial oxygen tension (PaO 2 ) above 60 mmHg. One should avoid SpO 2 > 96% due to oxygen toxicity ( Table 4 ).

Flow time tracing of a patient with persistence of flow at the end of expiration which indicates dynamic hyperinflation and pressure time tracing with a slope increase indicative of over-distension.

Initial ventilator settings in intubated patients with acute severe asthma exacerbation.

SaO 2 : Oxygen saturation; Peep: positive end expiratory pressure.

Limited data exist about the use of external PEEP when ventilating a patient with severe asthma. The use of progressively higher external PEEP from 5 to 15 cmH 2 O has been shown to have a deteriorating effect both in respiratory (deterioration of the end-inspiratory volume, the functional residual capacity and plateau pressure) and circulatory system (decrease of systolic arterial pressure and cardiac output) [ 271 ]. In one prospective study of patients undergoing control mode of ventilation, external PEEP worsened hyperinflation and had serious hemodynamic effects by worsening gas trapping [ 272 ]. On the other hand, other studies have shown that the application of external PEEP, may produce a paradoxical lung deflation by reducing lung volumes and airway pressures and increasing lung homogeneity [ 273 ]. In the case of assist mode of mechanical ventilation, the application of external PEEP at a value less than 80% of the intrinsic PEEP, or 5 cm H 2 O if intrinsic PEEP is <10 cm H 2 O can counterbalance the endogenous peep and reduce the work of breathing [ 274 ]. A trial of stepwise increase in PEEP can be used and terminated when indications of worsening of dynamic hyperinflation it is shown.

11.14. Permissive Hypercapnia

Hypercapnia is a common fact during mechanical ventilation of asthmatic patients. PaCO 2 levels up to 60 mmHg and pH values less than 7.20 are common on the first day of mechanical ventilation even with increased minute ventilation. The term permissive hypercapnia is a ventilating strategy that can be applied to mechanically ventilated asthma patients, that emphasizes on giving priority to the reduction of hyperinflation rather than normal minute ventilation. The reduction of minute ventilation through reduction of tidal volume and respiratory rate is used to decrease pulmonary hyperinflation. PaCO 2 levels should rise gradually during mechanical ventilation rather than rapidly, preferably at a rate of <10 mmHg per hour or even slower if the PaCO 2 exceeds 80 mmHg. Generally, a pH level of 7.20–7.25 is accepted, but the literature has failed to demonstrate a benefit from using alcalotic agents, such as bicarbonate infusion to accomplish that [ 274 ].

11.15. Additional and Unconventional Therapies for Acute Severe Asthma

11.15.1. oxygen delivery by high flow nasal canula.

Oxygen delivery via high flow nasal canula (HFNC) can be used to hypoxemic patients who are not expected to respond to conventional therapies. HFNC with flow up to 60 L/min of warmed and humidified oxygen, decreases inspiratory resistance, as well as the work of breathing, can wash out carbon dioxide, thus decreasing the anatomic dead space and may also produce a positive end expiratory pressure (up to 5 mmHg) by increasing the end expiratory lung volume. The role of HFNC in asthmatic adults is unknown. Studies in children have shown that its use reduces respiratory distress in moderate and severe asthma exacerbations and also reduces the need for intubation [ 275 , 276 ].

11.15.2. Extracorporeal Life Support (ECLS)

Extracorporeal membrane oxygenation (ECMO) is an invasive therapy, in which oxygenation and carbon dioxide removal are performed through an artificial membrane. Although evidence based on clinical trials for the use of ECMO in asthmatic patients is lacking [ 277 , 278 ], there is growing evidence on the subject, supporting the use of ECLS for patients receiving mechanical ventilation due to an asthmatic exacerbation. A 2009 review by Mikkelsen et al. has demonstrated that, when ECLS is used for status asthmaticus, it correlates with better outcomes in comparison to its use for other causes of respiratory failure [ 279 ]. In this study, they used data from the multicenter Extracorporeal Life Support Organization (ELSO), but included only a small number of patients. In 2017, there was another review of the same database, confirming that the use of ECMO is an acceptable option, and resulted in acceptable survival rates, although it is necessary to understand and reduce the ECMO related complications [ 280 ]. Di Lascio et al., using ECMO for asthmatic patients receiving IMV, showed that it could provide adjunctive pulmonary support for patients who remain severely acidotic and hypercapnic despite aggressive conventional therapy [ 281 ]. The writers conclude that ECMO should be considered as an early treatment in patients with status asthmaticus whose gas exchange is not satisfactory despite using conventional therapy, aiming to provide adequate gas change and to prevent ventilator induced lung injury.

A modified ECMO technique such as extracorporeal carbon dioxide removal (ECCO 2 R) may also play an important role in severe asthmatic patient in mechanical ventilation. In a difficult to safely ventilate asthmatic patient, due to extremely high airway pressures, hypoventilation and persistent severe respiratory acidemia are common issues. The usage of ECCO 2 R, considering the reversibility of the pathophysiology of asthma, provide the opportunity for more protective ventilation and more time for the bronchodilator agents to act and reverse inflammation and hyperinflation. There is no sufficient evidence to support a clear role of this technique in asthmatic patients, but there seems to be a growing interest on the subject [ 282 , 283 ]. Schneider et al. even presented a case where ECCO 2 R was used in an “awake” patient with a near fatal asthma attack, refractory to the use of pharmacological intervention and NIMV, resulting in avoidance of intubation [ 284 ]. However, more data are needed to establish an indication for this intervention in the context of an acute severe asthma exacerbation.

11.15.3. Anesthetic Agents

Some inhalational anesthetic agents such as halothane, isoflurane and sevoflurane act as bronchodilators, probably not only through a direct relaxation effect on airway smooth muscles but also by attenuating cholinergic tone [ 285 , 286 ]. This characteristic may have favorable effects in patients with refractory to conventional and optimized bronchodilatory therapy. Case report studies have indicated a positive effectiveness with halothane, but also with isoflurane and sevoflurane but with several limitations. Hypotension, myocardial depression, increased ventricular irritability especially in the presence of acidosis, beta-agonists and theophylline have been reported [ 287 , 288 , 289 ]. In addition, factors such as the expense of inhalational treatment, the need of a bedside anesthesiologist, the practical issues concerning the equipment for delivering the inhalational agents, the short time of duration of bronchodilation (immediate return of bronchoconstriction after discontinuation), and, finally, the absence of randomized trials to evaluate and confirm their efficacy in near-death adult asthmatic patients make the usage of anesthetic agents a last resort as a non- conventional bronchodilatory therapy for refractory near death asthma exacerbations [ 290 , 291 ].

11.15.4. Enoximone

Enoximone is an intravenous bronchodilatory agent that can be used in severe asthma exacerbation in adults. Enoximone, a selective phosphodiasterase inhibitor III, was tested in a study by Beute et al. on eight patients with status asthmaticus, six of whom had a respiratory arrest or hypercapnia [ 292 ]. The bronchodilatory effect was immediate. Even if the intravenous administration bypasses inhalation incapability in severe asthma, and no side-effects were observed in this study, phosphodiesterase inhibitors in general are associated with ventricular and atrial arrhythmias, hypotension, and hepatotoxicity. Further studies are needed to confirm enoximone efficacy and safety in patients with acute exacerbations of asthma that are refractory to conventional therapies.

12. Prognosis

Asthmatic patients who require mechanical ventilation, not only have increased hospital mortality (7%), but also long-term mortality [ 40 , 293 ]. Most of the long-term mortality is attributed to recurrent asthma [ 294 ]. Psychological disturbances such as depression and denial are also common features of asthmatic patients who survived a near fatal episode. Anxiety seems to be more common among close family members than the patients themselves [ 295 ]. Smoking cessation is one of the recognized factors that improves survival [ 151 ].

13. Prevention and Risk Reduction

GINA recommends that all adults and adolescents with asthma should receive ICS-containing controller treatment, either as-needed (in mild asthma) or daily, in order to reduce their risk of serious exacerbations and to control symptoms, [ 1 ] ( Figure 9 ). Asthma treatment should be optimized in patients continuing having poor symptom control and/or exacerbations, even though Step 4 and Step 5 treatments and contributing factors should be assessed, in order to treat modifiable risk factors that compromise disease stability (smoking, environmental exposures, allergen exposure (if sensitized on skin prick testing or specific IgE), and medications such as beta-blockers and NSAIDs) ( Table 5 ). It is imperative to optimize the inhaler technique and adherence to treatment, as well as overuse of SABAs, and medication side effects. Furthermore, comorbidities should be assessed including obesity, GERD, chronic rhinosinusitis, obstructive sleep apnea, anxiety, depression, and social difficulties. Non-pharmacological interventions (e.g., smoking cessation, exercise, weight loss, mucus clearance, and influenza vaccination) should also be recommended where indicated.

Personalized management for adults and adolescents to control symptoms and minimize future risk [ 1 ].

Modifiable risk factors that have to be treated in order to reduce exacerbations.

FEV 1 , forced expiratory volume in 1 s; HDM, house dust mite; ICS, inhaled corticosteroids; OCS, oral corticosteroids; SLIT, sublingual immunotherapy.

If the problems continue after having optimized all the above parameters, patients should refer to a specialist center for phenotypic assessment and consideration of add-on therapy including biologics ( Figure 10 ). The prevalence of severe, refractory asthma is generally estimated to be 5–10% of the total asthma population [ 77 , 151 ]. It is important to distinguish between asthma that is difficult to control and asthma that is truly severe. Severe asthma is defined by the joint European Respiratory Society/American Thoracic Society (ERS/ATS) guidelines according to the following criteria [ 151 ]:

• Requirement for treatment with high-dose inhaled corticosteroids (ICS) and a second controller (and/or systemic corticosteroids) to maintain control.
• Refractory to the treatment mentioned above.
• Incomplete management of comorbidities such as severe sinus disease or obesity.

Criteria for the choice of biologic as add on treatment in Th2 driven severe asthma.

The GINA 2019 guidelines for adolescents and adults with difficult-to-treat and severe asthma [ 77 ] recommend that assessment of the severe asthma phenotype should be done during high dose ICS treatment (or lowest possible dose of OCS), and biological treatment should be chosen accordingly ( Figure 8 ). Where relevant, test for parasitic infection should precede and be treated if present, before commencing Type 2 targeted treatment. The currently approved add-on biological treatments for severe asthma include anti-IgE treatment for severe allergic asthma (omalizumab), anti-IL5 or anti-IL5R for severe eosinophilic (mepolizumab, benralizumab, and reslizumab), and anti-IL4R for severe eosinophilic/Type 2 asthma or patients requiring maintenance OCS asthma (dupilumab) ( Table 6 ).

Currently available biologics: indications and adverse effects.

14. Conclusions

Severe asthma exacerbations are a major cause of disease morbidity, functional impairment, increased healthcare costs, and increased risk of mortality. Asthma patients experience exacerbations irrespective of underlying disease severity, phenotype, or despite optimal guideline-directed treatment, as a result of the ongoing inflammatory processes and loss of the disease control. Patients with frequent emergency department visits, patients requiring hospitalization, and, more importantly, patients intubated for an asthma exacerbation are at significantly increased risk for future severe exacerbations. It is evident that prevention of exacerbations remains a major unmet need in asthma management. The identification of patients at risk to have severe exacerbations is of paramount importance. Patient education and written plans of management, control of triggering/risk factors and co-morbid conditions, monitoring of asthma control and pulmonary function as well as optimal pharmacotherapy are needed to prevent and/or decrease exacerbations. A better understanding of the pathogenesis of asthma exacerbations will ultimately lead to better strategies and the development of novel treatments in the pursuit of preventing and treating severe asthma exacerbations.

Author Contributions

Conceptualization: N.R.; Literature search and data extraction: E.K. (Eirini Kostakou), E.K. (Evangelos Kaniaris), and N.R.; Writing—Original Draft Preparation: I.K., E.K. (Evangelos Kaniaris), and N.R.; Writing, Review and Editing: E.K. (Eirini Kostakou), E.K. (Evangelos Kaniaris), E.F., P.K., E.T., I.V., and N.R.; and Supervision: A.K., N.K, and N.R.

Conflicts of Interest

The authors declare no conflict of interest.