acute asthma exacerbation case study

Case of Acute Severe Asthma

Kane guthrie.

• Dec 2, 2022

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

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

Past Medical and Medication History

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

Asthma Epidemiology

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

Asthma Pathophysiology

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

Markers of severe asthma:

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

Complications of Asthma :

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

Conditions that may mimic acute asthma:

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

Diagnostic Test:

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

Management of Acute Severe Asthma

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

Beta-agonists:

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

Anticholinergics:

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

Adrenaline:

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

Aminophylline:

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

Magnesium Sulphate:

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

Antibiotics:

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

Airway Management

Non-Invasive Positive Pressure Ventilation:

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

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

“Asthmatic on BiPAP before being Intubated”

Mechanical Ventilation:

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

Criteria for Intubation:

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

Challenges:

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

Recommendations:

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

Initial Ventilator settings in paralysed patients:

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

• Brenner, B. Corbridge, T. & Kazzi, A. (2009). Intubation and mechanical ventilation of the asthmatic patient in respiratory failure. The Journal of Emergency Medicine. 37(2s), s23-s34.
• Camargo, C. Rachelefsky, G. & Schatz, M. (2009). Managing Asthma Exacerbation in the Emergency Department: Summary of the National Asthma Education and Prevention Program Expert Panel Report 3 Guidelines for the Management of Asthma Exacerbation.The Journal of Emergency Medicine. 37 (2S), S6-S17.
• Camargo, C. Spooner, C. & Rowe, B. (2009). Continuous versus intermittent beta-agonist for acute asthma (Review). http://www.thecochranelibrary.com.
• Chua, F. & Lai, D. (2007). Acute severe asthma: Triage, treatment and thereafter. Current Anaesthesia & Critical Care. 18, 61-68.
• Creagh-Brown, B. & Ball, J. (2007). An under-recognized complication of treatment of acute severe asthma. American Journal of Emergency Medicine. 26, 513-515.
• Hodder, R. et al. (2009). Management of acute asthma in adults in the emergency department: nonventilatory management.  CMAJ. 182(2), E55-E67.
• Holley, A. & Boots, R.(2009). Review article: Management of acute severe and near-fatal asthma. Emergency Medicine Australasia, (21) 259-268.
• Jones, L. & Goodacre, S. (2009). Magnesium sulphate in the treatment of acute asthma: evaluation of current practice in adult emergency departments. Emergency Medicine Journal. 26, 783-785.
• Melnick, E. & Cottral, J. (2010). Current Guidelines for Management of Asthma in the Emergency Department.  http://www.ebmedicine.net. 2(2). 1-13.
• Morris, F. & Fletcher, A. (Ed). (2009). ABC of Emergency Differential Diagnosis. Oxford: Blackwell Publishing
• National Asthma Council of Australia. Asthma management handbook: 2006. Accessed http://www.nationalasthma.org.au/cms/images/stories/amh2006_web_5.pdf, 12/02/2010
• Nowak, R. Corbridge, T. & Brenner, B. (2009). Noninvasive Ventilation. The Journal of Emergency Medicine. 37(2S), S18-S22.
• Peters, S. (2007). Continuous Bronchodilator Therapy. Chest. 131(1),1-5.
• Phipps, P. & Garrard, C. (2003). The pulmonary physician in critical care. 12: Acute severe asthma in the intensive care unit. Thorax. 58, 81-88.
• Ram, F. Wellington, S. Rowe, B. & Wedzicha, J. (2009). Non-invasive positive pressure ventilation for treatment of respiratory failure due to severe acute exacerbations of asthma (Review)
• Rodrigo, G. Pollack, C. Rodrigo, C. Rowe, B. (2010). Heliox for non-intubated acute asthma patents (Review).
• Rowe, B. Spooner, C. Ducharme, F. Bretzlaff, J. Bota, G. (2008). Early emergency department treatment of acute asthma with systemic corticosteroids (Review). http://www.thecochranelibrary.com.
• Rowe, B. et al. (2009). Magnesium sulfate for treating exacerbations of acute asthma in the emergency department (Review). http://www.thecochranelibrary.com.

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• Published: 16 October 2014

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

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

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

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• Health care

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

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

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

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

Supported self-management reduces asthma morbidity.

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

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

Personalised asthma action plans

Key features of effective self-management approaches are:

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

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

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

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

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

Supported self-management

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

The challenge of implementation

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

The solution will need a whole systems approach

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The case study continues...

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

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

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

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

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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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• Open access
• Published: 03 April 2020

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

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

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

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Introduction

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

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

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

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

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

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

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

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

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

Study setting and study design

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

Study population and sample size determination

Source population.

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

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

Study population

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

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

Eligibility criteria

Inclusion criteria.

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

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

Exclusion criteria

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

Sample size determination

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

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

Sampling technique and procedure

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

Study Variables

Dependent variable.

Acute asthma attack.

Independent variables

Socio-demographic variables.

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

Behavioral factors

Exercise, vigorous activity Smoking cigarette.

Environmental factors

Humidity, Kitchen smoke, dust, Season.

Medical and Clinical characteristics

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

Operational definitions

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

Acute Asthma Attack

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

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

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

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

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

Data collection tool

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

Data collection procedures

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

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

Data quality control techniques

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

Data analysis procedures

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

Ethical consideration

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

Sociodemographic characteristic of study participants

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

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

Behavioral characteristics of study participants

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

Medical & clinical characteristics of study participants

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

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

Environmental characteristics of study participants

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

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

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

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

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

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

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

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

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

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

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

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

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

Limitations

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

Availability of data and materials

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

Abbreviations

Adjusted Odds Ratio

Confidence Interval

Crude Odds Ratio

Central Statistical Agency

Interquartile Range

National Health Interview Survey

Out Patient Department

Tigray Region Health Development Agency

Upper Respiratory Tract Infection

Variance Inflation Factor

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Acknowledgments

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

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

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

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

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Annex I: English version structured interview questionnaire.

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

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DOI : https://doi.org/10.1186/s40733-020-00054-w

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Management of acute life-threatening asthma exacerbations in the intensive care unit.

1. Introduction

2. classifications of asthma severity, 3. management of acute asthma exacerbation, 3.1. oxygen therapy and targets, 3.2. nebulised bronchodilators, 3.3. systemic corticosteroids, 3.4. magnesium sulphate, 3.5. intravenous aminophylline, 3.6. intravenous salbutamol, 4. acute life-threatening asthma advanced management in the icu, 4.1. high-flow nasal oxygen (hfno), 4.2. non-invasive ventilation (niv), 4.3. intubation, 4.4. mechanical ventilation, 4.5. anaesthetic agents, 4.5.1. ketamine, 4.5.2. inhalational anaesthetic agents, 4.6. extracorporeal co 2 removal (ecco 2 r), 4.8. mucolytics, 4.8.1. nebulised heparin, 4.8.2. recombinant human deoxyribonuclease (rhdnase/dornase alfa), 4.9. heliox, limitations of this review, 5. conclusions, author contributions, institutional review board statement, informed consent statement, data availability statement, conflicts of interest.

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Talbot, T.; Roe, T.; Dushianthan, A. Management of Acute Life-Threatening Asthma Exacerbations in the Intensive Care Unit. Appl. Sci. 2024 , 14 , 693. https://doi.org/10.3390/app14020693

Talbot T, Roe T, Dushianthan A. Management of Acute Life-Threatening Asthma Exacerbations in the Intensive Care Unit. Applied Sciences . 2024; 14(2):693. https://doi.org/10.3390/app14020693

Talbot, Thomas, Thomas Roe, and Ahilanandan Dushianthan. 2024. "Management of Acute Life-Threatening Asthma Exacerbations in the Intensive Care Unit" Applied Sciences 14, no. 2: 693. https://doi.org/10.3390/app14020693

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• Published: 21 February 2018

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

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

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

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

Case presentation

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

Conclusions

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

Peer Review reports

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

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

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

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

Case presentations

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

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

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

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

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

Discussion and conclusions

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

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

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

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

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

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

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

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

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

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

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

Indications for omalizumab in children and adolescents with severe asthma

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

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

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

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

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

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

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

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

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

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

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

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

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

Abbreviations

Anti-immunoglobulin E

Body mass index

IgE receptor

Forced expiratory flow between 25% and 75%

Forced expiratory volume in the first second

Gastroesophageal reflux

Inhaled corticosteroids

Intensive care unit

Interleukin

Long-acting β 2 -agonist

Oral leukotriene receptor antagonist

Quality of life

Randomized controlled trials

Short-acting β 2 -agonists

Sleep-disordered breathing

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Acknowledgements

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

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

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

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Patients' experiences of asthma exacerbation and management: a qualitative study of severe asthma

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Exacerbation is a defining feature of severe asthma, and oral corticosteroids (OCSs) are frequently prescribed to manage exacerbations. This qualitative study was conducted to examine the experience of patients with severe asthma, with a focus on asthma exacerbation and OCS treatment.

Adults with severe asthma were recruited from three tertiary hospitals in South Korea. Data were collected through in-depth qualitative interviews. Verbatim transcripts were analysed using Colaizzi's phenomenological method to uncover the meaning of the participants’ experience. Recruitment of participants continued until thematic saturation.

14 patients with severe asthma were recruited. Four theme clusters emerged: 1) experience of asthma exacerbation; 2) impact on life; 3) OCS treatments; and 4) disease perception. The patients experienced severe physical and psychosocial distress from asthma exacerbations, felt helpless due to failed efforts to prevent exacerbation and were living a restricted life due to fear of exacerbation. They feared OCS side-effects but had no other choice than to rely on OCSs because other interventions were ineffective. Most had poor knowledge and understanding of severe asthma and the long-term health consequences.

Asthma exacerbation affects wide aspects of life in patients with severe asthma. Several components may underlie reliance on OCSs, including experience of distress during exacerbation, fear of future exacerbation and lack of proper knowledge about the long-term health consequences of severe asthma and OCS treatments. A multi-disciplinary approach is warranted to support the patients and to provide systematic education about the long-term health implications of severe asthma.

Exacerbation widely affects the lives of people with severe asthma. Distress during exacerbation and fear of future exacerbations may underlie oral steroid reliance. Systematic patient education is warranted about the long-term health implications. https://bit.ly/3lhsBiN

• Introduction

Severe asthma is a major health concern [ 1 ]. It is estimated to affect ∼5–10% of the asthmatic population, and >50% of asthma-related health costs are attributed to severe asthma [ 2 – 4 ]. Patients with severe asthma are prone to repeated exacerbation and progressive deterioration in lung function and may also experience side-effects from medications, such as oral corticosteroids (OCSs) [ 5 , 6 ]. These acute and long-term health outcomes are considered to be the major burdens [ 7 ]. This is reflected in the European Respiratory Society (ERS)/American Thoracic Society (ATS) guidelines [ 5 ], which define severe asthma not only as asthma that remains uncontrolled despite aggressive drug therapy, but also as asthma requiring aggressive therapy to prevent it from becoming uncontrolled.

Exacerbation is a defining feature of severe asthma [ 5 ]. Exacerbation is associated with the future risk of exacerbation, leading to progressive decline in lung function and health status of patients with severe asthma [ 7 ]. In the literature, several qualitative studies have described the experience of patients with severe asthma [ 8 – 15 ]; however, very few studies, and none in the Asian population, have focussed on patients’ experience of asthma exacerbation and the experiences that may lead to reliance on OCSs. Therefore, this qualitative study was conducted to examine the experience of Korean patients with severe asthma, with a focus on asthma exacerbation and OCS treatment.

• Materials and methods

Study design

This was an inductive qualitative research, aiming to understand the experience of patients with severe asthma, with a focus on asthma exacerbation and OCS treatment. Participants were recruited between September 2018 and June 2019 from specialist clinics at three tertiary hospitals in South Korea. The patients were invited to participate if they met the following inclusion criteria: 1) adults (≥18 years old); 2) currently having severe asthma defined according to the international ERS/ATS consensus guidelines [ 5 ]; and 3) willing to share his/her own experience. The exclusion criterion was presence of other serious psychiatric or physical illnesses, which may affect the quality of life considerably, such as malignancy, heart failure, stroke or other severe respiratory diseases. The study protocol was approved by the Institutional Review Board of each participating institution. The participants’ rights were explained during the recruitment process, which is about anonymity, privacy, confidentiality, self-determination regarding their free will to participate in the study, ability to withdraw from the study and recording of the interview. All participants provided informed consent prior to the qualitative interview.

Data collection

In-depth focussed interviews were conducted by an experienced principal investigator (W.J. Joung) using open-ended questions regarding the experience of asthma exacerbation and management of patients with severe asthma. The main probing questions are summarised in table 1 . The interviews were conducted in person or via the telephone. Each interview lasted for ∼60–90 min on average. All interviews were tape-recorded and transcribed verbatim as soon as possible. Additional telephone interviews were conducted if any clarifications were required. All interviews were originally conducted and transcribed in Korean, and the findings were translated to English by the primary investigators, and later reviewed and edited by a native English speaker.

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Main probing questions for study participants

Data analysis

The method of phenomenological approach and data analysis by C olaizzi [ 16 ] was followed to gain a deeper understanding of the phenomena and to describe the phenomena as they present themselves. The main author read all the participants’ descriptions several times to gain a general impression of their experiences and decipher them. Secondly, significant phrases and sentences pertaining to the experience of severe asthma were extracted, repetitions were eliminated and participants’ statements were transformed into general formulations. In the third step, the author attempted to identify the hidden meaning in each significant statement and formulated the meaning of these statements. In the fourth step, the formulated meaning was sorted into theme clusters. In the fifth step, the author integrated all of the results into a narrative description. The fundamental structure of the experience was then identified. Finally, the author performed the validation process by showing the study results to some participants to verify whether the findings accurately reflected the essence of their experience. The final number of patients was determined by content saturation.

Four criteria, i.e. , credibility, fittingness, auditability and confirmability, were applied to enhance the rigour of the findings [ 17 ]. The steps of purposeful sampling, in-depth individual interviews with open-ended questions and validation of these results were taken to ensure the credibility of the results. In addition, the primary investigators regularly discussed the emerging themes in the iterative processes of data collection and analyses. To achieve fittingness, the author attempted to identify cases rich in information to the point of saturation and to describe each participant's experience in detail. Auditability was achieved by closely following the analysis steps of C olaizzi [ 16 ] and carefully documenting the research procedures. Finally, confirmability was achieved by minimising personal prejudices or biases. In addition, participants’ comments were cited to help the readers confirm that the findings were derived from the patients’ data.

21 patients meeting the selection criteria were considered as potential candidates, and 14 patients were finally recruited. The recruitment stopped when content saturation was reached. Eight (57.1%) patients were women, and the median (range) age was 54 years (36–70 years). Asthma duration was 17 years (5–35 years). All participants had active disease, with a median of three exacerbations and two emergency room (ER) visits/hospitalisations for asthma in the last year. All had a documented variability in airflow obstruction, and eight had fixed airflow obstruction. Chronic rhinosinusitis was comorbid in eight patients. Although we did not intend to select patients with type 2 inflammation, all had at least one sign of type 2 inflammation and were taking OCSs (nine out of 14 were taking OCS as a maintenance therapy). Total OCS dose in the last 12 months was a median (range) of 900 mg (420–2775 mg, prednisolone equivalent). None of them was being treated with biologics at enrolment in this study. Their clinical characteristics are summarised in table 2 . Four theme clusters emerged from the analyses using the method by C olaizzi [ 16 ] ( figure 1 ).

Characteristics of study participants

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Conceptual diagram of the overarching theme clusters regarding asthma exacerbation and experience in patients with severe asthma. OCS: oral corticosteroid.

Theme cluster 1: experience of asthma exacerbations

This theme cluster is about the experiences and feelings of patients at the moment of asthma exacerbation.

Theme 1.1: distress, panic and fear of death during acute exacerbation

The participants described severe distress during exacerbations. They commonly referred to two symptoms, breathlessness and cough, as major factors causing distress during asthma exacerbation. Some patients described “fear of death” from sudden onset of shortness of breath ( table 3 ). Acute exacerbation was expressed as a “very lonely moment in life” that the patients should cope with by themselves, as they could not even call for help.

Cough was another major symptom during asthma worsening, which causes severe distress. Coughing also led to physical complications, including chest pain, rib fracture and voice change. Some patients reported experiencing serious anxiety and a sense of crisis with coughing attacks that were severe enough to “drain out energy” or “explode their body” ( table 3 ).

Poorly controlled symptoms got worse and harder to endure at night and took away patients’ night-time peace and resting. They frequently encountered difficulty in falling asleep and experienced intermittent wakening; they were unable to sleep all night because of persistent cough or breathlessness.

Theme 1.2: feeling helpless with failed efforts to prevent exacerbation

The participants commonly expressed that they “felt helpless”, as they recurrently failed to prevent exacerbation, despite substantial efforts, including pharmacotherapy and avoidance of triggers ( table 3 ). All described the “common cold” as the most dreaded event because it suddenly disrupted daily life and eventually led to asthma attacks, making their efforts in vain. Some patients experienced asthma attacks that were easily triggered by fatigue, lack of sleep, emotional stress or changes in seasons or climate. They were living in tension to avoid these triggers, but could not fully avoid them, as exposure to such triggers is inevitable.

Theme cluster 2: impact of severe asthma on life

This theme cluster concerns the impact of severe asthma on daily life and psychological well-being.

Theme 2.1: living a restricted life for fear of asthma re-worsening

Patients were living a restricted life with the fear of their asthma re-worsening. They put limits on their activities or jobs and gave up what they used to do. Some young patients found themselves being unable to “make a sprint” in life and felt they were lagging behind others. Some participants (six out of 14) quitted, changed or were considering changing their jobs due to asthma ( table 4 ). They frequently experienced difficulties even in using public transportation, as they feared going to a crowded place and becoming infected with viruses from others. They also experienced anxiety with respect to their asthma worsening owing to the possibility of exposure to dust, smoke or chemicals in public places.

Theme 2.2: psychosocial difficulties

Most felt discouraged, frustrated and depressed that their asthma had not improved but had repeatedly worsened despite their great efforts. Some described their efforts like “turning the wheel of a vicious cycle”. Some experienced severe depression from physical distress and fear of death during asthma exacerbation, fear of worsening, and restrictions in daily life and activities.

Psychosocial aspects of life were also influenced. They felt embarrassed or ashamed when symptoms got out of uncontrol, such as severe cough, in front of others. They felt their relationships with others were adversely affected, fearing that their uncontrollable coughing might bother people, or that some might want to avoid them or be reluctant to come near them ( table 4 ).

Compromise to relationships also occurred within their families. Most had mixed feelings about their family members but could not share emotional distress with them. On the one hand, they felt sorry that they could not take their full responsibility as a spouse, parent or family member, and blamed themselves. On the other hand, they felt sad that their family members did not fully understand the difficulties and distress that they were experiencing ( table 4 ).

Theme cluster 3: OCS treatment

This theme cluster is about the patient experience with OCS treatment. The first theme is about the reliance on OCSs, and the other is about experience of the adverse effects. There was no clear difference between patients receiving OCS maintenance treatments and those taking intermittent courses.

Theme 3.1: reliance on OCSs with mixed feelings

All had been taking OCSs for years, either regularly or intermittently. They knew that it was just a “quick-fix” or “stop-gap”, but not a cure. They harboured vaguely negative views on OCSs, especially the fear of adverse reactions. Some patients stated that taking OCSs is like “biting the bullet”. They had no other choice but to take OCSs because they believed there was no other alternative for controlling the acute worsening and preventing ER visits. The participants wanted to stop taking OCSs, but they did not hesitate to take them or increase the dosage of OCSs when they felt that the symptoms were worsening; their fear and anxiety regarding the worsening of their asthma and subsequent risk of hospitalisation were so great that there was no hesitation in their decision to take OCSs ( table 5 ).

Theme cluster 3: oral corticosteroid (OCS) treatment

Theme 3.2: OCS side-effects

All participants experienced at least one adverse effect from OCS therapy, such as weight gain, mood swings, morphological changes, osteoporosis, diabetes mellitus, hypertension or Cushing's syndrome. Some who developed progressive weight gain or morphological changes had subsequent depression and felt that their personal relationships were compromised ( table 5 ). However, surprisingly, most were poorly informed about the long-term side-effects of OCSs. The information about side-effects was given only after they developed specific adverse symptoms or signs.

Theme cluster 4: perception of severe asthma

This theme cluster addresses gaps in the perception of severe asthma among different patients, and between patients and physicians.

Theme 4.1: gaps in disease perception among patients

All participants met the diagnostic criteria of severe asthma, but few of them clearly recognised that they had severe asthma. Some of the patients had no insight about asthma, but a vague idea of severe or uncontrolled cold or bronchitis. They were not recognisant of the acute or long-term health impact of severe asthma. Those who lacked disease insight tended to perceive the disease mostly in terms of the symptoms. On the contrary, asthma was perceived as a fatal or seriously disabling condition by the patients whose asthma was not controlled despite treatment efforts, including OCSs ( table 6 ).

Theme 4.2: gaps between patients and health professionals

Most participants were unfamiliar with the term “severe asthma” or the concept of asthma severity ( table 6 ). While healthcare professionals clearly recognised the participants as having severe asthma, most patients did not have a clear knowledge or understanding about their diagnosis or the long-term health consequences. Indeed, they stated that they had no or little opportunity to get information about severe asthma. Many vaguely thought that they had poor respiratory functions or were experiencing a severe cold or bronchitis frequently.

In this study, we aimed to understand the patients’ experience of asthma exacerbation and its management in a group of patients with severe disease. Four theme clusters were identified: the experience of exacerbations, impact on life, OCS treatment and disease perception. The patients experienced severe physical and emotional distress from asthma exacerbation, felt helpless because of their failed efforts to prevent exacerbation and were living a restricted life due to the fear of re-worsening of asthma and hospitalisation, which altogether appear to underlie their reliance on OCSs. Most participants wanted to avoid OCSs but relied on them, as they found no other alternatives to effectively control their symptoms and prevent ER visits. Surprisingly, most had poor knowledge and understanding of severe asthma or the concept of asthma severity. They had very little awareness of the potential long-term health consequences of severe asthma, including OCS side-effects, suggesting the urgent need for systematic patient education. Collectively, this study provides an insight into which patient experience influences OCS reliance, and which patient and disease components should be targeted to improve long-term health outcomes in patients with severe asthma.

Use of OCSs is one of the most challenging issues in the management of severe asthma. Long-term OCS use is common among severely asthmatic patients across all countries (20%–70%) but is relatively more frequent among Asian patients [ 18 – 20 ]. OCSs are one of the few available options among conventional medicines to reduce asthma exacerbation and hospitalisations, apart from recently introduced biologics [ 1 ]. However, they are also associated with systemic side-effects or even with the risk of mortality, particularly when used repeatedly or over the long term [ 6 , 7 , 21 ], as illustrated by some of our participants referring to their use as “biting the bullet” or “taking poison”. In the literature, several qualitative studies addressed the experiences and concerns regarding the use of OCSs among severely asthmatic patients in Western countries [ 8 , 10 – 12 ], and two studies [ 8 , 10 ] particularly focussed on the experience of OCS burden, describing “oral steroid phobia”, major side-effects and cost–benefit considerations when taking OCSs. Our findings are generally in line with those of previous reports [ 8 , 10 – 12 ], in terms of the experience of side-effects and also the patients’ bivalent perception of the necessity of OCSs. However, our study is a meaningful addition to the literature and also extension to Korean patients, in that it reveals several factors underlying the patient's reliance on OCSs, such as agonising experience of exacerbations, fear of future re-worsening and also importantly the lack of proper prior knowledge about the side-effects of OCSs. Another issue is that OCSs may mask asthma activity and blunt the patient's perception of disease activity, strengthening the patient's decision to rely on OCSs, potentially leading to poorer long-term health outcomes [ 7 ]. Biologics targeting type 2 pathways in severe asthma may be effective therapeutic options while reducing the OCS burden [ 1 ], but they are not widely used due to the high cost. Thus, it is critical to develop and provide detailed educational programmes regarding potential harms of OCSs and self-management strategies.

All participants were living a restricted life due to the fear of asthma re-worsening. They also suffered from emotional problems, including frustration, depression and anxiety. Six participants had to quit or change or considered changing their jobs due to asthma. These findings are in line with previous observations that severe asthma is not just “bad” asthma but a serious threat to a whole life encompassing physical, emotional and personal relationships [ 11 , 13 , 22 ]. The career or job issue was similarly pointed out with the theme of “the body as a hindrance” in a study of Australian patients by F oster et al . [ 11 ]. Thus, multidisciplinary approaches are warranted to help these patients, including emotional, psychological and social support. There is a general consensus among specialist physicians that multidisciplinary care should be provided in clinics for severe asthma [ 3 , 23 – 26 ], but it is still unclear how this goal is being achieved, particularly how to provide a programme for physical and psychosocial support to the patients. Patient groups for severe asthma, where patients could meet and share experiences, may be helpful in supporting their psychosocial well-being.

Notably, our study participants had poor perception of and understanding about severe asthma. For most participants, the term or concept of “severe asthma” was not familiar. Rather, they tended to perceive their disease severity mostly by means of their symptoms, and not by long-term health effects. This finding may be partly due to the fact that some patients may be in denial of having their diagnosis of “severe” disease. However, a major reason is supposed to be the lack of proper education and information about the health implications of severe asthma, particularly the long-term health effects of the disease and OCSs.

Cough was a major symptom of acute exacerbation that greatly distressed the participants with severe asthma, physically and psychologically. It was a major factor related to psychosocial distress in daily life, as it made the patients feel embarrassed or caused others to distance themselves from the patients out of the fear of infectious disease. The findings suggest that cough is a frequently overlapping clinical trait in severe asthma but is not properly controlled by conventional asthma treatments. Indeed, the impact of cough is not well addressed in conventional assessment tools, such as the Asthma Control Test (ACT) or Asthma Control Questionnaire (ACQ) [ 27 , 28 ]. The ACT only refers to cough within a question asking about a group of “asthma symptoms” (wheezing, coughing, shortness of breath, chest tightness or pain) [ 28 ]. In the ACQ, cough was the 6th ranked item but was excluded due to the need to reduce the number of items [ 27 ]. The Asthma Quality of Life Questionnaire includes one item for cough [ 29 ], but it is unknown if it properly addresses cough-related morbidity. Thus, tools should be refined to capture the impact of cough in severe asthma. In therapeutics, biologics targeting type 2 inflammation may help to reduce cough in patients with severe eosinophilic asthma [ 30 ]. It is unknown whether novel treatment modalities targeting cough reflex pathways might be effective in severely asthmatic patients with cough who remain uncontrolled despite optimal anti-inflammatory therapy.

This study has several limitations. First, the results may not be generalised beyond the study population, although it is not the intention of a qualitative approach. Our findings primarily add to understanding of Korean patients’ perspectives on severe asthma and frequent exacerbations, and raise awareness in healthcare professionals about the patient's point of view. However, our findings are also applicable to patients with severe asthma worldwide, as most of the themes identified, such as experience of exacerbation, impact on life or OCS issues, are commonly observed in previous studies from other countries [ 8 , 10 , 11 , 15 ]. Meanwhile, the degree of a patient's understanding of severe asthma and its future risks (theme 4) may differ by population or healthcare system, but to our knowledge, such regional difference has not been well addressed in the literature. As proper understanding of the severity concept will help to reduce OCS overuse and associated complications, further studies are warranted to identify determinants for the level of understanding and effective education strategies to improve the levels. Second, our study participants were frequent exacerbators with high exposure to OCSs, which is likely a more severe subgroup even within severely asthmatic patients. However, it is due to our purposive sampling of patients who would provide unique and rich information on the experience of exacerbations as per our main questions ( table 1 ). Third, the sample size may appear small but is consistent with qualitative studies where the data is collected until content saturation is achieved. Finally, as the interviews were conducted in Korean, translation process might have influenced the findings, particularly colloquial expressions or proverbs. However, we believe the main themes and conclusions are unaffected by the translation process.

Using the qualitative methodology, this study described the experience of asthma exacerbation and management in patients with severe asthma in their own words and provided an insight into how the disease affects their life. Several major components were suggested to underlie reliance on OCSs, including severe distress during acute exacerbation, fear of future worsening, and lack of knowledge about long-term health consequences of severe asthma and OCS treatment. These findings indicate several components that should be targeted to improve long-term health outcomes in patients with severe asthma. Further, a systematic education programme is needed to provide information about severe asthma and its long-term clinical implications for patients.

Author contributions: W-J. Song and W.J. Joung designed the study, collected and interpreted the data, wrote the first draft of the manuscript, and critically reviewed the manuscript. W.J. Joung performed the analysis, and H-K. Won, S.Y. Lee, H-K. Park and Y.S. Cho collected and interpreted the data. K.F. Chung and L.G. Heaney interpreted the data and critically reviewed the manuscript. All authors approved the final version of the manuscript.

Conflict of interest: W-J. Song reports grants from AstraZeneca during the conduct of the study.

Conflict of interest: H-K. Won has nothing to disclose.

Conflict of interest: S.Y. Lee has nothing to disclose.

Conflict of interest: H-K. Park has nothing to disclose.

Conflict of interest: Y.S. Cho has nothing to disclose.

Conflict of interest: K.F. Chung has nothing to disclose.

Conflict of interest: L.G. Heaney has nothing to disclose.

Conflict of interest: W.J. Joung has nothing to disclose.

Support statement: This study was supported by a research grant from the Investigator-Initiated Studies Programme of AstraZeneca. The opinions expressed in this paper are those of the authors and do not necessarily represent those of AstraZeneca. Funding information for this article has been deposited with the Crossref Funder Registry .

• Received July 15, 2020.
• Accepted November 5, 2020.
• Copyright ©ERS 2021

This version is distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0. For commercial reproduction rights and permissions contact permissions{at}ersnet.org

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Related Articles

Case Study: Managing Severe Asthma in an Adult

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

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

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

Case presentation and patient history

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Published: April 16, 2018

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

More On This Topic

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

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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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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.

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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.

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• emDOCs Podcast – Episode 106: Asthma Exacerbation Part 2
• Aug 20th, 2024
• categories: Podcast

Episode 106: Asthma Exacerbation Part 2

Please see Part 1 for the ED evaluation .

Management:

• Based on severity: mild, moderate, severe.

• Provide for those with hypoxia; target saturation 93-95%. Hyperoxia associated with worse outcomes.
• First line therapies; treat bronchial hyperreactivity and reduce or even reverse airflow obstruction.
• Include short acting beta-2 agonists (SABA) and ipratropium bromide. Delivery can be a metered dose inhaler or gas driven nebulizer; current evidence does not demonstrate a difference in patient centered outcomes between the two routes. MDI recommended if possible. In severe exacerbation, continuous nebulized therapy is recommended.
• Albuterol is the most common SABA utilized in the ED; for severe asthma exacerbation, provide continuous nebulized albuterol at a dose of 10-20 mg for 1 hour (NNT of 10 to reduce hospitalization).
• Long-acting beta-2 agonists (LABA) include salmeterol and formoterol provide close to 12 hours of bronchodilation. LABAs are typically combined with an inhaled corticosteroid for therapy, and these can be considered for patients as a discharge prescription for maintenance therapy.
• Inhaled epinephrine may assist patients who have not improved with other SABA agents due to its alpha activity reducing airway edema, but current evidence has not demonstrated improved efficacy in comparison against SABA therapy.
• Ipratropium bromide inhibits muscarinic acetylcholine receptors in the pulmonary smooth muscle and results in bronchodilation. The time of onset approximates 15 minutes, and the peak effect is 60-90 minutes with a half-life of 6-8 hours. Ipratropium is administered in doses of 0.5-2 mg for the first hour.
• Use of ipratropium has been associated with reduced exacerbations, hospital admission, and length of stay in asthma; NNT 11 to reduce hospitalization in acute asthma.
• Upregulate beta receptors and reduce airway inflammation.
• Current guidelines recommend corticosteroids in those with moderate or severe exacerbation and those who do not initially respond to SABA therapy. Associated with over a 50% reduction in treatment failure and a NNT 9 to prevent one treatment failure. Reduce relapse rates and hospital length of stay with a NNT 8.
• Administer within first hour.
• Controversy regarding the optimal steroid, dose, administration route, and treatment duration. PO and parenteral steroids demonstrate similar bioavailability and patient outcomes, but PO steroids are less invasive and less expensive.  For critically ill patients who cannot tolerate PO administration, parenteral treatment is recommended.
• Inhaled corticosteroids administered with inhaled albuterol can improve smooth muscle relaxation and airway function.
• No benefit with systemic doses over prednisone 2 mg/kg per day or equivalent including treatment failure, need for airway intervention, or length of stay, but higher doses are associated with increased risk of adverse events including myopathy, hyperglycemia, infection, gastrointestinal bleeding, and neurologic effects.
• IV administration may result in pulmonary smooth relaxation. It may improve pulmonary function and reduce need for hospital admissions.
• GINA guidelines recommend its use in patients with severe exacerbations.
• Dosing is 2g IV administered over 20 minutes; may be repeated twice.
• Possible adverse events include weakness, hypotension, flushing, and changes in heart rate.
• Inhaled administration is controversial, with literature to date suggesting no benefit.
• Include epinephrine and terbutaline; potent bronchodilators and may decrease airway edema, mucous production, and inflammation. No high-quality prospective data supporting their use in severe exacerbation.
• Epinephrine is not recommended for routine use as a first-line therapy but should be considered in doses of 0.3-0.5 mg intramuscular in the anterolateral thigh every 20 minutes for 3 doses in those with severe asthma exacerbation who fail other therapies, or those with anaphylaxis or angioedema. For severe hypotension or refractory to IM administration, epinephrine IV 5-20 micrograms every 2-5 minutes should be considered.
• Terbutaline is a β2 agonist. It may be administered via inhalation or the subcutaneous or IV route. However, literature does not demonstrate improved patient outcomes when terbutaline is compared to standard SABAs.
• Dissociative analgesic that may be used in patients who are refractory to other therapies. Rapid onset of action within 60 seconds and a distribution of 7 to 11 minutes.  Ketamine is an N-methyl-D-aspartic acid (NMDA) receptor antagonist in the lung parenchyma, which can reduce pulmonary edema and bronchoconstriction; may reduce reduce production of nitric oxide, which reduces bronchospasm.
• Ultimately, ketamine can reduce airway hyperinflammation and hyperreactivity while decreased bronchospasm, with studies finding improved pulmonary function, reduced oxygen requirement, and decreased requirement for invasive ventilation.
• Administer only with appropriate monitoring.
• Two dosing strategies: sub-dissociative dose ketamine (0.05-0.4 mg/kg/hr) is used to reduce bronchospasm and improve pulmonary function while not sedating the patient, and dissociative dosed ketamine (0.5-2.0 mg/kg) can be used for delayed sequence intubation (DSI) or induction for rapid sequence intubation.
• Ketamine can also increase bronchial secretions and relieve mucous plugs.
• Mixture of helium and oxygen that can reduce airflow turbulence through narrow airways. It may also improve ventilation/perfusion matching and improve elimination of carbon dioxide.
• Controversial studies suggest that heliox-driven bronchodilation increases forced expiratory volume, forced vital capacity, and expiratory flow rate, with reduced ED admissions.
• If utilized, should be considered as an adjunct early in the patient course prior to increased oxygen requirements.
• Do not use routinely.
• Studies have evaluated azithromycin and other antibiotics; no benefit compared to placebo.
• Reserve for patients with evidence of bacterial infection (systemic symptoms of pneumonia such as fever, consolidation on x-ray).
• NIPPV may be effective in those with severe asthma exacerbation and respiratory distress by reducing the work of breathing and improving alveolar recruitment.
• Limited prospective data demonstrating benefit; a large retrospective study of patients admitted to the critical care setting found NIPPV reduced intubation and mortality.
• Consider NIPPV in those with severe respiratory distress who do not respond to other therapies, as NIPPV can improve ventilation, and there is little harm.
• Close monitoring of the patient is necessary to ensure improvement.
• Absolute contraindications include cardiac or respiratory arrest, while relative contraindications include the patient who is uncooperative, has copious secretions, has a deformity of the face or upper airway, and recent esophageal trauma or surgery. Altered mental status, pH < 7.25, and hypercarbia are not contraindications if the clinician can closely monitor the patient. NIV can improve mental status in patients with hypercarbia, as NIPPV improves ventilation.
• BPAP provides an inspiratory pressure and expiratory pressure, which likely is more beneficial compared to CPAP in obstructive lung disease (problem with ventilation rather than oxygenation except in those with respiratory failure).
• Initial settings should include an inspiratory pressure support of 5-10 mm Hg and PEEP of 3-5 mm Hg. If titrating, the inspiratory pressure should be increased while maintaining PEEP.
• HFNC may assist in those unable to tolerate a face mask or with contraindications to NIPPV.
• Endotracheal intubation and mechanical ventilation are reserved for those with progressing respiratory distress who fail typical therapies and NIV, those with respiratory or cardiac arrest, and those with altered mental status/coma.  
• Airway manipulation may worsen bronchospasm and result in laryngospasm. Mortality rates reach 20% in patients intubated with obstructive lung disease.
• Consider as a difficult airway, with the most experienced operator performing the procedure.
• Maximal preoxygenation and rapid sequence intubation are recommended.
• Ketamine is an optimal induction agent (1-2 mg/kg IV), as it relaxes bronchial smooth muscle and has analgesic and sedative properties. Propofol possesses some bronchodilating effects but can result in hypotension.
• Paralysis recommended to include first pass success (rocuronium 1.2 mg/kg IV).
• Optimize prior to intubation; administer fluid bolus and have vasopressors ready.
• Settings must prevent hyperinflation and auto-PEEP, which may result in hemodynamic collapse and barotrauma.
• Ventilator settings should utilized a reduced respiratory rate and tidal volume, shortened inspiratory and lengthened exhalation times, resulting in permissive hypercapnia.
• VC, RR 6-10 breaths per minute, TV 6-8cc/kg ideal body weight, inspiratory flow rate 80-120 L/min, inspiration-to-expiration ratio of > 1:4
• Administer scheduled inline, inhaled bronchodilator therapy.
• Deep sedation is recommended to improve patient lung mechanics. If decompensates, use DOPES/DOTTS.

• Final option in treatment-refractory patients.
• Consider in patients on mechanical ventilation with inadequate oxygenation or acidosis.
• Requires significant resources and support staff present in select centers.

Disposition

• Patients who improve, have no evidence of respiratory distress, and have follow-up can be discharged with oral steroids for a 5-day course, along with a SABA MDI with spacer (4 puffs every 3-4 hours).
• Inhaled steroids should be strongly considered for patients with asthma as a daily therapy, which is associated with greater symptom control and reduced asthma exacerbations, ED visits, and need for hospitalization. Current guidelines recommend use of inhaled steroids in asthma.
• Patients with continued symptoms or cardiorespiratory distress should be admitted.
• Asthma care plans are key parts of outpatient therapy. They improved patient outcomes and medication adherence while reducing exacerbation recurrence.
• Ensure follow-up within one week if discharging.

Part 2 Summary:

• ED management includes supplemental oxygen if oxygen saturation < 90%. Inhaled SABAs and SAMAs should be administered with MDI or nebulization. In moderate to severe exacerbation, continuous nebulization with SABAs and SAMAs for 1 hour is recommended.
• Systemic steroids should be administered within 1 hour of presentation via the oral route if able or intravenous route in patients with moderate or severe exacerbation. Inhaled steroids are a key component of outpatient management.
• Magnesium IV should be considered in those with severe exacerbation. Parenteral β2 agonists including epinephrine or terbutaline can also be considered in patients who fail to respond to standard therapies.
• Ketamine may be useful in select cases.
• Antibiotics such as azithromycin and inhaled magnesium are not associated with improved patient outcomes during an acute asthma exacerbation.
• Noninvasive positive pressure ventilation can be used in those with significant respiratory distress; endotracheal intubation and mechanical ventilation are necessary for those with respiratory failure.
• Ventilator settings must prevent hyperinflation and auto-PEEP, which may result in hemodynamic collapse and barotrauma.
• Disposition is based on treatment response, clinical course, and ability to follow-up.

References:

• Global Initiative for Asthma (GINA). 2022 GINA Report, Global Strategy for Asthma Management and Prevention. 2022. Available at: https://ginasthma.org/gina-reports/. Accessed June 12, 2023.
• Long B, Lentz S, Koyfman A, Gottlieb M. Evaluation and management of the critically ill adult asthmatic in the emergency department setting. Am J Emerg Med. 2021 Jun;44:441-451.
• Rowe BH. Continuous versus intermittent beta-agonists for acute asthma. Cochrane Database Syst Rev. 2011;(4):CD001115.
• Stoodley RG, Aaron SD, Dales RE. The role of ipratropium bromide in the emergency management of acute asthma exacerbation: a metaanalysis of randomized clinical trials. Ann Emerg Med. 1999 Jul;34(1):8-18.
• Rodrigo G, Rodrigo C, Burschtin O. A meta-analysis of the effects of ipratropium bromide in adults with acute asthma. Am J Med. 1999 Oct;107(4):363-70.
• 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 Jan 11;1(1):CD001284.
• Rowe BH, Spooner C, Ducharme FM, et al. Early emergency department treatment of acute asthma with systemic corticosteroids. Cochrane Database Syst Rev. 2001;(1):CD002178.
• 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 May 4;5(5):CD013518.
• Kew KM, Kirtchuk L, Michell CI. Intravenous magnesium sulfate for treating adults with acute asthma in the emergency department. Cochrane Database Syst Rev. 2014 May 28;(5):CD010909.
• Goodacre S, Cohen J, Bradburn M, et al; 3Mg Research Team. Intravenous or nebulised magnesium sulphate versus standard therapy for severe acute asthma (3Mg trial). Lancet Respir Med. 2013;1(4):293-300.
• Knightly R, Milan SJ, Hughes R, et al. Inhaled magnesium sulfate in the treatment of acute asthma. Cochrane Database Syst Rev. 2017;11:Cd003898.
• Travers AH, Milan SJ, Jones AP, et al. Addition of intravenous beta(2)-agonists to inhaled beta(2)-agonists for acute asthma. Cochrane Database Syst Rev. 2012 Dec 12;12:CD010179.
• Johnston SL, Szigeti M, Cross M, et al; AZALEA Trial Team. Azithromycin for acute exacerbations of asthma: the AZALEA randomized clinical trial. JAMA Intern Med. 2016;176(11):1630-1637.
• Althoff MD, Holguin F, Yang F, et al. Noninvasive Ventilation Use in Critically Ill Patients with Acute Asthma Exacerbations. Am J Respir Crit Care 2020 Dec 1;202(11):1520-1530.

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Titration of anti-IL-5 biologics in severe asthma: an open-label randomised controlled trial (the OPTIMAL study)

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• ORCID record for Marianne Baastrup Soendergaard
• For correspondence: [email protected]
• ORCID record for Ole Hilberg
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Overview of the OPTIMAL study. IL: interleukin.

Background Anti-interleukin (IL)-5 biologics effectively reduce exacerbations and the need for maintenance oral corticosteroids (mOCS) in severe eosinophilic asthma. However, it is unknown how long anti-IL-5 treatment should be continued. Data from clinical trials indicate a gradual but variable loss of control after treatment cessation. In this pilot study of titration, we evaluated a dose-titration algorithm in patients who had achieved clinical control on an anti-IL-5 biologic.

Methods In this open-label randomised controlled trial conducted over 52 weeks, patients with clinical control (no exacerbations or mOCS) on anti-IL-5 treatment were randomised to continue with unchanged intervals or have dosing intervals adjusted according to a titration algorithm that gradually extended dosing intervals and reduced them again at signs of loss of disease control. The OPTIMAL algorithm was designed to down-titrate dosing until signs of loss of control, to enable assessment of the longest dosing interval possible.

Results Among 73 patients enrolled, 37 patients were randomised to the OPTIMAL titration arm; 78% of patients tolerated down-titration of treatment. Compared to the control arm, the OPTIMAL arm tended to have more exacerbations during the study (32% versus 17%; p=0.13). There were no severe adverse events related to titration, and lung function and symptoms scores remained stable and comparable in both study arms throughout.

Conclusion This study serves as a proof of concept for titration of anti-IL-5 biologics in patients with severe asthma with clinical control on treatment, and the OPTIMAL algorithm provides a potential framework for individualising dosing intervals in the future.

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Titration of anti-IL-5 biologics is possible in most patients with severe asthma who have achieved clinical control on biological treatment. Further studies are needed to optimise titration strategies and determine the long-term prognosis of titration. https://bit.ly/4awOzar

• Introduction

The treatment of severe eosinophilic asthma has been revolutionised with the introduction of anti-interleukin (IL)-5 biological treatment. Anti-IL-5 biologics include mepolizumab, benralizumab and reslizumab, all of which target the IL-5 pathway; regulatory randomised controlled trials (RCTs) have shown that they are efficient in reducing exacerbation rates and the need for maintenance oral corticosteroids (mOCS) [ 1 – 6 ]. Real-life results from the use of anti-IL-5 biologics suggest that they have exceeded the expectations set by RCTs. Data from the nationwide Danish Severe Asthma Register (DSAR) showed that 58% of patients achieved a complete response with complete abrogation of the outcomes that set the indication for treatment: exacerbations and need for mOCS [ 7 ].

Anti-IL-5 biologics are considered safe and efficient long term [ 8 – 15 ]; however, they are costly, and it is unknown how long patients should continue treatment. Most patients return to the baseline level of blood eosinophils and exacerbations 3–6 months after stopping mepolizumab [ 16 – 18 ]. Results from the COMET study, in which patients were randomised to either continue mepolizumab or switch to placebo, demonstrated an increased risk of exacerbation in the placebo group 16 weeks after the final dose of mepolizumab [ 18 ]. It seems that sudden cessation of treatment may lead to loss of disease control after a few months, suggesting that gradual down-titration may be a more appropriate approach to evaluate whether patients can reduce or stop treatment. In rheumatology, where biological treatments have been available far longer than in respiratory medicine, down-titration of biological treatment after stabilisation of disease is the standard treatment strategy [ 19 ] and most patients with rheumatoid arthritis tolerate down-titration of their biological treatment [ 20 ]. A small observational study of patients with severe asthma well controlled on mepolizumab showed that dose extension up to 8 weeks was well tolerated, with no exacerbations or loss of lung function [ 21 ]. However, further down-titration or up-titration in case of loss of disease control was not examined. We hypothesised that by using a dose-titration algorithm, dosing could be individualised to the lowest required level by tapering biological treatment until signs of loss of disease control and subsequently escalating treatment again.

To conduct this pilot study on the titration of anti-IL-5 biologics in patients with clinical control on treatment, we proposed the OPTIMAL titration algorithm, that adjusts the dosing intervals of anti-IL-5 biologics, based on blood eosinophils, lung function and exacerbations. To evaluate this method of titration of anti-IL-5 biologics, we conducted an open-label RCT using a non-inferiority approach to compare the OPTIMAL titration algorithm against unaltered regular dosing intervals in a population of severe asthma patients with clinical control on an anti-IL-5 biologic.

Study design

OPTIMAL is a randomised, controlled, multicentre clinical trial. The study was conducted at five centres in Denmark: Bispebjerg University Hospital in Copenhagen, Gentofte University Hospital in Copenhagen, Odense University Hospital in Odense, Sygehus Lillebaelt in Vejle and Aarhus University Hospital in Aarhus. After providing written informed consent, patients were randomised 1:1 via RedCAP to the active arm and control arm stratified by the type of anti-IL-5. The active arm had their dosing of anti-IL-5 adjusted using the OPTIMAL algorithm and the control arm continued with normal dosing throughout the study. The study was open label, and the allocated groups were open to both the patients and investigators. Upon entering the study, all patients not already on high-dose inhaled corticosteroids (ICS) ( i.e. had ICS reduced while on a biologic) had ICS treatment adjusted so that they were on high-dose ICS according to the European Respiratory Society/American Thoracic Society guidelines [ 22 ].

The OPTIMAL study was approved by the National Ethics Committee (H-20052529) and the Danish Medicines Agency (2020-003358-63) and monitored by the Danish Good Clinical Practice Unit. The OPTIMAL study was registered at ClinicalTrials.gov ( NCT04648761 ).

Study population

Eligible patients were adults aged >18 years who had received anti-IL-5 biological treatment (mepolizumab, benralizumab or reslizumab) for at least 12 months. Patients eligible for this study had to be free from exacerbations and need for mOCS 12 months before inclusion, and blood eosinophils had to be ≤0.3×10 9 cells·L −1 . There were no requirements on lung function or symptoms scores as these are not significantly improved by anti-IL-5 biologics when compared to placebo [ 4 – 6 , 23 ]; hence, they are not part of the criteria for commencing a biologic.

OPTIMAL algorithm

The OPTIMAL algorithm was designed as a tool to determine the optimal dosage of anti-IL-5 for individual patients by adjusting the intervals between the administration of treatments ( figure 1 ). The dose remained the same at each administration; however, intervals were prolonged (down-titration) when there were no signs of loss of disease control and shortened again (up-titration) if there were signs of loss of disease control. Intervals were prolonged by 50% from normal at first and, if well tolerated, then by a further 50% from the first interval increase, i.e. 125% from normal intervals. If intervals prolonged by 125% were well tolerated, the patient entered a trial period with cessation of treatment. This meant that patients on mepolizumab or reslizumab first had dosing intervals increased to 6 weeks and then to 9 weeks before possible cessation, and patients on benralizumab first had dosing intervals increased to 12 weeks and then to 18 weeks before possible cessation. We defined signs of loss of disease control as either 1) a reduction in FEV 1 ≥15% from baseline, 2) blood eosinophils ≥0.3×10 9 cells·L −1 or 3) an exacerbation requiring OCS. These criteria most likely indicate a surge in inflammation that would otherwise be controlled by anti-IL-5 treatment. If one or more of the three occurred, the intervals were shortened to the previous step and no further down-titration was attempted.

The OPTIMAL titration algorithm with assessment of titration ability over 52 weeks. FEV 1 : forced expiratory volume in 1 s; OCS: oral corticosteroids.

Patients were followed for 52 weeks, with four scheduled visits. In case of asthma worsening, an extra visit was scheduled if possible. Visit 1 (baseline, week 0) was scheduled on the day the patient had their anti-IL-5 biologic administered. Visit 2 was scheduled at week 12, visit 3 at week 30 and visit 4 (end of the study) at week 52. The timing of the visits was designed such that they fit the administration times for the biologics in the prolonged interval progression according to the OPTIMAL algorithm. All patients randomised to the active arm had their intervals prolonged by 50% at visit 1 and then had intervals adjusted according to the OPTIMAL algorithm at the following visits, including any extra visits. At visit 4, patients in the active arm were assigned a final treatment interval according to the OPTIMAL algorithm. Patients in the control arm attended the same visits as patients in the active arm.

Statistical analyses

The OPTIMAL study was designed as a non-inferiority trial with the proportion of patients experiencing exacerbations in each randomised group as the primary outcome. We estimated a risk of exacerbation of approximately 30% in both the OPTIMAL and control groups, and originally chose a non-inferiority limit of 20%. Owing to difficulty in recruiting patients, an unscheduled interim analysis of the first 34 patients to complete the study was performed, and the non-inferiority limit was increased to 25%. With power set at 80% and a significance level of 5% and the risk of exacerbations in each group at the time of the interim analysis (31% and 33%, respectively), we needed to include 37 patients in each group to show non-inferiority.

The baseline characteristics of the two randomised groups and the final assigned treatment interval in the active arm were compared using descriptive statistics. No assumptions were made regarding missing values. For categorical variables, we applied the Chi-squared test or Fisher's exact test when there were five or fewer patients in a group. For continuous variables, we used the t-test for parametric data and the Mann–Whitney U-test for non-parametric data. Changes in forced expiratory volume in 1 s (FEV 1 ), blood eosinophils and Asthma Control Questionnaire (ACQ) over time between groups were analysed using a mixed model including randomised group and visit with an unstructured covariance. To test the significance of the randomised group on the outcomes, we applied an ANOVA test to the models. These models were employed to account for potential within-subject correlations due to repeated measurements over time. Log-transformation was applied to blood eosinophil counts. We used Kaplan–Meier analysis to compare the time to the first exacerbation between the two groups. To identify predictors of titration ability, we evaluated univariate factors with a p-value <0.20 using a multivariate logistic regression model adjusted for age and sex.

All data analyses and statistical procedures were performed using R version 4.3.0 ( www.r-project.org ).

Between 13 January 2021 and 27 September 2022, 73 patients were randomised to either have intervals between the administration of their anti-IL-5 biologic controlled by the OPTIMAL algorithm (active arm) or to continue with unchanged intervals (control arm). 37 patients were randomised to the active arm and 36 to the control arm ( figure 2 and table 1 ). One patient was lost to follow-up after the first visit; therefore, 72 patients were included in the analyses. Most patients in both arms remained free from exacerbations; however, in the active arm, 12 patients (32%) experienced an exacerbation, while in the control arm, six patients (17%) experienced an exacerbation (p=0.13). None of the exacerbations that occurred during the study required hospitalisation.

Flowchart of patients in the OPTIMAL study. IL: interleukin.

• View inline

Baseline characteristics

At the end of the trial, most patients had tolerated down-titration: eight of the 37 patients (22%) in the active arm were able to completely come off their anti-IL-5 biologic according to the OPTIMAL algorithm. At the final visit, 22 weeks after their last dose of anti-IL-5, they still had no exacerbations, no FEV 1 decline and blood eosinophils were <0.3×10 9 cells·L −1 . 14 patients (38%) tolerated intervals increased by 125% and seven patients (18%) tolerated intervals increased by 50%. The remaining eight patients (22%) in the active arm were unable to titrate their anti-IL-5 biologic according to the OPTIMAL algorithm.

Kaplan–Meier analysis of time to first exacerbation revealed no significant difference between the active and control arms (p=0.16) ( figure 3 ). We observed no significant difference in ACQ or FEV 1 between the randomised groups during the trial; however, we observed a significant increase in blood eosinophils in the active arm towards the end of the study (p<0.001) ( figure 4 ).

Kaplan–Meier plot of time to first exacerbation in the active and control arms. Boxes indicate timing of dosing interval increase of interleukin (IL)-5 treatment for patients in the active arm.

a) Forced expiratory volume in 1 s (FEV 1 ), b) Asthma Control Questionnaire (ACQ) and c) blood eosinophils in the active and control arms during the OPTIMAL study.

The reasons for up-titration (shortened intervals) are summarised in supplementary figure S1 . On two occasions, the cause of up-titration was listed as “other”. On both occasions, participants were unwilling to titrate the treatment further. The dosing was up-titrated because of a decline in FEV 1 15 times during the study. In four patients the decline was observed at visit 4; therefore, we did not have follow-up data. However, the 11 other patients regained their baseline lung function by the end of the study. They had a mean FEV 1 of 2.64 L at baseline, and a mean of 2.09 L at their lowest point, but at the end of the study, they had a mean FEV 1 of 2.54 L. The need for up-titration increased with extending intervals, occurring 16 times during the period of cessation of treatment, while only seven times during intervals increased by 50%. The progression of patients in the active arm is illustrated in supplementary figure S2 .

The baseline characteristics of patients titrated to different intervals by the OPTIMAL algorithm are summarised in table 2 . We observed a trend towards patients who were unable to titrate, having a higher ACQ at baseline (1.31 versus 0.66; p=0.11) and slightly less suppressed blood eosinophils (0.09 versus 0.05×10 9 cells·L −1 ; p=0.09). We also compared the baseline characteristics of patients who were able to completely come off anti-IL-5 biologics to those of patients who tolerated increased intervals. A smaller proportion of patients who were able to come off anti-IL-5 had been on mOCS prior to the initiation of biological therapy (13% versus 52%; p=0.09). They also tended to be less likely to have nasal polyposis (p=0.10) and had significantly fewer pack-years of tobacco exposure (8 versus 19; p=0.02). Potential predictors of titration ability were tested in multivariate models ( supplementary table S1 ) and no predictors were statistically significant.

Baseline characteristics according to ability to titrate

Six serious adverse events were reported during the trial, three in each randomised arm. One patient was diagnosed with cancer, one with stenosis in the cervical spine, one with pulmonary embolism, one with pneumonia, one had an operation due to newly diagnosed aortic valve stenosis and one had facial nerve paralysis due to Borrelia infection. None was suspected to be related to anti-IL-5 biologics or titration.

In this pilot study on the titration of anti-IL-5 biologics in patients with severe asthma who had achieved clinical control, we demonstrated that the majority were able to down-titrate treatment by applying a dose-titration algorithm, where the intervals between administrations of anti-IL-5 were titrated until signs of loss of disease control. Compared with the control group of patients who remained on regular dosing intervals, there was no permanent decline in lung function or severe adverse events related to titration in the active arm. The proportion of patients with exacerbations was higher in the active arm, although this difference was not statistically significant.

Our study is the first to evaluate a down-titration algorithm for anti-IL-5 biological treatment in a randomised controlled setting. Previously, two small observational studies evaluated the extension of dosing intervals in patients with asthma on biologics. One retrospective German study evaluated the effects of self-chosen prolonged intervals of mepolizumab administration for up to 8 weeks in 18 well-controlled patients. None had exacerbations on prolonged intervals, and lung function remained stable [ 21 ]. The same group performed a retrospective study comparing extended intervals with dose reduction in a small number of patients on omalizumab, where the extension of intervals was superior in sustaining asthma control [ 24 ]. A Spanish group evaluated a step-down protocol for omalizumab in 35 patients and found that a quarter of the patients could tolerate a reduced dose, and one-third of the patients could withdraw completely from treatment [ 25 ].

By comparing dose titration to a control group remaining on normal dosing intervals, we were able to demonstrate that dose titration can be performed in most patients without inducing worsening of symptoms, permanent loss of lung function or severe adverse events related to titration. The OPTIMAL algorithm included up-titration of dosing, and our results showed that this approach ensured that lung function was restored in patients who experienced a decline in FEV 1 during down-titration. Furthermore, our study was conducted in a real-life setting in multiple severe asthma centres across Denmark, with pragmatic exclusion and inclusion criteria and without blinding, which provides powerful external validity. However, the study also had limitations: the number of potential participants was restricted to those fulfilling the criteria in our real-life population; hence, due to the difficulty in recruiting patients, we had to perform an unscheduled interim analysis with adjustments of the power calculation. To ensure the feasibility of our study, the non-inferiority limit was increased from 20% to 25%, thereby reducing the required number of participants. Hence, the lack of statistical significance in the larger proportion of exacerbations in the active arm may reflect a power issue as the proportion of patients with exacerbations in the active arm exceeds our set non-inferiority limit. Our Kaplan–Meier analysis of the time to first exacerbation indicated that the difference in exacerbations between the two groups occurred towards the end of the study, during the trial period of cessation of anti-IL-5 for patients in the active arm. This observation suggests that while partial down-titration may be feasible in a large proportion of patients, fewer will tolerate cessation, highlighting the need for close monitoring if this is considered. We do not have data on ICS adherence during the trial and we cannot rule out that non-adherence played a part in exacerbations for some patients. Another potential limitation is the use of an open-label design. This was the more feasible option in the real-life setting, and it lends itself to the external validity of our study; however, it introduces the risk of bias. Awareness of extended intervals could lead to an expectation of poor outcomes both in patients and clinicians. We tried to accommodate this in our titration algorithm by including factors that are less likely to be affected by expectations, e.g. blood eosinophils and FEV 1 . Finally, the main limitation is the relatively short duration of our study, which precludes drawing conclusions on the long-term prognosis of titration.

In our study, 78% of patients in the active arm tolerated down-titration according to the OPTIMAL algorithm. It may be speculated that patients who achieve complete asthma control experience some form of “immunological remission” while on biological treatment, and therefore can down-titrate as a result. We observed a trend towards not being on mOCS prior to the initiation of biological treatment, predicting being able to come completely off it. We previously reported that patients in the DSAR on mOCS prior to initiation are less likely to achieve a complete response [ 7 ], and it is possible that early intervention with biologics could result in patients achieving a complete response to treatment and being able to down-titrate or come off it again with sustained disease control. There was a trend towards patients who were unable to titrate biologics having slightly higher eosinophils and ACQ at baseline, i.e. when stable on normal intervals of anti-IL-5 biologics. This could be due to a relatively higher IL-5 drive in these patients, causing them to lose disease control when IL-5 suppression is titrated and have more symptoms even at baseline. It could also be that they were unable to titrate due to other pathways driving inflammation. Further studies are needed to explore the immunological mechanisms at play during titration of anti-IL-5.

Clinical implications

The OPTIMAL study serves as a proof of concept for the titration of anti-IL-5 biological treatments in severe asthma. The OPTIMAL algorithm tapers anti-IL-5 biologics until signs of loss of disease control, which has shown that the majority of patients tolerate intervals prolonged by 50%, a large part tolerates intervals prolonged by 125% and that relatively few patients tolerate cessation, just as relatively few patients do not tolerate tapering at all. These results suggest that future clinical implementation of the OPTIMAL algorithm should mainly aim towards partial dose titration. Furthermore, the relatively short follow-up period also calls for long-term observations of the effects and safety of titration. Hence, our results call for a clinical implementation study to safely implement dose titration of anti-IL-5 biologics as a treatment strategy. Dose titration is a step towards ensuring rational pharmacotherapy in biological treatment for severe asthma by minimising the amount of medicine for the individual patient while sustaining disease control, and titration of biological treatments has the potential to optimise the utilisation of expensive treatments. Hence, dose titration is a topic of key clinical relevance to patients, healthcare providers and healthcare payers.

Our study is the first of its kind and offers a proof of concept that titration of anti-IL-5 biologics is possible in patients who have become stable on treatment. Further studies on the long-term prognosis of titration and potential adjustments to the OPTIMAL titration algorithm are now required, to enable clinical implementation of dose titration of biologics in severe asthma.

• Supplementary material

Supplementary Material

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• Data availability

Data can be shared upon reasonable request.

Ethics statement: The OPTIMAL study was approved by the National Ethics Committee (H-20052529) and the Danish Medicines Agency (2020-003358-63) and monitored by the Danish Good Clinical Practice Unit.

This clinical trial was prospectively registered at EudraCT with identifier number 2020-003358-63 and ClinicalTrials.gov with identifier number NCT04648761 .

Author contributions: M.B. Soendergaard contributed to conceptualisation, data curation, formal analysis, funding acquisition, investigation, methodology, project administration and writing. A-S. Bjerrum, L.M. Rasmussen, S. Lock-Johansson and O. Hilberg were involved in conceptualisation, investigation and writing. A. von Bulow contributed to conceptualisation and writing, while S. Hansen contributed to conceptualisation, data curation, formal analysis and writing. C. Porsbjerg oversaw conceptualisation, supervision, funding acquisition and writing.

Conflict of interest: M.B. Soendergaard reports payment or honoraria for lectures, presentations, manuscript writing or educational events from GSK and AstraZeneca, and participation on a data safety monitoring board or advisory board with AstraZeneca. A-S. Bjerrum reports payment or honoraria for lectures, presentations, manuscript writing or educational events from GSK and AstraZeneca. L.M. Rasmussen reports payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca, GSK, Teva and ALK, support for attending meetings from AstraZeneca and Chiesi, and participation on a data safety monitoring board or advisory board with AstraZeneca, GSK, Teva and Sanofi. A. von Bulow reports consultancy fees from Novartis, payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca, Novartis and GSK, and participation on a data safety monitoring board or advisory board with AstraZeneca and Novartis. C. Porsbjerg reports grants paid to their institution from AstraZeneca, GSK, Novartis, Teva, Sanofi, Chiesi and ALK, consultancy fees (paid both to institution and as personal honoraria) from AstraZeneca, GSK, Novartis, Teva, Sanofi, Chiesi and ALK, payment or honoraria for lectures, presentations, manuscript writing or educational events (paid both to institution and as personal honoraria) from AstraZeneca, GSK, Novartis, Teva, Sanofi, Chiesi and ALK, and participation on a data safety monitoring board or advisory board (fees paid both to institution and as personal honoraria) with AstraZeneca, Novartis, Teva, Sanofi and ALK. The remaining authors have no potential conflicts of interest to disclose.

Support statement: The study was funded by the Danish Regions Medicines Fund and the Lung Association's research fund. Funding information for this article has been deposited with the Crossref Funder Registry .

• Received February 27, 2024.
• Accepted May 14, 2024.
• Copyright ©The authors 2024.

This version is distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0. For commercial reproduction rights and permissions contact permissions{at}ersnet.org

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Asthma Exacerbations: Pathogenesis, Prevention, and Treatment

Jamee r. castillo.

a Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wis

Stephen P. Peters

b Wake Forest School of Medicine, Section on Pulmonary, Critical Care, Allergy and Immunologic Diseases, Winston-Salem, NC

William W. Busse

Guideline-based management of asthma focuses on disease severity and choosing the appropriate medical therapy to control symptoms and reduce the risk of exacerbations. However, irrespective of asthma severity and often despite optimal medical therapy, patients may experience acute exacerbations of symptoms and a loss of disease control. Asthma exacerbations are most commonly triggered by viral respiratory infections, particularly with human rhinovirus. Given the importance of these events to asthma morbidity and health care costs, we will review common inciting factors for asthma exacerbations and approaches to prevent and treat these events.

Despite optimal guideline-directed treatment, and irrespective of underlying disease severity, patients with asthma experience exacerbations, which are caused by an accentuation of existing inflammatory processes and a loss of disease control.

Asthma exacerbations are a major cause of disease morbidity, increases in health care costs, and, in some patients, a greater progressive loss of lung function. 1 The frequency of exacerbations can be reduced, but not always fully prevented, with adequate inhaled corticosteroid (ICS) treatment or combination ICS/long-acting β-agonists (LABA). 2 Because asthma exacerbations can break through standard treatment regimens, identifying at-risk patients and having a plan of management can improve disease control and patient well-being.

Asthma exacerbations remain a major reason for health care utilization and a significant financial burden to patients and society. Patients with asthma exacerbations have significantly higher total health care costs, $9223 versus $5011 (2007 dollars) per person per year, and asthma-specific costs, $1740 versus $847 per person per year, compared with matched patients without exacerbations. 3 In 2007, total expenditures for asthma were estimated to be $56 billion per year with productivity losses due to morbidity and mortality of $3.8 and $2.1 billion, respectively. 4 Moreover, patients requiring an emergency department (ED) visit or hospitalization for asthma are at significantly increased risk for future exacerbations independent of demographic and clinical factors, asthma severity, and asthma control, 5 collectively reflecting an ongoing need to develop better strategies to prevent and treat these events.

Pathogenesis

Viral respiratory infections.

The most common triggers for an exacerbation are viral respiratory infections with human rhinovirus (RV), particularly subtypes A and C, 6 , 7 most frequent. In school-age children, hospital admission rates for asthma exacerbations correlate with the seasonal increase of RV infections in September through December and again in the spring. 8 Similar asthma hospitalization peaks are observed in adults. 9

Other respiratory viruses also may cause exacerbations. During the 2009 H1N1 influenza A pandemic, mortality and admissions to the intensive care unit with H1N1 infections were frequently associated with asthma. 10 , 11 , 12 Respiratory syncytial virus, a frequent cause of wheezing in infants and young children, may also trigger acute asthma in adults, particularly, patients older than 65 years. 13 Coronaviruses, human metapneumoviruses, parainfluenza viruses, adenoviruses, and bocaviruses have all been detected in asthma exacerbations, but in low frequencies. 14

Patient risk factors

There are a number of susceptibility, or risk, factors that help to determine whether a viral respiratory infection causes an exacerbation ( Figure 1 ).

The interplay of the environment and host susceptibility factors in the pathogenesis of asthma exacerbations. Risk factors from Bateman et al. 15 ACQ , Asthma Control Questionnaire; BMI , body mass index; FEV1 , forced expiratory volume in 1 second; GINA , Global Initiative for Asthma; SABA , short-acting β 2 -agonist.

Allergy and defective anti-viral immunity

Allergic sensitization is a risk factor for wheezing with RV infection, particularly in children. Whether allergic inflammation often found with sensitization increases the susceptibility for viral infections or enhances their ability to provoke further inflammation is not entirely clear. 16 Type I interferons are important innate antiviral responses to respiratory viruses. 14 , 17 There is evidence that virus-induced interferon generation from peripheral blood mononuclear cells, 18 , 19 , 20 plasmacytoid dendritic cells, 21 and bronchial epithelial cells 22 , 23 is reduced in some patients with allergic asthma ( Figure 2 ). It has been show that IgE occupancy of their membrane receptors inhibits antiviral generation of IFN-α from plasmacytoid dendritic cells and may increase susceptibility to RV-induced wheezing and asthma exacerbations ( Figure 3 ). Deficient immune responses to viral infections may be present in type 2 inflammatory conditions with interferon production being inversely correlated with increasing airway eosinophilia, IL-4 levels, and total serum IgE. 23 Finally, the use of inhaled IFN-β at the time of an upper respiratory infection reduces the airway viral load and improves clinical symptoms in patients with asthma. 24

Impaired plasmacytoid dendritic cell (pDC) IFN-α response in patients with allergic asthma. pDCs from patients with physician-diagnosed asthma and allergic sensitization secreted less IFN-α on exposure to viruses compared with patients without asthma.

Effect of high-affinity IgE receptors (FcεRI) on plasmacytoid dendritic cells (pDCs) and antiviral immunity. In the absence of allergy, pDCs express low levels of cell surface FcεRI, some occupied by IgE. Rhinovirus (RV) infection induces secretion of interferon, thereby inhibiting viral replication. In the presence of allergen and allergic sensitization, FcεRI and IgE are increased, and cross-linking of IgE receptors by allergen can inhibit interferon secretion, resulting in increased viral replication, and an increased risk of asthma exacerbation.

Bacterial infections

Bacterial infections may impair mucociliary clearance and increase mucus production in the lung and may cause chronic lower airway inflammation. Evidence linking bacterial infections to acute asthma exacerbations has been limited. 25 , 26 However, respiratory viruses may impair the antibacterial defenses by human alveolar macrophages and thereby facilitate emergence of bacterial infections or change in the microbiome. 27 How these interrelationships contribute to exacerbations is not established, but they may be of potential therapeutic importance 28 to prevent acute asthma.

Allergen exposure

Environmental allergens can provoke asthma. 29 Furthermore, more than 80% of children with asthma are sensitized to environmental allergens, with indoor allergens being especially important to underlying asthma. 30 , 31 Mast cell activation by allergens releases 32 , 33 histamine, prostaglandin D2, and cysteinyl leukotriene generation to cause airway smooth muscle constriction, increased microvascular permeability, mucus secretion, and enhanced inflammation. Allergic sensitization is also associated with diminished innate immune responses and may be a susceptibility factor to viral-induced wheezing. This allergen associated inflammation also increases airway responsiveness to RV 34 to further enhance a loss of asthma control.

Mold sensitization and their seasonal increase parallel greater asthma severity and seasonal exacerbations. Patients sensitized to Alternaria alternata were approximately 5 times more likely to have asthma 35 and increased airway responsiveness, wheeze, and bronchodilator use. 36 Emergency visits for asthma exacerbations correlate with high airborne concentrations of mold. 37 Finally, Alternaria sensitization was found to be associated with an approximate 200-fold increase in the risk of respiratory arrest in children and adults. 28 , 38

Other contributing causes

Pollutants such as tobacco smoke, ozone, and particulate matter, along with occupational exposures, provoke asthma exacerbations. Tobacco smoke has also been implicated in the development of persistent wheezing 39 and greater asthma severity. 40 Hospitalizations and ED visits for asthma occur more frequently among cigarette smokers. 41

Particulate matter, ozone, nitrogen dioxide, sulfur dioxide, and diesel exhaust can increase airway inflammation and airway responsiveness. 32 , 33 , 42 Airway pollutants, together with a viral infection, may act synergistically to cause asthma exacerbations. The severity of lower respiratory tract symptoms increased and peak expiratory flow measurements fell with rising exposure to nitrogen dioxide in the week before a respiratory infection. 33

Prevention of exacerbations

Four essential components of asthma management include patient education, monitoring of symptoms and lung function, control of triggering factors and comorbid conditions, and pharmacologic therapy. Patient education on asthma decreases exacerbations and improves control. 43 , 44 However, because asthma severity varies and differs among individuals and age groups, it is essential to regularly monitor the effectiveness of asthma control to guide necessary treatment adjustments.

The Expert Panel Report 3 and Global Initiative for Asthma describe a stepwise treatment approach and strategy to reduce impairments and prevent future risks like asthma exacerbations. 45 , 46

Inhaled corticosteroids

ICS improve disease control and reduce asthma exacerbations. 47 , 48 , 49 In new onset, untreated persistent, asthma, low-dose inhaled budesonide reduces asthma exacerbations by almost 50%. 50 , 51 In asthmatic patients already taking moderate doses of ICS but under poor control, 50 Pauwels et al showed that high-dose budesonide further reduced severe asthma exacerbations, that is, need for systemic corticosteroids, by nearly 50% compared with treatment with low-dose ICS in adults. 50 However, as found by O'Byrne et al, 51 a doubling of the budesonide dose in patients poorly controlled on low-dose ICS also reduced exacerbation rates by 30%, but the degree of protection was less than those patients who recently started ICS. These findings indicate that dose-response benefits with ICS are relatively flat. 52 Overall, compared with placebo or a short-acting β 2 -agonist, ICS reduce clinically relevant exacerbations by nearly 55%. 53 ICS also reduce exacerbations in children 54 and are superior to a leukotriene antagonist, montelukast. 55

For patients with diminishing asthma control, quadrupling the recommended dose of ICS decreases the likelihood of an asthma exacerbation. 56 This protection does not occur with a doubling of the ICS maintenance. 57 , 58 However, the benefit of using an increase in ICS is time dependent to increased symptoms and need to be started early in the course of a cold. If higher doses of ICS are used pre-emptively at the onset of a respiratory tract infection and continued for 10 days, the need for oral corticosteroids is reduced. 59

The mechanisms by which ICS prevent virus-induced exacerbations, beyond anti-inflammatory activity, are poorly understood. ICS can reduce the number of airway eosinophils that presumably reflect enhanced inflammation with a respiratory infection. 60 , 61 As approximately 50% of asthma exacerbations are associated with an increase in airway eosinophils, these cells are a reasonable target. 62 This concept is substantiated by studies showing that a reduction in airway eosinophils significantly diminishes exacerbations ( Figure 4 ), 63 , 64 but this approach does not eliminate all exacerbations, particularly for patients with more severe asthma. 65 , 66 Furthermore, as airway neutrophils increase early in asthma exacerbations, 67 ICS treatment has no effect on these cells and alternative approaches will be needed. 68

Cumulative asthma exacerbations in the British Thoracic Society (BTS) asthma guidelines management group versus the sputum management group. There were significantly less asthma exacerbations in the sputum management group (35 vs 109; P  = .01), where inhaled corticosteroid dose was titrated to normalize induced sputum eosinophil counts and reduce symptoms.

Inhaled corticosteroids and long-acting β-agonists

In patients with poorly controlled asthma and a history of prior asthma exacerbations, the combination of budesonide and formoterol significantly reduces asthma exacerbations compared with ICS alone. 50 ICS/LABA have consistently been shown to prevent exacerbations. 69 , 70 , 71 The benefit of ICS/LABA to prevent exacerbations versus ICS alone is primarily seen in patients requiring higher doses of ICS, thus suggesting that combination therapy to prevent exacerbations should be reserved for patients with more severe disease.

Asthma control can vary even in the face of ongoing ICS/LABA treatment. Consequently, the use of ICS/LABA combinations both for maintenance and symptom relief has been investigated and shown to reduce exacerbations. 72 , 73 , 74 These benefits are also seen in children with a prior history of severe asthma exacerbations and poorly controlled moderate-to-severe persistent asthma despite the use of moderate doses of ICS. 75 The use of ICS/LABA as maintenance and reliever treatment should be restricted to formoterol because of its quick onset of action, 76 safety profile, 77 and dose-response effect. 78

How the addition of LABA to ICS reduces asthma exacerbations remains unclear as LABA do not affect inflammation. ICS/LABA, however, attenuate allergen-induced airway eosinophilia and lung function changes to a greater extent than ICS alone. 79 Edwards et al 80 demonstrated that combination treatment synergistically suppressed induction of rhinovirus-generated chemokines in bronchial epithelial cells. Thus, the synergistic benefits of both ICS and LABA on airway eosinophilic inflammation might explain a greater reduction in exacerbations. Alternatively, an early use of ICS/LABA for relief of symptoms might simply deliver additional ICS to the airway early in the course of an emerging exacerbation.

Leukotriene antagonists

Antileukotrienes reduce asthma exacerbations in children 72 , 81 and adults. 82 , 83 Montelukast reduced asthma exacerbations to RV infections that occurred on return to school in September. 81 , 84 In a systematic review and meta-analysis, compared with placebo, leukotriene modifiers/receptor antagonists lowered exacerbation rates by 41% but were inferior to ICS. 53

Adding montelukast to inhaled budesonide was as effective as doubling the dose of inhaled budesonide, with no difference in exacerbation rates and asthma free days. 85

The anticholinergic tiotropium reduces the frequency of asthma exacerbations and is FDA-approved for long-term, maintenance treatment for patients 6 years of age and older with persistent asthma, that is uncontrolled with ICS plus one or more controllers. In 2 replicate trials with a total of 912 adult patients with severe asthma and using ICS/LABA, adding tiotropium, 5 mcg, increased the time to first exacerbation by 56 days over placebo, and reduced exacerbations by 21% ( Figure 5 ). 86 In a systematic review of 13 randomized placebo-controlled trials, 87 tiotropium decreased rates of exacerbations and improved asthma control in patients with moderate symptomatic asthma already receiving medium-to-high doses of ICS or ICS/LABA. Studies in children aged 6 to 11 years demonstrate improvements in forced expiratory volume in 1 second (FEV 1 ) but not reductions in exacerbations, likely due to the short duration of the study. 88 However, given that decreases in the FEV 1 /forced vital capacity ratio are associated with an increased risk of exacerbations, 89 improvements in FEV 1 with tiotropium may be associated with reduced exacerbations in children.

Cumulative number of severe exacerbations in patients with severe asthma on inhaled corticosteroid/long-acting β-agonist treated with the addition of tiotropium versus placebo. There was a 21% risk reduction in asthma exacerbations (hazard ratio, 0.79; P  = .03 in pooled analysis) for the tiotropium group.

Environmental control

The benefit from environmental control measures to prevent exacerbations is limited. Perhaps, this is because environmental interventions usually focus on a single allergen, such as dust mites, 90 or environmental tobacco smoke, 91 and with this limited approach, no effect was seen on asthma morbidity. However, an Inner-City Asthma Study evaluated the effectiveness of a multifaceted, home-based, environmental intervention that used remediation of exposure to dust mites, passive smoking, cockroaches, pets, rodents, and mold 92 and was tailored to each child's skin-test sensitization profile and environmental exposures. The intervention group reported significantly fewer symptoms of asthma during both the intervention year and, interestingly, the follow-up year as well ( Figure 6 ), with significantly fewer unscheduled asthma-related visits to the ED or clinic for the intervention group ( P  = .04). The correlation between the reduction in levels of cockroach allergen on the bedroom floor and asthma-related morbidity was particularly strong during the active intervention. Although it is difficult to generalize these results to all children with asthma, a reduction in continuous exposure to environmental allergens and irritants, like those present in the homes of inner-city patients with asthma, may indicate the need for a more comprehensive intervention.

Mean maximal number of days with symptoms for every 2-week period before a follow-up assessment during the intervention year and follow-up year. The Inner-City Asthma Study evaluated the effectiveness of a multifaceted, home-based, environmental intervention for inner-city children with asthma. The difference between the 2 groups was significant in both the intervention year ( P < .001) and the follow-up year ( P < .001).

Targeted Biologic Therapy

Anti-ige (omalizumab).

Omalizumab is approved for use in patients 6 years of age and older with allergies and uncontrolled, persistent asthma despite moderate-to-high dose ICS. Omalizumab is a humanized monoclonal antibody directed against IgE and reduces the risk for asthma exacerbations in allergic asthmatic patients. 93 , 94 , 95 , 96 , 97 Omalizumab reduces asthma exacerbations when given with ICS 97 and shortens the duration of exacerbations 98 in adults and children. 99 , 100 , 101

Some patients with asthma and allergy have a diminished interferon response to an in vitro challenge with respiratory viruses, and this reduction is related to IgE. In a study of inner-city children, 99 omalizumab reduced seasonal exacerbations in the fall and spring, without altering the rates of infections with respiratory viruses, suggesting that omalizumab may not prevent viral infections, but rather modify the consequences of the infection. Teach et al 20 showed that omalizumab improved antiviral defenses by increasing release of IFN-α from peripheral blood mononuclear cells to RV stimulation; in those subjects with a greater restoration of IFN responses, fewer exacerbations occurred ( Figure 7 ). Thus, in addition to anti-inflammatory effects of omalizumab, a restoration of antiviral activity may prevent exacerbations.

Effect of omalizumab on IgE-mediated functions in virus-provoked asthma exacerbations. FcεRI , High-affinity IgE receptor; pDC , plasmacytoid dendritic cell; RV , rhinovirus.

Selecting patients most likely to benefit from omalizumab has been difficult. In a post hoc analysis, patients with elevated levels of fractional exhaled nitric oxide, blood eosinophils, and serum periostin, likely reflecting greater T2 inflammation, had a greater likelihood of benefitting from omalizumab. 102 , 103

Two anti-IL-5 monoclonal antibodies, mepolizumab and reslizumab, are approved as maintenance therapy for patients with uncontrolled, persistent eosinophilic asthma with an exacerbation phenotype despite high-dose ICS. IL-5 contributes to airway eosinophilic inflammation. Approximately 40% to 50% of patients with difficult-to-control asthma have persistent airway eosinophilia despite treatment with high-dose ICS. Although elevated sputum eosinophil counts predict the risk for asthma exacerbations, the use of sputum for routine measurements is impractical in clinical practice. Price et al 104 found a relationship between the intensity of peripheral blood eosinophilia and asthma-related outcomes; patients with asthma with blood eosinophil counts greater than 400 cells/μL experience more frequent severe exacerbations, and serves as a convenient biomarker for anti-IL-5 therapy.

Mepolizumab, given subcutaneously, reduces exacerbations by approximately 50% in patients with severe asthma who have blood eosinophil counts 150 cells/μL or greater ( Figure 8 ). 65 , 66 , 105 , 106 It has been FDA-approved for add-on maintenance treatment of severe asthma in patients 12 years of age or older. Although clinical trial data suggest that efficacy requires an absolute eosinophil count of at least 150 cells/μL, 107 the National Institute for Health and Care Excellence recommends a threshold of 300 cells/μL. Reslizumab is also FDA-approved for add-on maintenance therapy of severe asthma in patients 18 years or older who have an eosinophil count of 400 cells/μL or higher. In clinical trials, intravenous reslizumab reduced asthma exacerbations by approximately 50%. 108 , 109

Reduction in the cumulative number of asthma exacerbations with mepolizumab versus placebo.

RV infections lead to the generation of IL-5 and an increase in airway eosinophils, which correlate with exacerbation probability. 110 These relationships provide a probable explanation for why anti-IL-5 mAb treatment reduces asthma exacerbations.

Other biologics to prevent asthma exacerbations are under study.

Treating Exacerbations

Despite optimal maintenance therapy and asthma control, exacerbations occur. Therefore, early recognition and intervention are important to successfully stabilize asthma. A limited number of treatments are currently available to alleviate asthma exacerbations, and the evidence supporting their use has limits.

Short-acting β2-agonists

Inhaled or nebulized short-acting β 2 -agonists (SABAs), such as albuterol or levalbuterol, resolve acute symptoms of asthma and can initially be used every 15 to 20 minutes for the first hour during acute asthma. 107 Levalbuterol, the R-enantiomer of albuterol, and albuterol are equivalent. 111 , 112 , 113 Data are conflicting whether continuous nebulization with a SABA is superior to intermittent nebulization. 114 , 115 In very severe asthma exacerbations, continuous nebulization should be considered based on evidence of reduced admissions and improved pulmonary function. 114 , 116 , 117 , 118 SABAs provide symptomatic relief but have no effect on airway inflammation or sustained benefit.

Ipratropium bromide

Adding ipratropium bromide to an inhaled SABA in severe exacerbations decreases rates of hospitalizations and shortens ED stays for patients with severe or moderate-to-severe asthma exacerbations. 119 , 120 , 121 The benefit of ipratropium bromide to SABA therapy is seen primarily in more severe asthma exacerbations. 120 , 122

Corticosteroids

An underlying component of exacerbations is an increase in airway inflammation. 103 Numerous studies evaluated ICS and oral corticosteroids (OCS) in asthma exacerbations, but the evidence for their efficacy remains limited. Moreover, because ICS often do not prevent exacerbations, it is unlikely that an increase in inflammation with an exacerbation will be fully responsive to corticosteroids. Nonetheless, their use is a reasonable and expected first step.

The administration of high-dose ICS for asthma exacerbations should be reserved for patients with mild or intermittent asthma and those unable to tolerate OCS because of side effects such as diabetes or psychiatric effects. A systematic review analyzed 8 studies comparing the efficacy of ICS with placebo in acute asthma exacerbations and found that ICS appeared superior to placebo, especially when given at high doses, that is, >1 mg of budesonide or fluticasone. 123 However, patients in these studies were heterogeneous in severity, ICS dose and administration frequency, and outcomes measured. The role of ICS for asthma exacerbations remains to be established.

Comparisons between ICS and systemic corticosteroids have also been conflicting. OCS were superior to ICS in reducing hospital admission rates in some studies 124 , 125 , 126 and others showed superiority of ICS. 127 A systematic review of 12 trials concluded that there was no benefit to the addition of ICS to systemic corticosteroids in reducing the relapse rate of acute asthma. 128 At present, insufficient evidence exists to support using ICS rather than OCS for exacerbations.

Systemic corticosteroids

Early administration of systemic corticosteroids for the treatment of acute exacerbations is standard guideline management with beneficial effects of systemic corticosteroids usually delayed for approximately 4 hours. 129 Systemic glucocorticoids accelerate the rate of improvement when persistent airflow obstruction exists despite bronchodilator treatment. 130 However, an evidence-based evaluation reported neither an improvement in airflow obstruction nor reduction in hospitalization rates with systemic corticosteroids. 112 In contrast, a systematic review by Rowe et al 113 concluded that the use of systemic corticosteroids in adults and children reduces the rate of hospital admission in ED treatment settings, especially in patients with severe asthma and those not currently receiving corticosteroids.

The optimal dose for systemic corticosteroids in asthma exacerbations also remains to be convincingly established. Doses above 2 mg/kg, or 60-80 mg/day, do not add benefit to improving pulmonary function, rates of hospital admission, or length of hospital stay. 131 , 132 Furthermore, no differences are found between oral and intravenous administration of comparable doses. 133 , 134

Prescribing a short course of oral corticosteroids after ED treatment of acute asthma exacerbations reduces the rate of relapse. 113 Although the duration of therapy is not fully established, courses longer than 5 days did not provide additional benefit. 135 , 136 There is also no benefit from using a dose taper over a fixed-dose regimen and stopping. 122 Difficulties, however, arise in assessing approaches to treating exacerbations in patients already taking systemic corticosteroids. Optimal exacerbation treatment strategies for this patient population remain undefined and reflect the need for more targeted therapy.

A single dose of benralizumab, an anti-IL-5 receptor monoclonal antibody, reduces the rate and severity of subsequent exacerbations when given at the time of an initial exacerbation. 137 Thus, biologic therapy may also be beneficial in the acute treatment of asthma exacerbations to prevent subsequent events.

Conclusions

Asthma exacerbations can be prevented with ICS, ICS/LABA, and biologics in some patients. Exacerbations are more frequent in patients with severe disease and preventative strategies with biologics, such as anti-IgE and anti-IL-5, are seen. When exacerbations occur, systemic corticosteroids remain the primary intervention when bronchodilator therapy is not effective, but the evidence for their benefit has limitations. Prevention of exacerbations remains a major unmet need in asthma management. An improved understanding of the pathogenesis of asthma exacerbations will likely lead to new strategies to prevent and treat asthma exacerbations.

No funding was received for this work.

Conflicts of interest: J. R. Castillo declares no relevant conflicts of interest. W. W. Busse has received consultancy fees from Novartis, GlaxoSmithKline, Genentech, Roche, Boston Scientific, ICON, Boehringer Ingelheim, Regeneron, Sanofi, 3M, AstraZeneca, Circassia, and PrEPBiopharm; has received research support from the National Institutes of Health - National Institute of Allergy and Infectious Diseases and National Institutes of Health - National Heart, Lung, and Blood Institute; receives royalties from Elsevier; and has received payment for developing educational presentations from Medscape. S. P. Peters has received payment for preparing the manuscript from Medical Learning Institute, Inc.; has received consultancy fees from AstraZeneca, Teva, Novartis, National Institute of Allergy and Infectious Diseases, Elsevier, PRIME, Gilead, Sanofi-Regeneron, Quintiles, Haymarket Media, American Academy of Allergy, Asthma & Immunology, American College of Allergy, Asthma, and Immunology, InVivo Brands, and Johns Hopkins; receives royalties from UpToDate.