In this article, the authors look at the diagnostic challenges presented by asthma
Dr Jayesh M Bhatt Consultant Respiratory Paediatrician, RCPCH, Nottingham Children’s hospital
Dr Gabrielle Parker ST7 Paediatric Registrar, Nottingham Children’s Hospital
Laura, a 10 year old girl, presented to the paediatric outpatient department with a 12 month history of chest tightness after swimming, associated with shortness of breath and an intermittent cough. There was some relief with inhaled beta agonists. Over the previous year, appropriate doses of inhaled beclomethasone and salmeterol had been tried in primary care with no benefit.
There was no nocturnal cough, or cough associated with laughter, crying, running or cold weather. Laura’s physical examination was normal. Spirometry showed no evidence of reversible bronchoconstriction, and her exhaled nitric oxide level was normal, thus indicating a lack of eosinophilic airway inflammation. An exercise test showed no evidence of exercise-induced bronchoconstriction.
A diagnosis of dysfunctional breathing was made, and Laura was referred to the children’s physiotherapy team for advice on her breathing. Her asthma treatment was stopped, and her symptoms improved.
Asthma is the most common chronic disease in children in the United Kingdom.1 The diagnosis is a clinical one and is based on recognising a characteristic pattern of episodic respiratory symptoms and signs in the absence of an alternative explanation for them.2 These symptoms are non-specific, making it sometimes difficult to distinguish asthma from other respiratory diseases, as illustrated in the case history above.
In this article we will focus on the initial evaluation and diagnosis of childhood asthma. Pre-school wheeze has been discussed previously3 and will not be covered. The management of childhood asthma will be covered in the next issue of the journal.
Definition of asthma
The Global Initiative for Asthma (GINA) consensus definition of asthma is as follows: “Asthma is a heterogenous disease, usually characterized by chronic airway inflammation. It is defined by the history of respiratory symptoms such as wheeze, shortness of breath, chest tightness and cough that vary over time and in intensity, together with variable expiratory flow limitation.”4 Airway inflammation has only recently been assessed in clinical practice by measurement of exhaled nitric oxide.5
Airway hyper-responsiveness is the characteristic functional abnormality of asthma. It is the predisposition of the airways to narrow excessively in response to stimuli that would produce little or no effect in healthy subjects.6 The role of tests of airway hyper-reactivity in the diagnosis of childhood asthma is unclear.2
Establishing a diagnosis of asthma involves a process of history taking, physical examination, and diagnostic studies. The differential diagnosis must be carefully considered, particularly in infants and young children,2 for whom testing of reversible air flow obstruction is not possible outside specialist clinical or research settings.
Evaluating the presence of asthma symptoms is the first step in making the diagnosis. The most common reported symptoms are more than one of: wheeze (a high-pitched sound produced when air is forced through narrow airways), cough, shortness of breath and/or chest tightness.2 “Wheezing” can mean different things to patients and carers, and therefore it is important to establish precisely what is being described. As far as possible a “doctor confirmed wheeze” should be factored in the diagnosis. The cough seen in asthma is generally dry, or productive of clear, white, or pale yellow sputum. Isolated dry cough in the absence of wheeze is rarely due to asthma, and the label of “cough variant asthma” remains controversial.5
Asthma symptoms are generally episodic. Children may be asymptomatic in between exacerbations or there may be acute deterioration off the back of chronic symptoms.
Physiologically, pulmonary function dips in the early morning as part of the normal circadian rhythm.7 This is exacerbated in individuals with asthma, in whom symptoms are generally worse at night and in the early morning.
Characteristic triggers include exercise, emotional stress, laughter, tobacco smoke, cold or damp air, and exposure to allergens such as pets/pollen or dust mites. Viral upper respiratory tract infections are the most common trigger. However, symptoms which only occur with colds are more suggestive of viral-induced wheeze as opposed to asthma.
Past medical history
This may elicit a history of atopy. Alternatively there may be factors which make a diagnosis of asthma less likely, such as failure to thrive, recurrent infections, and a previous poor response to bronchodilators.
Asthma is a complex polygenic disease and using classic genetic calculations from twin studies, it is estimated that asthma is roughly 60% inheritable, but there are complex interactions between genetic, epigenetic, and environmental factors that determine the clinical presentation.8 Nevertheless, in children with asthma, there is often a family history of atopy or asthma.
‘Red flag’ symptoms
Red flag symptoms are not suggestive of asthma and require further investigation. These include a neonatal onset of symptoms, cough with feeding, sudden onset of cough (or a choking episode), night sweats weight loss, a chronic unremitting, progressing cough, a chronic moist cough with phlegm production, and haemoptysis.
The European Respiratory Society (ERS) task force on wheezing disorders in children recommends that the term asthma should probably not be used in preschool children because data regarding underlying inflammation is lacking. Instead, they offer a pragmatic classification of wheeze in this age group: Wheeze associated with viral upper respiratory tract infections or multi-trigger wheeze.9
During an exacerbation, physical examination may reveal the classical findings of wheeze, prolonged expiratory phase on auscultation (airway narrowing leads to increased respiratory resistance), hyperexpansion, and increased work and rate of breathing. Examination outside of an exacerbation is frequently normal. Signs of chronic lung disease, including clubbing, are “red flags” and are not associated with asthma.
A characteristic history, together with the presence of classical signs during an exacerbation, and improvement of symptoms with a trial of asthma medication, strongly indicates a diagnosis of asthma. To confirm the diagnosis, it is necessary to exclude alternative diagnoses, and (in children old enough to co-operate) to demonstrate variable expiratory airflow limitation (preferably by spirometry though this may not be routinely available in primary care). Trial of treatment with review A trial of inhaled bronchodilators or corticosteroids is widely used to help make a diagnosis of asthma. It may be difficult to assess response due to spontaneous remission. If it is unclear whether a child has improved, careful observation during a trial of withdrawing the treatment may clarify whether a response to asthma therapy has occurred.2
Peak expiratory flow
Peak expiratory flow is easy to measure in the primary care setting (in children over the age of about five years). It can be a useful measure for monitoring symptoms and assessing severity during an exacerbation. However, it should not be used alone for diagnosis, as readings can be hugely variable and differ according to the brand of the peak flow meter.10
Spirometry involves rapid forced exhalation into a mouthpiece attached to a spirometer. It is the preferred method of diagnosis of airflow obstruction. As it requires co-ordination and co-operation, it is recommended in children five years of age or older.10
Measurements include forced vital capacity, or FVC (the total amount of air exhaled), and the forced expiratory volume in one second (FEV1). A significant increase in FEV1 (>12% from baseline) after bronchodilator indicates reversible airflow obstruction, and supports the diagnosis of children. It is also predictive of a good response to corticosteroids. However, normal results on testing, particularly when the child is asymptomatic, do not exclude a diagnosis of asthma.2,10 This differs from COPD in adults, where a fixed, reduced FEV1/FVC is seen.
The more the clinician tries and fails to document variable airflow obstruction, the more the diagnosis of asthma should be treated with caution.11
Bronchoprovocation testing can be useful when the diagnosis remains in doubt. It involves the use of a stimulus to encourage bronchoconstriction; as mentioned above children with asthma have hyper-responsive airways. Bronchial challenges are generally carried out in the secondary care setting and can be indirect, direct, or allergen-mediated.
Indirect bronchoprovocation tests
These do not act directly on the airway smooth muscle, but work by causing the release of endogenous mediators which lead to airway smooth muscle contraction. They are preferable to direct tests as there are no late responses. Examples include exercise testing, inhaled adenosine 59-monophosphate (AMP), hyperventilation of cold dry air, and inhaled mannitol (osmohale). The latter is highly specific for asthma.
Direct bronchoprovocation tests
These include inhaled metacholine and histamine. Direct challenges are more sensitive, but less specific, for asthma.
Allergen bronchoprovocation testing
This has the potential to produce life-threatening bronchoconstriction, and is generally only performed in the research setting, or in the investigation of occupational asthma.
Exhaled nitric oxide
Raised levels of exhaled nitric oxide imply the presence of eosinophilic airway inflammation. Levels can be high in atopic individuals without asthma, but are consistently high in patients with untreated or poorly controlled asthma, and generally fall with inhaled glucocorticoid (ICS) treatment. Fraction of exhaled nitric oxide (FENO) can therefore be used to screen for asthma, monitor adherence, and titrate medications. It can be measured in unsedated children from 3-4 years of age.2
A recent study suggests that the addition of FENO in monitoring and titration could offer cost benefits.13,14 Because it is easy and convenient to measure, it has long been thought of as an ideal biomarker. However there is insufficient justification to advocate the routine monitoring of FENO.15,16 The draft NICE guidelines for consultation17 recommend FENO assessment in all patients with asthma.
However, the imitations of this test need to be considered; FENO is not specific for asthma and is elevated in atopic non-asthmatic children. In addition, FENO does not correlate with FEV1 or bronchial hyper-responsiveness, and remains elevated in some individuals despite treatment with inhaled corticosteroids.11,16 A recent review describes FENO as an objective index for individualising asthma control in children, although clinical trials have not consistently found benefit from adding FENO to a symptom-based approach to ICS treatment in children.18 Because of this, at present, there is insufficient evidence to support a role for markers of eosinophilic inflammation like FENO measurement in the diagnosis of asthma in children.2
There are many conditions that can present in a similar way to asthma. It should be possible to differentiate these based on history and examination +/- a trial of treatment and spirometry (Table 1).
Table 1: Conditions in children which can mimic asthma19,17
Dysfunctional breathing/vocal cord dysfunction
Recurrent (micro)aspiration, reflux, swallowing dysfunction
Prematurity and related lung disease
Congenital or acquired immune deficiency
Primary ciliary dyskinesia
Central airways obstruction/compression
Congenital malformations including vascular ring
Carcinoid or other tumour
Mediastinal mass/enlarged lymph node
Congenital heart disease
Summary of key points
1 Childhood asthma is extremely common but there is a potential for under and over diagnosis
2 Diagnosis involves a thorough history and examination, exclusion of other diagnoses, and a trial of treatment
3 Demonstration of expiratory airflow limitation can be performed in children over five years
4 A lack of clear diagnostic criteria, coupled with the difficulty in performing spirometry in young children, can make a definitive diagnosis difficult
5 Where symptoms do not settle with appropriate treatment, consider alternative diagnoses and check adherence to treatment
6 Isolated dry cough in the absence of wheeze is rarely due to asthma
1. Masoli M, Fabian D, Holt S, Beasley R. Allergy. 2004 May;59(5):469–78.
2. British Thoracic Society, Scottish Intercollegiate Guidelines Network, Thorax. 2014 Nov;69 Suppl 1:1–192.
3. Bhatt JM, British Journal of Family Medicine. Pavillion; 2013.
4. From the Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma (GINA) 2014. [Internet]. Available from: http://www.ginasthma.org/ [last accessed April 2015]
5. Bush A, Fleming L. BMJ. 2015 Mar 5;350(mar05 9):h996–h996.
6. Chapman DG, Irvin CG. Clin Exp Allergy. 2015 Apr;45(4):706–19.
7. Spengler CM, Shea SA. Am J Respir Crit Care Med. 2000 Sep;162(3 Pt 1):1038–46.
8. Olin JT, Wechsler ME. BMJ. 2014;349:g5517.
9. Brand PLP, Baraldi E, Bisgaard H, Boner AL, Castro-Rodriguez JA, Custovic A, et al. Eur Respir J. 2008 May 14;32(4):1096–110.
10. National Asthma Education and Prevention Program. Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma-Summary Report 2007. J Allergy Clin Immunol. 2007 Nov;120(5 Suppl):S94–138.
11. Pavord ID, Bush A, Holgate S. Lancet Respir Med [Internet]. Available from: http://linkinghub.elsevier.com/retrieve/pii/S2213260015000569 [last accessed April 2015]
12. Godfrey S. Paediatr Respir Rev. 2000 Jun;1(2):148–55.
13. Fleming L, Bush A. J Allergy Clin Immunol. 2015 Mar;135(3):689–90.e1.
14. Honkoop PJ, Loijmans RJB, Termeer EH, Snoeck-Stroband JB, van den Hout WB, Bakker MJ, et al. J Allergy Clin Immunol. 2015 Mar;135(3):682–8.e11.
15. Lu M, Wu B, Che D, Qiao R, Gu H. Medicine (Baltimore). 2015 Jan;94(4):e347.
16. Petsky HL, Cates CJ, Lasserson TJ, Li AM, Turner C, Kynaston JA, et al. Thorax. 2012 Mar;67(3):199–208.
17. Asthma - diagnosis and monitoring [Internet]. Available from: https://www.nice.org.uk [last accessed April 2015]
18. Turner S. Paediatr Respir Rev. 2014 Aug 7;
19. Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, et al. Eur Respir J. 2014 Feb 1;43(2):343–73.