Unmet needs in asthma

Figures & data

Table 1 Selected mono- and multifaceted studies investigating primary and secondary prevention measures in asthma

Study	Interventions	Key findings
Primary prevention measures^Citation16
Monofaceted interventions
Manchester Allergy and Allergy Study (NACMAAS)^Citation50	• Randomized controlled trial investigating whether a low-allergen environment reduces the risk of primary sensitization and development of atopic disease in high-risk children • HDM allergen avoidance vs no intervention	• Reduction of some respiratory symptoms in the first year of life in high-risk infants in the intervention group vs the control^Citation51 • Increased risk of mite sensitization, but lower specific airway resistance in high-risk children in the intervention group vs the control at 3 years of age^Citation52
Prevention and Incidence of Asthma and Mite Allergy (PIAMA) study^Citation53	• Population-based study in the Netherlands with follow-up until the age of 18 years investigating the influence of lifestyle and environment on the development of asthma and allergy • Reduced exposure to HDM, beginning during the prenatal period	• The intervention had no effect on sensitization or atopy up to the age of 4 years, or on asthma and allergy outcomes up to the age of 8 years^Citation53,Citation54
Study of Prevention of Allergy in Children in Europe (SPACE)^56	• European population-based study that aimed to prevent sensitization to HDM and food allergens, and the development of atopic symptoms, during infancy in high-risk children • HDM reduction strategies and education on the reduction of food and inhaled allergens	• The rate of sensitization to aero- and food allergens was decreased in the intervention group vs the control at 1 year of age^55 • At 2 years of age, there was no protective effect of HDM avoidance on the development of sensitization or symptomatic allergy vs the control group^56 • In 5- to 7-year-olds, HDM sensitization was reduced in the intervention group vs the control group^57
Zeiger study^58	• A prospective, randomized, controlled study of food allergen avoidance in infancy • Reduced exposure to allergenic food during the last trimester of pregnancy; staged introduction of foods in infancy	• A significant reduction in food allergy and milk sensitization was found before the age of 2 years • At age 7 years, there was no difference between the intervention and control groups in food allergy, atopic dermatitis, allergic rhinitis, asthma, any atopic disease, lung function, food/aeroallergen sensitization, serum IgE level, or the presence of nasal eosinophils or nasal basophilic cells^58
Multifaceted interventions
Canadian Asthma Primary Prevention Study (CAPPS)^Citation14	• The study aimed to minimize exposure to allergens (HDM, pet allergens, food allergens) and environmental tobacco smoke • Breastfeeding was encouraged in the first year of life (diet supplemented with hypoallergenic formula if required) • Strict elimination of allergenic foods to 12 months	• At 2 years of age, significantly fewer children had asthma in the intervention group compared with the control group (16.3% vs 23.0%)^Citation14 • At 7 years, there was a 56% reduction in the prevalence of pediatric asthma among high-risk children^Citation13 • Reduced risk of physician-diagnosed asthma, but not of other allergic outcomes, among females aged 15 years (RR 0.37, 95% CI 0.13–0.90)^59
Isle of Wight Prevention Study^60	• Study aimed to minimize exposure to food allergens during the prenatal period and to food and pet allergens, as well as HDM during infancy • Stepwise introduction of allergenic foods	• Demonstrated that allergic diseases (asthma, atopic dermatitis, rhinitis, atopy) can be reduced for at least the first 8 years of life by combined food- and HDM-allergen avoidance in infancy^60
Prevention of Asthma in Children (PREVASC) study^Citation17	• Aimed to reduce allergen (HDM, food allergens, and indoor pet allergens) exposure during the prenatal period and during early infancy • Exclusive breastfeeding to 6 months was encouraged, with the nonstandardized introduction of solid food thereafter	• No significant differences in total and specific IgE were found between the groups • The intervention was not effective at reducing asthma-like symptoms in high-risk children during the first 2 years of life, although it was modestly effective at 2 years^Citation17
Secondary prevention measures
Prevention of Early Asthma in Kids (PEAK) study^61	• Children (aged 2 and 3 years) who had a positive asthma predictive index score received either fluticasone (88 μg) or placebo bid for 2 years, followed by 1 year with no study medication	• No disease-modifying effect on asthma symptoms or lung function was observed during the treatment-free period^61
Inhaled Fluticasone Propionate in Wheezy Infants (IFWIN) study^62	• Infants received fluticasone propionate (100 μg bid) and were followed up until 5 years of age	• Early use of inhaled fluticasone propionate in preschool children with wheeze had no effect on the development of asthma or wheeze later in childhood^62
Preventive Allergy Treatment (PAT) study^63	• This study evaluated the preventive effect of SIT on asthma development over 7 years	• A 3-year course of SIT with standardized allergen extracts may prevent asthma development in children with allergic rhinoconjunctivitis up to 7 years after treatment^63

Abbreviations: bid, bis in die (twice daily); CI, confidence interval; HDM, house dust mite; IgE, immunoglobulin E; RR, risk reduction; SIT, specific immunotherapy.

Table 2 Sensitivity and specificity of objective tests in asthma diagnosis

Strategy	Description*	Parameter*	Range of predictive values* (note that a single value indicates datum from a single study)				Comments**
			Sensi	Specii	PPViii	NPViv
Clinical assessment
Symptoms and signs	The commonest symptoms assessed were cough and wheeze, and, in adults, shortness of breath	Cough in adults Wheeze in adults Dyspnea in adults Cough in schoolchildren^Citation21 Wheeze in children^Citation21 Cough in preschool children Wheeze in preschool children Shortness of breath in preschool children	16%–66% 9%–76% 11%–73% 63% 59% 88% 54% 76%	26%–64% 34%–87% 38%–71% 75% 93% 7% 57% 52%	8%–44% 10%–81% 41%–59% 14% 34% 76% 80% 84%	18%–92% 28%–94% 26%–70% 97% 97% 15% 27% 40%	As isolated symptoms cough, wheeze and shortness of breath are neither sensitive, nor specific for asthma. Most children with asthma have intermittent cough, wheeze and exercise-induced symptoms, but only about a quarter of children with these symptoms have asthma. Note that the single study in preschool children compared current symptoms with a diagnosis of asthma two years later.
	Symptom variability	Episodic symptoms in adults Diurnal symptoms in adults Symptoms after exercise in adults Episodic symptoms in children^Citation22,Citation23 Symptoms after exercise in children^Citation22,Citation23 Nocturnal symptoms in children^22.23	9%–40% 30%–56% 5%–40% 36%–93% 82%–94% 57%–84%	36%–91% 36%–83% 32%–93% 35%–93% 59%–73% 58%–78%	14%–86% 48%–76% 5%–81% 40%–94% 54%–86% 64%–85%	18%–93% 18%–67% 58%–84% 62%–90% 79%–91% 57%–82%	Asking about episodic symptoms improves the positive predictive values in children compared to current symptoms.
	Combinations of symptoms (typically cough, wheeze, chest tightness, dyspnea, exercise symptoms)	Symptom scores in adults Symptom scores in chiidren^Citation21^–^Citation23 Symptoms of cough and wheeze in preschool children	60% 45%–83% 49%	66% 85%–97% 59%	44%–94% 80%	66%–97% 51%	Combinations of symptoms are clinically more helpful than isolated symptoms, especially in children. For example, two thirds of children with a cluster of cough, wheeze, chest tightness, dyspnea and exercise symptoms have asthma. Asthma is unlikely if a child does not have at least some of these symptoms.
History of atopy	Personal/family history of atopic/allergic diseases	Personal history of atopy in adults Personal history of rhinitis/eczema in preschool children Family history of atopy in adults Family history of atopy in children	54%–55% 47%–62% 26%–60% 43%–44%	68%–74% 20%–75% 56%–83% 57%–70%	46%–76% 72%–86% 44%–74% 51%–77%	45%–79% 14%–30% 38%–70% 24%–62%	History (personal or family) of atopic disease has poor sensitivity and specificity for asthma.
Strategies for demonstrating airway obstruction
Spirometry	Regard an FEV1:FVC ratio of less than 70% as a positive test for obstructive airway disease	Obstructive spirometry in adults Obstructive spirometry in children (5–18 years)	23%–47% 52%	31%–100% 73%	45%–100% 75%	18%–73% 49%	In the four larger studies (adults and children), the NPV was between 18% and 54%, which means that more than half of patients being investigated who have normal spirometry will have asthma (ie, false negatives).
Strategies for demonstrating variability in airway obstruction
Bronchodilator reversibility	In adults, regard an improvement in FEV1 of ≥12% and ≥200 mL as a positive test. In children regard an improvement in FEV1 of ≥l2% as a positive test.	Bronchodilator reversibility in adults Bronchodilator reversibility in schoolchildren (using a threshold of 9% change in FEV1)^71	17%–69% 50%	55%–81% 86%	53%–82%	22%–68%	In these secondary care populations, about one in three people with a positive reversibility test will not have asthma (the cohorts all included people with COPD); and at least one in three people with a negative bronchodilator reversibility test will have asthma.
Challenge tests	Regard a PC20 value of 8 mg/mL or less as a positive test	Methacholine challenge in adults Methacholine challenge in children^Citation31,Citation43,^72	51%–100% 47%–86%	39%–100% 36%–97%	60%–100% 20%	46%–100% 94%	Challenge tests are a good indicator for those with a definitive diagnosis of asthma already (based upon clinical judgment, signs and symptoms and response to antiasthma therapy).
	Fall in FEV1 ≥15% at cumulative dose of ≤635 mg is positive Exercise challenge	Mannitol in adults Mannitol in children Exercise challenge in adults Exercise challenge in children	56% 63% 26%–80% 69%–72%	75% 81% 100% 69%–72%	80% 100% 90%–99%	49% 0% 5%–73%	These data are from a single study in adults and children with symptoms of asthma on questionnaire. The studies in adults had very small sample sizes. The larger study in children had a false positive rate of 1% (PPV 99%).
Peak flow charting	Monitor peak flows for 2–4 weeks, calculate mean variability. Regard ≥20% variability as a positive test	PEF charting in adults in a population study – using mean variability of >20% – using mean variability of >15% – using diurnal variation >15% on >3 days/week PEF charting in children – using variation >12.3% (95th centile)	46% 3%–5% 20% 50%	80% 98%–99% 97% 72%	97% 60%–67% 82% 48%	10% 60% 64% 74%	It is not clear whether the patients in these studies were symptomatic at the time of the charting, and results may not reflect clinical use in symptomatic populations. One study concluded that the number of days with diurnal variation was more accurate than calculating the mean variation.
Strategies for detecting eosinophilic inflammation or atopy
FeNO	Adults: Regard an FeNO level of 40 ppb or more as a positive test Children 5–16 years: regard an FeNO level of 35 ppb or more as a positive test.	FeNO in adults FeNO in schoolchildren	43%–88% 57%	60%–92% 87%	54%–95% 90%	65%–93% 49%	These studies are all in secondary care populations. Approximately one in five adults with a positive FeNO test will not have asthma (ie, false positives) and one in five adults with a negative FeNO test will have asthma (ie, false negatives).
Blood eosinophils	Suggested thresholds for blood eosinophils: Adults >4.15% Children ≥4%^65	Blood eosinophils in adults Blood eosinophils in children	15%–36% 55%–62%	39%–100% 67%–84%	39%–100% 56%–69%	27%–65% 73%	Elevated blood eosinophil level is poorly predictive. The threshold varies in these studies from 4.0% to 6.3%.
IgE		Any allergen-specific IgE >0.35 kU/l in adults Total IgE in adults >100 kU/I	54%–93% 57%	67%–73% 78%	5%–14% 5%	95%–99% 99%	A normal IgE substantially reduces the probability of asthma in adults with a false negative rate of less than one in 10, although a positive result is poorly predictive.
Skin-prick testing		Any positive test (wheal ≥3 mm) in adults Any positive test (wheal ≥3 mm) in children	61%–62% 44%–79%	63%–69% 56%–92%	14%–81% 65%–92%	39%–96% 36%–79%

Notes:

* Data derived from NICE evidence tables unless otherwise specified.⁶⁴ Only studies reporting sensitivity, specificity, PPV, and NPV included here;

** comments have been added by the guideline development group as an aid to interpretation of the data presented;

i probability of test being positive when asthma present;

ii probability of test being negative when asthma absent;

iii proportion of patients with positive test who actually have asthma (100 minus PPV is the proportion of patients with a false positive test);

iv proportion of patients with negative test who do not have asthma (100 minus NPV is the proportion of patients with asthma, but in whom test was negative). In most studies, the reference test was spirometry plus either bronchodilator reversibility or a challenge test, although some studies also included a “typical history of attacks” or diurnal variation, or used physician diagnosis. Studies evaluating methacholine-challenge tests used physician diagnosis or bronchodilator reversibility and/or diurnal peak flow variability. In children, reference tests used were physician-diagnosed asthma plus spirometry or documented history of wheeze on at least two occasions and variability in FEV₁ over time or on exercise testing. This table is reproduced from BTS/SIGN British Guideline on the management of asthma by kind permission of the British Thoracic Society.²²

Abbreviations: COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 second; FeNO, fractional exhaled nitric oxide; FVC, forced vital capacity; NICE, National Institute for Health and Care Excellence; NPV, negative predictive value; PC₂₀, provocative concentration causing a 20% fall in FEV₁; PEF, peak expiratory flow; PPV, positive predictive value; Sens, sensitivity; Spec, specificity.

Figure 1 Stepwise asthma management in adults, adolescents, and children aged 6–11 years.

Notes: *Not for children aged <12 years; **for children aged 6–11 years (preferred step 3 treatment medium-dose ICS); ^#for patients prescribed BDP/formoterol or BUD/ formoterol maintenance and reliever therapy; ^{^}tiotropium by mist inhaler is an add-on treatment for patients aged ≥12 years with a history of exacerbations. Copyright ©2018 Global Initiative for Asthma. Reproduced with permission from. Global Initiative for Asthma. Global strategy for asthma management and prevention. 2018. Available from: http://ginasthma.org/2018-gina-report-global-strategy-for-asthma-management-and-prevention/.¹²
Abbreviations: ICS, inhaled corticosteroid; BDP, beclomethasone dipropionate; BUD, budesonide; LABA, long-acting β₂-agonist; LTRA, leukotriene receptor antagonist; SABA, short-acting β₂-agonist.

Figure 2 Stepwise asthma management in children aged ≤5 years.

Note: Copyright ©2018 Global Initiative for Asthma. Reproduced with permission from. Global Initiative for Asthma. Global strategy for asthma management and prevention. 2018. Available from: http://ginasthma.org/2018-gina-report-global-strategy-for-asthma-management-and-prevention/.¹²
Abbreviations: ICS, inhaled corticosteroid; LTRA, leukotriene-receptor antagonist.

Figure 3 Key areas of unmet need in asthma.

Abbreviations: BMI, body mass index; ICS, inhaled corticosteroid.

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