Articles
Diagnostic accuracy of minimally invasive markers for detection of airway eosinophilia in asthma: a systematic review and meta-analysis

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Summary

Background

Eosinophilic airway inflammation is associated with increased corticosteroid responsiveness in asthma, but direct airway sampling methods are invasive or laborious. Minimally invasive markers for airway eosinophilia could present an alternative method, but estimates of their accuracy vary.

Methods

We did a systematic review and searched Medline, Embase, and PubMed for studies assessing the diagnostic accuracy of markers against a reference standard of induced sputum, bronchoalveolar lavage, or endobronchial biopsy in patients with asthma or suspected asthma (for inception to Aug 1, 2014). Unpublished results were obtained by contacting authors of studies that did not report on diagnostic accuracy, but had data from which estimates could be calculated. We assessed risk of bias with QUADAS-2. We used meta-analysis to produce summary estimates of accuracy.

Findings

We included 32 studies: 24 in adults and eight in children. Of these, 26 (81%) showed risk of bias in at least one domain. In adults, three markers had extensively been investigated: fraction of exhaled nitric oxide (FeNO) (17 studies; 3216 patients; summary area under the receiver operator curve [AUC] 0·75 [95% CI 0·72–0·78]); blood eosinophils (14 studies; 2405 patients; 0·78 [0·74–0·82]); total IgE (seven studies; 942 patients; 0·65 [0·61–0·69]). In children, only FeNO (six studies; 349 patients; summary AUC 0·81 [0·72–0·89]) and blood eosinophils (three studies; 192 patients; 0·78 [0·71–0·85]) had been investigated in more than one study. Induced sputum was most frequently used as the reference standard. Summary estimates of sensitivity and specificity in detecting sputum eosinophils of 3% or more in adults were: 0·66 (0·57–0·75) and 0·76 (0·65–0·85) for FeNO; 0·71 (0·65–0·76) and 0·77 (0·70–0·83) for blood eosinophils; and 0·64 (0·42–0·81) and 0·71 (0·42–0·89) for IgE.

Interpretation

FeNO, blood eosinophils, and IgE have moderate diagnostic accuracy. Their use as a single surrogate marker for airway eosinophilia in patients with asthma will lead to a substantial number of false positives or false negatives.

Funding

None.

Introduction

Historically, asthma control has been pursued by means of symptom and lung function monitoring.1 Although asthma medications are effective in controlling the disease in most patients, a minority deteriorates despite maximum treatment. Non-eosinophilic asthma responds poorly to corticosteroid therapy, the standard treatment for suppressing airway inflammation. About half of patients with asthma seem to be persistently non-eosinophilic.2

Bronchoalveolar lavage and endobronchial biopsy are the reference standards for identifying the extent of eosinophilic airway inflammation, but these tests are invasive and expensive. Another option is induced sputum, which has been clinically useful in guiding asthma treatment.3

A Cochrane review showed that the frequency of asthma exacerbations is significantly lower in patients in whom inhaled corticosteroids are tailored based on sputum eosinophil levels, compared with those in whom management is based on traditional methods of asthma monitoring.3 Recent guidelines recommend guiding treatment in severe asthma by sputum eosinophil counts in addition to clinical criteria in centres experienced in using this technique.1, 4 Sputum eosinophilia might also have prognostic value as a marker for persistent airflow limitation,5 deteriorating asthma over time,6 and responsiveness to future therapies specifically targeting eosinophilic inflammation, such as mepolizumab.7

Unfortunately, sputum induction is time-consuming, needs experienced laboratory personnel, and many patients are unable to produce adequate samples. Several minimally invasive markers of eosinophilic airway inflammation, such as fraction of exhaled nitric oxide (FeNO), blood eosinophils, and serum periostin, could have potential as a surrogate to replace sputum induction, but their accuracy to distinguish between patients with and without airway eosinophilia remains controversial.

We did a systematic review and meta-analysis to obtain summary estimates of the diagnostic accuracy8 of markers for airway eosinophilia in patients with asthma.

Section snippets

Search strategy and selection

A medical information specialist (RS) developed searches in Medline, Embase, and PubMed without date or language restrictions (appendix). We included studies if they had assessed the diagnostic accuracy of one or more blood, serum, nasal lavage, or exhaled breath markers9 (index test) in detecting airway eosinophilia (target condition) in patients with asthma or suspected asthma. Direct airway sampling methods (induced sputum, bronchoalveolar lavage, or endobronchial biopsy) were acceptable

Results

The searches retrieved 2919 unique records, all of them providing titles or abstracts in English language. Among these, we found 21 eligible diagnostic accuracy studies (figure 1). Another 18 studies fulfilled the eligibility criteria for the enrichment sample. Contacting the authors of these studies led to eight additional inclusions. We also included data from two studies from our own department, and one more identified through a conference poster. No additional studies were identified by

Discussion

We systematically reviewed studies on the diagnostic accuracy of minimally invasive markers for detecting airway eosinophilia in asthma. In adults, FeNO, blood eosinophils, and total IgE have been extensively investigated, but their ability to distinguish between patients with and without airway eosinophilia is restricted, with summary estimates of AUC, sensitivity, and specificity never exceeding 0·8. Other markers, such as volatile organic compound analysis, were reported to be more accurate

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