Diagnostic accuracy of fractional exhaled nitric oxide in predicting cough variant asthma and eosinophilic bronchitis in adult patients with chronic cough: A systematic review and meta-analysis

Cough is an important reflex we need to remove irritants from the airways, but for many people, a hypersensitive cough reflex can negatively affect quality of life.  A major trigger of chronic cough is airway inflammation from immune cells including type 2 helper T-cells (T_H2), but conventional tests required for diagnosis are technically challenging and often require specialist expertise.  Fortunately, measurement of the fractional exhaled nitric oxide (FENO), a potential marker of T_H2 airway inflammation, has become much more common in allergy and pulmonary practices.  In this month’s issue of JACI, Song and colleagues review the literature on the use of FENO to diagnose Cough-Variant Asthma (CVA) and Eosinophilic Bronchitis (EB), two major causes of T_H2-mediated chronic cough (J Allergy Clin Immunol 2017; 140(3): 701-709).

They looked at thousands of articles from multiple databases in order to answer the question “What is the diagnostic accuracy of FENO for CVA and/or EB in patients with chronic cough?”   After an exhaustive search, they found 15 studies with 2187 adult patients.  The authors then collected and compared the data to determine the accuracy.  Overall, when looking at either CVA or EB, the pooled sensitivity and specificity were 0.73 and 0.89.  For diagnosing CVA, they found moderate diagnostic accuracy, suggesting that the FENO test alone is not sufficient to diagnose CVA.  However, its high specificity means that it may be more useful as a rule-in test than as a rule-out test.  In contrast, results for EB suggested that FENO testing may not be precise enough for prediction. 

This article provides guidance on how to further research on how best to use FENO testing in patients with chronic cough. However, there remain many unanswered questions because of limitations of the review, including the limited number of studies, generalizability of studies which were mostly conducted in Asia, and the imprecision of current diagnostic criteria for CVA.  

Identification of airway mucosal type 2 inflammation by using clinical biomarkers in asthmatic patients

Asthma is a complex disease of the airways characterized by inflammation and dynamic airway obstruction.  Despite the single, more recent evidence suggests that asthma is mediated by a set of distinct immune abnormalities.  In this month’s issue of JACI, Silkoff and colleagues report the results of the ADEPT (Airways Disease Endotyping for Personal Therapeutics) study, in which 83 patients with mild, moderate, and severe asthma as well as 25 healthy non-asthmatic subjects were examined for biomarkers of asthma (J Allergy Clin Immunol 2017; 140(3): 710-719).  They underwent bronchoscopy to obtain tissue samples, and then had the biomarkers measured in the lab to characterize them as having either high or low levels of type 2 inflammatory mediators.  These were then correlated with clinical variables.

They determined the presence of type 2 inflammation based on airway expression of CCL26, periostin, and IL-13 in vitro signature (IVS).  They then looked at the clinical variables, including fraction of exhaled nitric oxide (FENO) levels, blood eosinophil counts, serum CCL26 expression and serum CCL17 expression.  What they found was that the combination of Fractional Excretion of Nitric Oxide (FENO), blood eosinophil counts, serum CCL17 and serum CCL26 had a positive predictive value of 100% for patients determined to be in the asthma group driven by type 2 inflammation.  This is important because individual clinical characteristics alone could not predict the pattern of type 2 inflammatory markers, and eosinophilic inflammation was associated with , but not limited to, gene expression for type 2 inflammation in airways.

By describing a set of relatively easily obtainable clinical markers consistent with type 2 inflammation, the authors report information that can help researchers and practitioners tailor the most appropriate therapy for those with asthma mediated by type 2 inflammation.

Patterns of Immune Development in Urban Preschoolers with Recurrent Wheeze and/or Atopy

Along with wheezing illnesses, allergic sensitization during infancy is a major risk factor for childhood asthma.  But how exactly this allergic sensitization occurs is not very well known.  In this month’s issue of JACI, Gern and colleagues look at cytokine responses in 467 inner-city children from the URECA study (Urban Environment and Childhood Asthma) at ages 1 and 3 years (J Allergy Clin Immunol 2017; 140(3): 836-844).  They then examined these cytokine responses in relation to environmental exposures to allergens and endotoxin as well as development of allergic sensitization and recurrent wheezing.

They found that cytokine responses increased as the children grew older, but responses at birth were not predictive for responses at ages 1 and 3 years. Exposure to cockroach, mouse, and house dust mite was associated with enhanced Interferon-alpha and IL-10 cytokine responses.  This contrasts with reduced IL-10 responses at birth, which was associated with recurrent wheeze.  Atopy was associated with (1) reduced respiratory syncytial virus-induced IL-8 responses as well as (2) heightened CpG-induced IL-12p40 and 5’-cytosine-phosphate-guanine-3’ (CpG)-induced IL-12p40 and (3) increased allergen-induced IL-4 responses.  Altogether, these findings suggest that exposure to animal proteins and microbes stimulates the immune system early in life and modulates cytokine responses in ways that may be protective for childhood asthma.