Can we predict fall asthma exacerbations? Validation of the seasonal asthma exacerbation index

Asthma affects about 1 in 11 American children, making it one of the most common diseases of childhood.  It carries a huge burden on families, especially during exacerbations when disease activity suddenly flares, leading to breathlessness and even death.  In this month’s issue of JACI, Hoch and colleagues discuss their research in validating the Seasonal Asthma Exacerbation Predictive Index, the saEPI (J Allergy Clin Immunol 2017; 140(4): 1130-1137).  The saEPI is a score ranging from 0 to 16 that can help predict how likely a child is to have an asthma flare.  Using data from the Preventative Omalizumab or Step-Up Therapy for Fall Exacerbations (PROSE) study, they looked at 348 children randomized to two groups: one with omalizumab, and another with guideline-based therapy alone.  They then calculated and validated the saEPI, moreover the authors looked at other factors that were associated with exacerbations.  In short, they found that children who required more aggressive treatment (high doses of inhaled corticosteroids), had higher blood eosinophils, and were younger were more likely to have a flare.  The saEPI, on the other hand, was better at determining which children were unlikely to have an asthma exacerbation.  The authors encourage providers to use data such as this to personalize their care of children at risk for asthma exacerbations. Because the children that were part of the PROSE study were largely from inner-city and minority populations and the study inclusion criteria limited some children from particpating, a similar analysis should also be performed in a more general population of children, as well as adults.  Regardless, the researchers conclude by noting the importance of such an index in managing children with asthma until even better methods are identified to classify children with asthma at risk for an asthma exacerbation.

Role of viral infections in the development and exacerbation of asthma in children

Wheezing is a common complaint among parents of infants.  About 1 in 5 children have acute wheezing illnesses in their first two years of life.  This is important because an overwhelming majority of these wheezing illnesses are related to viruses, and are linked to asthma development.  In this month’s issue of JACI, Jartti and Gern review the role of viral infections in the development of asthma in children (J Allergy Clin Immunol 2017; 140(4): 895-906). 

They survey the viruses -rhinoviruses, respiratory syncytial viruses, and others – and how they impact the developing set of lungs.  Genetic variation and low interferon responses are two factors that increase the risk of these types of infections.  In addition, increased eosinophil counts in blood and nasal mucus and atopic eczema all increase the risk of later asthma. 

Additionally, viral infections can lead to exacerbations in children who already have asthma.  This may explain why the rates of asthma exacerbations are higher during the fall and winter, and why omalizumab, a potent medication for asthma control, may help to prevent exacerbations due to viruses like rhinovirus.  The authors conclude that these insights may allow for new strategies to help prevent and manage viral wheezing illnesses so that they don’t lead to and worsen later asthma.

Promising approaches for the treatment and prevention of viral respiratory illnesses

There are hundreds of viruses that cause respiratory tract infections.  While most of us think about them as nuisances causing cough and wheezing, they bear a huge toll on health, especially in people who have lung diseases like asthma and COPD, as well as an economic toll in lost workdays and inappropriate use of medical resources.  In this month’s issue of JACI, Papadopoulos and colleagues look at the treatment and prevention of these diseases (J Allergy Clin Immunol 2017; 140(4): 921-932). 

They look at new medications that target the specific viruses in their reproductive phases.  In addition, they review how natural products like echinacea can prevent recurrent respiratory tract infections.  On the other side, there are promising insights about the use of immunostimulators in order to boost the body’s own responses to these viruses.  Vitamin D, probiotic supplements, exercise and meditation are all helpful in resolving these infections. But perhaps the most promising strategies are in prevention, where vaccines are being developed to prime the immune system to fight against viruses.  Currently, vaccines are available only against influenza virus.  There are other developments on the horizon and may have a tremendous effect on addressing these diseases. The authors conclude that multiple strategies are necessary and that there may be tremendous benefits in such research, especially when it comes to dealing with more severe diseases that can cause epidemics and pandemics.

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.

Eosinophilic airway inflammation in asthmatic patients is associated with an altered airway microbiome

Until a few years ago, it was thought that microbes don’t live in the lung’s passages.  But now we know that there is a diverse range of microbiota that lives there.  In this month’s issue of JACI, Sverrild and colleagues examine the relationship between these microbes and patterns of airway inflammation in healthy patients and in asthmatics who have not taken steroids (J Allergy Clin Immunol 2017; 140(2): 407-417).  In order to do so, they took 10 healthy participants and 23 nonsmoking steroid-free asthmatics and had them undergo bronchoscopy so that they could get fluid from the lower passageways.  They then sequenced bacterial DNA and looked at the number and type of immune cells.  The 33 participants also had their asthma better characterized through other standardized measures of disease severity like airway hyperresponsiveness to mannitol and fraction of exhaled nitric oxide.

They found that patients with eosinophilic asthma and those with hyperresponsiveness to mannitol, had  changes in microbial composition.  This was in contrast to patients with neutrophilic asthma.  Those asthmatics with the lowest numbers of eosinophils also had differences compared to healthy controls; they had more Neisseria, Bacteroides, and Rothia species while having less Sphingomonas, Halomonas, and Aeribacillus species.  These results suggest that the level of eosinophilic inflammation correlates with variations in bacterial composition.  This may point the way to newer diagnostic tools and therapies to help better identify and control asthma.