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.

A single intervention for cockroach control reduces cockroach exposure and asthma morbidity in children

Cockroaches are small, scurrying insects that we just don’t like to think about.  But as small as they are, they have a large impact on asthma and allergies.  In this month’s issue of JACI, Rabito and colleagues look at the effect of cockroach elimination on asthma outcomes (J Allergy Clin Immunol 2017; 140(2): 565-570).  They build on previous work showing that integrated pest management (IPM) reduces cockroach levels.  But because IPM is s costly and requires special expertise, it is generally not practical for low-income families.  Instead, the authors looked at the efficacy of insecticidal bait, which is much cheaper and can be done by almost anybody. 

They followed 102 children (between the ages of 5 and 17) who live in New Orleans. At the beginning of the study, field technicians laid traps for cockroaches.  Over the next 12 months, 53 of the children’s houses were visited six times to place the bait, and asthma was evaluated every 2 months by standardized questionnaires. The remaining 49 were in the control group, meaning that they did not get the insecticidal bait placed in their houses.

After 12 months, they found that cockroach levels were reduced in both groups, although the intervention had near complete elimination.  Compared to the control group, the group that had the baits place had 47 fewer days with symptoms over the year, and a 17% reduction in unscheduled Emergency room and unscheduled clinic visits.  Although benefit was mostly seen in children with cockroach allergy, the benefits were also seen in children without cockroach allergies, suggesting that irritation may also be a large part of why cockroach exposure drives asthma symptoms.

The investigators conclude by noting that because insecticidal bait is inexpensive and placement has a measurable impact on asthma outcomes, this could be a promising way to help reduce the burden of childhood asthma in other settings.  However, more studies are needed to replicate the findings on a larger scale.

Impact of school peanut-free policies on epinephrine administration

Food allergies are seen in up to 1 in 12 school-age children in the United States today, and peanut is one of the most common allergens.  In response, many schools have started to have peanut-free policies, but the effect of these policies has not yet been rigorously assessed.  In this month’s issue of JACI, Bartnikas and colleagues examine how peanut-free policies affect the rate of potentially fatal allergic reactions to peanut (J Allergy Clin Immunol 2017; 140(2): 465-473).  They looked at 2,223 public schools in Massachusetts during a five-year period, of which 6.3-10.3% banned peanuts from being brought from home, 56.6-59.1% banned peanuts from being served in school, 90.1-91.1% had peanut-free tables and 65.6-67.4% had peanut-free classrooms.  Among these schools, 46 (1.5-2.9%) self-designated as being a “peanut-free school,” but there was considerable variability in how these schools defined a self-designated “peanut-free school,” with 28.9% still allowing peanuts to be brought from home and 4.4% not providing peanut-free tables or classrooms. In the five-year study, 149 students had peanut or tree-nut exposure that required epinephrine, of which two were in self-designated peanut-free schools and one was in a school that did not self-designate as peanut-free but banned peanuts from both being brought from home and served by school.

What they found is that schools with peanut-free tables have lower rates of epinephrine administration, presumably because of fewer life-threatening allergic reactions.  Epinephrine administration rates were not significantly different in schools that had policies restricting peanuts from home, served in schools, or having peanut-free classrooms compared to those that didn’t have such policies. No policy resulted in complete absence of allergic reactions.

The investigators do note that there are limitations to their study.  There may be variability in how policies are interpreted and enforced and not all allergic reactions may have been accounted for if they were not treated with epinephrine.  Nevertheless, this study provides the first evidence to help guide schools in drafting policies regarding peanuts to help better safeguard children with peanut allergy.

Features of the bronchial bacterial microbiome associated with atopy, asthma and responsiveness to inhaled corticosteroid treatment

It’s been known that asthmatic lungs are different from healthy lungs in many aspects, including housing different strains of bacteria.  So far, studies haven’t been able to tell whether these differences are due to asthma, associated allergies (atopy), or treatment with different drugs.  They also haven’t been able to determine how these differences affect the way asthma manifests itself and how asthma can be treated.  In this month’s issue of JACI, Durack and colleagues aim to answer these pressing questions (J Allergy Clin Immunol 2017; 140(1): 63-75).

Durack and other investigators looked at the bacterial communities in 84 individuals, split into three groups: (1) 42 atopic asthmatic subjects, (2) 21 atopic non-asthmatic subjects, and (3) 21 non-atopic non-asthmatic, otherwise healthy, subjects.  They also looked at inflammatory markers and changes in bronchial hyperresponsiveness after 6 weeks of treatment with fluticasone, an inhaled steroid commonly used for asthma treatment.

What they found is that the types of bacteria in each of the three groups were significantly different. This included the group with atopy without asthma, suggesting that atopy itself is associated with different patterns of bacterial colonization of the bronchi, but these patterns also differed from those in the subjects with atopic asthma.  The bacteria seen in the asthmatic patients expressed genes for different metabolic pathways that result in products previously linked to risks for asthma development.  And subjects with high levels of allergy/atopy-related inflammation markers in their bronchial epithelium (“T2-high asthma”) had overall lower amounts of bacteria.  Differences were also found in the asthmatic subjects who responded to fluticasone, in that their bronchial bacteria were less different from those in healthy subjects than were the bronchial bacteria in the non-responsive asthmatics.  

Overall these findings suggest that bacterial composition in the lungs is associated with various immunologic and clinical features of the disease.  It also suggests that targeting these bacteria may be a way to help prevent, or even treat, asthma in the future.

Early-life Farm Exposures and Adult Asthma and Atopy in the Agricultural Lung Health Study

Allergies and asthma are growing public health problems, as rates have continued to increase over the past 50 years.  In that same time period, there has been a dramatic movement of people away from farms into cities and towns.  Previous studies have suggested that these may be related and data do exist to show childhood farm animal exposures and consumption of unpasteurized milk reduces the risk of childhood asthma and allergies.  But what about early-life farm exposures and adult asthma and allergic sensitization?  In this month’s issue of JACI, House and colleagues studied more than 3000 farmers and their spouses to help answer this question (J Allergy Clin Immunol 2017; 140(1): 249-256).

Specifically, they looked at 1746 farmers and 1555 spouses from Iowa and North Carolina enrolled in the Agricultural Lung Health Study.  They used questionnaires to identify current asthma and early-life farming exposure, and then measured blood levels of allergen-specific IgE, the type of antibody that suggests allergic sensitization to a given allergen.

After analyzing all the data, they found that exposure to a farming environment when still in the womb, living on a farm when born, exposure to farm animals before the age of 6 years, and drinking raw milk were all associated with a decreased risk of allergic sensitization. Among these, the strongest association was between the mother performing farm activities while pregnant and future atopy.   There was little correlation between these factors and asthma development in adulthood.

This study builds upon previous research supporting “the hygiene hypothesis,” that is, exposures to diverse types of germs early in life promotes immune tolerance and reduces the risk of allergies throughout life.  This information can guide further research in the prevention and treatment of allergies.