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Tuesday, September 19, 2017

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 (TH2), 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 TH2 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 TH2-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.  

Tuesday, September 12, 2017

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.

Friday, September 8, 2017

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.

Tuesday, August 29, 2017

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.

Tuesday, August 22, 2017

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.


Tuesday, August 15, 2017

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.

Thursday, July 13, 2017

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.

Monday, July 10, 2017

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.

Monday, June 5, 2017

Cardiovascular and cerebrovascular events among patients receiving omalizumab: Results from EXCELS, a prospective cohort study in moderate to severe asthma

Omalizumab is a potent medication approved to treat asthma, which has been shown to improve symptoms as well as decrease flares and use of rescue medications.  When it first became available, its long-term safety was not solidly clarified.  In the May 2017 issue of JACI, Iribarren and colleagues discuss the results of the post-marketing observational study called EXCELS, which followed patients for five years to determine the long-term effects of omalizumab, with a particular focus on cardiovascular (CV) and cerebrovascular (CBV) events, such as heart attacks and strokes (J Allergy Clin Immunol 2017; 139(5): 1489-1495).  Pooled results from previous studies showed a higher incidence of these events, but no clear association with omalizumab use was found. 

Iribarren and colleagues looked at nearly 5000 patients on omalizumab and compared them to nearly 3000 that were not on omalizumab.  They found that omalizumab is effective for moderate-to-severe asthma.  Because more severe asthma, for which omalizumab would be indicated, is both directly and indirectly associated with risks for CV/CBV events, it was expected that there would be a higher rate of CV/CBV adverse events in the omalizumab group.  The results showed that patients were 32% more likely to have a CV/CBV event after controlling for other factors. 

However, this doesn’t mean that omalizumab causes CV/CBV events.  Due to asthma severity and other risk factors, such as the presence of other diseases, the authors conclude that an increased risk cannot be ruled out.  Healthcare professionals should be aware of this potential association when counseling patients about starting omalizumab.

The nasal methylome and childhood atopic asthma

It has long been known that many diseases, like asthma, are the result of complex interactions between genes and the environment.  But how exactly do these two factors contribute to atopic asthma?  In the May 2017 issue of JACI, Yang and colleagues discuss the epigenetic factors involved in the development of childhood asthma (J Allergy Clin Immunol 2017; 139(5): 1478-1488).  They looked at nasal brushings from 36 inner-city children with asthma between the ages of 10 and 12 and compared them with nasal brushings from 36 children without asthma.  They then looked at patterns of methylation, a way that genes can be chemically modified in order to change their expression. They found that 186 genes were modified in this way.  The median percentage in methylation changes between allergic patients and non-allergic patients was 6.8%.  This is in line with previous research that shows that there are significant changes in methylation in other airway diseases like chronic obstructive pulmonary disease (COPD) and with cigarette smoking exposure.

This research is important, because it opens up new targets for research, diagnosis, and perhaps even treatment.  Future research can focus on what specific environmental changes lead to differences in genetic expression.  Additionally, because the normal bacteria in the nose affect methylation patterns, researchers may be able to look at which specific bacterial species impact gene expression. The authors speculate that the methylation markers can be checked to determine disease activity in the future.   

Wednesday, May 31, 2017

Prevalence of atopic dermatitis in infants by domestic water hardness and season of birth: Cohort study

Atopic dermatitis is a chronic skin disorder in which the skin becomes dry, itchy and thickened.  Even though it is very common in children, its exact causes are not well-known.  Because water is a known skin irritant and the skin of infants are very sensitive, it has been thought that hard water, that is water that contains high calcium carbonate, may be a risk factor.  In this month’s issue of JACI, Engebretsen and colleagues investigate whether early exposure to hard domestic water is associated with the prevalence of atopic dermatitis (J Allergy Clin Immunol 2017; 139(5): 1568-1574).

To do this, they looked at the Danish National Birth Cohort study which collected nearly 100,000 children born between 1996 and 2002.  Out of these, the mothers of 55,092 children completed an interview at 6 and 18 months to get more information on atopic dermatitis.  What the authors found was that hard water is associated with a higher incidence of atopic dermatitis.  This effect was dose-dependent, and they attribute a 2% risk for atopic dermatitis on hard domestic water.  In addition, they found that children born in autumn and winter had a higher incidence as well.  However, combined evaluation of these two effects did not cause an even greater incidence on atopic dermatitis.

The reasons for this association are unclear.  The authors suggest that hard water may change the acidity of skin and thus change the activity of skin enzymes, or maybe that it requires more irritant soap for lather production with hard water.  It may even be that hard water changes the growth of bacteria on the skin that may modulate risks for atopic dermatitis.   It also opens a lot of other questions that have not yet been explored.  Can water softening reduce the risk of developing AD?  What role do skin moisturizers and other emollients have in preventing hard water-induced skin damage? Does this effect extend to infants outside of Denmark and other Nordic countries?   Although these are all unanswered, this study opens a new window for research and helps point the way for further directions.

Monday, April 10, 2017

Effectiveness of bronchial thermoplasty in patients with severe refractory asthma: clinical and histopathological correlations

Asthma is a disease in which the airways of the lung become very sensitive to certain triggers, leading to spasms, in turn causing shortness of breath, coughing and wheezing.  The ultimate cause of asthma is unclear, but it has been shown in previous studies that there is remodeling of the airways in severe asthma. Airway smooth muscle (ASM) increases, along with fibrosis, infiltration of new blood vessels, and growth of cells that line the airways.   Recently, a procedure called bronchial thermoplasty (BT) has been developed, in which an endoscope is inserted into the airways.  This endoscope then delivers a temperature-controlled radio frequency to the airway wall.  In this month’s issue of JACI, Pretolani and colleagues look at bronchial thermoplasty and its effect on various clinical and histopathological findings (J Allergy Clin Immunol 2017; 139(4): 1176-1185).

In order to do this, they recruited 15 patients with severe uncontrolled asthma that did not respond to medications.  They looked at the symptoms through the Asthma Control Test (ACT) and the Asthma Quality of Life Questionnaire (AQLQ), as well as breathing patterns via spirometry and biopsy samples.  Bronchial thermoplasty was then performed.  At 3 and 12 months, the clinical and airway effects were examined.

What they found is that asthma control and quality of life increased considerably.  Exacerbations requiring oral steroids, emergency room visits, and hospitalizations were also decreased by approximately 90%.  Biopsy samples from 3 months showed a decrease in ASM size, as well as nerve fibers and neuroendocrine cells.

Based on these results, Pretolani and colleagues conclude that bronchial thermoplasty is an option for severe, uncontrolled, treatment refractory asthma.  Bronchial thermoplasty seems to affect the structure of airways, especially muscle size and nerve connections.  Targeting these structures, through thermoplasty or other means may be an effective way to help control these difficult-to-control cases.

Thursday, April 6, 2017

A prospective study on the natural history of patients with profound combined immunodeficiency (P-CID): an interim analysis

The immune system is complex, composed of numerous cells, proteins, and other components.  Among them, the T-cells are essential in fighting off infectious agents and regulating the functions of the immune system.  People with reduced or dysfunctional T-cells can have life-threatening complications, and may require interventions like hematopoietic stem cell transplant (HSCT), gene therapy, or enzyme replacement. If a T cell deficiency is severe (severe combined immunodeficiency, SCID), these treatment decisions are clear. However, in patients with moderate T cell deficiency (profound combined immunodeficiency, P-CID), prognosis is unclear and transplant decisions are difficult. These patients have so far received little attention.  In this month’s issue of JACI, Speckmann and colleagues report the first 51 P-CID patients  enrolled in a long-term prospective study (J Allergy Clin Immunol 2017; 139(4): 1302-1310). The patients suffer from heterogenous T cell deficiencies including: (1) ‘bona fide’ CID, where deficiencies are typically associated with profound T-cell deficiencie, (2) atypical severe combined immunodeficiency (SCID), in which T-cell dysfunction is due to less life-threatening mutations in SCID-associated genes, and (3) T cell deficiencies with genetically unidentified cause.  They analyzed  the clinical and molecular characteristics at study entry to determine disease severity.  Ultimately, the aim is to identify parameters predicting  when the risks of untreated disease outweigh the risks of performing HSCT.

They found that patients with P-CID have a high rate of morbidity and mortality as well as a lower quality of life.  One-third of patients underwent HSCT within the first year of inclusion into the study, 5 patients died.  The genetic diagnosis has limited value as a predictor of disease evolution and thus as a guidance for HSCT decisions, with the age of onset, quality of life, and severity of disease not significantly different between patients with atypical SCID, bona fide CVID, or genetically undefined disease.  This was in line with the authors’ expectations, but what they didn’t expect was that basic measures of T-cell immunity also did not predict the prognosis and course of their disease.

Speckmann and colleagues continue to enroll patients and hope to eventually reach their target of 120.  Parallel long-term follow-up of transplanted and of non-transplanted patients will better identify predictors for the natural progress of P-CID, and, in turn, give better guidance about how, and when, to treat with HSCT.

Thursday, March 23, 2017

Omalizumab facilitates rapid oral desensitization for peanut allergy

Food allergy is the leading cause of anaphylaxis, a serious and life-threatening systemic allergic reaction, among American children today.  Although it can be managed by avoidance and supportive management, there are few options for disease modification.  Oral immunotherapy (OIT) whereby increasing doses of an allergen are given, has been a promising investigational treatment, but the high rates of adverse reactions and intolerance of symptoms lead to high drop-out rates. In this month’s issue of JACI, MacGinnitie et al look at the use of omalizumab, an anti-IgE medication used in asthma, in helping to facilitate OIT (J Allergy Clin Immunol 2017; 139(3): 873-881).

To do this, they randomized 37 participants to receive either omalizumab or a placebo for 19 weeks, in addition to oral immunotherapy.  Neither the patients nor the researchers knew the assignment of the groups.  6 weeks after stopping the omalizumab, it was found that a majority (79%) of the omalizumab group was able to achieve the 2000-mg maintenance dose.  Even 12 weeks after stopping the omalizumab, 76% were able to tolerate even higher doses of peanut protein (4000mg).  Even though the reaction rates were not statistically different between the two groups, the omalizumab group was also exposed to higher doses of peanut proteins.

Despite the small number of participants, this is encouraging news for the use of omalizumab as an adjunct for peanut oral desensitization.  The authors suggest that the benefits of omalizumab-enabled OIT may outweigh the downsides of its expense, repeat injections, and risk of hypersensitivity reactions.

Body fat mass distribution and interrupter resistance, fractional exhaled nitric oxide, and asthma at school-age

Obesity and asthma are two of the most common childhood chronic diseases, seen in 25% and 10% of children, respectively.  There are increasing lines of evidence suggesting that they may be inter-dependent : fat may be the source of proinflammatory mediators and may change the mechanics of lung function. 

However, not all fat is considered equal.  The android distribution of fat along the abdomen, compared to gynoid distribution along the hips, is more closely associated with a variety of cardiometabolic diseases.  Similarly, visceral fat, situated just above the guts in the belly, is considered a marker of inflammatory status, compared to more superficial subcutaneous fat deposits.  In this month’s issue of JACI, den Dekker and colleagues discuss the effect of body fat mass distribution on asthma and airway function in children (J Allergy Clin Immunol 2017; 139(3): 810-816).

To do this, they looked at the medical histories and physical characteristics of 6178 children.  They focused on body-mass index (BMI), total and abdominal fat measures using ultrasonography and dual energy x-ray absorptiometry (DEXA), respiratory resistance (Rint), fractional exhaled nitric oxide (FENO), wheezing, and asthma.   They found that a higher BMI was associated with increased respiratory resistance and current wheezing.  They also noted that more visceral fat was associated with a higher FENO, while a higher android (belly)/gynoid (hip) ratio was associated with a lower FENO. 

Altogether, these results suggest that local fat deposition, especially visceral fat, is more closely related to asthma.  Even though the reasons for this are unclear, the authors speculate that maybe the different metabolic profiles of visceral vs. subcutaneous fat and the mechanical effects may be responsible for these differences.  Regardless, understanding the finer details of fat composition and distribution may help to explain part of the increased prevalence of childhood asthma.

Novel baseline predictors of adverse events during oral immunotherapy in children with peanut allergy

Food allergy is a huge problem affecting 3 to 8% of school-age children.  So far, avoidance and supportive management have been the mainstays of therapy, but this is rapidly changing with studies showing the efficacy of oral immunotherapy (OIT), especially for peanut allergies.  In peanut OIT, gradually increasing doses of peanut are given as part of the buildup, with steady doses given during maintenance.  The hope is to desensitize the immune system so that reactions are not as severe.  In this month’s issue of JACI, Virkud and colleagues discuss the safety of oral immunotherapy to peanut by examining 104 patients from 3 peanut OIT trials (J Allergy Clin Immunol 2017; 139(3): 882-888).  They look at the past medical history, parental reports, daily symptom diaries, and relationship to dose escalations to determine the risks and predictors of adverse effects (AEs). 

The rate of AEs was high, with 80% experiencing at least 1 episode, and over 90% of these occurring at home.  42% of AEs were systemic reactions, but fewer than 50% received epinephrine, indicating a need for better patient education.  About half of these AEs were gastrointestinal, and half of the patients who dropped out did so due to these gastrointestinal AEs; this amounted to 10% of all enrolled patients.

Overall, allergic rhinitis and the wheal size on peanut skin prick testing (SPT) were significant predictors of AEs.  Allergic rhinitis approximately doubled the likelihood of having an AE, and seemed to explain why there was a higher rate of AEs during the spring and the fall.  Asthma was also predictive of AEs during maintenance, but not in the buildup phase.  Gastrointestinal AEs, like abdominal pain, nausea, vomiting, difficulty swallowing, and diarrhea, were also associated with the peanut SPT wheal size. 

While there remains a lot to be learned about oral immunotherapy, this study helps to determine who would be the best candidates for this promising means of treating food allergies.  Virkud and colleagues conclude that until there are rigorous well-designed and controlled trials, avoidance should remain the current standard of care.

Treatment of infants identified as having severe combined immunodeficiency by means of newborn screening

Severe Combined Immunodeficiency (SCID) is a set of fatal immune disorders in which infants are born without proper functioning immune systems needed to fight off infections.  Fortunately, in recent years, there has been a push in several states for newborn screening (NBS) for early identification and life-saving treatment of these children.  In this month’s issue of JACI, Dorsey and colleagues describe the protocol that they use in California, which has successfully identified 32 SCID patients and 46 non-SCID patients with decreased levels of T-cells (J Allergy Clin Immunol 2017; 139(3): 733-742).

Newborn screening is performed by measuring TRECs (T-cell receptor excision circles) which are formed upon gene rearrangement of the T-cell receptor.  Peripheral blood count with differential and flow cytometry is the first follow up testing to determine the number of lymphocytes. This is followed by functional lymphocyte testing. If SCID is suspected, then children are placed in protective isolation and aggressively treated with antibiotics if needed.  A SCID social worker coordinates with family in order to manage workup and identify needs for support, including emotional support. 

 Because allogenic and autologous hematopoietic stem cell (HSC) transplant is life-saving, Dorsey and colleagues relay that they apply three principles: (1) use of a donor with the least likelihood of graft-versus-host disease (GVHD), (2) minimize the duration of waiting for the SCT, and (3) use the least amount of chemotherapy necessary.  Adherence to these principles has led to good outcomes: among the 32 that underwent transplant, 29 (94%) are alive and well. 

Among the non-SCID patients, the protocol is more reliant on the degree of immunodeficiency, but nevertheless, they are followed up very closely by immunologists in the coming years to identify the status of their immune dysfunction.  There remains a lot of work to be done in order to find out the best way to identify and treat SCID, but nationwide screening promises to accelerate our reaching that goal.

Tuesday, February 28, 2017

Humoral and cellular responses to casein in patients with food protein–induced enterocolitis to cow's milk

Food protein-induced enterocolitis syndrome (FPIES) is a type of food allergy in which children who eat milk, soy, or other foods develop repetitive vomiting and sometimes diarrhea.  This can lead to dehydration, and, in the longer run, failure to thrive.  But unlike more typical food allergies, FPIES isn’t mediated by IgE antibodies.  In fact, what causes FPIES is still a bit of a mystery.  In this month’s issue of JACI, Caubet and colleagues discuss results of their study on the immune responses seen in FPIES due to cow milk (CM-FPIES) (J Allergy Clin Immunol 2017; 139(2): 572-583).

To do this, they looked that the levels of antibodies, cytokines (chemical messengers), cell counts, and tryptase levels in 38 patients with active and resolved CM-FPIES.  Oral food challenges (OFCs) were performed, and the results from positive OFCs were compared to those from negative OFCs.

What they found is that neutrophils could be responsible cells, which were found to be higher in patients with positive oral food challenges.  The high levels of IL-8, a chemoattractant for neutrophils, also supported their conclusion.  Mast cells may also participate, since IL-9 that was also high is produced by mast cells, and baseline tryptase levels were elevated.  But interestingly, tryptase levels didn’t increase with the positive oral food challenge, meaning that mast cells weren’t activated during a challenge.  Regulatory cytokines, such as IL-10 are likely related to the development of oral tolerance in FPIES.  Additionally, levels of antibodies specific to casein, a key component of milk, were low in children with CM-FPIES.    There remain a lot of unanswered questions about FPIES, but this study helps to shine some light on this mysterious type of food allergy.

Tuesday, February 14, 2017

Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study

The immune system is very complicated, and sometimes, a mutation in a single protein can cause major problems.  One such protein is Phosphoinositide 3-kinase (PI3Kδ), which, may interfere with the body’s ability to fight off disease upon activation.  In this month’s issue of JACI, Coulter and colleagues look at 53 patients with Activated PI3Kδ Syndrome (APDS) (J Allergy Clin Immunol 2017; 139(2): 597-606).

These 53 patients were found worldwide, and the diagnosis was confirmed by genetic sequencing.  They then looked at the laboratory findings, radiographs, and other clinical features to better understand the presentation of APDS. 

All in all, the presentation of APDS was highly variable.  Some were asymptomatic through adulthood while others developed infections early in childhood, leading to death.  Three required a bone marrow transplantation.  The most common infectious complication was recurrent respiratory tract infections.  Much like other antibody deficiency syndromes, there was a high rate of bronchiectasis.  Almost half of patients had difficulty fighting viruses like herpes, EBV, and CMV.  Swollen lymph nodes and hepato-splenomegaly were also very common.

Interestingly, PI3K mutations didn’t just effect the ability to fight infections.  Eighteen also had inflammatory/autoimmune diseases, most commonly autoimmune cytopenias. Seventeen had nodular mucosal lymphoid hyperplasia and seven developed lymphoma.  Since PI3K3D is associated with the central nervous system, there was also noted to be a high rate of neurodevelopmental morbidity, ranging from speech delays to global developmental delay.

This study provides a description of APDS, a newly recognized form of immunodeficiency.  It can present in so many different ways, so physicians should keep an eye out in patients who have recurrent infections, especially those involving the respiratory tract or those due to herpes viruses.  Treatment with hematopoietic stem cell transplant may be curative, and clinical trials for selective PI3Kδ inhibitors are currently underway.

Factors influencing the infant gut microbiome at age 3-6 months: Findings from the ethnically diverse Vitamin D Antenatal Asthma Reduction Trial (VDAART)

In the gut, there are millions of bacteria and other micro-organisms, collectively called the gut microbiome.  Microbes in the gut are known to be important modulators of the developing immune system.   In this month’s issue of JACI, Sordillo and colleagues look at predictors of the gut microbiome in infancy (J Allergy Clin Immunol 2017; 139(2): 482-491).  Microbes present in this early life window may ultimately affect the risk of allergic disease later in childhood. 

They looked at stool samples in over 300 infants born to mothers in the Vitamin D Antenatal Asthma Reduction Trial (VDAART), a trial in which pregnant women took vitamin D to see how it would impact their children’s health.  In the stool, they looked at the bacterial genes to see what bacteria were present.

They found that race, mode of delivery, and formula-feeding are associated with different composition of gut bacteria.  Black race and caesarean section were independent predictors of having lower levels of Bacteroides.  This is important because lower Bacteroides abundance has already been associated with immune changes predisposing to asthma and allergic disease.  In addition, formula feeding was linked to higher levels of Clostridia.  Previous studies have suggested a link between Clostridia and development of atopic dermatitis, wheezing and allergic sensitization.

This study points out that factors with the potential to increase allergic disease risk are also associated with alterations in the infant gut microbiome, but there are still a lot of unanswered questions.  Do these factors (race, mode of delivery, formula feeding) act via changes in the infant gut microbiome to increase allergic disease risk?  Do these changes in the gut microbiome persist through childhood?  Can breastfeeding change the microbiome and reduce the risk of allergic disease?  Finally, can we figure out which species and subspecies are most closely associated with these risks?  Further research is needed, but this study provides a meaningful step towards providing answers.