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Wednesday, May 6, 2015

Celiac Disease

Given an increasing awareness of gluten-related disorders, medical professionals are encountering patients diagnosed with celiac disease or thought to have food intolerance to gluten. Green et al provide a review of the pathogenesis, clinical manifestations, diagnosis, and management of celiac disease (J Allergy Clin Immunol 2015; 135(5):1099-1106).

There are currently three major wheat-related food illnesses: celiac disease (CD), non-celiac gluten sensitivity (NCGS), and wheat allergy. CD is an autoimmune disorder involving both an innate and adaptive response in genetically predisposed individuals. Unlike food allergies, the pathogenesis of CD is not mediated by an immediate hypersensitivity reaction via an immunoglobulin (IgE) dependent mechanism. Instead, gluten protein is a pathogenic agent activated by the enzyme tissue transglutaminase (TTG) allowing its presentation to CD4+ T cells in the small intestine. NCGS is a term that refers to a spectrum of clinical phenotypes, without the identification of characteristic histologic or serologic abnormalities. Wheat allergy is distinct from both, in that it is an IgE mediated hypersensitivity response that occurs within minutes to hours of wheat ingestion.

Celiac disease has prevalence of nearly 1% among Western nations. Its distribution extends into such disparate populations as the Middle East, South America, Asia, and North Africa. A proposed reason for this trend is a globalizing world market bringing wheat-based foods into cultures that traditionally relied on gluten-free grains. There is evidence CD is a missed diagnosis in many children where infection and malnutrition are the presumed etiology for diarrheal illness. Its pathogenesis depends on the interaction of three factors. The first is predisposing genes, HLA DQ2 and DQ8, and the second is exposure to gluten. The third, environmental factors, includes many under investigation, including breastfeeding and the intestinal microbiome.

There is increasing evidence that CD includes extra-intestinal manifestations, and the terminology for describing it is changing to allow for these. Common presentations include anemia and osteoporosis. Despite increased awareness of the condition and gluten, the rate of diagnosis in the US remains low, with less than 20% of those with the actual condition having been diagnosed. The IgA TTG assay is the initial test of choice to detect antibodies associated with CD. Treatments in addition to the gluten-free diet, such as intraluminal agents, immunomodulators, and vaccination, are currently under investigation.

Question for the authors: 
Is there data available for the prevalence of wheat allergy in Western nations?

Although some overlap exists in the symptoms attributed to wheat allergy, specific pathophysiological reactions to wheat are currently classified into three categories: 1) IgE hypersensitivity associated wheat allergy 2) autoimmune IgA related celiac disease and 3) non celiac gluten sensitivity (NCGS). The prevalence of IgE related wheat allergy, which is most common in childhood, is estimated around 0.4-1.3%. Our review describes the prevalence of celiac disease near 1% in Western nations; however, the incidence of celiac disease has increased over time, and there is evidence of its underdiagnosis among the general population. NCGS is currently not as well understood as the other two wheat related allergies, and estimates of its prevalence are wide-ranging from 0.5-6%.

Immunopathophysiology of food protein-induced enterocolitis syndrome

Food protein-induced enterocolitis syndrome (FPIES) and food protein-induced proctocolitis are non-IgE-mediated gastrointestinal allergies. Our current understanding of the mechanisms of these allergies linking exposure to the typical symptoms of vomiting, hypotension, and diarrhea falls behind that of other food-induced allergic disorders. Accompanying a comprehensive review of clinical features by Nowak-Wegrzyn that also appears in this issue, Berin assesses the state of our knowledge of the immune mechanisms of FPIES (J Allergy Clin Immunol 2015; 135(5):1108-1113).

FPIES is most commonly triggered by the protein component in cow’s milk, but a host of other foods can be triggers as well. Many of the foods that trigger FPIES reactions are also IgE-mediated food allergens, such as soy, fish, wheat, and egg, but many are not common in that regard. For example, rice is the third most common cause of FPIES in US cohorts, followed by oats. The fact that a range of common foods have the potential to trigger it is in contrast to celiac disease, in which pathology is triggered by a well-defined antigen in a restricted subset of foods.

Studies have demonstrated FPIES leads to changes in the intestinal architecture in response to chronic exposure to a trigger such as milk. Avoiding milk results in normalization, and its reintroduction results in a recurrence of partial villous atrophy. While this is similar to celiac disease, the two conditions differ in pathophysiology. For example, the latter is thought to be a food antigen-triggered autoimmunity. There is a lack of evidence for an autoimmune component in FPIES, but there is an association between it and atopy. There is mast cell degranulation in common between the two, which is an important factor that requires investigation.


The facts that FPIES commonly develops in response to the first food introduced into the diet and adverse reactions can develop in response to many foods that are not typically allergenic suggests there may be a regulatory defect in patients with FPIES. The presence and phenotype of food-specific T cells in the intestinal mucosa of patients with FPIES needs to be demonstrated, as has been done with celiac patients. There is even less data to explain the immune basis of acute FPIES reactions. In one case study, milk administered via enema resulted in diarrhea and weight loss, whereas drinking the milk induced vomiting, pallor, and diarrhea in the same infant. Thus, the chronic and acute manifestations of FPIES can be triggered at different sites. Is processing of the allergen during digestion required to trigger symptoms? Much remains to be investigated about its underlying immune mechanisms.

Anaphylaxis: Unique aspects of clinical diagnosis and management in infants (birth to age 2 years)

Anaphylaxis is reported to occur with increasing frequency in infants. An illustrated Rostrum on the diagnosis, treatment, and long-term management of anaphylaxis in this age group has been published by Simons and Sampson (J Allergy Clin Immunol 2015;135: 1125-31).
Foods such as milk, egg, and peanut are by far the most common triggers of anaphylaxis in infancy, although medications and other triggers can also be implicated. Infants with anaphylaxis typically present with sudden onset of skin signs such as generalized urticaria, respiratory symptoms such as cough, wheeze, stridor, and dyspnea, and/or gastrointestinal symptoms such as persistent vomiting.
Clinical criteria for diagnosis of anaphylaxis are validated for use in children and adults, but have not yet been validated for use in infants. A high index of suspicion is required to diagnose anaphylaxis in babies, as they cannot describe symptoms such as itching, and signs of infant anaphylaxis such as flushing, dysphonia, incontinence, and behavior changes (irritability, somnolence) also occur in healthy infants.
The differential diagnosis of anaphylaxis in infancy includes unique entities such as congenital abnormalities of the respiratory tract or gastrointestinal tract, and food protein-induced enterocolitis syndrome. Epinephrine injection is the treatment of choice in both clinical and community settings.
Co-morbidities that increase the risk of severe anaphylaxis are not well-defined, but probably include croup, bronchiolitis, or asthma; likewise, amplifying co-factors are not well-defined in this age group.
Long-term management focuses on follow-up with a physician, preferably an allergy/immunology specialist who can train caregivers of infants to recognize and treat anaphylaxis in the community and help them to prevent anaphylaxis episodes.
Epinephrine auto-injectors (EAIs) are under-prescribed and under-used for anaphylaxis in infants. In a study in which a minority of infants with severe anaphylaxis were treated with epinephrine, reasons for not using it included failure to recognize anaphylaxis symptoms and being afraid to inject epinephrine.
Strict avoidance of exposure to culprit allergens (as confirmed by skin prick tests and specific IgE measurements) prevents recurrences but requires sustained vigilance from all the infant’s caregivers. Natural desensitization to foods such as milk or egg eventually occurs in many infants and children, especially those with mild initial reactions and low levels of sensitization.
Simons and Sampson have outlined specific goals for research on anaphylaxis in infancy. These include validation of the clinical criteria for diagnosis, studies of infant co-morbidities and amplifying co-factors that increase the risk of severe anaphylaxis, development of EAIs containing a 0.1 mg epinephrine dose suitable for this age group, and inclusion of infants in prospective studies of immune modulation to prevent anaphylaxis.


 Question for the authors: In addition to being alert to the possibility of some infants eventually undergoing natural desensitization to milk or egg and helping to facilitate this desensitization, what other possibilities for prevention of anaphylaxis in infants do you see?
Answer: In an important prospective randomized trial in carefully-selected, high-risk infants age 4-11 months (Du Toit G et al, N Engl J Med 2015;372:803-13), early introduction of peanut significantly decreased the frequency of the development of peanut allergy and modulated immune responses to peanut. Although it remains to be proven whether these findings can be translated to other foods such as milk and egg and additional questions need to be addressed, this research suggests that the increase in prevalence of food-induced anaphylaxis in infants might eventually be halted. 

Tuesday, April 14, 2015

Biomarker-based asthma phenotypes of corticosteroid response

Inhaled corticosteroids (ICSs) are the mainstay of treatment of asthma. However, a considerable proportion of asthmatic patients do not respond to ICSs based on lung function, or other clinical outcomes, or both. Therefore, biomarkers relevant to the underlying pathophysiologic process, the response to treatment, or both would be useful in personalizing care of asthmatic patients. This need led Cowan et al to follow up from an original study of a 2 phase trial consisting of a steroid-naïve phase 1 and a 28-day trial of ICSs (phase 2) during which fraction of exhaled nitric oxide (FENO) values, eosinophil counts, and urinary bromotyrosine (BrTyr) levels were measured in asthmatic patients (J Allergy Clin Immunol 2015; 135(4): 877-883).

Over the last decade, FENO values and sputum eosinophil counts have been used as biomarkers of airway inflammation and predictors of steroid responsiveness. FENO values are correlated with airway eosinophilia and associated with airway hyper-responsiveness. Moreover, studies indicate that high FENO values in asthmatic patients indicate an at-risk phenotype for exacerbations and predict clinical response to ICSs or oral corticosteroids. Eosinophils are well recognized as biomarkers of active atopic inflammation and a relationship exists between sputum eosinophil counts and exacerbation of withdrawal of steroids. Upon activation, eosinophils undergo respiratory burst, generating high levels of reactive oxygen species and eosinophil peroxidase that is unique in its ability to convert respiratory burst-generated hydrogen peroxide into hypobromous acid, a reactive brominating oxidant that modifies protein tyrosine residues forming urinary BrTyr.

The authors compared the utility of a panel of biomarkers consisting of FENO, sputum eosinophils, and urine BrTyr that identify the presence of atopic inflammation and oxidative stress for prediction of clinical response to steroids. They show that the effect of ICSs on inflammatory biomarkers was not uniformly concordant, although there were substantial parallel decreases among biomarkers. Each of the biomarkers had utility for predicting steroid responsiveness; the combination of high FENO values and high urinary BrTyr levels had particular power to predict a favorable clinical response to ICS therapy with either improvement in Asthma Control Questionnaire score, FEV1 or airway reactivity. Cowan concludes that future studies must focus on evaluation of biomarker panels for assessment of exacerbation risk and whether the magnitude of change in biomarker values might predict the magnitude of clinical benefit with treatments.

Question for the authors:
Do you see other applications for this biomarker panel for the clinical benefit of asthma, such as aiding in the determination of asthma subtypes early in diagnosis?

Response from the authors:

Our study highlights the potential for utilizing the combination of urinary Br Tyr and FENO to predict the likelihood of steroid responsiveness in asthmatic individuals, without resorting to sputum induction, preparation and analysis.  These measurements could be made at the first clinic visit so that treatment can be tailored to the individual allowing steroids to be prescribed in a targeted fashion whilst also allowing the earlier consideration of other treatments in non-steroid responsive asthma subtypes.  Further studies should focus on the identification of alternative treatments in these steroid-unresponsive phenotypes.

Friday, April 10, 2015

Overweight children report qualitatively distinct asthma symptoms: Analysis of validated symptom measures

The relationship between overweight/obesity and asthma phenotype in children remains inadequately defined. Several large epidemiologic studies have demonstrated that obesity increases the risk of physician-diagnosed asthma and is associated with greater asthma-related health utilization and asthma that is more problematic and difficult to control. This discrepancy regarding the impact of obesity suggests that more in-depth and novel assessments of lean and obese asthmatic children may be required. Specifically, few studies have addressed how obese patients perceive and report asthma symptoms. This led Lang et al to determine the qualitative differences in symptoms between lean and overweight/obese children with early-onset, atopic asthma (J Allergy Clin Immunol 2015; 135(4): 886-893).

The authors conducted a cross-sectional analytic study of lean and overweight/obese 10-17 year old children with persistent, early-onset asthma. Participants provided a complete history, qualitative and quantitative asthma symptom characterization, and lung function testing. They determined associations between weight status and symptoms using multivariable linear and logistic regression methods. The authors report that overweight/obese and lean children displayed similar baseline spirometry values. However, despite lower fraction of exhaled nitric oxide and reduced methacholine responsiveness, overweight/obese children reported requiring rescue treatments more than 3x that of lean children. Weight status affected the child’s primary symptom reported with loss of asthma control; overweight/obese children more often reported shortness of breath and less often reported cough.   Using three validated questionnaires for assessing asthma symptom control, the authors showed that overweight/obese status was consistently associated with greater symptom reporting.  Subscale analysis suggested that shortness of breath and self-medication with rescue medication consistently drove the worse asthma scoring.  Gastroesophageal reflux (GER) scores were higher in overweight/obese children and appear to mediate overweight/obesity-related asthma symptoms.

Lang concludes that overweight/obese children with early-onset asthma display poorer asthma control and a distinct pattern of symptoms. Moreover, greater shortness of breath and β-agonist use appears to be partially mediated via esophageal reflux symptoms, which may lead to overweight children with asthma falsely attributing exertional dyspnea and esophageal reflux to asthma and excess rescue medication use. Because dyspnea from asthma is a major driver of anxiety, reduced quality of life, health care utilization, and medication use, a greater understanding of the distinct sensory mechanisms of dyspnea is needed. Until systematic weight loss interventions become more feasible, respiratory physicians may serve their patients better by considering and discussing alternative causes of dyspnea in self-management plans.

Question for the authors:
Are there other factors associated with obesity that may be a factor in the severity of asthma symptoms, such as socioeconomic and health related factors?


Several comorbidities associated with obesity are also likely to influence asthma either directly or by complicating its perception and management.  The best examples include snoring/sleep apnea, immune and metabolic derangements and impaired cardiopulmonary reserve.  We adjusted for presence of snoring in our analysis which did not affect our results (as did adjusting for GER scores).  Lower socioeconomic status has been associated in the past with greater prevalence of obesity and worse asthma control, thereby making it a possible confounding factor.  However, several socioeconomic and environmental factors were measured in our study including race, ethnicity, parental education, income, inutero smoking and later environmental smoke exposure.  None of these measures were associated with overweight/obesity status in our study.  We did not measure for levels of activity.  The effect of daily activity on disease activity, response to controller therapy, and perception of asthma symptoms requires more investigation and may provide important insights into the relationship between obesity and asthma.  

Wednesday, April 8, 2015

The prevalence of severe refractory asthma

Severe asthma is characterized by difficulty to achieve disease control despite high-dose inhaled glucocorticoids plus long acting β2 –agonists (LABAs) or oral corticosteroids (OCSs). In 2011, the Innovative Medicine Initiative (IMI) published an international consensus statement in which a more accurate definition of severe asthma was proposed. In this statement, a clear distinction was made between “difficult to control asthma” and “severe refractory asthma.” In patients with difficult to control asthma, the lack of asthma control is due to other factors than asthma itself, such as nonadherence to treatment or incorrect inhalation technique. On the other hand, in patients with severe refractory asthma, the disease remains uncontrolled despite addressing and removing all possible factors that might aggravate the underlying disease. Hekking et al sought to estimate the prevalence of severe refractory asthma as defined by the IMI consensus (J Allergy Clin Immunol 2015; 135(4): 896-902).

Adult patients with a prescription for high-intensity treatment were extracted from 65 Dutch pharmacy databases, representing 3% of the population. Questionnaires were sent to patients and about half (2312) were analyzed. The diagnosis of asthma and degree of asthma control were derived from the questionnaires to identify patients with difficult-to-control asthma and inhalation technique was assessed in a random sample of 60 adherent patients. The authors determined that patients with difficult to control asthma, adherence to treatment, and a correct inhalation technique were qualified as having severe refractory asthma. The results indicated that of asthmatic adults, 3.6% qualified for a diagnosis of severe refractory asthma, representing 10.4 patients per 10,000 inhabitants.

The authors speculate about the reasons for the difference between the prevalence of severe refractory asthma mentioned in the literature (5%-10%) and their results (3.6%). Estimations in the literature are based on expert opinion and clinical experience, it is reasonable to believe that not all factors that negatively influence asthma control are receiving full attention in the consulting room. Therefore clinical overestimation of the prevalence of truly severe refractory asthma might easily occur because of misclassification of patients with difficult-to-control asthma as patients with severe refractory asthma. Clinicians should be aware of the distinction between these 2 conditions and check potential aggravating factors, in particular poor adherence with treatment and inadequate inhalation technique. Another important result of this study is because the prevalence of this condition might be lower than previously thought, severe refractory asthma could fulfill the criteria of a rare disease and qualifies for niche drugs. Together, these data will hopefully facilitate the development and reimbursement of novel targeted treatments. 

Wednesday, March 18, 2015

Pioglitazone restores mitochondrial oxidant production in CGD phagocytes and enhances their bactericidal capacity

In addition to having a nonfunctional NADPH oxidase, activated phagocytes from patients with chronic granulomatous disease (CGD) and gp91phox-/- mice (modeling X-linked CGD) lack oxidant production from mitochondria, as reported by authors Fernandez-Boyanapalli et al (http://www.jacionline.org/article/S0091-6749%2814%2901576-0/abstract) . Specifically, neutrophils and monocytes from blood, as well as recruited neutrophils and macrophages from inflamed tissues of CGD mice, failed to produce mitochondrial oxidants when activated. Deficient mitochondrial oxidant production was shown to contribute to impaired bactericidal activity against Staphylococcus aureus and Burkholderia cepacia in vitro. Importantly, the researchers demonstrated that mitochondrial oxidant production was restored (see Figure) following short-term treatment of CGD mice with pioglitazone, a PPAR? agonist approved for treatment of type 2 diabetes. Pioglitazone is known to induce metabolic changes that mimic “starvation signaling,” including altering mitochondrial functions. Treatment of CGD mice with pioglitazone restored the bactericidal activity of their phagocytes to approximately 30% of normal murine phagocytes and enhanced early bacterial clearance of S aureus in a peritonitis model. Treatment of monocytes from X-linked CGD patients with pioglitazone ex vivo similarly restored mitochondrial oxidant production supporting the hypothesis that pioglitazone may be useful therapeutically in the treatment of CGD.