Juan Carlos Cardet

Inflammatory and Comorbid Features of Patients with Severe Asthma and Frequent Exacerbations

Rationale: Reducing asthma exacerbation frequency is an important criterion for approval of asthma therapies, but the clinical features of exacerbation‐prone asthma (EPA) remain incompletely defined. Objectives: To describe the clinical, physiologic, inflammatory, and comorbidity factors associated with EPA. Methods: Baseline data from the NHLBI Severe Asthma Research Program (SARP)‐3 were analyzed. An exacerbation was defined as a burst of systemic corticosteroids lasting 3 days or more. Patients were classified by their number of exacerbations in the past year: none, few (one to two), or exacerbation prone (≥3). Replication of a multivariable model was performed with data from the SARP‐1 + 2 cohort. Measurements and Main Results: Of 709 subjects in the SARP‐3 cohort, 294 (41%) had no exacerbations and 173 (24%) were exacerbation prone in the prior year. Several factors normally associated with severity (asthma duration, age, sex, race, and socioeconomic status) did not associate with exacerbation frequency in SARP‐3; bronchodilator responsiveness also discriminated exacerbation proneness from asthma severity. In the SARP‐3 multivariable model, blood eosinophils, body mass index, and bronchodilator responsiveness were positively associated with exacerbation frequency (rate ratios [95% confidence interval], 1.6 [1.2‐2.1] for every log unit of eosinophils, 1.3 [1.1‐1.4] for every 10 body mass index units, and 1.2 [1.1‐1.4] for every 10% increase in bronchodilatory responsiveness). Chronic sinusitis and gastroesophageal reflux were also associated with exacerbation frequency (1.7 [1.4‐2.1] and 1.6 [1.3‐2.0]), even after adjustment for multiple factors. These effects were replicated in the SARP‐1 + 2 multivariable model. Conclusions: EPA may be a distinct susceptibility phenotype with implications for the targeting of exacerbation prevention strategies. Clinical trial registered with www.clinicaltrials.gov (NCT 01760915).

Alcohol-induced Respiratory Symptoms Are Common in Patients With Aspirin Exacerbated Respiratory Disease

BACKGROUND A large percentage of patients with aspirin exacerbated respiratory disease (AERD) report the development of alcohol-induced respiratory reactions, but the true prevalence of respiratory reactions caused by alcoholic beverages in these patients was not known. OBJECTIVE We sought to evaluate the incidence and characteristics of alcohol-induced respiratory reactions in patients with AERD. METHODS A questionnaire designed to assess alcohol-induced respiratory symptoms was administered to patients at Brigham and Womens Hospital and Scripps Clinic. At least 50 patients were recruited into each of 4 clinical groups: (1) patients with aspirin challenge-confirmed AERD, (2) patients with aspirin-tolerant asthma (ATA), (3) patients with aspirin tolerance and with chronic rhinosinusitis, and (4) healthy controls. Two-tailed Fisher exact tests with Bonferroni corrections were used to compare the prevalence of respiratory symptoms among AERD and other groups, with P ≤ .017 considered significant. RESULTS The prevalence of alcohol-induced upper (rhinorrhea and/or nasal congestion) respiratory reactions in patients with AERD was 75% compared with 33% with aspirin-tolerant asthma, 30% with chronic rhinosinusitis, and 14% with healthy controls (P < .001 for all comparisons). The prevalence of alcohol-induced lower (wheezing and/or dyspnea) respiratory reactions in AERD was 51% compared with 20% in aspirin-tolerant asthma and with 0% in both chronic rhinosinusitis and healthy controls (P < .001 for all comparisons). These reactions were generally not specific to one type of alcohol and often occurred after ingestion of only a few sips of alcohol. CONCLUSION Alcohol ingestion causes respiratory reactions in the majority of patients with AERD, and clinicians should be aware that these alcohol-induced reactions are significantly more common in AERD than in controls who are aspirin tolerant.

Prostaglandin E2 resistance in granulocytes from patients with aspirin-exacerbated respiratory disease

BACKGROUND Aspirin-exacerbated respiratory disease (AERD) is an inflammatory condition of the respiratory tract and is characterized by overproduction of leukotrienes (LT) and large numbers of circulating granulocyte-platelet complexes. LT production can be suppressed by prostaglandin E(2) (PGE(2)) and the cyclic AMP-dependent protein kinase A (PKA). OBJECTIVE To determine if PGE(2)-dependent control of LT production by granulocytes is dysregulated in AERD. METHODS Granulocytes from well-characterized patients with and without AERD were activated ex vivo and subjected to a range of functional and biochemical analyses. RESULTS Granulocytes from subjects with AERD generated more LTB4 and cysteinyl LTs than did granulocytes from controls with aspirin-tolerant asthma and controls without asthma. When compared with controls, granulocytes from subjects with AERD had comparable levels of EP(2) protein expression and PGE(2)-mediated cAMP accumulation, yet were resistant to PGE(2)-mediated suppression of LT generation. Percentages of platelet-adherent neutrophils correlated positively with LTB4 generation and inversely with responsiveness to PGE(2)-mediated suppression of LTB(4). The PKA inhibitor H89 potentiated LTB4 generation by control granulocytes but was inactive in granulocytes from individuals with AERD and had no effect on platelet P-selectin induction. Both tonic PKA activity and levels of PKA catalytic gamma subunit protein were significantly lower in granulocytes from individuals with AERD relative to those from controls. CONCLUSIONS Impaired granulocyte PKA function in AERD may lead to dysregulated control of 5-lipoxygenase activity by PGE(2), whereas adherent platelets lead to increased production of LTs, which contributes to the features of persistent respiratory tract inflammation and LT overproduction.

Immunology and Clinical Manifestations of Non-Clonal Mast Cell Activation Syndrome

There is a spectrum of disorders that clinically manifest as a result of mast cell activation. A non-clonal form has emerged in the literature where many of the clinical features of systemic mastocytosis are shared despite having a distinct mast cell biology. In this review, we summarize key features of the science behind mast cell activation relevant to what is now known as non-clonal mast cell activation syndrome (nc-MCAS). We highlight the clinical manifestations of nc-MCAS with a focus on diagnosis and treatment.

Vitamin D Supplementation and the Risk of Colds in Patients with Asthma.

RATIONALE Restoration of vitamin D sufficiency may reduce asthma exacerbations, events that are often associated with respiratory tract infections and cold symptoms. OBJECTIVES To determine whether vitamin D supplementation reduces cold symptom occurrence and severity in adults with mild to moderate asthma and vitamin D insufficiency. METHODS Colds were assessed in the AsthmaNet VIDA (Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness) trial, in which 408 adult patients were randomized to receive placebo or cholecalciferol (100,000 IU load plus 4,000 IU/d) for 28 weeks as add-on therapy. The primary outcome was cold symptom severity, which was assessed using daily scores on the 21-item Wisconsin Upper Respiratory Symptom Survey. MEASUREMENTS AND MAIN RESULTS A total of 203 participants experienced at least one cold. Despite achieving 25-hydroxyvitamin D levels of 41.9 ng/ml (95% confidence interval [CI], 40.1-43.7 ng/ml) by 12 weeks, vitamin D supplementation had no effect on the primary outcome: the average peak WURSS-21 scores (62.0 [95% CI, 55.1-68.9; placebo] and 58.7 [95% CI, 52.4-65.0; vitamin D]; P = 0.39). The rate of colds did not differ between groups (rate ratio [RR], 1.2; 95% CI, 0.9-1.5); however, among African Americans, those receiving vitamin D versus placebo had an increased rate of colds (RR, 1.7; 95% CI, 1.1-2.7; P = 0.02). This was also observed in a responder analysis of all subjects achieving vitamin D sufficiency, regardless of treatment assignment (RR, 1.4; 95% CI, 1.1-1.7; P = 0.009). CONCLUSIONS Our findings in patients with mild to moderate asthma undergoing an inhaled corticosteroid dose reduction do not support the use of vitamin D supplementation for the purpose of reducing cold severity or frequency.

Insulin resistance modifies the association between obesity and current asthma in adults.

Insulin resistance potentiates the association between obesity and childhood asthma, but this relationship appears inconsistent in relatively small studies of adults. We investigated effect modification in adults using the National Health and Nutrition Examination Survey 2003–2012, a large, nationally representative database. Insulin resistance and a history of physician-diagnosed current asthma were obtained from 12 421 adults, ages 18–85 years. We used logistic regression to determine associations between obesity and current asthma, adjusting for age, sex, race/ethnicity, poverty income ratio and smoking status. An interaction term evaluated effect modification by insulin resistance of the obesity–asthma association. As expected, obesity was positively associated with current asthma. Insulin resistance modified this association, with obesity measured as body mass index, waist circumference or waist-to-height ratio. The relationship between obesity and current asthma was stronger with increasing insulin resistance tertiles (OR 2.05, 95% CI 2.76–3.00; p-value for interaction 0.03). This association was robust to adjustments for other components of the metabolic syndrome (hypertriglyceridaemia, hypertension, hyperglycaemia and systemic inflammation). None of these components were themselves effect modifiers of the obesity–asthma association. In this large, nationally representative sample, insulin resistance modified the association between obesity and current asthma in adults. Targeting insulin resistance may represent a novel therapeutic strategy for obese patients with asthma. Insulin resistance potentiates the obesity–asthma association and may be a therapeutic target in obese asthmatics http://ow.ly/Zu9bb

Update on reslizumab for eosinophilic asthma.

Introduction: Patients with severe eosinophilic asthma have an unmet need for novel and efficacious treatments. Reslizumab is one of the three monoclonal antibodies targeting the IL-5 pathway and has been found in Phase IIIb clinical trials to reduce asthma exacerbations, control asthma-related symptoms and improve pulmonary function in patients with eosinophilic asthma. Areas covered: In this article, we discuss the results of asthma clinical trials using reslizumab, beginning with a discussion of the relationship between eosinophils, IL-5 and asthma. We conducted PubMed searches using the terms ‘reslizumab’, ‘anti-IL-5’, ‘eosinophilic asthma’, ‘IL-5 asthma’. We also searched ClinicalTrials.gov for ‘reslizumab’, ‘reslizumab asthma’, ‘SCH 55700’, ‘SCH 55700 asthma’, ‘Cinquil’ and ‘Cinquil asthma’. Expert opinion: Reslizumab and other anti-IL-5 therapies have seen success in recent trials through more stringent study participant selection targeting eosinophilic inflammation. This selection can now be based on simple blood counts. These drugs have shown a very good safety profile, but long-term safety data are not yet available. Approval for these drugs is eagerly awaited by clinicians and patients alike.

Baseline Features of the Severe Asthma Research Program (SARP III) Cohort: Differences with Age

BACKGROUND The effect of age on asthma severity is poorly understood. OBJECTIVES The objective of this study was to compare the baseline features of severe and nonsevere asthma in the Severe Asthma Research Program (SARP) III cohort, and examine in cross section the effects of age on those features. METHODS SARP III is a National Institutes of Health/National Heart Lung Blood Institute multisite 3-year cohort study conducted to investigate mechanisms of severe asthma. The sample included 188 children (111 severe, 77 nonsevere) and 526 adults (313 severe, 213 nonsevere) characterized for demographic features, symptoms, health care utilization, lung function, and inflammatory markers compared by age and severity. RESULTS Compared with children with nonsevere asthma, children with severe asthma had more symptoms and more historical exacerbations, but no difference in body weight, post-bronchodilator lung function, or inflammatory markers. After childhood, and increasing with age, the cohort had a higher proportion of women, less allergen sensitization, and overall fewer blood eosinophils. Enrollment of participants with severe asthma was highest in middle-aged adults, who were older, more obese, with greater airflow limitation and higher blood eosinophils, but less allergen sensitization than adults with nonsevere asthma. CONCLUSIONS The phenotypic features of asthma differ by severity and with advancing age. With advancing age, patients with severe asthma are more obese, have greater airflow limitation, less allergen sensitization, and variable type 2 inflammation. Novel mechanisms besides type 2 inflammatory pathways may inform the severe asthma phenotype with advancing age.

Addition of mycophenolate mofetil to tacrolimus is associated with decreases in food-specific IgE levels in a pediatric patient with liver transplantation-associated food allergy

104 Transplantation-associated food allergy is most commonly seen in pediatric liver transplant recipients on tacrolimus and may be associated with atopic dermatitis, eosinophilic gastrointestinal disease, poor weight gain, and clinical reactivity to multiple foods. Reducing the dose of tacrolimus and adding mycophenolate mofetil to the immunosuppressive regimen may lead to resolution of this condition. Clinical trials should investigate whether mycophenolate mofetil facilitates resolution or confers protection from transplantation-associated food allergy.

Income Is an Independent Risk Factor for Worse Asthma Outcomes

Background: Socioeconomic status (SES) is associated with asthma morbidity in observational studies, but the factors underlying this association are uncertain. Objective: We investigated whether 3 SES correlates—low income, low education, and high perceived stress—were independent risk factors for treatment failure and asthma exacerbations in the context of a randomized controlled trial. Methods: The effect of low SES (household income of <