Tolly Epstein

Surveillance of systemic reactions to subcutaneous immunotherapy injections: year 1 outcomes of the ACAAI and AAAAI Collaborative Study

BACKGROUND Although systemic reactions (SRs) to subcutaneous immunotherapy (SCIT) injections are not uncommon, life-threatening and fatal reactions are rare. The annual incidence of injection-related SRs of varying severity is not well-defined. OBJECTIVE To determine the annual frequencies of SCIT reactions in North America via a longitudinal surveillance program initiated among practicing allergists in 2008. METHODS Physicians were asked to complete a Web-based survey reporting numbers of injections administered, injection- and skin test-related fatal reactions, and all nonfatal SRs in their clinical practices during the previous 12 months. The SR events were classified as mild (grade 1: cutaneous or upper respiratory symptoms), moderate (grade 2: asthma with reduced lung function), or severe (grade 3: life-threatening airway compromise or hypotension). RESULTS In the initial year of the program, 806 physicians responded, representing 1,922 SCIT prescribers. No fatal reactions to SCIT injections were identified during the first 12 months, although 6 SCIT fatal reactions were reported retrospectively between 2001 and 2007. Eighty-two percent of practices reported 8,502 SRs to SCIT (10.2 SRs per 10,000 = 0.1% of injection visits). Most were grade 1 (74%) or grade 2 (23%) SRs. However, 3% (n = 265) were grade 3 anaphylactic events (3 severe reactions for every 100,000 injection visits). CONCLUSIONS We demonstrated the feasibility of annual surveillance of SRs associated with SCIT injections. This surveillance study will continue to monitor SCIT adverse events in parallel with vigorous efforts instituted by members of professional organizations aimed at reducing the risk of severe reactions.

AAAAI/ACAAI Surveillance Study of Subcutaneous Immunotherapy, Years 2008-2012: An Update on Fatal and Nonfatal Systemic Allergic Reactions

BACKGROUND Before 2002, there were an estimated 3.4 fatal reactions per year to subcutaneous allergen immunotherapy (SCIT). Recent incidences of SCIT-related systemic allergic reactions (SR) and fatal reactions are not well defined. OBJECTIVE To define the incidence of and clinical practices associated with SRs to SCIT and skin testing. METHODS From 2008 to 2012, 27% to 49% of the American College of Allergy, Asthma, and Immunology and American Academy of Allergy, Asthma, and Immunology members completed an annual survey of SCIT-related fatal and nonfatal SRs of varying severity. A shortened version of the World Allergy Organization (WAO) classification system for SRs was adopted in 2011 (grade 1, mild; grade 2, moderate; grade 3, severe; grade 4, very severe). From 2011 to 2012, data were collected regarding nonfatal SRs to skin testing and strategies to lower the risk of SRs from SCIT. RESULTS Between 2008 and 2012, data were gathered on 23.3 million injection visits. One confirmed fatality occurred in 2009. Overall SR rates remained stable at 0.1%. The rate of very severe, WAO grade 4, SRs was similar to previously reported rates of near-fatal reactions (1 in 1 million injections). Although almost one-third of practices experienced at least 1 SR from skin testing, no WAO grade 3 or 4 SRs from skin testing were reported. A lower target dose during cluster buildup before transitioning to maintenance may be associated with a lower risk of WAO grade 3 SRs (P = .07). Dose adjustment during pollen seasons was associated with fewer WAO grade 3 or 4 SRs (P < .001). CONCLUSIONS Although SR rates have remained stable and fatalities appear to be declining, continued vigilance regarding SCIT safety is recommended. Additional surveillance and study regarding methods to decrease the risk of severe SRs is warranted.

Current and Emerging Management Options for Hereditary Angioedema in the US

Hereditary angioedema (HAE) is a rare disorder characterized by recurrent attacks of swelling that may involve multiple anatomical locations. In the majority of patients, it is caused by a functional or quantitative defect in the C1 inhibitor (C1-INH), which is an important regulator of the complement, fibrinolytic, kallikrein-kinin and coagulation systems. Standard treatments used for other types of angioedema are ineffective for HAE. Traditional therapies for HAE, including fresh frozen plasma, ε-aminocaproic acid and danazol, may be well tolerated and effective in some patients; however, there are limitations both in their safety and efficacy.Several novel therapies have completed phase III trials in the US, including: (i) plasma-derived C1-INH replacement therapies (Berinert P® and Cinryze®); (ii) a recombinant C1-INH replacement therapy (conestat alfa; Rhucin®); (iii) a kallikrein inhibitor (ecallantide [DX-88]); and (iv) a bradykinin-2-receptor antagonist (icatibant). Both Berinert P® and Cinryze® are reported to have excellent efficacy and safety data from phase III trials. Currently, only Cinryze® has been approved for prophylactic use in the US. US FDA approval for other novel agents to treat HAE and for the use of Cinryze® in the treatment of acute attacks is pending.

Risk factors for fatal and nonfatal reactions to subcutaneous immunotherapy: National surveillance study on allergen immunotherapy (2008–2013)

BACKGROUND In 2008, an annual surveillance study of systemic reactions (SRs) from subcutaneous immunotherapy (SCIT) injections was initiated in North America. OBJECTIVE To define the incidence of SRs to SCIT. METHODS From 2008 to 2013, 27% to 51% of American Academy of Allergy, Asthma, and Immunology and American College of Asthma, Allergy, and Immunology members completed an annual survey of SCIT-related SRs of varying severity. From 2012 to 2013, data were collected regarding SRs with off-label sublingual immunotherapy (SLIT), selection of patients with asthma for SCIT, and strategies for dose adjustment during pollen seasons. RESULTS From 2008 to 2013, data were gathered on 28.9 million injection visits, including 344,480 patients for 2012 to 2013. Since 2008, a total of 2 confirmed fatalities were directly reported that occurred under the care of allergists. Two additional fatalities occurred under the care of nonallergists. The rate of SRs from SCIT remained stable, occurring in 1.9% of patients, with 0.08% and 0.02% experiencing grade 3 and 4 SRs. SRs occurred in 1.4% of patients receiving off-label SLIT, including 0.03% with grade 3 SRs. There were no SLIT-related grade 4 SRs or fatalities. Practices that never administered SCIT in patients with uncontrolled asthma (Asthma Control Test score <20) had significantly fewer grade 3 and 4 SRs (odds ratio, 0.7; 95% confidence interval, 0.5-1.0, and odds ratio, 0.3; 95% confidence interval, 0.1-0.8, respectively). Lowering doses during pollen seasons for patients with highly positive skin tests reduced SRs of all severity grades (P < .05). CONCLUSIONS SCIT-related fatality rates may be decreasing, but continued vigilance regarding modifiable risk factors, including careful patient selection, is needed. Dose adjustment during pollen seasons for highly sensitive patients may reduce risks. Potential risk for SRs from off-label SLIT exists.

Genetic and Environmental Risk Factors for Childhood Eczema Development and Allergic Sensitization in the CCAAPS Cohort

Eczema is very common and increasing in prevalence. Prospective studies investigating environmental and genetic risk factors for eczema in a birth cohort are lacking. We evaluated risk factors that may promote development of childhood eczema in the Cincinnati Childhood Allergy and Air Pollution Study (CCAAPS) birth cohort (n=762) of infants with at least one atopic parent. Objective environmental exposure data were available for each participant. At annual physical examinations, children underwent skin prick tests (SPTs), eczema was diagnosed by a clinician, and DNA was collected. Among Caucasian children, 39% developed eczema by age 3. Children with a pet dog were significantly less likely to have eczema at age one (odds ratio (OR)=0.62, 95% confidence interval (CI): 0.40-0.97) or at both ages 2 and 3 (OR=0.54, 95% CI: 0.30-0.97). This finding was most significant among children carrying the CD14-159C/T CC genotype. Carriers of the CD14-159C/T and IL4Ralpha I75V single-nucleotide polymorphisms (SNPs) had an increased risk of eczema at both ages 2 and 3 (OR=3.44, 95% CI: 1.56-7.57), especially among children who were SPT+. These results provide new insights into the pathogenesis of eczema in high-risk children and support a protective role for early exposure to dog, especially among those carrying the CD14-159C/T SNP. The results also demonstrate a susceptibility effect of the combination of CD14 and IL4Ralpha SNPs with eczema.

Systemic Reactions to Subcutaneous Allergen Immunotherapy

Subcutaneous allergen immunotherapy (SCIT) has been practiced for 100 years. Many trials have established the efficacy of SCIT in reducing symptoms of both seasonal allergic rhinitis and asthma due to aeroallergens. However, clinical benefits of SCIT are tempered by risks of injection-related systemic reactions and life-threatening anaphylaxis. This article reviews data derived from retrospective surveys conducted to define the incidence, prevalence, and factors contributing to injection-related fatal anaphylactic and near-fatal systemic reactions, as well as recently initiated longitudinal surveillance studies of SCIT reactions.

Optimum Predictors of Childhood Asthma: Persistent Wheeze or the Asthma Predictive Index?

BACKGROUND The Asthma Predictive Index (API) and persistent wheezing phenotypes are associated with childhood asthma, but previous studies have not assessed their ability to predict objectively confirmed asthma. OBJECTIVE To determine whether the University of Cincinnati API Index (ucAPI) and/or persistent wheezing at age 3 can accurately predict objectively confirmed asthma at age 7. METHODS Data from the Cincinnati Childhood Allergy and Air Pollution Study, a high-risk prospective birth cohort, was used. Asthma was defined as parent-reported or physician-diagnosed asthma objectively confirmed by a change in FEV1 of ≥12% after bronchodilator or a positive methacholine challenge (PC20 ≤ 4 mg/mL); or as prior treatment with daily asthma controller medication(s). Multivariate logistic regression was used to investigate the relationship between confirmed asthma at age 7 and a positive ucAPI (adapted and modified from prior published API definitions) and persistent wheezing at age 3. RESULTS At age 7, 103 of 589 children (17.5%) satisfied the criteria for asthma. Confirmed asthma at age 7 was significantly associated with a positive ucAPI (adjusted odds ratio [aOR] 13.3 [95% CI, 7.0-25.2]; P < .01) and the persistent wheezing phenotype (aOR 9.8 [95% CI, 4.9-19.5]; P < .01) at age 3. Allergic persistent wheezing was associated with a significantly higher risk of asthma (aOR 10.4 [95% CI, 4.1-26.0]; P < .01) than nonallergic persistent wheezing (aOR 5.4 [95% CI, 2.04-14.06]; P < .01). CONCLUSION Both a positive ucAPI and persistent wheeze at age 3 were associated with objectively confirmed asthma at age 7; however, the highest risk was associated with ucAPI. These results demonstrate the ucAPI as a clinically useful tool for predicting future asthma in school-age children.

Duration of day care attendance during infancy predicts asthma at the age of seven: the Cincinnati Childhood Allergy and Air Pollution Study

Studies vary with respect to the reported effects of day care attendance on childhood asthma.

Current Evidence on Safety and Practical Considerations for Administration of Sublingual Allergen Immunotherapy (SLIT) in the United States

Liquid sublingual allergen immunotherapy (SLIT) has been used off-label for decades, and Food and Drug Administration (FDA)-approved grass and ragweed SLIT tablets have been available in the United States since 2014. Potentially life-threatening events from SLIT do occur, although they appear to be very rare, especially for FDA-approved products. Practice guidelines that incorporate safety precautions regarding the use of SLIT in the United States are needed. This clinical commentary attempts to address unresolved issues including controversy regarding the FDA mandate for the prescription of epinephrine autoinjectors for patients on SLIT; how to approach polysensitized patients; optimal timing and duration of SLIT administration; how to address gaps in therapy; whether antihistamines can prevent local reactions, if certain patient populations (such as persistent asthmatics) should not receive SLIT; and when to instruct patients to self-administer epinephrine. Key points are that physicians should focus on educating patients regarding: (1) when not to administer SLIT; (2) how to recognize a potentially serious allergic reaction to SLIT; and (3) when to administer epinephrine and seek emergency care.

Chronic traffic pollution exposure is associated with eosinophilic, but not neutrophilic inflammation in older adult asthmatics

Abstract Objective: Airway inflammatory patterns in older asthmatics are poorly understood despite high asthma-related morbidity and mortality. In this study, we sought to define the relationship between exposure to traffic pollutants, biomarkers in induced sputum, and asthma control in older adults. Methods: Induced sputum was collected from 35 non-smoking adults ≥65 years with a physician’s diagnosis of asthma and reversibility with a bronchodilator or a positive methacholine challenge. Patients completed the Asthma Control Questionnaire (ACQ), and Elemental Carbon Attributable to Traffic (ECAT), a surrogate for chronic diesel particulate exposure, was determined. Equal numbers of subjects with high (≥0.39 µg/m3) versus low (<0.39 µg/m3) ECAT were included. Differential cell counts were performed on induced sputum, and myeloperoxidase (MPO) and eosinophil peroxidase (EPO) were measured in supernatants. Regression analyses were used to evaluate the relationship between sputum findings, ACQ scores, and ECAT. Results: After adjustment for potential confounders, subjects with poorly controlled asthma based on ACQ ≥ 1.5 (n = 7) had significantly higher sputum eosinophils (median = 4.4%) than those with ACQ < 1.5 (n = 28; eosinophils = 2.6%; β = 10.1 [95% CI = 0.1–21.0]; p = 0.05). Subjects with ACQ ≥ 1.5 also had significantly higher sputum neutrophils (84.2% versus 65.2%; β = 7.1 [0.2–14.6]; p = 0.05). Poorly controlled asthma was associated with higher sputum EPO (β = 2.4 [0.2–4.5], p = 0.04), but not MPO (p = 0.9). High ECAT was associated with higher eosinophils (β = 10.1 [1.8–18.4], p = 0.02) but not higher neutrophils (p = 0.6). Conclusions: Poorly controlled asthma in older adults is associated with eosinophilic and neutrophilic inflammation. Chronic residential traffic pollution exposure may be associated with eosinophilic, but not neutrophilic inflammation in older asthmatics.