Dupilumab for COPD with Blood Eosinophil Evidence of Type 2 Inflammation.

BACKGROUND: Dupilumab, a fully human monoclonal antibody that blocks the shared receptor component for interleukin-4 and interleukin-13, key and central drivers of type 2 inflammation, has shown efficacy and safety in a phase 3 trial involving patients with chronic obstructive pulmonary disease (COPD) and type 2 inflammation and an elevated risk of exacerbation. Whether the findings would be confirmed in a second phase 3 trial was unclear. METHODS: In a phase 3, double-blind, randomized trial, we assigned patients with COPD who had a blood eosinophil count of 300 cells per microliter or higher to receive subcutaneous dupilumab (300 mg) or placebo every 2 weeks. The primary end point was the annualized rate of moderate or severe exacerbations. Key secondary end points, analyzed in a hierarchical manner to adjust for multiplicity, included the changes from baseline in the prebronchodilator forced expiratory volume in 1 second (FEV1) at weeks 12 and 52 and in the St. George's Respiratory Questionnaire (SGRQ; scores range from 0 to 100, with lower scores indicating better quality of life) total score at week 52. RESULTS: A total of 935 patients underwent randomization: 470 were assigned to the dupilumab group and 465 to the placebo group. As prespecified, the primary analysis was performed after a positive interim analysis and included all available data for the 935 participants, 721 of whom were included in the analysis at week 52. The annualized rate of moderate or severe exacerbations was 0.86 (95% confidence interval [CI], 0.70 to 1.06) with dupilumab and 1.30 (95% CI, 1.05 to 1.60) with placebo; the rate ratio as compared with placebo was 0.66 (95% CI, 0.54 to 0.82; P<0.001). The prebronchodilator FEV1 increased from baseline to week 12 with dupilumab (least-squares mean change, 139 ml [95% CI, 105 to 173]) as compared with placebo (least-squares mean change, 57 ml [95% CI, 23 to 91]), with a significant least-squares mean difference at week 12 of 82 ml (P<0.001) and at week 52 of 62 ml (P = 0.02). No significant between-group difference was observed in the change in SGRQ scores from baseline to 52 weeks. The incidence of adverse events was similar in the two groups and consistent with the established profile of dupilumab. CONCLUSIONS: In patients with COPD and type 2 inflammation as indicated by elevated blood eosinophil counts, dupilumab was associated with fewer exacerbations and better lung function than placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; NOTUS ClinicalTrials.gov number, NCT04456673.).

Dupilumab for COPD with Type 2 Inflammation Indicated by Eosinophil Counts.

BACKGROUND: In some patients with chronic obstructive pulmonary disease (COPD), type 2 inflammation may increase exacerbation risk and may be indicated by elevated blood eosinophil counts. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4 and interleukin-13, key drivers of type 2 inflammation. METHODS: In a phase 3, double-blind, randomized trial, we assigned patients with COPD who had a blood eosinophil count of at least 300 per microliter and an elevated exacerbation risk despite the use of standard triple therapy to receive dupilumab (300 mg) or placebo subcutaneously once every 2 weeks. The primary end point was the annualized rate of moderate or severe exacerbations of COPD. Key secondary and other end points that were corrected for multiplicity were the change in the prebronchodilator forced expiratory volume in 1 second (FEV1) and in the scores on the St. George's Respiratory Questionnaire (SGRQ; range, 0 to 100, with lower scores indicating a better quality of life) and the Evaluating Respiratory Symptoms in COPD (E-RS-COPD; range, 0 to 40, with lower scores indicating less severe symptoms). RESULTS: A total of 939 patients underwent randomization: 468 to the dupilumab group and 471 to the placebo group. The annualized rate of moderate or severe exacerbations was 0.78 (95% confidence interval [CI], 0.64 to 0.93) with dupilumab and 1.10 (95% CI, 0.93 to 1.30) with placebo (rate ratio, 0.70; 95% CI, 0.58 to 0.86; P<0.001). The prebronchodilator FEV1 increased from baseline to week 12 by a least-squares (LS) mean of 160 ml (95% CI, 126 to 195) with dupilumab and 77 ml (95% CI, 42 to 112) with placebo (LS mean difference, 83 ml; 95% CI, 42 to 125; P<0.001), a difference that was sustained through week 52. At week 52, the SGRQ score had improved by an LS mean of -9.7 (95% CI, -11.3 to -8.1) with dupilumab and -6.4 (95% CI, -8.0 to -4.8) with placebo (LS mean difference, -3.4; 95% CI, -5.5 to -1.3; P = 0.002). The E-RS-COPD score at week 52 had improved by an LS mean of -2.7 (95% CI, -3.2 to -2.2) with dupilumab and -1.6 (95% CI, -2.1 to -1.1) with placebo (LS mean difference, -1.1; 95% CI, -1.8 to -0.4; P = 0.001). The numbers of patients with adverse events that led to discontinuation of dupilumab or placebo, serious adverse events, and adverse events that led to death were balanced in the two groups. CONCLUSIONS: Among patients with COPD who had type 2 inflammation as indicated by elevated blood eosinophil counts, those who received dupilumab had fewer exacerbations, better lung function and quality of life, and less severe respiratory symptoms than those who received placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; BOREAS ClinicalTrials.gov number, NCT03930732.).

COVID-19 severity in asthma patients: a multi-center matched cohort study.

OBJECTIVE: The evidence pertaining to the effects of asthma on Coronavirus disease 2019 outcomes has been unclear. To improve our understanding of the clinically important association of asthma and Coronavirus disease 2019. METHODS: A matched cohort study was performed using data from the Mass General Brigham Health Care System (Boston, MA). Adult (age ≥18 years) patients with confirmed Coronavirus disease 2019 and without chronic obstructive pulmonary disease, cystic fibrosis, or interstitial lung disease between March 4, 2020 and July 2, 2020 were analyzed. Up to five non-asthma comparators were matched to each asthma patient based on age (within 5 years), sex, and date of positive test (within 7 days). The primary outcomes were hospitalization, mechanical ventilation, and death, using multivariable Cox-proportional hazards models accounting for competing risk of death, when appropriate. Patients were followed for these outcomes from diagnosis of Coronavirus disease 2019 until July 2, 2020. RESULTS: Among 562 asthma patients, 199 (21%) were hospitalized, 15 (3%) received mechanical ventilation, and 7 (1%) died. Among the 2686 matched comparators, 487 (18%) were hospitalized, 107 (4%) received mechanical ventilation, and 69 (3%) died. The adjusted Hazard Ratios among asthma patients were 0.99 (95% Confidence Internal 0.80, 1.22) for hospitalization, 0.69 (95% Confidence Internal 0.36, 1.29) for mechanical ventilation, and 0.30 (95% Confidence Internal 0.11, 0.80) for death. CONCLUSIONS: In this matched cohort study from a large Boston-based healthcare system, asthma was associated with comparable risk of hospitalization and mechanical ventilation but a lower risk of mortality.

Trends in US hospitalizations for anaphylaxis among infants and toddlers: 2006 to 2015.

BACKGROUND: Anaphylaxis is a potentially fatal acute allergic reaction. Its overall prevalence appears to be rising, but little is known about US hospitalization trends among infants and toddlers. OBJECTIVE: To identify the trends and predictors of hospitalization for anaphylaxis among infants and toddlers. METHODS: We used the nationally representative National Inpatient Sample (NIS), from 2006 to 2015, to perform an analysis of trends in US hospitalizations for anaphylaxis among infants and toddlers (age, <3 years) and other children (age, 3-18 years). For internal consistency, we identified patients with anaphylaxis by the International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code and excluded those with the International Classification of Diseases, Tenth Revision, Clinical Modification (late 2015). We calculated trends in anaphylaxis hospitalizations over time by age group and then used multivariable logistic regression to describe anaphylaxis hospitalizations among infants and toddlers. RESULTS: Among infants and toddlers, there was no significant change in anaphylaxis hospitalizations during the 10-year study period (Ptrend = .14). Anaphylaxis hospitalization among infants and toddlers was more likely in males, with private insurance, in the highest income quartile, with chronic pulmonary disease, who presented on a weekend day, to an urban teaching hospital, located in the Northeast. In contrast, anaphylaxis hospitalizations among older children (age, 3-<18 years) rose significantly during the study (Ptrend < .001). CONCLUSION: Anaphylaxis hospitalizations among infants and toddlers in the United States were stable from 2006 to 2015, whereas hospitalizations among older children were rising. Future research should focus on the trends in disease prevalence and health care utilization in the understudied population of infants and toddlers.

Emergency department revisits and rehospitalizations among infants and toddlers for acute allergic reactions.

Background and Objective: Allergic reactions, including anaphylaxis, are rising among children. Little is known about health care utilization among infants and toddlers. Our objective was to characterize health care utilization and charges for acute allergic reactions (AAR). Methods: We conducted a retrospective cohort study of trends in emergency department (ED) visits and revisits, hospitalizations and rehospitalizations, and charges among infants and toddlers (ages < 3 years), with an index ED visit or hospitalization for AAR (including anaphylaxis). We used data from population-based multipayer data: State Emergency Department Databases and State Inpatient Databases from New York and Nebraska. Multivariable logistic regression was used to identify factors associated with ED revisits and rehospitalizations. Results: Between 2006 and 2015, infant and toddler ED visits for AAR increased from 27.8 per 10,000 population to 35.2 (Ptrend < 0.001), whereas hospitalizations for AAR remained stable (Ptrend = 0.11). In the one year after an index AAR visit, 5.1% of these patients had at least one AAR ED revisit and 5.9% had at least one AAR rehospitalization. Factors most strongly associated with AAR ED revisits included an index visit hospitalization and receipt of epinephrine. Total charges for AAR ED visits (2009-2015) and hospitalizations (2011-2015) were more than $29 million and $11 million, respectively. Total charges increased more than fourfold for both AAR ED revisits for AAR rehospitalizations during the study period. Conclusion: Infants and toddlers who presented with an AAR were at risk for ED revisits and rehospitalizations for AAR within the following year. The charges associated with these revisits were substantial and seemed to be increasing.

Advances in drug allergy, urticaria, angioedema, and anaphylaxis in 2018.

Many notable advances in drug allergy, urticaria, angioedema, and anaphylaxis were reported in 2018. Broad-spectrum antibiotic use and, consequently, antibiotic resistance are widespread, and algorithms to clarify ß-lactam allergy and optimize antibiotic use were described. Meaningful data emerged on the pathogenesis of delayed drug hypersensitivity reactions. Progress not only in defining biomarkers but also in understanding the effect on quality of life and developing better treatments has been made for patients with chronic idiopathic urticaria. Patients with hereditary angioedema (HAE) have gained additional access to highly efficacious therapies, with associated improvements in quality of life, and some progress was made in our understanding of recurrent angioedema in patients with normal laboratory results. Guidelines have defined clear goals to help providers optimize therapies in patients with HAE. The epidemiology and triggers of anaphylaxis and the mechanisms underlying anaphylaxis were elucidated further. In summary, these disorders (and labels) cause substantial burdens for individual persons and even society. Fortunately, publications in 2018 have informed on advancements in diagnosis and management and have provided better understanding of mechanisms that potentially could yield new therapies. This progress should lead to better health outcomes and paths forward in patients with drug allergy, urticaria, HAE, and anaphylaxis.

Assessment of long-term safety and efficacy of dupilumab in children with asthma (LIBERTY ASTHMA EXCURSION): an open-label extension study.

BACKGROUND: Dupilumab efficacy and safety in children aged 6-11 years with uncontrolled, moderate-to-severe asthma were shown in the VOYAGE study-a 52-week, multinational, multicentre, phase 3 randomised, double-blind, placebo-controlled trial. We aimed to evaluate the long-term safety and efficacy of dupilumab in children with moderate-to-severe asthma who previously participated in the VOYAGE study. METHODS: 365 of 408 children with moderate-to-severe asthma from VOYAGE enrolled in EXCURSION, a 52 week, open-label extension study conducted at 70 centres across 17 countries. 240 children continued with add-on dupilumab (dosed according to bodyweight: 100 mg for those weighing ≤30 kg and 200 mg for those weighing more than 30 kg at EXCURSION baseline) once every 2 weeks administered by subcutaneous injection (dupilumab/dupilumab group) and 125 children on placebo during VOYAGE initiated dupilumab (100 or 200 mg, according to bodyweight), once every 2 weeks administered by subcutaneous injection (placebo/dupilumab group). Following a protocol amendment, for a subset of children weighing 30 kg or less, the dose was changed to 300 mg once every 4 weeks. The primary endpoint for the open-label extension study was the number and proportion of patients with any treatment-emergent adverse event (TEAE) during the 52-week study period in the overall population (defined as children aged 6-11 years old with moderate-to-severe asthma who previously completed VOYAGE). Statistical analyses were descriptive. This study is registered with ClinicalTrials.gov (NCT03560466; EXCURSION). FINDINGS: Children who completed VOYAGE were eligible to enrol in EXCURSION between June 21, 2018 and Aug 18, 2020. During EXCURSION, the safety profile and proportion of patients reporting TEAEs were consistent with those observed during the parent study (VOYAGE). In the overall population, 232 (63·6%) of 365 patients experienced at least one TEAE (dupilumab/dupilumab: 147 [61·3%]; placebo/dupilumab: 85 [68·0%]). The most frequently reported TEAEs were nasopharyngitis, pharyngitis, and upper respiratory tract infections. INTERPRETATION: In EXCURSION, long-term treatment with dupilumab was well tolerated with an acceptable safety profile. FUNDING: Sanofi and Regeneron Pharmaceuticals.

Application of Asthma Prediction Tools in a Cohort of Infants with Severe Bronchiolitis.

Background: Severe bronchiolitis is a strong childhood asthma risk factor. Early and accurate asthma prediction is key. We applied the Asthma Predictive Index (API), the modified Asthma Predictive Index (mAPI), and the Pediatric Asthma Risk Score (PARS) in a cohort of high-risk infants to predict asthma at age 6 years. Methods: We conducted a 17-center cohort of infants (age <1 year) hospitalized with severe bronchiolitis during 2011-2014. We used only infancy data to predict asthma at age 6 years. Results: The prevalence of parent-reported asthma at age 6 years was 328/880 (37%). The prevalences of a positive index/score for stringent and loose API, mAPI, and PARS were 21%, 51%, 11%, and 34%, respectively. Area under the receiver operating characteristic curves [95% confidence interval (CI)] ranged from 0.57 (95% CI 0.55-0.60) for mAPI to 0.66 (95% CI 0.63-0.70) for PARS. Conclusions: An asthma prediction tool for high-risk infants is needed to identify those who would benefit most from asthma prevention interventions.

Clinical Phenotypes of Immediate First-Dose Reactions to mRNA COVID-19: A Multicenter Latent Class Analysis.

BACKGROUND: Although immediate potentially allergic reactions have been reported after dose 1 of mRNA coronavirus disease 2019 (COVID-19) vaccines, comprehensively defined subtypes have not been clearly distinguished. OBJECTIVE: To define distinct clinical phenotypes of immediate reactions after dose 1 of mRNA COVID-19 vaccination, and to assess the relation of clinical phenotype to mRNA COVID-19 vaccine second dose tolerance. METHODS: This retrospective study included patients with 1 or more potentially allergic symptoms or signs within 4 hours of receiving dose 1 of an mRNA COVID-19 vaccine and assessed by allergy/immunology specialists from 5 U.S. academic medical centers (January-June 2021). We used latent class analysis-an unbiased, machine-learning modeling method-to define novel clinical phenotypes. We assessed demographic, clinical, and reaction characteristics associated with phenotype membership. Using log-binomial regression, we assessed the relation between phenotype membership and second dose tolerance, defined as either no symptoms or mild, self-limited symptoms resolving with antihistamines alone. A sensitivity analysis considered second dose tolerance as objective signs only. RESULTS: We identified 265 patients with dose-1 immediate reactions with 3 phenotype clusters: (1) Limited or Predominantly Cutaneous, (2) Sensory, and (3) Systemic. A total of 223 patients (84%) received a second dose and 200 (90%) tolerated their second dose. Sensory cluster (all patients had the symptom of numbness or tingling) was associated with a higher likelihood of second dose intolerance, but this finding did not persist when accounting for objective signs. CONCLUSIONS: Three novel clinical phenotypes of immediate-onset reactions after dose 1 of mRNA COVID-19 vaccines were identified using latent class analysis: (1) Limited or Predominantly Cutaneous, (2) Sensory, and (3) Systemic. Whereas these clinical phenotypes may indicate differential mechanistic etiologies or associations with subsequent dose tolerance, most individuals proceeding to their second dose tolerated it.

Proton Pump Inhibitors in Allergy: Benefits and Risks.

Proton pump inhibitors (PPIs) are widely prescribed and are indicated for the treatment of several gastrointestinal disorders. Allergists may prescribe PPIs as a result of the coincidence of gastroesophageal reflux disease with asthma or rhinitis, or when gastroesophageal reflux disease presents as chronic cough. Furthermore, long-term, high-dose PPI therapy is a recommended option for managing eosinophilic esophagitis, resulting in histologic remission in approximately 40% of patients. Here, we discuss current recommendations for PPI use, its deescalation, and its side effect profile. We review evidence supporting the epidemiologic link between the use of acid-suppressant medication and the subsequent development of allergic disorders.

Infant Exposure to Acid Suppressant Medications Increases Risk of Recurrent Wheeze and Asthma in Childhood.

BACKGROUND: Acid suppressant medications (ASMs) are commonly prescribed in infancy. Little is known about the relationship between ASM exposure and risk of childhood asthma and atopic conditions. OBJECTIVE: We sought to examine the association between infant ASM exposure and risk for developing recurrent wheeze, allergen sensitization, and asthma in early childhood. METHODS: We used data from a diverse, multicenter, prospective cohort study of 921 infants with a history of bronchiolitis. ASM exposure (histamine-2 receptor antagonists and/or proton pump inhibitors) during infancy (age: <12 months) was ascertained by parent report and medical record review. The outcomes were recurrent wheeze by age 3 years, early childhood allergen sensitization (serum specific IgE), and asthma by age 6 years. We constructed multivariable Cox proportional hazards models and multivariable logistic regression models adjusting for multiple confounders. RESULTS: Of the 921 children in the cohort, 202 (22%) were exposed to ASMs during infancy. Compared with unexposed children, those exposed to ASM were more likely to develop recurrent wheeze by age 3 years (adjusted hazard ratio: 1.58, 95% confidence interval [CI]: 1.20-2.08, P = .001) and asthma by age 6 years (adjusted odds ratio: 1.66, 95% CI: 1.22-2.27, P = .001). ASM exposure during infancy was not significantly associated with the development of early childhood allergen sensitization (adjusted odds ratio: 1.00, 95% CI: 0.70-1.44, P = .99). CONCLUSIONS: Although exposure to ASMs during infancy does not increase the risk of allergen sensitization in early childhood, ASM exposure during infancy increases the risk of recurrent wheeze and asthma during early childhood.

Seeing the Forest for the Trees: Evaluating Population Data in Allergy-Immunology.

A population-level study is essential for understanding treatment effects, epidemiologic phenomena, and health care best practices. Evaluating large populations and associated data requires an analytic framework, which is commonly used by statisticians, epidemiologists, and data scientists. This document will serve to provide an overview of these commonly employed methods in allergy and immunology research. We will draw upon recent examples from the allergy-immunology literature to contextualize discrete principles of relevance to population-level analysis that include statistical features of a study population, elements of statistical inference, regression analysis, and an overview of machine learning practices. Our intent is to guide the reader through a practical description of this important quantitative discipline and facilitate greater understanding about data and result display in the medical literature.

Trends in US Emergency Department Visits for Anaphylaxis Among Infants and Toddlers: 2006-2015.

BACKGROUND: Anaphylaxis is a potentially life-threatening allergic reaction. The overall prevalence of anaphylaxis appears to be rising in children, but temporal trends among infants and toddlers are not well studied. OBJECTIVE: To characterize the trends in US emergency department (ED) visits and hospitalizations among infants and toddlers with anaphylaxis from 2006 to 2015. METHODS: We conducted a study of temporal trends in anaphylaxis among children (age <18 years) and, more specifically, infants and toddlers (age <3 years) presenting to the ED between 2006 and 2015 using a large, nationally representative database. For internal consistency, we defined anaphylaxis using International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes and excluded visits with International Classification of Diseases, Tenth Revision, Clinical Modification diagnosis codes (late 2015). We calculated trends in the number and proportion of ED visits and hospitalizations and used multivariable logistic regression to identify predictors of hospitalization. RESULTS: Among infants and toddlers, the proportion of ED visits for anaphylaxis per year increased from 20 per 100,000 visits to 50 per 100,000 visits (Ptrend < .001). The rate of ED visits for anaphylaxis increased from 15 to 32 ED visits per 100,000 population of infants and toddlers (Ptrend < .001). Food was the most commonly identified trigger. The proportion of hospitalization among anaphylaxis-related ED visits decreased from 19% to 6% (Ptrend < .001). Among ED patients, those more likely to be hospitalized were male, privately insured, from higher income families, and presenting to urban, metropolitan teaching hospital EDs. CONCLUSIONS: In a large, nationally representative US database, from 2006 to 2015, ED visits by infants and toddlers with anaphylaxis increased, whereas hospitalization of these patients decreased.

A comparison of case definitions for infant atopic dermatitis in a multicenter prospective cohort study.

This study identified two infant AD case definitions that were strongly associated with known AD risk factors. These case definitions can be used to study novel AD risk factors in large cohort studies, potentially providing new insights into the epidemiology of infant AD.