Conjunctivitis in dupilumab clinical trials.

BACKGROUND: Dupilumab blocks the shared receptor component for interleukin (IL)-4 and IL-13. It is approved in the U.S.A. for patients aged ≥ 12 years with moderate-to-severe atopic dermatitis (AD) uncontrolled by topical prescription medicines or who cannot use topical medicines, for patients in Japan whose AD is uncontrolled with existing therapies, for patients with moderate-to-severe AD in Europe who are candidates for systemic therapy and for patients aged ≥ 12 years for maintenance treatment of moderate-to-severe asthma uncontrolled with their current medicines. AD trials have reported increased incidence of conjunctivitis for dupilumab vs. placebo. OBJECTIVES: To characterize further the occurrence and risk factors of conjunctivitis in dupilumab clinical trials. METHODS: We evaluated randomized placebo-controlled trials of dupilumab in AD (n = 2629), asthma (n = 2876), chronic rhinosinusitis with nasal polyps (CRSwNP) (n = 60) and eosinophilic oesophagitis (EoE) (n = 47). RESULTS: In most AD trials, dupilumab-treated patients had higher conjunctivitis incidence than placebo controls. Higher baseline AD severity and previous history of conjunctivitis were associated with increased conjunctivitis incidence. Conjunctivitis was mostly mild to moderate. Most cases recovered or resolved during the treatment period; two patients permanently discontinued dupilumab due to conjunctivitis or keratitis. Common treatments included ophthalmic corticosteroids, antibiotics, and antihistamines or mast cell stabilizers. Most cases were diagnosed by the investigators. In asthma and CRSwNP trials, the incidence of conjunctivitis was lower for both dupilumab and placebo than in AD trials; dupilumab did not increase the incidence compared with placebo. In the EoE trial, no patients had conjunctivitis. CONCLUSIONS: Conjunctivitis was more frequent with dupilumab treatment in most AD trials. In dupilumab trials in other type 2 diseases, incidence of conjunctivitis was overall very low, and was similar for dupilumab and placebo. In AD, the incidence of conjunctivitis was associated with AD severity and prior history of conjunctivitis. The aetiology and treatment of conjunctivitis in dupilumab-treated patients require further study. What's already known about this topic? Ocular disorders, including allergic conjunctivitis, are common in patients with atopic dermatitis (AD). In most dupilumab AD trials, dupilumab-treated patients had higher conjunctivitis incidence than those receiving placebo. Most cases were mild to moderate and recovered or were recovering during study treatment; study treatment discontinuation due to conjunctivitis was rare. Conjunctivitis incidence was very low and similar for dupilumab and placebo in clinical trials in asthma, chronic rhinosinusitis with nasal polyps and eosinophilic oesophagitis. What does this study add? This analysis confirms and extends the results of the individual clinical trials. Baseline disease-related factors, including AD severity, prior conjunctivitis history and certain biomarkers (thymus and activation-regulated chemokine, IgE, eosinophils), were associated with increased incidence of conjunctivitis. Patients who responded well to dupilumab had reduced incidence of conjunctivitis. Further study is needed to elucidate the aetiology and treatment of conjunctivitis in dupilumab-treated patients with AD.

Risk factors for the development of bronchiolitis obliterans in children with bronchiolitis.

BACKGROUND: Bronchiolitis obliterans (BO) is an uncommon and severe form of chronic obstructive lung disease in children that results from an insult to the lower respiratory tract. METHODS: A case-control study of children under the age of 3 years was performed in 109 cases and 99 controls to determine risk factors for the development of BO. Participants were evaluated by immunofluorescence viral tests, pulmonary function tests, and questions to assess tobacco and other exposures. RESULTS: Bronchiolitis due to adenovirus (odds ratio (OR) 49, 95% confidence interval (CI) 12 to 199) and the need for mechanical ventilation (OR 11, 95% CI 2.6 to 45) were strongly and independently associated with an increased risk for BO. Factors not associated with post-infectious BO included age of the child, sex, and environmental tobacco exposure (either in utero or during infancy). CONCLUSIONS: Adenovirus infection and need for mechanical ventilation are significant risk factors for developing BO in children. Further research is needed to determine why these risk factors are so strong and how they may contribute to the development of the disease.

Lung function in infants with chronic pulmonary disease after severe adenoviral illness.

OBJECTIVE: To evaluate pulmonary function and bronchodilator responses in young children with chronic pulmonary disease (CPD) after a severe adenoviral lower respiratory tract infection. METHODS: Pulmonary function tests were performed in 13 patients (mean age, 1.32 +/- 0.8 years) with CPD and were compared with a control group of 13 healthy infants (mean age, 1.16 +/- 0.4 years). RESULTS: Respiratory rate, peak tidal expiratory flow (PTEF), PTEF/tidal volume, absolute time up to PTEF, time percentage to PTEF, volume percentage for PTEF, and compliance and resistance of the respiratory system were significantly affected in the CPD group. Similarly, maximal flow at functional residual capacity (V'maxFRC) was 56.0 +/- 42 mL/s and 373 +/- 107 mL/s in the CPD and control groups, respectively (P =.001). No within-group differences with baseline values or between-group differences were noted in response to treatment with ipratropium bromide or albuterol. CONCLUSION: Young children with CPD caused by adenovirus have pulmonary function changes characterized by severe obstruction and diminished lung distensibility not responsive to the administration of inhaled ipratropium bromide or albuterol.