Dupilumab leads to better-controlled asthma and quality of life in children: the VOYAGE study.

BACKGROUND: Dupilumab has shown long-term treatment benefits in children with uncontrolled asthma. We assessed in more detail the impact of dupilumab on asthma control and health-related quality of life (HRQoL) in children and their caregivers. METHODS: Children aged 6-11 years with uncontrolled moderate-to-severe type 2 asthma (baseline blood eosinophils ≥150 cells·µL-1 or fractional exhaled nitric oxide ≥20 ppb; n=350) were treated with dupilumab or placebo for 52 weeks in the VOYAGE study. Primary outcomes of these analyses were asthma control (change from baseline in Asthma Control Questionnaire 7 Interviewer-Administered (ACQ-7-IA) and achieving a clinically meaningful response of ≥0.5 points); proportion of patients achieving well-controlled asthma or better (ACQ-7-IA ≤0.75 points); effect on patients' (Standardised Paediatric Asthma Quality of Life Questionnaire Interviewer-Administered (PAQLQ(S)-IA)) and caregivers' (Paediatric Asthma Caregiver's Quality of Life Questionnaire (PACQLQ)) HRQoL; and allergic rhinitis-related QoL. RESULTS: Dupilumab versus placebo significantly improved children's ACQ-7-IA scores by week 4 with sustained improvements through week 52 (least squares mean difference at week 52: -0.44, 95% CI -0.59- -0.30; p<0.0001); a higher proportion achieved a clinically meaningful response (week 52: 86% versus 75%; p=0.0051). At weeks 24 and 52, more children who received dupilumab achieved well-controlled asthma (ACQ-7-IA ≤0.75 points: 61% versus 43%; p=0.0001 and 70% versus 46%; p<0.0001, respectively). Significant improvements in PAQLQ(S)-IA and PACQLQ scores were observed by week 52. CONCLUSIONS: In children aged 6-11 years with moderate-to-severe type 2 asthma, dupilumab treatment was associated with rapid, sustained improvements in asthma control. HRQoL was significantly improved for children and their caregivers.

An International, Retrospective Study of Off-Label Biologic Use in the Treatment of Hypereosinophilic Syndromes.

BACKGROUND: Treatment of hypereosinophilic syndrome (HES) often requires the use of immunomodulators with substantial side effect profiles. The emergence of biologics offers an alternative treatment modality. OBJECTIVE: To examine real-world practice data to describe the safety and consequences of various biologics suspected to directly or indirectly affect eosinophilic inflammation for the treatment of HES. METHODS: Retrospective data from 13 centers were collected via an online Research Electronic Data Capture repository. Inclusion criteria included (1) peripheral eosinophil count of 1,500/mm3 or greater without a secondary cause; (2) clinical manifestations attributable to the eosinophilia; and (3) having received mepolizumab (anti-IL-5), benralizumab (afucosylated anti-IL-5 receptor α), omalizumab (anti-IgE), alemtuzumab (anti-CD52), dupilumab (anti-IL-4 receptor α), or reslizumab (anti-IL-5) outside a placebo-controlled clinical trial. RESULTS: Of the 151 courses of biologics prescribed for 121 patients with HES, 59% resulted in improved HES symptoms and 77% enabled tapering of other HES medications. Overall, 105 patients were receiving daily systemic glucocorticoids at the time of a biologic initiation and were able to reduce the glucocorticoid dose by a median reduction of 10 mg of daily prednisone equivalents. Biologics were generally safe and well-tolerated other than infusion reactions with alemtuzumab. Thirteen of 24 patients had clinical improvement after switching biologics and nine patients responded to increasing the dose of mepolizumab after a lack of response to a lower dose. CONCLUSIONS: Biologics may offer a safer treatment alternative to existing therapies for HES, although the optimal dosing and choice for each subtype of HES remain to be determined. Limitations of this study include its retrospective nature and intersite differences in data collection and availability of each biologic.

Treatment by biomarker-informed endotype vs guideline care in children with difficult-to-treat asthma.

BACKGROUND: Asthma is heterogeneous, contributing to difficulty in disease management. OBJECTIVE: To develop a biomarker-informed treatment model for difficult-to-treat (DTT) asthma and conduct a pilot feasibility study. METHODS: School-aged children (n = 21) with DTT asthma were enrolled and completed 3 medical visits (V1-V3). V2 and V3 were completed approximately 3.5 months and 12 months after V1, respectively. At V1, guideline care and adherence interventions were initiated, and blood samples were collected for asthma biomarker assessment. A personalized treatment algorithm was developed based on biomarkers (treatment by endotype) and was implemented at V2. Asthma outcomes were compared from V1 to V2 (guideline-based care) to V2 to V3 (guideline + biomarker-informed care). RESULTS: Overall retention was 86%. There was an even distribution of participants with allergy, without allergy, and with mixed allergies. The participants received an average of 5.9 interventions (range, 3-9). The allergic phenotype was characterized by increased CDHR3 risk genotype and high transepidermal water loss. High serum interleukin-6 level was most notable in the mixed allergic subgroup. The nonallergic phenotype was characterized by vitamin D deficiency and poor steroid treatment responsiveness. The personalized treatment plans were associated with decreased emergency department visits (median, 1 vs 0; P = .04) and increased asthma control test scores (median, 22.5 vs 23.0; P = .01). CONCLUSION: The biomarker-based treatment algorithm triggered interventions on top of guideline care in all children with DTT asthma studied, supporting the need for this type of multipronged approach. Our findings identify the minimal biomarker set that is informative, reveal that this treatment-by-endotype intervention is feasible and may be superior to guideline care alone, and provide a strong foundation for a definitive trial. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04179461.

Evaluation of Risk Scores to Predict Pediatric Severe Asthma Exacerbations.

BACKGROUND: Asthma exacerbations commonly lead to unplanned health care utilization and are costly. Early identification of children at increased risk of asthma exacerbations would allow a proactive management approach. OBJECTIVE: We evaluated common asthma risk factors to predict the probability of exacerbation for individual children aged 0-21 years using data from the electronic medical record (EMR). METHODS: We analyzed longitudinal EMR data for over 3000 participants with asthma seen at Cincinnati Children's Hospital Medical Center over a 7-year period. The study population was divided into 3 age groups: 0-4, 5-11, and 12-21 years. Each age group was divided into a derivation cohort and a validation cohort, which were used to build a risk score model. We predicted risk of exacerbation in the next 12 months, validated the scores by risk stratum, and developed a clinical tool to determine the risk level based on this model. RESULTS: Risk model results were confirmed with validation cohorts by calendar year and age groups. Race, allergic sensitization, and smoke exposure were each important risk factors in the 0-4 age group. Abnormal spirometry and obesity were more sensitive predictors of exacerbation in children >12 years. For each age group, a higher expanded score was associated with a higher predicted probability of an asthma exacerbation in the subsequent year. CONCLUSION: This asthma exacerbation prediction model, and the associated clinical tool, may assist clinicians in identifying children at high risk for exacerbation that may benefit from more aggressive management and targeted risk mitigation.

Anti-Siglec-8 Antibody for Eosinophilic Gastritis and Duodenitis.

BACKGROUND: Eosinophilic gastritis and duodenitis are characterized by gastrointestinal mucosal eosinophilia, chronic symptoms, impaired quality of life, and a lack of adequate treatments. Mast-cell activity may contribute to the pathogenesis of the conditions. AK002 (lirentelimab) is an anti-Siglec-8 antibody that depletes eosinophils and inhibits mast cells and that has shown potential in animal models as a treatment for eosinophilic gastritis and duodenitis. METHODS: In this phase 2 trial, we randomly assigned adults who had symptomatic eosinophilic gastritis, eosinophilic duodenitis, or both conditions in a 1:1:1 ratio to receive four monthly infusions of low-dose AK002, high-dose AK002, or placebo. The primary end point was the change in gastrointestinal eosinophil count from baseline to 2 weeks after the final dose; to maximize statistical power, we evaluated this end point in the placebo group as compared with the combined AK002 group. Secondary end points were treatment response (>30% reduction in total symptom score and >75% reduction in gastrointestinal eosinophil count) and the change in total symptom score. RESULTS: Of the 65 patients who underwent randomization, 43 were assigned to receive AK002 and 22 were assigned to receive placebo. The mean percentage change in gastrointestinal eosinophil count was -86% in the combined AK002 group, as compared with 9% in the placebo group (least-squares mean difference, -98 percentage points; 95% confidence interval [CI], -121 to -76; P<0.001). Treatment response occurred in 63% of the patients who received AK002 and in 5% of the patients who received placebo (difference, 58 percentage points; 95% CI, 36 to 74; P<0.001). The mean change in total symptom score was -48% with AK002 and -22% with placebo (least-squares mean difference, -26 percentage points; 95% CI, -44 to -9; P = 0.004). Adverse events associated with AK002 were similar to those with placebo, with the exception of higher percentages of patients having mild-to-moderate infusion-related reactions with AK002 (60% in the combined AK002 group and 23% in the placebo group). CONCLUSIONS: In patients with eosinophilic gastritis or duodenitis, AK002 reduced gastrointestinal eosinophils and symptoms. Infusion-related reactions were more common with AK002 than with placebo. (Funded by Allakos; ENIGMA ClinicalTrials.gov number, NCT03496571.).

Eosinophilic Esophagitis: an Important Comorbid Condition of Asthma?

Eosinophilic esophagitis and asthma are frequently found as comorbid conditions in children and adults along with other manifestations of atopic diathesis. These two conditions have similar T helper 2 responses-driven pathophysiology and share common management strategies such as using systemic corticosteroids and targeted anti-cytokine biologic therapies. Review of the literature finds that asthma is often a comorbid condition in eosinophilic esophagitis in both children and adults; however, the EoE-asthma relationship remains poorly characterized mechanistically and clinically. EoE and asthma commonly share several comorbid conditions such as allergic rhinitis and gastroesophageal reflux disease; therefore, addressing these comorbid conditions has the potential to improve and/or maintain control in both diseases. Similar to asthma, patients with EoE frequently demonstrate elevations in serum markers of atopy, including serum IgE levels, peripheral eosinophil counts, and T helper 2-related cytokines. Gastroesophageal reflux disease is thought to affect asthma through microaspirations, airway hyperresponsiveness, and increased vagal tone. The understanding of the relationship between gastroesophageal reflux and EoE is still evolving but seems to be bidirectional and interactive. In terms of treatment, similar classes of medications have been used in both EoE and asthma. In both children and adults, EoE remission can be achieved by food trigger avoidance and use of corticosteroids and biologic therapies. Asthma control is mostly achieved through inhaled corticosteroids, and long but biologic therapies are increasingly used in severe subsets of the disease. Significant clinical and mechanistic work needs to be accomplished to better understand the relationship between asthma, EoE, and their interaction with other allergic diseases. Understanding whether shared mechanisms exist can lead to the development of new diagnostic and therapeutic strategies. The following review examines the existing literature regarding prevalence, common comorbidities, and potential therapeutic approach and identifies gaps in knowledge and future directions.

Effect of exogenous interferons on rhinovirus replication and airway inflammatory responses.

BACKGROUND: Human rhinoviruses (HRVs) are the most common cause of asthma exacerbations. In airway epithelial cells, the primary site of HRV infection, decreased production of interferons (IFNs) may result in greater susceptibility to HRV and worsened symptoms. Thus, exogenous IFN could supplement the innate immune response and provide a treatment for virus-induced asthma exacerbations. Furthermore, the effects of exogenous IFN could be type specific in part because of the cellular distribution of type 1 and type 2 IFN receptors. OBJECTIVE: To investigate the effects of exogenous IFNs on HRV replication in bronchial epithelial cells. METHODS: Frozen stocks of primary human bronchial epithelial cells from healthy donors were cultured in monolayers; pretreated (24 hours) with 0.1-ng/mL, 1-ng/mL, or 10-ng/mL doses of IFN-α, -ß, -λ1, or -λ2; and infected with HRV-1A. Viral replication was quantified using real-time reverse transcription-polymerase chain reaction, and cytokine and chemokine secretion 24 hours after infection was measured by multiplex enzyme-linked immunosorbent assay. RESULTS: Compared with untreated samples, IFN-α, IFN-ß, IFN-λ1, and IFN-λ2 (0.1 ng/mL) significantly reduced HRV replication after high- (P < .02) and low-dose inoculation (P < .05). Similar effects were seen in 1-ng/mL and 10-ng/mL doses of IFN, where HRV replication was significantly decreased in both high- (P < .001) and low-dose inoculation (P < .001). Treatment with IFNs also enhanced HRV-induced IFN-γ-induced protein 10 secretion (P < .001). Finally, treatment with either IFN-λ1 or IFN-λ2 significantly increased HRV-induced secretion of RANTES (regulated on activation, normal T-expressed, and presumably secreted) (P < .05) but not IL-1ß or vascular endothelial growth factor. CONCLUSION: These findings suggest that exogenous IFNs, IFN-λ1 in particular, warrant further study as a potential therapy for virus-induced asthma exacerbations.

Innate immune responses to rhinovirus are reduced by the high-affinity IgE receptor in allergic asthmatic children.

BACKGROUND: Children with allergic asthma have more frequent and severe human rhinovirus (HRV)-induced wheezing and asthma exacerbations through unclear mechanisms. OBJECTIVE: We sought to determine whether increased high-affinity IgE receptor (FcεRI) expression and cross-linking impairs innate immune responses to HRV, particularly in allergic asthmatic children. METHODS: PBMCs were obtained from 44 children, and surface expression of FcεRI on plasmacytoid dendritic cells (pDCs), myeloid dendritic cells, monocytes, and basophils was assessed by using flow cytometry. Cells were also incubated with rabbit anti-human IgE to cross-link FcεRI, followed by stimulation with HRV-16, and IFN-α and IFN-λ1 production was measured by Luminex. The relationships among FcεRI expression and cross-linking, HRV-induced IFN-α and IFN-λ1 production, and childhood allergy and asthma were subsequently analyzed. RESULTS: FcεRIα expression on pDCs was inversely associated with HRV-induced IFN-α and IFN-λ1 production. Cross-linking FcεRI before HRV stimulation further reduced PBMC IFN-α (47% relative reduction; 95% CI, 32% to 62%; P< .0001) and IFN-λ1 (81% relative reduction; 95% CI, 69% to 93%; P< .0001) secretion. Allergic asthmatic children had higher surface expression of FcεRIα on pDCs and myeloid dendritic cells when compared with that seen in nonallergic nonasthmatic children. Furthermore, after FcεRI cross-linking, allergic asthmatic children had significantly lower HRV-induced IFN responses than allergic nonasthmatic children (IFN-α, P= .004; IFN-λ1, P= .02) and nonallergic nonasthmatic children (IFN-α, P= .002; IFN-λ1, P= .01). CONCLUSIONS: Allergic asthmatic children have impaired innate immune responses to HRV that correlate with increased FcεRI expression on pDCs and are reduced by FcεRI cross-linking. These effects likely increase susceptibility to HRV-induced wheezing and asthma exacerbations.