Effectiveness of T2 biologics in patients with common variable immune deficiency and allergic respiratory disease

Abstract

IntroductionMany patients with common variable immune deficiency (CVID) have a history suggestive of allergic respiratory disease including chronic rhinosinusitis (CRS) and asthma. The underlying immunologic defect, the presence of comorbid conditions such as bronchiectasis or interstitial lung disease, and recurrent infections may make the diagnosis of these conditions difficult. T2 biologics targeting allergic inflammatory pathways are now the standard of care for severe persistent asthma and CRS with nasal polyposis (CRSwNP). The efficacy of these agents in patients with CVID is unknown. MethodsWe performed a retrospective analysis of patients with CVID at a single academic medical center and identified those who had ever been prescribed a T2 biologic. ResultsWe identified 8 patients with CVID who had ever been prescribed T2 biologics: 6 patients with severe persistent asthma and 2 patients with CRSwNP. All patients had CVID without inflammatory complications with therapeutic IgG levels on immune globulin replacement therapy. Comorbid bronchiectasis was identified in 3 patients and no patients had GLILD. Two patients were taking omalizumab, two on mepolizumab, 1 on benralizumab, and 1 on dupilumab for severe persistent asthma and 2 on dupilumab for CRSwNP. Only 4 patients in this group (50%) had subjective improvement of symptoms and objective clinical benefit based on ability to wean off of corticosteroids and fewer exacerbations per year. Only 1 of these patients had objective improvement in FEV1 by >200mL. Neither of the 2 patients treated with dupilumab for CRswNP reported improvement and the biologic was discontinued. Of the 2 patients with asthma who were found to have eosinophilia on bronchoalveolar fluid analysis, both of these patients had clinical improvement on eosinophil-targeted biologic therapy. All 3 patients who were tested were found to have elevated serum T2 cytokines including IL-4, but this did not predict response to therapy.Table 1(abstract: 191) Demographic and immunologic data of 8 patients with CVID on T2 biologiesAgeGenderT2 biologicIndicationBronchiectasisIncrease in FEV1 by >200mLClinical responseIgG (mg/dL)IgA (mg/dL)IgM (mg/dL)IgE (kU/L)Absolute eosinophil count(K/μL)CD19B cell count (cells/μL)Th2 Cytokine PanelBAL Eosinophils%CT ThoraxBronchoscopy-Pathology82Fomalizumabsevere persistent asthmayesnono1551522923430049Not availableNot availableBasal abnormalitycharacterized by ground glass opacities (GGO), centrilobular nodularity with small focus of consolidation posterior right lower lobe (RLL). Additional focus of patchy groundglass posterior right lung (RL).Not available74Mmepolizumabsevere persistent asthmayesnoyes11681623141681600176Not available25Resolution of right upper lobe (RUL) apical nodule and branching tubular opacity. New clustered nodularity in the posterior RLL with faint GGO in the upper lobes. Moderate bronchial wall thickening, greatest in the lower lobes.Bronchial wall with smooth muscle hypertrophy. Lung parenchyma without evidence of inflammation, fibrosis, or malignancy.57Fomalizumabsevere persistent asthmanonoyes89725221687100103Not available0Diffuse bronchial dilation without bronchial wall thickening. Mild patchy air trapping.Largely denuded and edematous bronchial wall with minima] chronic inflammation, focal subepithelial elastosis, focal expansion of the subbasal lamina, mild increase in mucous secretion.37Fdupilumabchronic rhinosinusitis with nasal Polyposisnonot applicableno787<10<20<2100187elevated IL-4, IL-6Not availableResolved patchy GGO with exception of a new tiny focus of GGO in the basal RLL. Stable mild diffuse bronchial wall thickening.Not available73Fbenralizumabsevere persistentnoyesyes84635<20<2100179Not available4Mild to moderate airway inflammation and diffuse air-trapping. Minimal left basilar linear atelectasis/scarring is new. TracheobronchomalaciaBronchial wall with moderate chronic inflammation and eosionphils (peak 12/hpf), thickened subbasal lamina, mild smooth muscle hypertrophy.43Fdupilumabsevere persistent asthmanonot availableyes12614313556.5056elevated IL-4, IL-5, IL-6Not availableBenign right oblique fissure. 2 small nodules.Not available56Fdupilumabyesnot applicableno95476602.625027Not available1chronic rhinosinusitis with nasal polyposisMultiple new areas of peribronchovascular consolidation and confluent GGO. Widespread tree-inbud nodularity. Mild cylindricalbronchiectasis. Dilated main pulmonary trunk.Bronchial wall with moderate chronic inflammation and scattered eosinophils (6/hpf), thickened subbasal lamina. No granulomas. Right lung bronchial wall with moderate chronic inflammation. Lung parenchyma with airway centered mild interstitial chronic inflammation49 Fmepolizumabsevere persistent asthmanonono166845189510049Not available0Mild bronchial wall thickening and scattered air trapping. Patchy GGO in the left upper lobe with minimal involvement of the lower lobes. Dynamic expiratory images demonstrates evidence of tracheobronchomalacia.Bronchial wall with patchy mild to moderate chronic inflammation with rare neutrophils and eosinophils. Mild smooth muscle hypertrophy. Patchy squamous metaplasia and respiratory bronchiolitis in the left lung.*Clinical response is measured by reduction in exacerbations and/or ability to wean off of corticosteroids for individuals with severe asthma and is measured by improvement in sinonasal symptoms and reduced nasal polypoid burden for CRSwNP. [Display omitted] [Display omitted] ConclusionPatients with CVID may benefit from more direct sampling of nasal mucosal and bronchial secretions (sputum, bronchoalveolar lavage) to determine the potential benefit from T2 biologics in severe allergic respiratory disease. Prospective analyses in larger cohorts following objective indices of improvement as well as changes in serum and mucosal biomarkers are necessary.