Interstitial Lung Disease Frequently Precedes CVID Diagnosis

Abstract

To the editor: Common variable immunodeficiency disorder (CVID) is the most frequent clinically relevant primary immunodeficiency, and pulmonary infections, often leading to the development of bronchiectasis, are a major clinical finding in CVID patients [1]. However, non-infectious manifestations of the lung occur frequently too, with previous studies reporting interstitial lung diseases (ILD) in 10–20% of patients with CVID [1–3] and a disease onset of non-infectious pulmonary manifestations after 8 years [2]. CVID patients suffering from ILD have a poorer clinical prognosis [4]. Due to its main clinical manifestations, the term “granulomatous lymphocytic interstitial lung disease (GLILD)” was coined; however, clinical and histopathological findings show substantial heterogeneity, and a clear and universal definition is missing. Other non-infectious manifestations, like immune thrombocytopenia or autoimmune hemolytic anemia, often precede the clinical symptoms and diagnosis of CVID [5], an observation that helps to improve early recognition of this rare disease. It is unknown what percentage of CVID patients presents with clinical symptoms of interstitial lung diseases preceding the diagnosis of immunodeficiency. We conducted a cross-sectional study on non-infectious respiratory manifestations, i.e., the presence of ILD, in 105 adult patients with CVID. CVID was diagnosed according to ESID (European Society for Immunodeficiencies) criteria at the Outpatient Clinic for Immunodeficiencies, Charité Universitätsmedizin Berlin, Germany. Patient charts were reviewed for clinical courses, immunological parameters, pulmonary function tests, radiological features in CT scan, differential cytology in bronchoalveolar lavage fluid (BALF), histopathological findings, treatment, and results of genetic testing. Thoracic CT scans were part of the routine diagnostics at the time of PID diagnosis in our clinic. Three patients without pulmonary symptoms had not undergone thoracic CT scans and were excluded from the study. ILD was diagnosed in patients with radiomorphological changes in their CTscans and clinical symptoms (coughing, dyspnea) +/− impairment in pulmonary function testing (TLC (total lung capacity) < 80% and/or KCO (transfer coefficient of the lung for carbon monoxide) < 75%). For thoracic CT analysis, both mediastinal and lung window setting images were reviewed by different radiologists and all images were re-evaluated by a respiratory physician. Apart from solitary micronodules, there were no accidental findings of ILD in CT scans in asymptomatic patients. All patients were non-smokers. The study was approved by the local ethics committee, and informed consent was obtained from all individual participants included in the study. In our cohort of 105 adult CVID patients, we identified 19 patients (18%) with interstitial lung diseases. In 53% (10/19 patients), a pulmonary diagnosis of ILD had preceded the diagnosis of CVID with a median delay of 36 months (see Table 1). Demographic and clinical characteristics are listed in supplemental table S1. Patients affected with ILD presented with a much higher frequency of splenomegaly (74% vs. 31%; p value < 0.001) and lymphadenopathy (63% vs. 14%; p value < 0.001). Bronchiectasis occurred more frequently in patients with ILD than without ILD (37% vs. 16%; p value 0.04). Rates for autoimmune cytopenia and recurrent pneumonias did not differ significantly (supplemental table S1). In contrast to the recently described significant T-lymphopenia in patients with ILD [1], in our cohort, no significant differences in the immunological phenotype between patient groups were found (see supplemental table S2). Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10875-019-00708-2) contains supplementary material, which is available to authorized users.