Evaluation of the clinical, immunological and genetic characteristics and follow-up results of patients presenting with a common variable immunedeficiency phenotype

Aim: Common variable immunodeficiency (CVID), significant low level of Immunoglobulin G (IgG), which is accompanied by low levels of Immunoglobulin A (IgA) and/or Immunoglobulin (IgM), are used to define a heterogeneous group of disorders, which are characterized by poor or absent antibody response to vaccines and absence of isohemagglutinin response. The clinical spectrum of CVID is broad. The most common clinical findings in CVID patients are recurrent sinopulmonary and gastrointestinal infections. Noninfectious findings include progressive lung disease, autoimmunity, gastrointestinal inflammatory diseases, liver disease, lymphoid hyperplasia and cancers, especially lymphoma. The heterogeneous clinical presentation of CVID patients cause different diagnoses other than primary immunodeficiency, delay in diagnosis, various complications and organ damage. The aim of our study is to evaluate the demographic characteristics, reasons for applying to the doctor, clinical and immunological characteristics, the relationship between diagnostic delay and organ damage, and the prognosis of 51 CVID patients who have been diagnosed and followed up in our clinic over a 20-year period. Materials and Methods: 60 patients were evaluated, who were diagnosed with Common Variable Immunodeficiency according to the ESID/PAGID 1999 diagnostic criteria before 2014 and ESID 2014 after 2014, referred to Ankara University Faculty of Medicine, Department of Pediatric Allergy and Immunology between January 2002 and December 2022. 9 patients whose file information could not be reached were excluded from the study and thus, 51 patients were included . Patients were scanned retrospectively through archive files and hospital operating system. Results: Of the 51 cases included in the study, 28 (54.9%) were male, and 23 (45.1%) were female. The median age of symptom onset was three years (0.05-46 years), the median age of diagnosis was 11.08 years (between 4-27.91 years), and the mean delay in diagnosis was 6.20±4.94 years. The most common reasons for admission were sinopulmonary infections (96%) and gastrointestinal infections (47.1%). The most common non-infectious finding was lymphoproliferation, with a rate of 41.1%. Autoimmunity was the second most common non-infectious finding detected after lymphoproliferation. Bronchiectasis was found in 41.1%, enteropathy in 11.8%, malignancy in 5.9%, and granulomatous disease in 5.9% of the patients. No significant difference between the presence of bronchiectasis and enteropathy and the delay in diagnosis has been detected. The relationship between autoimmune disease and splenomegaly has been evaluated and the incidence of splenomegaly in patients with autoimmune disease (53.3%) is found significantly higher than the rate of splenomegaly in patients without autoimmune disease (24.2%). In our study, the relationship between the clinical findings of the patients and the laboratory findings has been evaluated. The switched memory B cell value of patients with bronchiectasis has been found significantly lower than the value of the patients without bronchiectasis (p=0,020). The RTE level and naive CD4+ T cell value of the patients with lymphoproliferation were found significantly lower than the patients without lymphoproliferation (p<0,001) (p=0,005). The naive CD4+ T cell value of the malignant group was significantly lower than the value of the non-malignant group (p=0,006). CD21lo B cell value of patients with splenomegaly has been found significantly higher than the value of the patients without splenomegaly (p=0,016). Genetic analysis was performed in 40 of 51 cases, and a genetic defect was detected in 35% of the patients who underwent genetic testing. In genetic analysis, TACI defect in 4 patients (10%), ICOS defect in 2 patients (5%), NFKB2 defect in 2 patients (5%), NFKB1 defect in 1 patient (2.5%), CD40 defect in 1 patient (2.5%) CD40L defect in 1 patient (2.5%), BTK defect in 1 patient (2.5%), IL21 defect in 1 patient (2.5%), and GIMAP5 defect in 1 patient (2.5%) was found. There was a significant decrease in hospitalizations due to infection after Ig replacement therapy (hospitalization rate before Ig replacement therapy: 71.4%, hospitalization rate after Ig replacement therapy: 9.8%). Conclusion: CVID cases may present with various infectious and non-infectious clinical findings. Early diagnosis and treatment can reduce the development of organ damage and improve the quality of life in these patients. Genetic analysis should be performed on every patient who presents with a CVID clinic. Detection of genetic defects in these cases will surely provide a better understanding of immunopathogenesis and will bring up different and new treatment options. Keywords: Common variable immunodeficiency, delay in diagnosis, awareness