Discussion

CVID is the most common symptomatic primary immunodeficiency in adults and is characterized by hypogammaglobulinemia, impaired antibody production, and recurrent infections [1,2]. Because of its marked clinical heterogeneity, patients may present not only with recurrent infections but also with autoimmune, granulomatous, and lymphoproliferative manifestations, making the diagnosis particularly challenging and frequently delayed [3].

The present case illustrates this diagnostic challenge. Despite recurrent lower respiratory tract infections over one year, the persistence of mediastinal lymphadenopathy prompted extensive investigations for tuberculosis, sarcoidosis, lymphoma, and other infectious or inflammatory disorders. Histopathological examinations demonstrated only reactive changes, while microbiological investigations, including bronchoalveolar lavage and Xpert MTB/RIF, remained negative. The diagnosis was ultimately established only after serum protein electrophoresis revealed marked hypogammaglobulinemia.

Respiratory involvement is the leading cause of morbidity in patients with CVID and is reported in up to 90% of cases [4]. Recurrent pneumonia is the most common clinical presentation and may precede the diagnosis by several years. Chest CT findings are heterogeneous and include consolidations, bronchiectasis, pulmonary nodules, ground-glass opacities, and mediastinal lymphadenopathy [5]. In our patient, the initial tree-in-bud micronodules suggested an infectious bronchiolitis. However, follow-up imaging demonstrated complete resolution of the pulmonary micronodules while mediastinal lymphadenopathy persisted, supporting the need for further diagnostic evaluation beyond infectious causes.

Delayed diagnosis remains a major concern in CVID because recurrent respiratory infections are frequently attributed to common infectious diseases rather than to an underlying primary immunodeficiency. Several studies have shown that prolonged diagnostic delay is associated with irreversible pulmonary complications, particularly bronchiectasis and chronic lung disease [6]. Early recognition is therefore essential to reduce long-term morbidity.

Persistent lymphadenopathy represents a well-recognized non-infectious manifestation of CVID and reflects chronic immune dysregulation rather than active infection in many patients [7]. Histopathological examination usually reveals reactive follicular hyperplasia, as observed in our patient, although granulomatous inflammation may occasionally be present. Because these findings closely resemble lymphoma, tuberculosis, or sarcoidosis, many patients undergo repeated invasive investigations before CVID is considered [8].

Although CVID can occur at any age, diagnosis is most commonly established during the second to fourth decades of life. Nevertheless, the current European Society for Immunodeficiencies (ESID) diagnostic criteria recognize that the disease may also be diagnosed later in adulthood after exclusion of secondary causes of hypogammaglobulinemia [9]. Our patient illustrates that advanced age should not exclude the diagnosis when recurrent respiratory infections are associated with persistent unexplained lymphadenopathy.

The diagnosis of CVID relies on reduced serum IgG associated with low IgA and/or IgM concentrations, together with impaired antibody responses after exclusion of secondary causes of hypogammaglobulinemia [10]. In the present case, serum protein electrophoresis was the pivotal investigation that prompted quantitative immunoglobulin testing and established the diagnosis. This observation emphasizes the value of including serum protein electrophoresis early in the evaluation of adults with recurrent respiratory infections and persistent lymphadenopathy.

Immunoglobulin replacement therapy remains the cornerstone of CVID management and significantly reduces the frequency of infections, prevents progressive pulmonary damage, and improves long-term prognosis [11]. Consequently, early diagnosis not only avoids unnecessary investigations but also allows prompt initiation of appropriate treatment before irreversible complications develop.

This case highlights the importance of considering CVID in adults presenting with recurrent respiratory infections and persistent mediastinal lymphadenopathy after infectious, malignant, and granulomatous diseases have been excluded. Increased awareness of this uncommon presentation may shorten diagnostic delay, facilitate timely immunological evaluation, and ultimately improve patient outcomes [12].