When Recurrent Infections Don’t Always Reveal a Primary Immunodeficiency

Background Recurrent infections often suggest an underlying immunodeficiency, particularly when local (e.g., an overlooked intrabronchial foreign body) or systemic (e.g., retroviral infection) causes are excluded. Primary immunodeficiencies (PIDs) are a heterogeneous group of inherited disorders characterized by immune system defects, leading to increased susceptibility to infections, autoimmunity, and malignancies. Recurrent respiratory infections are a key clinical feature of PIDs and often prompt extensive immunological evaluations. However, even when immune workups and cystic fibrosis testing are inconclusive, conditions that mimic PID must be considered to prevent misdiagnosis and treatment delays. Objectives This study aims to discuss cases of patients with recurrent infections initially suspected of having a PID and to evaluate the role of genetic testing in establishing a definitive diagnosis. Methods Patients with unexplained recurrent respiratory infections underwent a systematic evaluation, including immunoglobulin level measurements (IgG, IgA, IgM, and IgE), lymphocyte subset analysis, a sweat test for cystic fibrosis, HIV screening, and whole-exome sequencing (WES) to detect inborn errors of immunity and ciliopathy-related mutations. Results Seven patients (five males and two females) with a median age of 12.7 years were evaluated. Immunological testing was normal in five patients, while two had abnormal immune profiles: one female was diagnosed with combined immunodeficiency and one male with Wiskott-Aldrich syndrome. Notably, WES identified, in all seven patients, a homozygous pathogenic mutation in primary ciliary dyskinesia (PCD)-related genes, a disorder caused by defective ciliary function. Conclusion This study underscores the importance of considering PCD in the differential diagnosis of patients with recurrent respiratory infections suspected of PID, particularly when immunological tests yield inconclusive results. Additionally, PCD may coexist with other immunodeficiencies, complicating the diagnostic process. In populations with high consanguinity, incorporating genetic testing into routine diagnostic workflows is critical for accurate diagnosis, ultimately improving patient outcomes and preventing complications related to delayed treatment.