Tuberculosis remains a leading infectious cause of mortality worldwide. Patients with inborn errors of immunity (IEI) are at increased risk of infections, including tuberculosis and non-tuberculous mycobacterial disease. Certain IEI subtypes (for example, Mendelian susceptibility to mycobacterial diseases, chronic granulomatous disease, and severe combined immunodeficiency) are classically linked to heightened mycobacterial susceptibility, while the relationship between antibody deficiencies (such as common variable immunodeficiency) and tuberculosis is less certain. Existing guidelines define TST positivity thresholds for some high-risk groups (eg, ≥5 mm for people with HIV), but validated cutoffs for individuals with IEI are lacking. This study aimed to assess the prevalence and distribution of tuberculosis in adults with IEI and to evaluate the diagnostic utility of the tuberculin skin test (TST) within a systematic screening algorithm.
This single-center cohort included 117 adult patients with confirmed IEI who provided informed consent and were evaluated between 2013 and 2024 at the Allergy and Immunology Outpatient Clinic of Istanbul University. Diagnoses were established per International Union of Immunological Societies and European Society for Immunodeficiencies criteria. The screening protocol combined a comprehensive exposure history, symptom assessment, TST (with repeat testing for initial indurations of 0–4 mm), and chest imaging (radiography and CT when available). Patients meeting screening criteria underwent further pulmonology evaluation, sputum AFB studies, and CT as indicated. Treatment for latent tuberculosis infection (LTBI) and active disease followed national guidelines.
TST was performed using the Mantoux technique (0.1 ml PPD intradermally on the volar forearm) and read at 72 hours by the administering clinician. For initial indurations of 0–4 mm a repeat TST was performed after 1–4 weeks to detect a booster phenomenon. Screening thresholds were applied pragmatically: patients with TST induration ≥5 mm, tuberculosis-related symptoms, suspicious imaging, or close contact history underwent further evaluation. The dual-TST approach was used to improve detection in immunocompromised hosts.
The cohort median age was 35 years (IQR 26–45.5), with 60 men (51.3%) and 57 women (48.7%). Median disease duration was 6 years (IQR 3–12.75) and median age at diagnosis was 30 years (IQR 17–39). Antibody deficiencies accounted for 82.1% of patients; the common variable immunodeficiency phenotype was the single largest subgroup (48.7%). Immunoglobulin replacement therapy and prophylactic antibiotics were used in subsets of patients. Genetic testing was performed in 67 patients, with molecular diagnoses established in 20 when feasible.
All patients had evidence of prior BCG vaccination. Six patients (5.1%) reported a family history of tuberculosis. Nineteen patients (16.2%) had previously been diagnosed and treated for tuberculosis; pulmonary involvement was the most frequent site (59.1%). Three patients experienced two episodes of tuberculosis. Treatment durations for prior episodes followed recommended site-specific regimens (eg, 6 months for most forms, extended courses for CNS or skeletal disease when applicable).
Of 117 patients screened, 105 underwent TST. Forty-nine of these had induration ≥5 mm; 12 of those were converters on repeat testing after an initial 0–4 mm result. The screening protocol identified five patients with newly diagnosed mycobacterial disease, including pulmonary, gastrointestinal, and lymph node tuberculosis and non-tuberculous mycobacterial lung disease. Reported TST indurations in identified active tuberculosis cases included values of 22 mm, 9 mm, and 9 mm for three patients with pulmonary, gastrointestinal, and lymph node disease, respectively. Two patients later diagnosed with non-tuberculous mycobacterial lung disease had TST measurements of 12 mm and 6 mm. Median TST induration among patients with tuberculosis was 9 mm (IQR 1.5–14.25) versus 4 mm (IQR 0–10.5) in those without tuberculosis.
Patients meeting screening criteria underwent multidisciplinary evaluation including pulmonology consultation, sputum AFB staining and culture, and chest CT when indicated. Imaging obtained for other clinical reasons (including many CTs performed during the COVID-19 pandemic) was reassessed for post-tuberculosis sequelae when not attributable to acute processes. LTBI and active tuberculosis treatments were administered per national guidelines. The cohort included one treatment-related mortality: a patient with pulmonary disease who died of hemoptysis and pulmonary complications despite antituberculosis therapy.
This study provides a comprehensive, systematic assessment of tuberculosis screening in adults with IEI. Pulmonary tuberculosis was the predominating clinical presentation. Notably, several active tuberculosis cases had TST indurations below the conventional 15-mm cutoff used in the general population; the median TST among tuberculosis cases was 9 mm. These data support re-evaluating TST positivity thresholds for patients with IEI and suggest consideration of lower cutoffs—analogous to the 5-mm threshold used for people with HIV—to improve detection in this vulnerable population. The authors implemented a structured screening algorithm combining history, symptoms, dual-TST testing, and imaging as a practical approach in a BCG-vaccinated cohort.
Limitations include single-center design and heterogeneous IEI subtypes with majority antibody-deficiency representation, which may limit generalizability. Genetic testing was not uniformly available due to resource constraints. The study follows ethical standards with institutional approvals and written informed consent. Further studies are needed to validate optimal TST or IGRA cutoffs in diverse IEI populations and to compare TST with interferon-gamma release assays for LTBI detection in immunodeficient adults.