---
title: "Tuberculosis screening and tuberculin skin test performance in adults with inborn errors of immuni"
id: "frontiers-in-immunology-11-tuberculosis-screening-in-adult-patients-with-inborn-errors-of-immunity-a"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-11-tuberculosis-screening-in-adult-patients-with-inborn-errors-of-immunity-a"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1888729"
published_at: "2026-07-24T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Tuberculosis screening and tuberculin skin test performance in adults with inborn errors of immuni
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/frontiers-in-immunology-11-tuberculosis-screening-in-adult-patients-with-inborn-errors-of-immunity-a
- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1888729)
- **Published At:** 2026-07-24T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- This single-center cohort evaluated tuberculosis screening and **tuberculin skin test (TST)** performance in 117 adult patients with confirmed inborn errors of immunity (IEI). All patients had prior BCG vaccination. The median age was 35 years (IQR 26–45.5). Antibody deficiencies comprised 82.1% of the cohort. - A total of 105 patients underwent TST. Repeat TST after 1–4 weeks was performed when initial induration was 0–4 mm to assess booster responses. Overall, 49 patients had a TST induration ≥5 mm; 12 of these were converters on repeat testing. - Nineteen patients (16.2%) had a history of treated tuberculosis; pulmonary disease was the most common site (59.1%). Three patients had recurrent tuberculosis (two episodes each). - Five new mycobacterial disease cases were identified through the screening protocol, including pulmonary, gastrointestinal, and lymph node tuberculosis and non-tuberculous mycobacterial lung disease. TST indurations among active tuberculosis cases ranged from 6 mm to 22 mm in reported examples. - Median TST induration was 9 mm (IQR 1.5–14.25 mm) in patients with tuberculosis versus 4 mm (IQR 0–10.5 mm) in those without. Several active tuberculosis cases had TST responses below the conventional 15-mm threshold used for the general population. - The authors applied a standardized screening algorithm combining exposure history, symptom assessment, **TST** (with booster testing), and chest imaging; patients meeting screening criteria underwent pulmonology evaluation, sputum AFB studies, and CT when indicated. - Management followed national guidelines for LTBI and active tuberculosis; the study documents one death from pulmonary complications despite treatment. Genetic testing was performed in a subset (67/117), with molecular diagnoses in 20 patients when feasible. - The study highlights limited evidence on LTBI/TST thresholds in IEI, suggests that **lower TST cutoffs** may be appropriate for this population (analogous to HIV recommendations), and proposes routine, systematic screening for patients with IEI. Resource and testing limitations (e.g., variable use of genetic testing) were noted in the cohort.
## Clinical Analysis & Structured Key Points
Frontiers | Tuberculosis screening in adult patients with inborn errors of immunity: a single-center cohort study ORIGINAL RESEARCH article Front. Immunol. , 24 July 2026 Sec. Primary Immunodeficiencies Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1888729 Published in Frontiers in Immunology Primary Immunodeficiencies 7 impact factor 11.3 citescore Editor & Reviewers Edited by H A Hamoud Al-Mousa Reviewed by A A Ahmed Aziz BOUSFIHA S B Safa Baris Outline Figures and Tables Figure 1 View in article Figure 2 View in article Figure 3 View in article Table 1 Demographics and clinical characteristics of the patients. View in article Table 2 Classification of patients according to the International Union of Immunological Societies (IUIS). View in article Table 3 Second tuberculin skin test (TST) evaluation and treatment decisions in patients with inborn errors of immunity (IEI). View in article Table 4 Detailed tuberculin skin test (TST) documentation of tuberculosis and non-tuberculosis mycobacterial infection cases. View in article ORIGINAL RESEARCH article Front. Immunol. , 24 July 2026 Sec. Primary Immunodeficiencies Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1888729 Tuberculosis screening in adult patients with inborn errors of immunity: a single-center cohort study P K Pelin Korkmaz * İ D İlkim Deniz Toprak M H Merve Hormet Igde O O Osman Ozan Yegit S D Semra Demir N K Nevzat Kahveci A F Ayse Feyza Aslan M E Mehmet Emin Sezgin M D Merve Dilsad Atasever Ş Ç Şule Çelik Kamacı D E Deniz Eyice Karabacak B E Bircan Erden Z K Zeynep Kilinc M S Mehmet Sait Yordam I G Isil Gogem Imren Aksit D U Derya Unal +8 more A G Aslı Gelincik Department of Internal Medicine, Division of Immunology and Allergy Diseases, Istanbul Universitesi Istanbul Tip Fakultesi, İstanbul, Türkiye Article metrics View details Abstract Background: Data on tuberculosis, a leading cause of infectious disease mortality, in patients with inborn errors of immunity (IEI) are limited. Objective: This study aimed to evaluate the burden of tuberculosis and the diagnostic utility of the tuberculin skin test (TST) in patients with IEI and to propose a tuberculosis screening strategy. Methods: Evaluation comprised a comprehensive exposure history, symptom assessment, TST (which was repeated after 1–4 weeks if the initial result was 0–4 mm), and chest imaging including radiography and computed tomography where available. Patients underwent standard clinical assessment for tuberculosis, followed by appropriate treatment and follow-up. Results: Among 117 patients with IEI [median age = 35 years, interquartile range (IQR) = 26–45.5 years], antibody deficiencies were the most common subgroup (82.1%). All patients had previously received a Bacillus Calmette–Guérin (BCG) vaccination. Of the 105 patients who underwent TST, 19 had a history of tuberculosis, the majority of whom had pulmonary involvement (59.1%), and three had recurrent disease. Three patients diagnosed with pulmonary, gastrointestinal, and lymph node tuberculosis had TST values of 22, 9, and 9 mm, respectively. Two patients with TST measurements of 12 and 6 mm were diagnosed with non-tuberculous mycobacterial lung disease. The median TST was 9 mm (IQR = 1.5–14.25 mm) in patients with tuberculosis and was 4 mm (IQR = 0–10.5 mm) in those without. Conclusion: This study represents the first comprehensive evaluation of tuberculosis screening and TST assessment in patients with IEI. Pulmonary tuberculosis was the most common site of involvement. In BCG-vaccinated patients with IEI who developed tuberculosis, the TST responses remained below the conventional 15-mm threshold, highlighting the need for revised cutoff values in this population, similar to those recommended for patients with HIV. Introduction Inborn errors of immunity (IEI) are genetic disorders that impair the development or function of the immune system, resulting in heightened susceptibility to various infections, including tuberculosis and non-tuberculous mycobacterial infections ( 1 – 3 ). Certain IEI subtypes, such as Mendelian susceptibility to mycobacterial diseases (MSMD), are particularly associated with mycobacterial infections ( 4 ). Chronic granulomatous disease (CGD) and severe combined immunodeficiency (SCID) also increase the risk of tuberculosis. However, the association between antibody deficiencies, including common variable immunodeficiency (CVID), and tuberculosis remains uncertain ( 5 , 6 ). Globally, tuberculosis reclaimed its position as the leading cause of mortality attributable to a single infectious pathogen in 2023, having been overtaken by coronavirus disease 2019 (COVID-19) for 3 years. According to the 2024 World Health Organization (WHO) report, an estimated 10.8 million individuals [95% uncertainty interval (UI) = 10.1–11.7 million] contracted tuberculosis in 2023 ( 7 ). In the same report, Türkiye continues to be classified among countries that have achieved a 20%–49% reduction in tuberculosis incidence, with an estimated incidence rate of 10–49 cases per 100,000 inhabitants per year ( 7 ). Although these figures indicate progress, the target remains an incidence rate of fewer than 10 cases per 100,000 population per year. In 2023, tuberculosis was estimated to have caused approximately 1.25 million deaths globally (95% UI = 1.13–1.37 million), with approximately 1.09 million occurring in HIV-negative individuals and approximately 161,000 among those living with HIV ( 7 ). Latent tuberculosis infection (LTBI) is defined as a persistent immune response to antigens of Mycobacterium tuberculosis in the absence of clinically evident active tuberculosis. Although LTBI remains asymptomatic and non-infectious, it is estimated to affect approximately 33% of the global population. Immunocompromised individuals with LTBI are at increased risk of progression to active tuberculosis, particularly within the first 2 years of exposure ( 8 , 9 ). Therefore, prompt diagnosis and treatment of LTBI are essential to prevent progression to active tuberculosis and to limit its spread, thereby reducing the global burden of tuberculosis ( 10 ). Currently, evidence-based data on LTBI in IEI are lacking. The tuberculin skin test (TST) or interferon-gamma release assay (IGRA) may be used to detect LTBI. The TST involves the intradermal administration of a purified protein derivative (PPD), eliciting a delayed-type hypersensitivity response: a positive result is determined by the size of the induration. The dual-TST approach, which addresses the booster phenomenon, improves the accuracy of LTBI detection in high-risk or immunocompromised individuals ( 11 – 14 ). A TST induration of ≥5 mm is considered positive in individuals with HIV infection, whereas an induration of ≥15 mm is the threshold for positivity in the general population ( 7 ). However, the TST positivity thresholds for individuals with IEI remain poorly defined. Although guidelines designate an induration of 5 mm or more as positive in certain high-risk groups—such as individuals with HIV infection, recent contacts of persons with active tuberculosis, those exhibiting fibrotic changes on chest radiographs consistent with previous tuberculosis, organ transplant recipients, and immunosuppressed patients, including those undergoing prolonged corticosteroid therapy or receiving tumor necrosis factor alpha (TNF-α) inhibitors—no validated cutoff value has been established for patients with IEI ( 15 , 16 ). Since these patients may not be adequately represented in existing studies, applying the same criteria to this population poses challenges, highlighting the need for further research in this area. Given their heightened susceptibility to infections, whether routine screening—as recommended for HIV-infected individuals—should be implemented for patients with IEI remains an open question. Individuals with IEI are considered to be at higher risk of tuberculosis. However, data on its prevalence, clinical distribution, and prevention in this population remain scarce. To address this knowledge gap, the present study aimed to determine the prevalence of previous and active tuberculosis, identify the most common sites of involvement, assess the utility of the TST, and propose a systematic approach to tuberculosis screening in patients with IEI. Methods Study population and study design Between 2013 and 2024, a total of 340 adult patients evaluated for suspected IEI at the Allergy and Immunology Outpatient Clinic of Istanbul University, Istanbul Faculty of Medicine, were screened for eligibility. Of these, 223 patients were excluded due to secondary immunodeficiency ( n = 88), unconfirmed diagnosis ( n = 17), death prior to enrollment ( n = 12), pregnancy ( n = 1), or refusal to participate ( n = 105). Consequently, 117 adult patients with a confirmed diagnosis of IEI who provided written informed consent were included in the final analysis ( Supplementary Figure 1 ). IEI diagnoses were established in accordance with the criteria set by the International Union of Immunological Societies (IUIS) and the European Society for Immunodeficiencies (ESID) ( 17 – 20 ). Screening protocol for tuberculosis infection All patients with a confirmed diagnosis of IEI were evaluated according to our center’s tuberculosis screening protocol at the Adult Allergy and Immunology Outpatient Clinic of Istanbul University, Istanbul Faculty of Medicine, which provides a systematic framework for tuberculosis screening and management ( Figure 1 ). As part of our routine clinical assessment, all adult patients diagnosed with IEI undergo TST evaluation both as an in vivo measure of cell-mediated immunity and as an integral component of systematic tuberculosis screening. This protocol has been adopted because patients with IEI may be at increased risk of mycobacterial infections and because tuberculosis remains a significant public health concern in Türkiye. The diagnostic assessment and the clinical management of patients with IEI at our center are conducted in accordance with current international guidelines and regional expert recommendations, including the assessment of mycobacterial susceptibility and potential BCG-related complications ( 21 ). Figure 1 Institutional tuberculosis screening algorithm. TST, Tuberculin skin test; LTBI, Latent tuberculosis infection; CT, Computed tomography. Age at evaluation, age at diagnosis, sex, body mass index (BMI), smoking and alcohol use, clinical features, family history, and physical examination findings were systematically documented. Tuberculosis-related information was also obtained, including BCG vaccination status, the presence of a BCG scar, history of tuberculosis, use of antituberculosis therapy, and history of close contact with individuals with active tuberculosis. BCG vaccination status was assessed primarily through patient self-report and verification of a BCG scar during physical examination. Close contact was defined as residing with a tuberculosis patient or having frequent interactions with individuals with the disease. Detailed records were kept on prior tuberculosis infections, including the sites of involvement. Symptoms suggestive of tuberculosis, such as chronic cough, weight loss, night sweats, and fever, were systematically assessed. Given their immunocompromised status, patients were additionally screened for palpable lymphadenopathy and gastrointestinal symptoms, including diarrhea. The TST was performed by a trained healthcare professional at the tuberculosis dispensary utilizing the Mantoux technique. Specifically, 0.1 ml of PPD was administered intradermally into the volar surface of the left forearm using a tuberculin syringe. The injection site was selected on intact skin to ensure valid test results. The results were evaluated 72 h after administration by the healthcare professional who performed the test. Induration at the injection site was measured in millimeters and interpreted accordingly ( 9 , 22 ). For individuals with TST results of 0–4 mm, the test was repeated after 1–4 weeks to assess for a booster response. As part of ongoing clinical monitoring for IEI, many patients had previously undergone computed tomography (CT) imaging—the majority of which was obtained during the COVID-19 pandemic—which was subsequently reassessed by radiologists and pulmonologists. These images were systematically reviewed for post-tuberculosis sequelae, and findings were documented only when they could not be attributed to acute infectious processes, such as COVID-19 pneumonia ( 23 , 24 ). Patients presenting with a TST induration of ≥5 mm, tuberculosis-related symptoms, suspicious findings on chest imaging, or a history of close contact with an individual with active tuberculosis underwent additional evaluation for active tuberculosis. Patients meeting at least one screening criterion were evaluated in consultation with a pulmonologist. Further investigations included sputum acid-fast bacillus (AFB) staining and cultures, as well as chest CT scans when indicated. Treatment for LTBI and active tuberculosis was administered according to national guidelines ( Figure 1 ) ( 11 ). Statistical analysis The Statistical Package for Social Sciences (SPSS) version 27 and Microsoft Excel were utilized for data analysis. The normality of numerical variables was evaluated using the Kolmogorov–Smirnov and Shapiro–Wilk tests. As the data did not conform to a normal distribution, continuous variables were presented as medians and interquartile ranges (IQR, 25th–75th percentile). Spearman’s rank correlation analysis was employed to examine associations between variables. Statistical significance was established at p -values less than 0.05. Ethical considerations This study received approval from the Ethics Committee of Istanbul Faculty of Medicine and the Internal Review Board of the Department of Internal Medicine (approval no. 24.06.2024-2602043). Human ethics and consent to participate declarations All procedures conducted in studies involving human participants adhered to the ethical standards set forth by the relevant institutional and/or national research committees, as well as the principles outlined in the 1964 Helsinki Declaration and its subsequent amendments. In addition, written informed consent was secured from each participant involved in the study. Results Demographic and clinical characteristics and IEI classification Of the patients, 60 (51.3%) were men, with a median age of 35 years (IQR = 26–45.5). The median disease duration was 6 years (IQR = 3–12.75), and the median age at diagnosis was 30 years (IQR = 17–39). Detailed demographic and clinical data are presented in Table 1 . Table 1 Characteristic Patients (n = 117) Age (years), median (IQR, 25–75) 35 (26–45.5) Women/men, n (%) 57/60 (48.7/51.3) Disease duration (years), median (IQR, 25–75) 6 (3–12.75) Smoker, n (%) 20 (17.1) Social alcohol consumer, n (%) 11 (9.4) BMI BMI ≤ 18.5, n (%) 12 (12.5) BMI = 18.6–24.9, n (%) 49 (51) BMI ≥ 25, n (%) 35 (36.5) Immunoglobulin replacement therapy IVIG, n (%) 28 (23.9) SCIG, n (%) 31 (26.5) Prophylactic antibiotics 29 (24.8) Sulfamethoxazole and trimethoprim combination 17 (14.5) Azithromycin 5 (4.3) Amoxicillin and clavulanic acid 5 (4.3) Sulfamethoxazole and trimethoprim combination, fluconazole and sirolimus 1 (0.9) Demographics and clinical characteristics of the patients. IQR, interquartile range; BMI, body mass index; IVIG, intravenous immunoglobulin; SCIG, subcutaneous immunoglobulin. The most common disease category was antibody deficiencies, accounting for 82.1% of the patients. Patient distribution according to the IUIS classification ( 18 , 19 ) is presented in Table 2 . Although genetic testing was available at our center, its use was limited by financial constraints and restricted accessibility. Molecular genetic analysis was conducted when clinically indicated and feasible. In total, 67 of the 117 patients underwent genetic testing, yielding a molecular diagnosis in 20 patients ( Supplementary Table 1 ). Whole-exome sequencing was used as the primary genetic testing modality. Table 2 IEI phenotypic classification, n (%) Patients (n = 117) 1) Immunodeficiencies affecting cellular and humoral immunity 2 (1.7) Combined immunodeficiency (unspecified) 2 (1.7) 2) Combined immunodeficiencies with associated or syndromic features 7 (6) DiGeorge/velocardiofacial syndrome, Chr22q11.2 deletion 1 (0.9) Diseases currently considered as hyper IgE syndromes (HIES) 3 (2.6) Tricho-hepato-enteric syndrome 1 (0.9) Ataxia telangiectasia 1 (0.9) POLE1 (polymerase subunit 1) deficiency (FILS syndrome) 1 (0.9) 3) Predominantly antibody deficiencies 96 (82.1) Common variable immunodeficiency phenotype 57 (48.7) Selective IgA deficiency 19 (16.2) IgG subclass deficiency with IgA deficiency 9 (7.7) IgG subclass deficiency 3 (2.6) X-linked agammaglobulinemia 3 (2.6) Hyper IgM syndromes 4 (3.4) 4) Diseases of immune dysregulation 5 (4.3) LRBA deficiency 1 (0.9) CTLA4 deficiency 3 (2.6) RLTPR (CARMIL2) deficiency 1 (0.9) Diseases associated with EBV susceptibility 1 (0.9) 5) Congenital defects of phagocyte number or function 4 (3.4) GATA2 deficiency 1 (0.9) Chronic granulomatous disease 3 (2.6) 6) Defects in intrinsic and innate immunity 2 (1.7) WHIM (warts, hypogammaglobulinemia, infections, myelokathexis) syndrome 1 (0.9) Predisposition to HPV 1 (0.9) 7) Phenocopies of inborn errors of immunity 1 (0.9) Thymoma with hypogammaglobulinemia (Good syndrome) 1 (0.9) Classification of patients according to the International Union of Immunological Societies (IUIS). IEI, inborn errors of immunity; HPV, human papillomavirus; EBV, Epstein–Barr virus. Tuberculosis history and disease distribution All patients had a BCG vaccination scar. Six patients (5.1%) reported a family history of tuberculosis, while 19 patients (16.2%) had been previously diagnosed with tuberculosis and had completed antituberculosis treatment. Among these, pulmonary involvement was the most common site, accounting for 59.1% of cases. In addition, three patients had experienced two episodes of tuberculosis. Each episode of tuberculosis was treated according to the recommended treatment durations based on the site of involvement: 12 months for central nervous system tuberculosis, 9 months for skeletal tuberculosis, and 6 months for all other forms. Details of the sites of involvement in prior tuberculosis episodes and the corresponding IEI diagnoses are shown in Figure 2 . Figure 2 Tissue/organ involvement of previous tuberculosis diseases according to IEI classification. TST results and tuberculosis screening outcomes Of the 117 patients with IEI who underwent tuberculosis screening, 105 were assessed with TST. Of these, 49 had an induration of ≥5 mm, including 12 who converted on repeat testing after an initial result of 0–4 mm ( Figure 3 ). Figure 3 Assessment of active and latent tuberculosis infection. *The patient had a history of pulmonary tuberculosis and was newly diagnosed with gastrointestinal tuberculosis following the screening. TST, Tuberculin skin test; LTBI, Latent tuberculosis infection. Our screening approach identified five patients with newly diagnosed mycobacterial disease. The characteristics of these five patients are presented in Supplementary Table 2 . Patient 1 died of hemoptysis and pulmonary complications despite receiving antituberculosis treatment. Patient 2 was diagnosed with gastrointestinal tuberculosis based on endoscopic biopsy findings, while sputum cultures were negative for M. tuberculosis . Patient 3 presented with palpable axillary lymphadenopathy. According to our clinical protocol, the patient underwent further evaluation, including chest CT, which revealed scattered non-calcified consolidations at the right lung apex. AFB staining and cultures were negative; however, the consolidations did not respond to non-antituberculosis antibiotics. Based on the
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