Clinical Features, Genetic Background, and Outcomes in Children with Mendelian Susceptibility to Mycobacterial Disease Diagnosed with Mycobacterial Tuberculosis Complex in Saudi Arabia: Case Series

Introduction

The Bacillus Calmette-Guérin (BCG) vaccine was developed in France, in 1908, by Albert Calmette and Camille Guérin. It was produced by in-vitro at-tenuation of Mycobacterium bovis strains, and first used in 1921 [1]. In 1974, the World Health Organization (WHO) included the vaccine in its Expanded Program of Immunization (EPI) [2]. While the BCG vaccine is well tolerated by most children, it carries the risk of adverse reactions, ranging from regional suppurative lymphadenitis to fatal disseminated BCG infection (BCGosis). The estimated incidence of such reactions is 1 to 3.4 per million, with a high case-fatality ratio reaching 50-71% of cases [3,4]. Patients with Mendelian susceptibility to mycobacterial disease (MSMD) and severe combined immunodeficiency (SCID), respectively, have the highest rates of complications and mortality [5], and early anti-mycobacterial therapy is therefore crucial in this cohort. However, management approaches to BCG vaccination complications remain a subject of debate. Here, we present cases of disseminated BCGitis, as well as the associated clinical and diagnostic investigations and underlying primary diseases, in a retrospective cohort of 14 MSMD patients at a single center in Saudi Arabia.

Materials and Methods

The study included data collected from January 2009 to December 2022, as part of larger study of Mycobacterial tuberculosis complex samples submitted to the Microbiology Department of a single tertiary center in Saudi Arabia. All samples were from patients under 14 years of age with confirmed genetic mutations for Mendelian susceptibility to mycobacterial disease. Data were collected from the Patient Electronic Medical Record System and the Microbiology Department’s data record using a questionnaire. To ensure anonymity, no patient identifiers were used. Variables included baseline information such as sex, age, nationality, clinical symptoms, underlying primary immunodeficiency conditions, treatment, and prognosis of BCGosis in the studied patients. This case series was approved by the Institutional Review Board (IRB) on 5 May 2020 (IRB log Number 20-271).

III. RESULTS

Demographics: We evaluated 14 patients with MSMD of whom 7 were male and 7 female (Table 1). Consanguinity was found in the families of 7 patients (50%). Primary immunodeficiency (PID) in child relatives was confirmed in 6 cases (42.8%), and clinically suspected in 2 (14.2%). Majority of patients had received a BCG vaccination at birth, under the previous Saudi national immunization plan. One patient had been vaccinated at 6 months, in accordance with the updated immunization plan, the exact timing of BCG vaccination for one patient is unknown. Post-vaccination Complications: Disseminated BCG infection was diagnosed in 12 of the patients (85.7%), while 6 (42.8%) developed generalized lymphadenopathy. The most common symptom was fever, in 9 patients (64.2%). Nine patients (64.2%) were screened for HIV, all were negative. PCR and Culture: Samples were collected via fine-needle aspiration or swabs, depending on the site of infection and clinical presentation (Table 2). All patients exhibited evidence of M. tuberculosis complex on culture, and PCR testing was positive in 11 (78.5%). As all isolates were resistant to pyrazinamide, the pathogens were most likely Mycobacterium bovis BCG strains. Management and Prognosis: All patients received anti-tuberculosis medications irrespective of their diagnosis (BCGitis or BCGosis), the duration of treatment ranging from 6 months to 1.5 years or more, depending on clinical response. In addition, 3 patients (21.4%) started rhIFN-γ therapy out of 14 patients, and 5 patient were followed up at our hospital until the time of publication or until their death. Among the remaining 9 patients, 7 were lost to follow-up (some were referred for transplant). It is worth mentioning that 2 of the 14 patients (14.2%) died. Immunological Screening and Genetic Analysis: The patients’ immunological screening results are detailed in Table 3. A lymphocyte subset count was ordered for 12 patients (85.7%), and was only within normal age-specific range in 5 of the 12. Serum immunoglobulin levels were measured in 11 of the 14 patients (78.5%), elevated IgA levels (above 1.2 g/l) were observed in 6 patients, and elevated IgM levels (above 1.6 g/l) were also found in 6 patients. Additionally, IgG levels exceeded the normal range (10.6 g/l) in 8 patients. Further details are provided in Table 3. The genetic analysis, conducted for all patients (Table 3), revealed an IL12B gene mutation in 6 out of 14 patients (42.8%). Three patients (P1, P12, and P14) had a STAT1 gene deletion affecting exons 3 and 4. One patient (P1) had a mutation affecting IL12RB1, and another (P2) had a homozygous mutation affecting IFNGR2. An interesting case (P11) was found to have a dual mutation affecting both interferon receptors IFNAR1 and IFNGR2. Only three patients (P1, P7, and P13) received interferon gamma therapy. The genetic testing reports for four patients (P6, P7, P9, P10) were difficult to retrieve.

Discussion