We present a unique case series of eight siblings from a family originating from a country with a high incidence of tuberculosis, all of whom lived in the same apartment and were diagnosed with MDR tuberculosis in Germany within an 18-month period, reminiscent of the catastrophic consequences for families affected by tuberculosis in previous centuries [4]. In two healthy contact siblings, tuberculosis disease and M. tuberculosis infection were initially excluded after intensive investigations. Given the negative IGRA results and the lack of recommendations for preventive therapies for contacts of index patients with drug-resistant tuberculosis without M. tuberculosis infection at that time, a “watch and wait” strategy was suggested. Both siblings subsequently developed tuberculosis.

The high rate of secondary MDR tuberculosis cases in this family is noteworthy. Household contacts of tuberculosis patients are at increased risk of infection and disease due to prolonged and intense exposure to index cases, with 90% of tuberculosis cases occurring within the first two years [5]. Meta-analyses have shown that between 30 and 47% of household contacts of MDR/RR tuberculosis patients have M. tuberculosis infection and that only between 3 and 8% develop active disease [5, 6]. There is no evidence that infection or disease rates in contacts differ between drug-resistant and drug-susceptible tuberculosis [7]. There were no predisposing factors for tuberculosis in any of the eight siblings, and whole exome sequencing failed to identify any variant known to be linked with known Mendelian or increased susceptibility to mycobacterial infection or disease. Hence, the precise factors contributing to the high rate of secondary tuberculosis cases remain elusive.

An important question arising from this case series is whether the administration of tuberculosis preventive treatment to the two youngest siblings, who initially had no evidence of M. tuberculosis infection or active disease could have prevented disease progression. According to the WHO recommendations, confirmation of Mycobacterium tuberculosis infection by tuberculin skin test (TST), tuberculosis antigen-based skin test (TBST) or IGRA is not required before starting TPT for MDR/RR-TB for child contacts and people with HIV or other immunocompromising conditions. In other populations, preventive treatment without confirmation of M. tuberculosis infection is not generally recommended, but the lack of test availability should not be a barrier to providing preventive treatment to those at risk of MDR/RR tuberculosis. The 2024 WHO Operational Handbook on Tuberculosis now recommends six months of daily levofloxacin monotherapy for contacts of people with MDR/RR tuberculosis [8]. This recommendation is based on evidence from the two randomised controlled trials CHAMP and V-QUIN, a systematic review of studies on the use of preventive treatment for MDR/RR tuberculosis and studies on the programmatic feasibility and acceptability of this regimen. While the TB-CHAMP [9] and V-QUIN trials [10] did not achieve statistical significance, a meta-analysis of these trials showed a 60% relative reduction in TB incidence among adult and child household MDR tuberculosis contacts [11]. In addition to these studies, the ongoing randomised prospective PHOENIx trial (NCT03568383) aims to evaluate the efficacy of tuberculosis preventive treatment with delamanid or isoniazid in preventing tuberculosis disease in high-risk household contacts of adults with MDR/RR- tuberculosis.

As the two youngest siblings tested negative on IGRA in September 2019, the clinicians decided to withhold tuberculosis preventive treatment and provide close outpatient follow-up. In retrospect, it can be argued that IGRA should have been repeated during follow-up to potentially detect early seroconversion and reassess the need for tuberculosis preventive treatment. Alternatively, tuberculosis preventive treatment should have been initiated despite the absence of a reactive IGRA due to the significant epidemiological risk. Importantly, the general sensitivity of IGRAs for the diagnosis of culture-proven active tuberculos isonly around 80% [12, 13]. Risk factors for negative IGRA resluts include immunodeficiency, young or advanced age, extrapulmonary tuberculosis, disseminated tuberculosis, concomitant tuberculosis treatment and smoking [14]. This underscores the importance of cautious interpretation of negative results in high-risk populations. Preventive treatment may have averted not only the development of severe pulmonary MDR tuberculosis but also the subsequent post-tuberculosis lung disease, which left one of the two children with residual bipulmonary cavitary lesions and persistent restrictive lung disease [15].

Delayed diagnosis of TB in migrants remains a significant challenge, often due to barriers such as limited access to health care, language difficulties, fear of stigma and unfamiliarity with local health systems. These delays can result in advanced disease progression by the time of diagnosis, as documented in our case series. Targeted public health interventions are needed to address this problem, including improved screening programmes, culturally sensitive health care approaches, and improved access to diagnostic services for migrant populations [16].