Tuberculosis-associated hemophagocytic lymphohistiocytosis: diagnostic challenges and determinants of outcome

Abstract Background Tuberculosis (TB) can induce secondary hemophagocytic lymphohistiocytosis (HLH), a severe inflammatory syndrome with high mortality. To improve insight into optimal diagnostic and treatment strategies, we integrated all published reports of adult HIV-negative TB-associated HLH (TB-HLH) globally to define clinical characteristics and therapeutic approaches associated with improved survival. Methods PubMed, Embase, and Global Index Medicus were searched for eligible records. TB-HLH cases were categorized into patients with a confirmed TB diagnosis receiving antituberculosis treatment while developing HLH, and patients presenting with HLH of unknown cause later diagnosed with TB. We integrated patients’ clinical characteristics, diagnostic test results, and pre-specified parameters associated with survival into a logistic regression model. Results We identified 115 individually reported cases, 45 (39.1%) from low TB incidence countries (<10/100.000 per year). Compared to HLH patients with known TB (n=21), patients with HLH of unknown cause (n=94), more often had extrapulmonary TB (88.3% vs. 66.7%), while the opposite was true for pulmonary disease (59.6% vs. 91.5%). Overall, Mycobacterium tuberculosis was identified in the bone marrow in 78.4% of patients for whom examination was reported (n=74). Only 10.5% (4/38) of patients tested had a positive tuberculin skin test or interferon gamma release assay. In-hospital survival was 71.9% (69/96) in those treated for TB and 0% (18/18) in those who did not receive antituberculosis treatment (p < 0.001). Conclusions Tuberculosis should be considered as a cause of unexplained HLH. TB-HLH is probably under-reported, and the diagnostic work-up of HLH patients should include bone marrow examination for evidence of M. tuberculosis infection. Prompt initiation of antituberculosis treatment will likely improve survival. Key points Hemophagocytic lymphohistiocytosis is an underreported complication of tuberculosis, often manifesting as extrapulmonary or miliary disease. TST and IGRA mostly show an anergic response. Threshold should be low bone marrow investigation for evidence of M. tuberculosis, and commencement of antituberculosis treatment.