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. We integrated all published reports of adult HIV-negative TB-associated HLH (TB-HLH) to define clinical characteristics, diagnostic strategies, 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 (1) patients with a confirmed TB diagnosis receiving antituberculosis treatment while developing HLH and (2) patients presenting with HLH of unknown cause later diagnosed with TB. We used a logistic regression model to define clinical and diagnostic parameters associated with survival.

Results: We identified 115 individual cases, 45 (39.1%) from countries with low TB incidence (<10/100 000 per year). When compared with patients with HLH and known TB (n = 21), patients with HLH of unknown cause (n = 94) more often had extrapulmonary TB (66.7% vs 88.3%), while the opposite was true for pulmonary disease (91.5% vs 59.6%). 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 result upon a tuberculin skin test or interferon-γ release assay. In-hospital mortality was 28.1% (27/96) in those treated for TB and 100% (18/18) in those who did not receive antituberculosis treatment (P < .001).

Conclusions: Tuberculosis should be considered a cause of unexplained HLH. TB-HLH is likely underreported, and the diagnostic workup of patients with HLH should include bone marrow investigations for evidence of Mycobacerium tuberculosis. Prompt initiation of antituberculosis treatment likely improves survival in TB-HLH.

Keywords: anergy; bone marrow; hemophagocytic lymphohistiocytosis; mortality; tuberculosis.

Figure 1.

PRISMA diagram of articles reporting ≥1 cases of TB-HLH. ATT, antituberculosis treatment; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-analyses; TB, tuberculosis; TB-HLH, tuberculosis-associated hemophagocytic lymphohistiocytosis.

Figure 2.

Geographic distribution of TB-HLH cases: number of reported TB-HLH cases according to country of origin for published report. Gray, no TB-HLH cases reported. TB-HLH, tuberculosis-associated hemophagocytic lymphohistiocytosis.

Figure 3.

T cell–based immunoassay results in TB-HLH. Test results: TST (left) and IGRA (right). Results are presented as the proportion of all patients with TB-HLH in which test results were reported. Four patients had both TST and IGRA results. IGRA, interferon-γ release assay; TB-HLH, tuberculosis-associated hemophagocytic lymphohistiocytosis; TST, tuberculin skin test.