Hemophagocytic lymphohistiocytosis: An unusual complication in disseminated Mycobacterium tuberculosis

Abstract

Background: Hemophagocytic lymphohistiocytosis (HLH) is an uncommon, potentially fatal, hyperinflammatory syndrome that may rarely complicate the clinical course of disseminated Mycobacterium tuberculosis (MTB). The clinical course of tuberculosis-associated HLH (TB-HLH) has been reported to be unpredictable.

Materials and methods: Here we describe the clinicopathological features, laboratory parameters, management, and outcome data of a patient who satisfied the 2004 diagnostic criteria for HLH secondary to disseminated MTB; we also do a systematic review of the international literature on TB-HLH. The literature review (January 1975-March 2014) found that HLH complicated the clinical course of 63 tuberculosis patients (41 males, 22 females, mean age = 45 ± 23.5 years) with a high mortality rate of 49% (31/63 died). The mean serum ferritin level (n = 44/63) was 5963 ng/mL (range 500-38,539 ng/mL); and a higher proportion (54.2%) of patients had pancytopenia at presentation. On univariate analysis (n = 53/63), age >30 years [hazard ratio (HR): 2.79, 95% confidence interval (CI):1.03-7.56, P = 0.03], presence of comorbidities (HR 4.59, CI: 1.08-19.52, P = 0.04), marked hemophagocytosis in bone marrow (HR: 2.65, CI: 1.16-6.05, P = 0.02), and nonusage/delayed usage of antitubercular therapy (ATT) (HR: 3.44, CI: 1.51-7.87, P = 0.003) were associated with decreased survival, though none of these parameters attained statistical significance (P > 0.05) in multivariate analysis. Usage of corticosteroids and/or immunomodulator drugs (HR 1.00, CI: 0.66-3.22, P = 0.35) did not alter the outcome in these patients.

Conclusion: HLH should be considered as a differential diagnosis in patients with tuberculosis who present with cytopenias, organomegaly, and coagulopathy. Strong clinical suspicion and early usage of ATT might be useful in reducing the morbidity and mortality. The utility of immunosuppressive/immunomodulator therapy lacks general concensus among treating physicians, and warrants further studies.

Keywords: Antitubercular therapy; hemophagocytic lymphohistiocytosis; survival; tuberculosis.

Flow chart 1

Diagnostic algorithm of all cases of tuberculosis who presented with hemophagocytic lymphohistiocytosis. +; positive, *; in 3 cases, no information was available. Note: in 33 of 60 cases, the disease was evident in ≥ 2 anatomic sites. Mycobacterium kansasii[21] and Mycobacterium avium intracellulare complex (MAC)[10] were isolated in one case each; and rest cases were attributable to Mycobacterium tuberculosis

Figure 1

(Survival patterns in patients with tuberculosis associated hemophagocytic lymphohistiocytosis (TB-HLH) in relation to different parameters by Kaplan-Meier analysis using log-rank test. (a) Overall survival in patients with TB-HLH was approximately 45% after 3 months. On univariate analysis, (b) age > 30 years (P = 0.03); (c) presence of co-morbidity (P = 0.02); (d) evidence of moderate to marked degree of bone marrow hemophagocytosis (P = 0.01); and (e) non usage/delayed usage of antitubercular therapy (P = 0.001) were significantly associated with decreased survival. Usage of immunomodulators and/or immunosuppressive drugs (f) did not contribute significantly (P = 0.33) to the improved survival. High ferritin (>1000 ng/ml) was associated with poor survival; though it was not statistically significant (P = 0.25) (g)d