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Hemophagocytic lymphohistiocytosis: An unusual complication in disseminated Mycobacterium tuberculosis.

Padhi S, Ravichandran K, Sahoo J, Varghese RG, Basheer A - Lung India (2015 Nov-Dec)

Bottom Line: 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.Strong clinical suspicion and early usage of ATT might be useful in reducing the morbidity and mortality.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Pondicherry Institute of Medical Sciences, Puducherry, India.

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.

No MeSH data available.


Related in: MedlinePlus

(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
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Figure 2: (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

Mentions: The biological behavior of cases with TB-HLH was unpredictable, with a mortality rate of 49% (31/63 died); the overall survival at 3 months was 45% [Figure 1a]. Fifty-four of the 62 cases where data were available received treatment: either ATT alone (n = 16; 10 survived, 62.5%) or in combination with immunosuppressive (steroids and/or intravenous immunoglobulin) and/or immunomodulators (n = 37; 20 survived, 54%). The following immunomodulator drugs were used: Cyclosporine in 3, etoposide in 2, cyclosporine and etoposide in 1, vincristine in 1, chlorambucil and fludarabine in 1, and IL-1 receptor antagonist in 2 cases. None of the 8 cases who did not receive any therapy survived, and 1 who received only immunotherapy also did not survive. In most cases, the failure of therapy was attributed to delayed diagnosis and/or initiation of therapy late in the course of the illness. On univariate analysis, age >30 years (HR: 2.79, 95% CI: 1.03–7.56, P = 0.03), presence of comorbidities (HR: 4.59, CI: 1.08–19.52, P = 0.04), presence of marked hemophagocytosis in bone marrow (HR: 2.65, CI: 1.16–6.05, P = 0.02), and delayed/nonusage of ATT (HR: 3.44, CI: 1.51–7.87, P = 0.003) were significantly associated with decreased survival [Table 3, Figure 1b-g].


Hemophagocytic lymphohistiocytosis: An unusual complication in disseminated Mycobacterium tuberculosis.

Padhi S, Ravichandran K, Sahoo J, Varghese RG, Basheer A - Lung India (2015 Nov-Dec)

(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
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4663863&req=5

Figure 2: (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
Mentions: The biological behavior of cases with TB-HLH was unpredictable, with a mortality rate of 49% (31/63 died); the overall survival at 3 months was 45% [Figure 1a]. Fifty-four of the 62 cases where data were available received treatment: either ATT alone (n = 16; 10 survived, 62.5%) or in combination with immunosuppressive (steroids and/or intravenous immunoglobulin) and/or immunomodulators (n = 37; 20 survived, 54%). The following immunomodulator drugs were used: Cyclosporine in 3, etoposide in 2, cyclosporine and etoposide in 1, vincristine in 1, chlorambucil and fludarabine in 1, and IL-1 receptor antagonist in 2 cases. None of the 8 cases who did not receive any therapy survived, and 1 who received only immunotherapy also did not survive. In most cases, the failure of therapy was attributed to delayed diagnosis and/or initiation of therapy late in the course of the illness. On univariate analysis, age >30 years (HR: 2.79, 95% CI: 1.03–7.56, P = 0.03), presence of comorbidities (HR: 4.59, CI: 1.08–19.52, P = 0.04), presence of marked hemophagocytosis in bone marrow (HR: 2.65, CI: 1.16–6.05, P = 0.02), and delayed/nonusage of ATT (HR: 3.44, CI: 1.51–7.87, P = 0.003) were significantly associated with decreased survival [Table 3, Figure 1b-g].

Bottom Line: 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.Strong clinical suspicion and early usage of ATT might be useful in reducing the morbidity and mortality.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Pondicherry Institute of Medical Sciences, Puducherry, India.

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.

No MeSH data available.


Related in: MedlinePlus