Serial measurement of M. tuberculosis in blood from critically-ill patients with HIV-associated tuberculosis

Barr, David; Schutz, Charlotte; Balfour, Avuyonke; Shey, Muki; Kamariza, Mireille; Bertozzi, Carolyn R.; Wet, Timothy J. de; Dinkele, Ryan; Ward, Amy; Haigh, Kathryn; Kanyik, Jean-Paul; Mizrahi, Valerie; Nicol, Mark P.; Wilkinson, Robert J.; Lalloo, David G.; Warner, Digby F.; Meintjes, Graeme; Davies, Gerry

doi:10.1016/j.ebiom.2022.103949

Cited by 11 publications

(9 citation statements)

References 48 publications

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“…TB should therefore be considered in patients with unexplained HLH [ 29 ], and the diagnostic workup for TB in suspected or confirmed HLH should include bone marrow histology and microbiological testing for M tuberculosis . If bone marrow sampling is not possible, mycobacterial blood cultures may provide additional diagnostic benefit, but their slow turnaround time means that molecular and antigen tests that detect M tuberculosis , which are currently limited to research, may become useful in this setting [ 30 , 31 ].…”

Section: Discussionmentioning

confidence: 99%

Tuberculosis-Associated Hemophagocytic Lymphohistiocytosis: Diagnostic Challenges and Determinants of Outcome

Kurver,

Seers,

van Dorp

et al. 2024

Open Forum Infectious Diseases

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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 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 used a logistic regression model to define clinical and diagnostic parameters associated with survival. Results We identified 115 individual 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 (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 tuberculin skin test or interferon gamma 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 < 0.001). Conclusions Tuberculosis should be considered as a cause of unexplained HLH. TB-HLH is likely to be under-reported, and the diagnostic work-up of HLH patients should include bone marrow investigations for evidence of M. tuberculosis. Prompt initiation of antituberculosis treatment likely improves survival in TB-HLH.

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Section: Discussionmentioning

confidence: 99%

Tuberculosis-Associated Hemophagocytic Lymphohistiocytosis: Diagnostic Challenges and Determinants of Outcome

Kurver,

Seers,

van Dorp

et al. 2024

Open Forum Infectious Diseases

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“…TB should therefore be considered in patients with unexplained HLH, and the diagnostic workup for TB in suspected or confirmed HLH should include bone marrow histology and microbiological testing for M. tuberculosis. If bone marrow sampling is not possible, mycobacterial blood cultures may provide additional diagnostic benefit, but their slow turnaround time means molecular and antigen tests that detect M tuberculosis , currently limited to research, may become particularly useful in this setting [29,30].…”

Section: Discussionmentioning

confidence: 99%

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

Kurver,

Seers,

van Dorp

et al. 2023

Preprint

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BackgroundTuberculosis (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.MethodsPubMed, 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.ResultsWe 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 tuberculosiswas 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).ConclusionsTuberculosis 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 ofM. tuberculosisinfection. Prompt initiation of antituberculosis treatment will likely improve survival.Key pointsHemophagocytic 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 ofM. tuberculosis,and commencement of antituberculosis treatment.

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“…Human studies have demonstrated early bactericidal activity (EBA) for moxi oxacin that approximates isoniazid. EBA is de ned as the fall in the log (10) colony forming units (cfu) of Mycobacterium tuberculosis per ml sputum per day. The mean EBA for moxi oxacin in one study was 0.53 (95% CI 0.28-0.59) and that for isoniazid 0.77 (95% CI 0.54-1.00) (24).…”

Section: B) Addition Of Levo Oxacinmentioning

confidence: 99%

“…A sub-study quanti ed mycobacterial load in blood and changes over the rst 72 hours of anti-tuberculosis treatment using three tests: Xpert Ultra, Myco/F lytic culture and a novel microscopy technique using a uorescent probe 4-N,N-dimethylaminonaphthalimide-trehalose (DMN-Tre). Patients who died had a higher probability of having a higher mycobacterial load at all time points compared to survivors and showed some evidence of slower clearance of these markers on anti-tuberculosis treatment (10).…”

Section: Introduction Background and Rationale {6a}mentioning

confidence: 97%

Testing Novel Strategies for Patients Hospitalized with HIV-associated Disseminated Tuberculosis (NewStrat-TB): Protocol for a Randomised Controlled Trial

Namale,

Boloko,

Vermeulen

et al. 2024

Preprint

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Background HIV-associated tuberculosis (TB) contributes disproportionately to global tuberculosis mortality. Patients hospitalized at the time of the diagnosis of HIV-associated disseminated TB are typically severely ill and have a high mortality risk despite initiation of tuberculosis treatment. The objective of the study is to assess the safety and efficacy of both intensified TB treatment (high dose rifampicin plus levofloxacin) and immunomodulation with corticosteroids as interventions to reduce early mortality in hospitalised patients with HIV-associated disseminated TB. Methods This is a phase III randomised controlled superiority trial, evaluating two interventions in a 2x2 factorial design: 1) high dose rifampicin (35mg/kg/day) plus levofloxacin added to standard TB treatment for the first 14 days versus standard tuberculosis treatment; and 2) adjunctive corticosteroids (prednisone 1.5 mg/kg/day) versus identical placebo for the first 14 days of TB treatment. The study population is HIV-positive patients diagnosed with disseminated TB (defined as being positive by at least one of the following assays: urine Alere LAM, urine Xpert MTB/RIF Ultra, or blood Xpert MTB/RIF Ultra) during a hospital admission. The primary endpoint is all-cause mortality at 12 weeks comparing, first, patients receiving intensified TB treatment to standard of care and, second, patients receiving corticosteroids to those receiving placebo. Analysis of the primary endpoint will be by intention to treat. Secondary endpoints include all-cause mortality at 2 and 24 weeks. Safety and tolerability endpoints include hepatoxicity evaluations and corticosteroid-related adverse events. Discussion Disseminated TB is characterised by a high mycobacterial load and patients are often critically ill at presentation, with features of sepsis, which carries a high mortality risk. Interventions that reduce this high mycobacterial load or modulate associated immune activation could potentially reduce mortality. If found to be safe and effective, the interventions being evaluated in this trial could be easily implemented in clinical practice. ClinicalTrials.gov ID: NCT04951986. Trial registration Registered on 7 July 2021 https://clinicaltrials.gov/study/NCT04951986

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Serial measurement of M. tuberculosis in blood from critically-ill patients with HIV-associated tuberculosis

Cited by 11 publications

References 48 publications

Tuberculosis-Associated Hemophagocytic Lymphohistiocytosis: Diagnostic Challenges and Determinants of Outcome

Tuberculosis-Associated Hemophagocytic Lymphohistiocytosis: Diagnostic Challenges and Determinants of Outcome

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

Testing Novel Strategies for Patients Hospitalized with HIV-associated Disseminated Tuberculosis (NewStrat-TB): Protocol for a Randomised Controlled Trial

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