Early Deaths During Tuberculosis Treatment Are Associated With Depressed Innate Responses, Bacterial Infection, and Tuberculosis Progression

Waitt, Catriona; Banda, Ndaziona Peter; White, Sarah; Kampmann, Beate; Kumwenda, Jean; Heyderman, Robert S.; Pirmohamed, Munir; Squire, S. Bertel

doi:10.1093/infdis/jir265

Cited by 35 publications

(43 citation statements)

References 11 publications

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“…Studies from industrialised countries have shown the poor predictive performance of CRB65 and PSI in young patient cohorts overall [36], [37]. By contrast, simple indicators such as advanced wasting and the inability to walk unaided, which may be surrogates for advanced HIV infection in a young population, proved strong predictors of poor outcome in our study, findings paralleled by studies of adult medical admissions in Tanzania [17] and tuberculosis patients in Malawi [18].…”

Section: Discussionsupporting

confidence: 80%

Severity Assessment of Lower Respiratory Tract Infection in Malawi: Derivation of a Novel Index (SWAT-Bp) Which Outperforms CRB-65

Birkhamshaw

Waitt

2013

PLoS ONE

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ObjectiveTo assess the validity of CRB-65 (Confusion, Respiratory rate >30 breaths/min, BP<90/60 mmHg, age >65 years) as a pneumonia severity index in a Malawian hospital population, and determine whether an alternative score has greater accuracy in this setting.DesignForty three variables were prospectively recorded during the first 48 hours of admission in all patients admitted to Queen Elizabeth Central Hospital, Malawi, for management of lower respiratory tract infection over a two month period (N = 240). Calculation of sensitivity and specificity for CRB-65 in predicting mortality was followed by multivariate modeling to create a score with superior performance in this population.ResultsMedian age 37, HIV prevalence 79.9%, overall mortality 18.3%. CRB-65 predicted mortality poorly, indicated by the area under the ROC curve of 0.649. Independent predictors of death were: Male sex, “S” (AOR 2.6); Wasting, “W” (AOR 6.6); non-ambulatory, “A” (AOR 2.5); Temp >38°C or <35°C, “T” (AOR 3.2); BP<100/60, “Bp” (AOR 3.7). Combining these factors to form a severity index (SWAT-Bp) predicted mortality with high sensitivity and specificity (AUC: 0.867). Mortality for scores 0–5 was 0%, 3.3%, 7.4%, 29.2%, 61.5% and 87.5% respectively. A score ≥3 was 84% sensitive and 77% specific for mortality prediction, with a negative predictive value of 95.8%.ConclusionCRB-65 performs poorly in this population. The SWAT-Bp score can accurately stratify patients; ≤2 indicates non-severe infection (mortality 4.4%) and ≥3 severe illness (mortality 45%).

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Section: Discussionsupporting

confidence: 80%

Severity Assessment of Lower Respiratory Tract Infection in Malawi: Derivation of a Novel Index (SWAT-Bp) Which Outperforms CRB-65

Birkhamshaw

Waitt

2013

PLoS ONE

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“…Depressed monocyte responses may be one of the reasons why HIV-infected patients with advanced immunosuppression are at high risk of bacterial infections. [17] Our study and a previous study from a hospitalized cohort in Cape Town [8], confirm that drug-resistant bacteria which require the use of carbapenems and other costly antibiotics are causing HAI. These antibiotics are generally unavailable at district or secondary level hospitals in developing countries and there is therefore often a delay in treating these infections appropriately resulting in high mortality.…”

Section: Discussionsupporting

confidence: 77%

Complications of Antiretroviral Therapy Initiation in Hospitalised Patients with HIV-Associated Tuberculosis

et al. 2013

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BackgroundHIV-associated tuberculosis is a common coinfection in Sub-Saharan Africa, which causes high morbidity and mortality. A sub-set of HIV-associated tuberculosis patients require prolonged hospital admission, during which antiretroviral therapy initiation may be required. The aim of this study was to document the causes of clinical deterioration of hospitalised patients with HIV-associated tuberculosis starting antiretroviral therapy in order to inform healthcare practice in low- to middle-income countries.MethodsProspective, observational cohort study of adult inpatients with HIV-associated tuberculosis starting antiretroviral therapy in a dedicated tuberculosis hospital in Cape Town, South Africa. Causes of clinical deterioration and outcome were recorded in the first 12 weeks of antiretroviral therapy. Patients with rifampicin-resistant tuberculosis were excluded.ResultsBetween May 2009 and November 2010, 112 patients (60% female), with a median age of 32 years were enrolled. At baseline the median CD4 count was 55 cells/mm3 (IQR 31–106) and HIV viral load 5.6 log copies/mL. All patients had significant comorbidity: 82% were bed-bound, 65% had disseminated tuberculosis and 27% had central nervous system tuberculosis. Seventy six patients (68%) developed 144 clinical events after starting antiretroviral therapy. TB-IRIS, hospital-acquired infections and significant drug toxicities occurred in 42%, 20.5% and 15% of patients respectively. A new opportunistic disease occurred in 15% of patients and a thromboembolic event in 8%. Mortality during the 12 week period was 10.6%.ConclusionsHigh rates of TB-IRIS, hospital-acquired infections and drug toxicities complicate the course of patients with HIV-associated tuberculosis starting antiretroviral therapy in hospital. Despite the high morbidity, mortality was relatively low. Careful clinical management and adequate resources are needed in hospitalised HIV-TB patients in the 1st three months following ART initiation.

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“…Disseminated M. tuberculosis is well described in populations with high HIV seroprevalence and depressed CD4 T-cell counts and is associated with a high risk of mortality (54,55). Although the importance of CD4 T-cell function in TB immunity is well established, the contribution of innate immunity to TB outcome also has been described in this group (56,57). Accordingly, it may be the case that in our Ugandan population, impaired adaptive responses in the setting of HIV infection amplifies the immunologic impact of MIF genotype on macrophage TB control.…”

Section: Discussionmentioning

confidence: 99%

Macrophage migration inhibitory factor (MIF) is a critical mediator of the innate immune response to Mycobacterium tuberculosis

Das

Koo²,

Kim

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

110

112

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Significance Failure of the host immune system to control infection with Mycobacterium tuberculosis is a major determinant of tuberculosis (TB) disease. In this work, we examined the role of macrophage migration inhibitory factor (MIF), a cytokine that is encoded in a functionally polymorphic locus in humans, in TB. We found genetic low expressers of MIF to be enriched in a population of patients with HIV and disseminated TB. From our work in cellular and mouse models, we propose a key mechanism by which MIF regulates bacterial recognition as the first step in triggering inflammatory pathways to enable mycobacterial control.

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Early Deaths During Tuberculosis Treatment Are Associated With Depressed Innate Responses, Bacterial Infection, and Tuberculosis Progression

Cited by 35 publications

References 11 publications

Severity Assessment of Lower Respiratory Tract Infection in Malawi: Derivation of a Novel Index (SWAT-Bp) Which Outperforms CRB-65

Severity Assessment of Lower Respiratory Tract Infection in Malawi: Derivation of a Novel Index (SWAT-Bp) Which Outperforms CRB-65

Complications of Antiretroviral Therapy Initiation in Hospitalised Patients with HIV-Associated Tuberculosis

Macrophage migration inhibitory factor (MIF) is a critical mediator of the innate immune response to Mycobacterium tuberculosis

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