Predictive value of C-reactive protein for tuberculosis, bloodstream infection or death among HIV-infected individuals with chronic, non-specific symptoms and negative sputum smear microscopy.

BACKGROUND: C-reactive protein (CRP) is an inflammatory biomarker that may identify patients at risk of infections or death. Mortality among HIV-infected persons commencing antiretroviral therapy (ART) is often attributed to tuberculosis (TB) or bloodstream infections (BSI). METHODS: In two district hospitals in southern Malawi, we recruited HIV-infected adults with one or more unexplained symptoms present for at least one month (weight loss, fever or diarrhoea) and negative expectorated sputum microscopy for TB. CRP determination for 452 of 469 (96%) participants at study enrolment was analysed for associations with TB, BSI or death to 120 days post-enrolment. RESULTS: Baseline CRP was significantly elevated among patients with confirmed or probable TB (52), BSI (50) or death (60) compared to those with no identified infection who survived at least 120 days (269). A CRP value of >10 mg/L was associated with confirmed or probable TB (adjusted odds ratio 5.7; 95% CI 2.6, 14.3; 87% sensitivity) or death by 30 days (adjusted odds ratio 9.2; 95% CI 2.2, 55.1; 88% sensitivity). CRP was independently associated with TB, BSI or death, but the prediction of these endpoints was enhanced by including haemoglobin (all outcomes), CD4 count (BSI, death) and whether ART was started (death) in logistic regression models. CONCLUSION: High CRP at the time of ART initiation is associated with TB, BSI and early mortality and so has potential utility for stratifying patients for intensified clinical and laboratory investigation and follow-up. They may also be considered for empirical treatment of opportunistic infections including TB.

Women's choices regarding HIV testing, disclosure and partner involvement in infant feeding and care in a rural district of Malawi with high HIV prevalence.

The influence of HIV-related stigma on women's choices with regard to HIV testing, disclosure and partner involvement in infant feeding and care is not well understood in rural Malawi but may influence the risk of vertical HIV transmission and infant health. In a study of HIV-infected and -uninfected women in 20 rural locations in Zomba District, Malawi, mothers were questioned at 18-20 months post-partum about these issues. Ten per cent of women claimed unknown HIV status in labour so HIV testing should be routinely offered in Labour & Delivery wards. HIV-infected women were somewhat less likely to disclose to their partners than HIV-uninfected women (89 and 97%, respectively; p = 0.007) or to be cohabiting with partners during pregnancy (74 and 86%, respectively; p = 0.03). Partners of women were less inclined to disclose their HIV testing or HIV status (49 and 66% of partners of HIV-infected and -uninfected women, respectively). Greater partner testing and disclosure may improve prevention of mother to child transmission of HIV (PMTCT) in this population. A majority of women were inclined to make feeding decisions on their own, whereas most felt that other health-related decisions should also involve the father. Most mothers believe that exclusive breast feeding (EBF) is the best infant feeding method (for the first six months) but it was actually practiced by a minority of women (20% of HIV-infected and 5% of HIV-uninfected mothers; p = 0.01). EBF needs systematic support in order to be practised.

Mortality and health outcomes of HIV-exposed and unexposed children in a PMTCT cohort in Malawi.

BACKGROUND: Mortality and morbidity among HIV-exposed children are thought to be high in Malawi. We sought to determine mortality and health outcomes of HIV-exposed and unexposed infants within a PMTCT program. METHOD: Data were collected as part of a retrospective cohort study in Zomba District, Malawi. HIV-infected mothers were identified via antenatal, delivery and postpartum records with a delivery date 18-20 months prior; the next registered HIV-uninfected mother was identified as a control. By interview and health record review, data on socio-demographic characteristics, service uptake, and health outcomes were collected. HIV-testing was offered to all exposed children. RESULTS: 173 HIV-infected and 214 uninfected mothers were included. 4 stillbirths (1.0%) occurred; among the 383 livebirths, 41 (10.7%) children died by 20 months (32 (18.7%) HIV-exposed and 9 unexposed children (4.3%; p<0.0001)). Risk factors for child death included: HIV-exposure [adjOR2.9(95%CI 1.1-7.2)], low birthweight [adjOR2.5(1.0-6.3)], previous child death (adjOR25.1(6.5-97.5)] and maternal death [adjOR5.3(11.4-20.5)]. At 20 months, HIV-infected children had significantly poorer health outcomes than HIV-unexposed children and HIV-exposed but uninfected children (HIV-EU), including: hospital admissions, delayed development, undernutrition and restrictions in function (Lansky scale); no significant differences were seen between HIV-EU and HIV-unexposed children. Overall, no difference was seen at 20 months among HIV-infected, HIV-EU and HIV-unexposed groups in Z-scores (%<-2.0) for weight, height and BMI. Risk factors for poor functional health status at 20 months included: HIV-infection [adjOR8.9(2.4-32.6)], maternal illness [adjOR2.8(1.5-5.0)] and low birthweight [adjOR2.0(1.0-4.1)]. CONCLUSION: Child mortality remains high within this context and could be reduced through more effective PMTCT including prioritizing the treatment of maternal HIV infection to address the effect of maternal health and survival on infant health and survival. HIV-infected children demonstrated developmental delays, functional health and nutritional deficits that underscore the need for increased uptake of early infant diagnosis and institution of ART for all infected infants.

Six-month mortality among HIV-infected adults presenting for antiretroviral therapy with unexplained weight loss, chronic fever or chronic diarrhea in Malawi.

BACKGROUND: In sub-Saharan Africa, early mortality is high following initiation of antiretroviral therapy (ART). We investigated 6-month outcomes and factors associated with mortality in HIV-infected adults being assessed for ART initiation and presenting with weight loss, chronic fever or diarrhea, and with negative TB sputum microscopy. METHODS: A prospective cohort study was conducted in Malawi, investigating mortality in relation to ART uptake, microbiological findings and treatment of opportunistic infection (OIs), 6 months after meeting ART eligibility criteria. RESULTS: Of 469 consecutive adults eligible for ART, 74(16%) died within 6 months of enrolment, at a median of 41 days (IQR 20-81). 370(79%) started ART at a median time of 18 days (IQR 7-40) after enrolment. Six-month case-fatality rates were higher in patients with OIs; 25/121(21%) in confirmed/clinical TB and 10/50(20%) with blood stream infection (BSI) compared to 41/308(13%) in patients with no infection identified. Median TB treatment start was 27 days (IQR 17-65) after enrolment and mortality [8 deaths (44%)] was significantly higher among 18 culture-positive patients with delayed TB diagnosis compared to patients diagnosed clinically and treated promptly with subsequent culture confirmation [6/34 (18%);p = 0.04]. Adjusted multivariable analysis, excluding deaths in the first 21 days, showed weight loss >10%, low CD4 count, severe anemia, laboratory-only TB diagnosis, and not initiating ART to be independently associated with increased risk of death. CONCLUSIONS: Mortality remains high among chronically ill patients eligible for ART. Prompt initiation of ART is vital: more than half of deaths were among patients who never started ART. Diagnostic and treatment delay for TB was strongly associated with risk of death. More than half of deaths occurred without identification of a specific infection. ART programmes need access to rapid point-of-care-diagnostic tools for OIs. The role of early empiric OI treatment in this population requires further evaluation in clinical trials.

High prevalence of tuberculosis and serious bloodstream infections in ambulatory individuals presenting for antiretroviral therapy in Malawi.

BACKGROUND: Tuberculosis (TB) and serious bloodstream infections (BSI) may contribute to the high early mortality observed among patients qualifying for antiretroviral therapy (ART) with unexplained weight loss, chronic fever or chronic diarrhea. METHODS AND FINDINGS: A prospective cohort study determined the prevalence of undiagnosed TB or BSI among ambulatory HIV-infected adults with unexplained weight loss and/or chronic fever, or diarrhea in two routine program settings in Malawi. Subjects with positive expectorated sputum smears for AFB were excluded. Investigations Bacterial and mycobacterial blood cultures, cryptococcal antigen test (CrAg), induced sputum (IS) for TB microscopy and solid culture, full blood count and CD4 lymphocyte count. Among 469 subjects, 52 (11%) had microbiological evidence of TB; 50 (11%) had a positive (non-TB) blood culture and/or positive CrAg. Sixty-five additional TB cases were diagnosed on clinical and radiological grounds. Nontyphoidal Salmonellae (NTS) were the most common blood culture pathogens (29 cases; 6% of participants and 52% of bloodstream isolates). Multivariate analysis of baseline clinical and hematological characteristics found significant independent associations between oral candidiasis or lymphadenopathy and TB, marked CD4 lymphopenia and NTS infection, and severe anemia and either infection, but low positive likelihood ratios (<2 for all combinations). CONCLUSIONS: We observed a high prevalence of TB and serious BSI, particularly NTS, in a program cohort of chronically ill HIV-infected outpatients. Baseline clinical and hematological characteristics were inadequate predictors of infection. HIV clinics need better rapid screening tools for TB and BSI. Clinical trials to evaluate empiric TB or NTS treatment are required in similar populations.