The effect of a tuberculosis chest X-ray image reference set on non-expert reader performance.

OBJECTIVES: In low-resource settings, limitations in diagnostic accuracy of chest X-rays (CXR) for pulmonary tuberculosis (PTB) relate partly to non-expert interpretation. We piloted a TB CXR Image Reference Set (TIRS) to improve non-expert performance in an operational setting in Malawi. METHODS: Nineteen doctors and clinical officers read 60 CXR of patients with suspected PTB, at baseline and using TIRS. Two officers also used the CXR Reading and Recording System (CRRS). Correct treatment decisions were assessed against a "gold standard" of mycobacterial culture and expert performance. RESULTS: TIRS significantly increased overall non-expert sensitivity from 67.6 (SD 14.9) to 75.5 (SD 11.1, P = 0.013), approaching expert values of 84.2 (SD 5.2). Among doctors, correct decisions increased from 60.7 % (SD 7.9) to 67.1 % (SD 8.0, P = 0.054). Clinical officers increased in sensitivity from 68.0 % (SD 15) to 77.4 % (SD 10.7, P = 0.056), but decreased in specificity from 55.0 % (SD 23.9) to 40.8 % (SD 10.4, P = 0.049). Two officers made correct treatment decisions with TIRS in 62.7 %. CRRS training increased this to 67.8 %. CONCLUSION: Use of a CXR image reference set increased correct decisions by doctors to treat PTB. This tool may provide a low-cost intervention improving non-expert performance, translating into improved clinical care. Further evaluation is warranted. KEY POINTS: • Tuberculosis treatment decisions are influenced by CXR findings, despite improved laboratory diagnostics. • In low-resource settings, CXR interpretation is performed largely by non-experts. • We piloted the effect of a simple reference training set of CXRs. • Use of the reference set increased the number of correct treatment decisions. This effect was more marked for doctors than clinical officers. • Further evaluation of this simple training tool is warranted.

An audit of Heart failure management among ambulatory adult patients at Queen Elizabeth Central Hospital (QECH), Malawi.

Background: There are limited data on the clinical characteristics and use of guideline directed medical therapy among patients with heart failure in Malawi. We conducted a study to assess patient characteristics and clinical management given to heart failure patients at Queen Elizabeth Central hospital in Malawi. Methods: In a cross sectional study, patients with a diagnosis of heart failure who were followed up in the adult chest clinic at QECH were recruited to ascertain their characteristics and the therapy they were receiving. Echocardiograms and electrocardiograms were performed to identify abnormalities. Results: A total of 79 patients were recruited and 62% (49 out of 79) were female. The median age was 60 years (IQR 40.5-70.5). Most patients were hypertensive with NYHA (New York Heart Association) class I and II symptoms. Left ventricular(LV) systolic dysfunction was found in 55% (36 out of 65), with 68% (39 out of 65) having features of left ventricular remodeling. Most patients were on at least a single neurohormonal drug with 77% (61 out of 79) on ACEI (angiotensin converting enzyme inhibitor), 52% (42 out of 79) on a beta blocker and 34%(27 out of 79) on aldosterone antagonists. The recommended doses of medications were achieved in 14% (9 out 61), 24% (10 out 42), 22% (6 out of 27) on ACEI, beta blockers and aldosterone antagonists respectively. Conclusions: Hypertension is the commonest comorbidity in patients with heart failure, who are mostly females with NYHA class I or II symptoms. Most had LV remodeling changes and are on at least one neurohormonal antagonist but most remain sub optimally treated.

Sepsis carries a high mortality among hospitalised adults in Malawi in the era of antiretroviral therapy scale-up: a longitudinal cohort study.

OBJECTIVE: To assess mortality risk among adults presenting to an African teaching hospital with sepsis and severe sepsis in a setting of high HIV prevalence and widespread ART uptake. METHODS: Prospective cohort study of adults (age ≥16 years) admitted with clinical suspicion of severe infection between November 2008 and January 2009 to Queen Elizabeth Central Hospital, a 1250-bed government-funded hospital in Blantyre, Malawi. Demographic, clinical and laboratory information, including blood and cerebrospinal fluid cultures were obtained on admission. RESULTS: Data from 213 patients (181 with sepsis and 32 with severe sepsis; M:F = 2:3) were analysed. 161 (75.6%) patients were HIV-positive. Overall mortality was 22%, rising to 50% amongst patients with severe sepsis. The mortality of all sepsis patients commenced on antiretroviral therapy (ART) within 90 days was 11/28 (39.3%) compared with 7/42 (16.7%) among all sepsis patients on ART for greater than 90 days (p = 0.050). Independent associations with death were hypoxia (OR = 2.4; 95% CI, 1.1-5.1) and systolic hypotension (OR 7.0; 95% CI: 2.4-20.4). CONCLUSIONS: Sepsis and severe sepsis carry high mortality among hospitalised adults in Malawi. Measures to reduce this, including early identification and targeted intervention in high-risk patients, especially HIV-positive individuals recently commenced on ART, are urgently required.

A prospective study of mortality from cryptococcal meningitis following treatment induction with 1200 mg oral fluconazole in Blantyre, Malawi.

OBJECTIVE: We have previously reported high ten-week mortality from cryptococcal meningitis in Malawian adults following treatment-induction with 800 mg oral fluconazole (57% [33/58]). National guidelines in Malawi and other African countries now advocate an increased induction dose of 1200 mg. We assessed whether this has improved outcomes. DESIGN: This was a prospective observational study of HIV-infected adults with cryptococcal meningitis confirmed by diagnostic lumbar puncture. Treatment was with fluconazole 1200 mg/day for two weeks then 400mg/day for 8 weeks. Mortality within the first 10 weeks was the study end-point, and current results were compared with data from our prior patient cohort who started on fluconazole 800 mg/day. RESULTS: 47 participants received fluconazole monotherapy. Despite a treatment-induction dose of 1200 mg, ten-week mortality remained 55% (26/47). This was no better than our previous study (Hazard Ratio [HR] of death on 1200 mg vs. 800 mg fluconazole: 1.29 (95% CI: 0.77-2.16, p = 0.332)). There was some evidence for improved survival in patients who had repeat lumbar punctures during early therapy to lower intracranial pressure (HR: 0.27 [95% CI: 0.07-1.03, p = 0.055]). CONCLUSION: There remains an urgent need to identify more effective, affordable and deliverable regimens for cryptococcal meningitis.

High mortality amongst adolescents and adults with bacterial meningitis in sub-Saharan Africa: an analysis of 715 cases from Malawi.

UNLABELLED: Mortality from bacterial meningitis in African adults is significantly higher than those in better resourced settings and adjunctive therapeutic interventions such as dexamethasone and glycerol have been shown to be ineffective. We conducted a study analysing data from clinical trials of bacterial meningitis in Blantyre, Malawi to investigate the clinical parameters associated with this high mortality. METHODS: We searched for all clinical trials undertaken in Blantyre investigating bacterial meningitis from 1990 to the current time and combined the data from all included trial datasets into one database. We used logistic regression to relate individual clinical parameters to mortality. Adults with community acquired bacterial meningitis were included if the CSF culture isolate was consistent with meningitis or if the CSF white cell count was >100 cells/mm(3) (>50% neutrophils) in HIV negative participants and >5 cells/mm(3) in HIV positive participants. Outcome was measured by mortality at discharge from hospital (after 10 days of antibiotic therapy) and community follow up (day 40). RESULTS: Seven hundred and fifteen episodes of bacterial meningitis were evaluated. The mortality rate was 45% at day 10 and 54% at day 40. The most common pathogens were S.pneumoniae (84% of positive CSF isolates) and N.meningitidis (4%). 607/694 (87%) participants tested were HIV antibody positive. Treatment delays within the hospital system were marked. The median presenting GCS was 12/15, 17% had GCS<8 and 44.9% had a seizure during the illness. Coma, seizures, tachycardia and anaemia were all significantly associated with mortality on multivariate analysis. HIV status and pneumococcal culture positivity in the CSF were not associated with mortality. Adults with community acquired bacterial meningitis in Malawi present with a severe clinical phenotype. Predictors of high mortality are different to those seen in Western settings. Optimising in-hospital care and minimising treatment delays presents an opportunity to improve outcomes considerably.

A prospective longitudinal study of the clinical outcomes from cryptococcal meningitis following treatment induction with 800 mg oral fluconazole in Blantyre, Malawi.

INTRODUCTION: Cryptococcal meningitis is the most common neurological infection in HIV infected patients in Sub Saharan Africa, where gold standard treatment with intravenous amphotericin B and 5 flucytosine is often unavailable or difficult to administer. Fluconazole monotherapy is frequently recommended in national guidelines but is a fungistatic drug compromised by uncertainty over optimal dosing and a paucity of clinical end-point outcome data. METHODS: From July 2010 until March 2011, HIV infected adults with a first episode of cryptococcal meningitis were recruited at Queen Elizabeth Central Hospital, Blantyre, Malawi. Patients were treated with oral fluconazole monotherapy 800 mg daily, as per national guidelines. ART was started at 4 weeks. Outcomes and factors associated with treatment failure were assessed 4, 10 and 52 weeks after fluconazole initiation. RESULTS: Sixty patients were recruited. 26/60 (43%) died by 4 weeks. 35/60 (58.0%) and 43/56 (77%) died or failed treatment by 10 or 52 weeks respectively. Reduced consciousness (Glasgow Coma Score <14 of 15), moderate/severe neurological disability (modified Rankin Score >3 of 5) and confusion (Abbreviated Mental Test Score <8 of 10) were all common at baseline and associated with death or treatment failure. ART prior to recruitment was not associated with better outcomes. CONCLUSIONS: Mortality and treatment failure from cryptococcal meningitis following initiation of treatment with 800 mg oral fluconazole is unacceptably high. To improve outcomes, there is an urgent need for better therapeutic strategies and point-of-care diagnostics, allowing earlier diagnosis before development of neurological deficit.

Glycerol adjuvant therapy in adults with bacterial meningitis in a high HIV seroprevalence setting in Malawi: a double-blind, randomised controlled trial.

BACKGROUND: Southern Africa has a high incidence of bacterial meningitis in adults, often associated with HIV co-infection. Mortality exceeds 50%, even with appropriate antibiotic therapy, and is not improved with corticosteroids. Glycerol adjuvant therapy reduces long-term morbidity in bacterial meningitis in children, and its use is being promoted. We aimed to assess the effectiveness of glycerol as an adjuvant therapy for adults with bacterial meningitis in Africa. METHODS: The study was done in two phases. First, in an open-label dose-finding study, 45 adult patients with symptoms, signs, and cerebrospinal fluid findings consistent with bacterial meningitis received either 50 mL, 75 mL, or 100 mL of glycerol four times a day for 4 days. We then did a randomised, double-blind, placebo-controlled trial of oral glycerol in adults with bacterial meningitis. Patients with clinical and cerebrospinal fluid findings suggestive of bacterial meningitis were randomly assigned in blocks of 12 by use of a random number list produced by an independent statistician to receive either glycerol or an equivalent volume of sugar solution. Glycerol and placebo were indistinguishable by colour or taste. The primary outcome was mortality at 40 days, with secondary outcomes including disability and mortality restricted to pneumococcal disease. All patients were analysed for the primary outcome excluding those who were lost to follow-up. This trial is registered at controlled-trials.com, number ISRCTN70121840. FINDINGS: 75 mL glycerol four times a day was the highest tolerated dose, and was used for the main study. 265 patients were assigned treatment: 137 glycerol and 128 placebo. The trial was stopped early on the advice of the data and safety monitoring board after a planned interim analysis. By day 40, 61 (49%) of 125 patients in the placebo group and 86 (63%) of 136 in the glycerol group had died (adjusted odds ratio 2.4, 95% CI 1.3-4.2, p=0.003). There was no benefit from glycerol for death and disability by day 40, and glycerol did not improve death and disability by day 40 or death at day 40 in patients with proven bacterial disease or pneumococcal disease. Two serious adverse events occurred that were possibly due to the study drug. INTERPRETATION: Oral glycerol therapy cannot be recommended as an adjuvant therapy in adults with bacterial meningitis in resource-poor settings with a high HIV prevalence. FUNDING: Meningitis Research Foundation.