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Use of a WHO-recommended algorithm to reduce mortality in seriously ill patients with HIV infection and smear-negative pulmonary tuberculosis in South Africa: an observational cohort study

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Summary

Background

In 2007, WHO released revised recommendations and an algorithm for the diagnosis and treatment of smear-negative pulmonary tuberculosis in seriously ill people living with HIV/AIDS. We aimed to assess the effect of the recommendations on clinical outcome in patients in South Africa.

Methods

We enrolled seriously ill patients (aged ≥15 years) with HIV infection and suspected smear-negative pulmonary tuberculosis from three hospitals in KwaZulu-Natal, South Africa. Patients were consecutively enrolled into two cohorts: the first cohort was managed according to standard practice, and the second according to the WHO-recommended algorithm. The primary endpoints were rates of continued stay in hospital at 7 days after admission and survival at 8 weeks after admission.

Findings

338 patients were enrolled in the standard practice cohort between August, 2008, and February, 2009, and 187 were enrolled in the algorithm cohort between March, 2009, and December, 2009. 7 days after hospital admission, 27% (n=50) of patients in the algorithm cohort were still in hospital, compared with 38% (n=130) in the standard practice cohort (rate ratio 0·70, 95% CI 0·53–0·91; p=0·009). 8 weeks after admission, 83% (n=156) of patients in the algorithm cohort were alive, compared with 68% (n=230) in the standard practice cohort (1·23, 1·11–1·35; p=0·0001), with effect modified by hospital location.

Interpretation

In seriously ill patients with HIV infection and suspected smear-negative pulmonary tuberculosis, early antituberculosis treatment according to the WHO algorithm could significantly reduce mortality in South Africa.

Funding

US President's Emergency Plan for AIDS Relief.

Introduction

Diagnosis and treatment of tuberculosis in people living with HIV/AIDS remains a major public health challenge because of the global burden of both diseases, programmatic limitations in many high burden countries, and the atypical manner in which people living with HIV/AIDS might manifest tuberculosis disease.1 The tuberculosis and HIV pandemics continue to collide in sub-Saharan Africa, resulting in increased incidence and mortality.2 In this region, the contribution of AIDS-related smear-negative pulmonary tuberculosis to disease-specific mortality is unknown because of increased incidence, under-recognition and underdiagnosis, and poor management practices.2 In 2007, an estimated 58% of patients with tuberculosis in South Africa were infected with HIV.3 South Africa probably has the most people (about 1 million) living with both tuberculosis disease and HIV infection.4 In 2005, the prevalence of smear-negative pulmonary tuberculosis was 1891 cases per 100 000 people living with HIV/AIDS and 238 cases per 100 000 people not infected with HIV.5 Tuberculosis was the leading cause of death in South Africa in 20076 and 2008.7 However, the effect of untreated smear-negative pulmonary tuberculosis on treatment outcomes, mortality, and continued transmission has not yet been assessed.

Many people with HIV infection and pulmonary tuberculosis have absent or non-specific symptoms, an absence of acid-fast bacilli on sputum smear microscopy, and non-specific findings from chest radiography.8 People living with HIV/AIDS are more likely to have smear-negative tuberculosis than are people not infected with HIV (difference of 24–61%),2, 9, 10 and the probability of smear-negative disease and atypical pulmonary features increases as immunosuppression increases.1 The atypical presentation and decreased sensitivity of smear microscopy for diagnosis of tuberculosis in people living with HIV/AIDS often leads to delayed diagnosis and treatment, so worsening outcomes. Prompt and accurate diagnosis of tuberculosis is needed to reduce mortality in people living with HIV/AIDS.

In 2007, WHO published revised recommendations for the diagnosis of smear-negative pulmonary tuberculosis to address the diagnostic and treatment challenges of HIV-associated tuberculosis in HIV-prevalent and resource-constrained settings.11 The recommendations include two algorithms for diagnosis and treatment of smear-negative pulmonary tuberculosis, one for seriously ill patients and one for ambulatory patients. The algorithms aim to improve the sensitivity of and minimise delays in diagnosis and treatment of smear-negative pulmonary tuberculosis, thereby increasing the survival of people living with HIV/AIDS. The recommendations are targeted towards patients infected (or showing strong clinical evidence of infection) with HIV and patients aged 15 years or older. WHO has five key recommendations: all patients with suspected tuberculosis should undergo HIV counselling and testing; no trial period with antibiotics is needed to diagnose smear-negative pulmonary tuberculosis; two sputum specimens, with one obtained in the morning, are sufficient for initial diagnosis of tuberculosis; diagnosis of smear-positive tuberculosis can be made if at least one of two specimens is positive for acid-fast bacilli; and sputum culturing for Mycobacterium tuberculosis should be done for all patients with smear-negative sputum for the purpose of diagnosis, but not exclusion, of tuberculosis. However, the recommended algorithms for ambulatory and seriously ill patients have not been fully assessed, and a shift towards routine sputum culture and early treatment might lead to a substantial increase in laboratory and pharmaceutical costs in resource-limited settings.

We did a two-phase observational study to compare the effect of the 2007 WHO-recommended algorithm on clinical outcome compared with standard practice in seriously ill adults with HIV infection and suspected smear-negative pulmonary tuberculosis in KwaZulu-Natal, South Africa. We aimed to provide information to inform public health decisions and to encourage participating health-care facilities to implement a standardised and evidence-based approach to care for these patients.

Section snippets

Patients

Two cohorts of patients were enrolled consecutively and managed at three primary care inpatient hospitals in KwaZulu-Natal, South Africa (hospitals A, B, and C). We recruited participants from inpatient adult medical wards and casualty (emergency) services 7 days a week. The standard practice cohort was enrolled between August, 2008, and February, 2009, and the algorithm cohort was enrolled between March, 2009, and December, 2009. Hospital C is a large district hospital serving a geographically

Results

We screened 6196 potential participants during the first enrolment period for the standard practice cohort, and 3424 during the second enrolment period for the algorithm cohort. Fewer patients were screened during the second period because of cutbacks in the health sector, resulting in the closure of several hospital wards and fewer admissions. The most common reasons for exclusion of potential participants in the standard practice cohort and the algorithm cohort were smear-positive sputum (34%

Discussion

Findings of our study showed that the WHO-recommended algorithm was associated with a reduced proportion of patients in hospital at 7 days after admission and increased survival at 8 weeks after admission. Survival did not differ significantly between the cohorts in patients given antituberculosis treatment. However, in the standard practice cohort, survival was significantly higher in patients given antituberculosis treatment than in those not treated. Therefore, the increased survival in the

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