Based on a review of the clinical records, the immediate cause of death was judged to be tuberculosis in 29 out of 47 patients (10 pulmonary tuberculosis and 19 extrapulmonary) and was a contributory cause of death in a further 11 patients. The reviewing internist and attending doctor differed over seven patients, because the former did not include tuberculosis as a cause of death, but at autopsy five of the seven were found to have tuberculosis (Table 3); one had interstitial lung disease and one salmonella septicaemia as their cause of death. In 25 patients (53%), the immediate cause of death judged from clinical review was identical to that of the autopsy. There was an overlap between the immediate or contributory causes of death in the remainder, except for one with insufficient premortem information. Premortem investigations confirmed tuberculosis in 23 patients (49%). Thirteen were sputum smear positive, nine were tuberculosis culture positive (six blood, two pleural fluid and one sputum), and one was diagnosed by cytological assessment of a fine needle aspiration biopsy. The antibiotics that patients had received at least one dose of before death were: prophylactic cotrimoxazole (18), high-dose cotrimoxazole (four), amoxicillin/clavulanate (22) and ciprofloxacin (seven).
The record review of five patients suggested Addisons's disease, of whom three had autopsy-confirmed adrenal pathology. Significant pathology found at autopsy but not ascertained by record review was a perforated duodenal ulcer, a perforated gastric ulcer, cerebral tuberculoma, tuberculous meningitis, disseminated Kaposi's sarcoma, fulminant hepatitis, pulmonary thromboembolism, a subdural hemorrhage, and two pelvic abscesses. In addition, seven out of seven cadavers with autopsy-determined cytomegalovirus pneumonitis, four out of five with Pneumocystis pneumonia, one out of two with disseminated cryptococcosis and one with cerebral toxoplasmosis were not diagnosed premortem.
Thirty-one cadavers had pleural effusions at autopsy of which 25 were bilateral. Six of the 31 did not have tuberculosis at autopsy of whom two had Pneumocystis pneumonia (one with co-existent cytomegalovirus pneumonitis), two had cytomegalovirus pneumonitis alone and one each had bronchopneumonia or interstitial lung disease.
A range of kidney diseases was found at autopsy. Fourteen had renal tuberculosis and 27 had other renal pathology: interstitial nephritis (nine), acute or chronic pyelonephritis (seven), acute tubular necrosis (five), cryptococcal infection (two), simple renal cysts (two), HIV-associated nephropathy (one) and dystrophic calcification (one). Thirteen cadavers had adrenal pathology at autopsy, of whom eight had adrenal tuberculosis. Cryptoccocal and cytomegalovirus infection was found in the adrenal glands of one patient each. The remainder had non-specific adrenal cortical atrophy or lipid depletion. Eighteen cadavers had hepatic tuberculosis, 12 had steatosis and six had portal triaditis. Three had severe hepatic necrosis, which was probably caused by tuberculosis therapy. One cadaver had hepatic cryptococcal infection. No hepatic cytomegalovirus infections were found. Only two had increased liver iron. Twenty-five cadavers had autopsy-confirmed tuberculous lymphadenitis and both of those with disseminated cryptococcosis had lymph node involvement. Tuberculosis was found in the spleens of 22 cadavers. Examination of the hearts showed one with myocardial cryptococcal infection, two with mitral valve disease, and seven with subendocardial pallor detected on nitrobluetetrazolium enzyme analysis, suggesting subendocardial ischemia. Twelve cadavers had pericarditis, eight were non-specific, three were adhesive and one was tuberculous. Two brains were not examined microscopically but four of the remaining 45 had evidence of tuberculosis. Nineteen brains had HIV-associated meningoencephalitis, one of whom had a B-cell lymphoma. Cryptococcal infection was found in two brains as part of disseminated disease. Cerebral toxoplasmosis and an infarct in the left basal ganglia was found in a 29-year-old man treated for tuberculosis for 2 months before death in whom pulmonary tuberculosis, but not pulmonary toxoplasmosis, was confirmed at autopsy. One patient died of a subdural hemorrhage. In summary, therefore, lung, lymph nodes, spleen, liver and kidney were the leading sites of tuberculosis found at autopsy.
The major limitations of this study are its small sample size and bias inherent in an autopsy study, exacerbated by the very low consent rate. There are limited data available from the two hospitals that describes the epidemiology of deaths in patients with a premortem diagnosis of tuberculosis. The median ages of 747 women and 813 men (male to female ratio 1.1: 1) who died at CHBH in 2006 with a premortem diagnosis of tuberculosis (including 32 children less than 15 years of age) was 38 [interquartile range (IQR) 30–45] and 40 (IQR 33–48) years, respectively, (M.E. Edginton, unpublished data) and at TBC the average age of 592 men and 411 women (male to female ratio 1.4: 1) dying in 2001–2003 was 42 and 37 years, respectively (D.E. Douglas, unpublished data). This is similar to our study. The median age of all 50 cadavers was 35 years (IQR 30–40) and the male to female ratio was 1.1: 1. Further generalization of the results of this study are limited because recruitment was not restricted to adults with bacteriologically confirmed tuberculosis and we only recruited patients from two hospitals in Soweto, reflecting disease patterns endemic to this locale. Finally, categorizing causes of death from lists of serious pathologies is subjective and may vary between internists and pathologists.
We recommend that prospective studies be undertaken to define risk factors for death in adult tuberculosis patients, and that the epidemiology and clinical significance of cytomegalovirus pneumonitis in sub-Saharan African countries should be better understood and its premortem diagnosis improved. Furthermore, trials of potent antibiotics to prevent and treat NTS and other severe bacterial infections should be considered. Deaths from tuberculosis will continue in high HIV prevalence settings until a combination of population HIV and tuberculosis preventive measures in conjunction with improved diagnosis and early treatment of tuberculosis and other common life-threatening opportunistic infections are implemented.
The authors would like to thank the families of the deceased for providing consent for autopsy, and Mr Thomas Mdingi for assisting in obtaining consents.
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