Causes of death in hospitalized adults with a premortem diagnosis of tuberculosis: an autopsy study
Martinson, Neil Aa,b; Karstaedt, Alanc; Venter, WD Francoisd; Omar, Tanvierc; King, Petere; Mbengo, Tumib; Marais, Elsef; McIntyre, Jamesb; Chaisson, Richard Ea; Hale, Martine
From the aJohns Hopkins University Center for TB Research, Baltimore, Maryland, USA
bPerinatal HIV Research Unit, University of the Witwatersrand, Soweto, South Africa
cDepartment of Medicine, Chris Hani Baragwanath Hospital and University of the Witwatersrand, Soweto, South Africa
dReproductive Health and HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa
eDepartment of Anatomical Pathology, National Health Laboratory Service and University of the Witwatersrand, Johannesburg, South Africa
fDepartment of Clinical Microbiology and Infectious Diseases, University of the Witwatersrand, Johannesburg, South Africa.
Received 23 March, 2007
Revised 28 May, 2007
Accepted 15 June, 2007
Correspondence to Neil A. Martinson, Perinatal HIV Research Unit, PO Box 114, Diepkloof 1864, South Africa. E-mail: firstname.lastname@example.org
Objective: To ascertain the immediate and underlying causes of death in adults who died in hospital with a premortem diagnosis of tuberculosis.
Design: Causes of death were assessed independently by internists and pathologists in 50 adults admitted to two Soweto hospitals who died 24 h or more after admission. Detailed record reviews and complete autopsies including HIV tests when not performed premortem were performed. In addition, a variety of postmortem microbiological tests were performed.
Results: Forty-seven patients had HIV infection; all were antiretroviral naive. Their median age was 34.5 years, median CD4 cell count was 48 cells/μl and median length of hospitalization before death was 6 days. Autopsy confirmed the premortem diagnosis of tuberculosis in 37 HIV-infected patients (79%), whereas 10 (21%) did not demonstrate tuberculosis. Bronchopneumonia and cytomegalovirus pneumonitis were the leading pathologies in these 10 patients. In 47 HIV-infected cadavers immediate or contributory causes of death were: extensive pulmonary tuberculosis, 32 (68%); disseminated tuberculosis, 28 (60%); bacterial pneumonia, 13 (26%); cytomegalovirus pneumonitis in seven (15%); cytomegalovirus DNA was found in 31 (66%) and Pneumocystis pneumonia was found in five cadavers (11%). The lung, followed by lymph nodes, liver and kidney, were the commonest sites of tuberculosis. Mycobacterium tuberculosis was cultured from 19 spleens, one of which was multidrug resistant, and Salmonella spp. was cultured from 11 splenic specimens.
Conclusion: We demonstrated disseminated, extensive tuberculosis associated with advanced HIV disease. Severe bacterial infections, including salmonellosis, were the leading co-morbidity, suggesting that hospitalized HIV-infected adults in whom tuberculosis is suspected may benefit from broad-spectrum antibiotic therapy.
Millennium development goals for tuberculosis control include reducing death rates from tuberculosis by 50% compared with 1990 levels . In high HIV prevalence settings, however, death rates from tuberculosis are increasing as tuberculosis has become the leading clinical manifestation of HIV infection [2,3]. Almost a quarter of hospitalized HIV-infected adults started on tuberculosis treatment die, the majority in the first days [4,5] to weeks [6,7] after admission. In South Africa, which ranks third globally by tuberculosis incidence , it is estimated that 18.7% of a total of 339 000 tuberculosis patients died while receiving tuberculosis treatment in 2004 . Increasing access to antiretroviral drugs in areas of high tuberculosis prevalence  will prolong the lives of those HIV-infected individuals receiving them by decades. Ensuring HIV/tuberculosis co-infected adults survive their first weeks of tuberculosis treatment may allow the subsequent initiation of antiretroviral therapy (ART).
Despite high tuberculosis case fatality rates, the causes of mortality in HIV/tuberculosis co-infected adults are poorly described. Several autopsy studies from sub-Saharan Africa [10–15] confirmed tuberculosis as the leading cause of death in HIV-infected adults, but did not focus on other causes of death in those with tuberculosis. To prevent mortality in co-infected adults, a better understanding of its aetiology is needed. Our objective was to describe the immediate and contributing causes of death in HIV-infected adults with an antemortem diagnosis of tuberculosis in a country with a high burden of both epidemics.
Data were prospectively collected from 50 adults with a provisional premortem diagnosis of tuberculosis, who died after admission to either Chris Hani Baragwanath Hospital (CHBH), or the adjacent Charles Hurwitz TB Centre (TBC), both in Soweto, South Africa. CHBH is a 2700-bed public sector, tertiary institution, admitting an average of 100 adults per day to its medical wards, most via the emergency room. TBC is a medium term, 350-bed, low-care, inpatient tuberculosis facility that admits patients from tuberculosis clinics or hospitals in the region, either because of concerns about adherence or because they require hospital care. In 2005, Gauteng Province, in which Soweto is situated, reported 44 000 tuberculosis cases .
Eligibility criteria for this study were: tuberculosis included in the premortem diagnoses by the attending doctor, age 18 years or older and death occurring 24 h or more after admission, allowing some premortem clinical investigation. Exclusion criteria were traumatic and postoperative deaths. The next of kin of eligible subjects were approached to provide consent for autopsy, including an HIV test if not performed premortem. Those consenting were given the choice of a full explanation of the results including the deceased's HIV status. The study was approved by the Ethics Committee of the University of the Witwatersrand.
Causes of death were categorized as immediate, contributory and underlying by internists reviewing the records and pathologists and then coded using International Classification of Diseases version 10 . Poorly descriptive terms such as ‘respiratory failure’ were avoided. The immediate cause of death was defined as pathology that resulted in death, without which the death would not have occurred at that time. A contributory cause of death was defined as co-existing pathology that was involved in causing death but was not primarily responsible for death. HIV/AIDS was the underlying cause of death in all HIV-infected patients.
A detailed clinical chart review was performed by an infectious diseases certified internist (A.K. or W.D.F.V.) with experience in treating HIV and tuberculosis. The identification and categorization of causes of death were based solely on premortem data, as the reviewers were blinded to autopsy results.
A modified evisceration was performed. Brain, lungs, heart, kidneys, liver, adrenals, spleen, and pancreas were removed. Pelvic organs were examined in situ. The veins of the calves and thighs were examined if there was evidence of pulmonary thromboembolism. Representative sections from organs were stained with hematoxylin and eosin and examined microscopically. In addition, sections of all lung specimens were stained with Ziehl–Neelsen to detect mycobacteria, Grocott's silver methanamine stain to detect fungal elements and Pneumocystis, a modified Gram's stain to detect the presence of Gram-positive and Gram-negative bacteria, and immunohistochemical stains to detect cytomegalovirus (with positive and negative controls). Sections of other organ systems were subjected to special stains if indicated. Brains were fixed in formalin for 6 weeks or more before sectioning and microscopic examination. A study pathologist (M.H. or P.K.) supervised the dissections and reviewed histology. Pathologists did not have access to postmortem microbiological analyses, and their causes of death were based on autopsy and histopathological findings.
Tissue samples, excised from both lungs and the spleen of each cadaver, were placed into sterile containers and transported to the laboratory the same day. Five grams from each tissue were crushed and subjected to standard bacterial culture. Splenic tissue was cultured for mycobacteria using the Bactec MGIT system (Becton Dickinson, Franklin Lakes, New Jersey, USA) at the Johannesburg Tuberculosis Reference Laboratory. Salmonellae were serotyped according to the Kauffmann–White scheme . Detection of Mycoplasma pneumoniae, cytomegalovirus and Pneumocystis jirovecii was by polymerase chain reaction (PCR) techniques previously described [19–21] using DNA extracted from lung tissue with the QIAamp DNA mini kit (Qiagen, Valencia, California, USA). PCR reactions were performed with Master Mix (Roche Applied Science, Indianapolis, Indiana, USA). DNA from cultures of the appropriate organisms, samples with no DNA and the human β globin gene  were amplified as controls, and standard precautions were taken to prevent contamination.
We report the absolute numbers of a condition and, when appropriate, calculated percentages. The sample size was dictated by the available budget.
From December 2003 to March 2005, the next of kin of over 1000 eligible adults who died in hospital with a clinical premortem diagnosis of tuberculosis were approached, either telephonically or in person. A total of 515 considered consenting, usually requesting time to consult with family. Of these, 69 consented. Ten subsequently withdrew consent and nine autopsies were cancelled as a result of the unavailability of a pathologist or autopsy room. Of 50 autopsies performed, 42 died at CHBH. Forty-seven were HIV infected, none of whom had been exposed to ART. The causes of death of the three HIV-negative adults are shown in Table 1. The premortem characteristics of the 47 HIV-infected adults are shown in Table 2. Forty-one (87%) had CD4 cell counts less than 200 cells/μl, but none was receiving ART at the time of death.
Record review of HIV-infected adults
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.
Autopsy results of HIV-infected adults
The leading autopsy-determined causes of death were pulmonary tuberculosis, disseminated tuberculosis and bacterial pneumonia (Table 4). Two cadavers had disseminated cryptococcosis. Additional autopsy-determined immediate causes of death in one cadaver each were toxoplasma meningoencephalitis, gastroenteritis, salmonella septicemia, subdural hematoma, perforated duodenal ulcer, severe pulmonary edema on a background of milliary tuberculosis in the lung, and a large empyema from which Streptococcus pneumoniae was cultured postmortem. Autopsy confirmation of tuberculosis was found in 37 cadavers (79%) of whom 34 had disseminated tuberculosis (Table 3). Of 33 with pathological evidence of tuberculosis in their lungs, 17 had milliary tuberculosis of the lungs, 10 had tuberculous bronchopneumonia, five had cavitations and there was one with a Gohn focus. Acid-fast bacilli were not found in the lung sections of nine of these cadavers, whereas four had scanty, 11 moderate, and nine abundant acid-fast bacilli. Co-existing pulmonary pathology in those with autopsy-confirmed pulmonary tuberculosis was bacterial pneumonia (three), Pneumocystis pneumonia (two), cytomegalovirus pneumonitis (two), pulmonary thromboembolic disease (two), interstital lung disease (two) and bronchiolitis oblitererans pneumonia (one) and a massive empyema. Extensive bilateral, multilobe pulmonary pathology was a prominent finding irrespective of whether pulmonary tuberculosis was present or not. Ten cadavers had no autopsy evidence of tuberculosis, and none had premortem bacteriological confirmation of tuberculosis. Immediate and contributory causes of death in these 10 included: bronchopneumonia (six), cytomegalovirus pneumonitis (five), toxoplasmosis (one), disseminated Kaposi's sarcoma (two), cryptococcosis (one), hepatic necrosis (one) and interstitial pneumonitis (one). Six of the 10 had been started on tuberculosis treatment at the time of death. Two of the cadavers with cytomegalovirus pneumonitis had no other pulmonary pathology.
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.
Microbiological results of HIV-infected adults
Mycobacterium tuberculosis was cultured from the spleens of 19 cadavers and Mycobacterium avium complex from two (Table 5). Drug sensitivities to first-line tuberculosis agents were available from 11 cultures, of which one was multidrug resistant. Of 37 with autopsy diagnosed tuberculosis, 18 had positive splenic cultures for M. tuberculosis. A wide variety of bacteria was cultured, however, Salmonella was cultured from the spleens of 11 cadavers, four of whom also had positive lung cultures. Eight were typed as Salmonella typhimurium, two of these had positive premortem blood cultures for S. typhimurium, one was Salmonella isangi and two were not typed. Seven out of eleven with positive Salmonella cultures had autopsy-confirmed tuberculosis. Cytomegalovirus DNA was detected in 31 lung specimens and that of P. jirovecii in 13. Seven out of seven and three out of five of those who had histopathological evidence of cytomegalovirus and Pneumocystis pneumonia were DNA PCR positive, respectively. M. pneumoniae DNA was not detected in any lung samples.
In our sample of 47 HIV-infected adults with a premortem diagnosis of tuberculosis one fifth did not have tuberculosis at autopsy. Most of those with tuberculosis had disseminated disease. Moreover, other severe co-morbid conditions were frequent but were often clinically unrecognized before death, and almost half had a severe bacterial infection and one fifth had cytomegalovirus implicated in their death.
Studies of autopsy-determined causes of death in HIV/tuberculosis co-infected adults are infrequent, retrospective and give scant detail on other causes of death [23–25]. Similar findings to ours were reported from Abidjan, where 14 HIV-infected adults who died while on, or shortly after, tuberculosis treatment had a variety of ‘primary’ and ‘associated’ causes of death . Two studies reported causes of death in HIV-infected cadavers with autopsy-confirmed tuberculosis [11,24]. First, in a subgroup of HIV-infected adults from Botswana , tuberculosis was the primary cause of death in 38 out of 42, and cerebral hemorrhage and Kaposi's sarcoma the primary cause in the remaining four. Second, a study from Sao Paulo  reported the leading co-morbid conditions in 100 cadavers to be Pneumocystis pneumonia, cerebral toxoplasmosis, wasting syndrome, pyogenic pneumonia and cytomegalovirus. In the pre-ART era, researchers from Milan  reported that 36% of 78 HIV-infected patients were diagnosed clinically but not at autopsy with mycobacterial disease; however, almost half their cases were non-tuberculous mycobacteria. The clinical ‘overdiagnosis’ of tuberculosis may reflect not only differences in study inclusion criteria but also physicians' experience, increasing demand for hospital care by HIV-infected patients and referral, admission and treatment policies. In addition, many of our sample had been on tuberculosis treatment before admission, which may alter the classic clinical or autopsy presentation of tuberculosis. Moreover, our study suggests that in those with advanced HIV disease, physicians' ability to discriminate between pulmonary and extrapulmonary disease premortem is poor, and that in those who die most have extrapulmonary tuberculosis, confirming the findings of previous autopsy studies in HIV-infected adults [10–15]. This has obvious implications for World Health Organization clinical staging of HIV disease, and by extension, timing of the initiation of ART.
Salmonellae, particularly non-Typhi Salmonellae (NTS), are frequent bacteremic pathogens in HIV-infected adults in sub-Saharan Africa [27–30], and their presence is linked to very high mortality rates [29,31,32]. Although the significance of positive postmortem bacterial cultures for enterobacteriaceae, which normally colonize the gut, is questionable [33,34], the postmortem presence of NTS in the lung or spleen is likely to be abnormal. Our data, and those from a report of premortem bacteremic pathogens in HIV-infected adults with tuberculosis or a history of tuberculosis , suggest a predilection of HIV-infected adults with tuberculosis to NTS. In addition, the high proportion of severe bacterial pulmonary infections diagnosed at autopsy in our study and other autopsy studies of HIV-infected adults [11,15,24] suggest that a course of directed antibiotic therapy with activity at least against Salmonellae at the initiation of tuberculosis therapy could contribute to a reduction in mortality in settings with a high prevalence of HIV.
The seroprevalence of cytomegalovirus in adults and children in sub-Saharan Africa is high irrespective of HIV status [36,37], and cytomegalovirus DNA was detected in two-thirds of the lungs of our sample of whom seven had histological evidence of cytomegalovirus. This is similar to other autopsy studies in HIV-infected patients from sub-Saharan Africa and to the prevalence reported in cadavers with autopsy-confirmed tuberculosis from Sao Paulo, Brazil , and in the pre-HAART era, 69 and 66% of postmortem samples from Mexico City  and London  had evidence of cytomegalovirus pathology and infection, respectively. Differences in the prevalence of cytomegalovirus-related pathology are probably related to eligibility criteria, methods of determining the presence of cytomegalovirus and the local epidemiology of cytomegalovirus. The clinical relevance of the pathological findings of pulmonary cytomegalovirus is, however, unclear, as it is diagnosed only if there is no other histological explanation. Difficulties in pathological diagnosis are compounded by the absence of both accurate premortem diagnostic tests and inexpensive, effective therapy for cytomegalovirus pneumonitis, with the result that there are a paucity of epidemiological data on this condition, from HIV-infected adults in sub-Saharan Africa. On the other hand, Pneumocystis and tuberculosis are recognized co-pathogens in HIV-infected adults [40–42]. M. avium complex was cultured from the spleens of two patients and is not uncommon in our setting . Low hemoglobin levels were found in most of our patients, in keeping with studies of the predictors of mortality in HIV-infected adults [44,45] and adults with tuberculosis , but the autopsy is a poor tool in assessing the contribution of anemia to mortality.
The earlier diagnosis and treatment of both HIV and tuberculosis may prevent the advanced stage of disease we found in this group. Adults who are HIV infected should receive care that includes active case finding  and preventive treatment for tuberculosis . Cotrimoxazole preventive treatment for other opportunistic infections , especially for those receiving tuberculosis treatment , coupled with ongoing immune monitoring and the prompt initiation of ART may reduce the high tuberculosis-associated mortality seen in sub-Saharan Africa.
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.
Sponsorship: This study was supported by AIDS Care Research in Africa (ACRiA).
Conflicts of interest: None.
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cryptococcus; cytomegalovirus; Pneumocystis; Salmonella; toxoplasmosis; tuberculosis
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