Document peQRE1knnvyLqKLO6gzy578bd

Safety in Mines Research Advisory Committee Final Report Clinico-Pathologicical Study to reduce the rate of missed and misdiagnosis of Pulmonary Tuberculosis in the South African Mining Industry Dr. Jill Murray Dr. Phyllis Back National Centre for Occupational Health, Department of Health. Prof. Peter Lowe Ms Lizet Coetzee SIMHEALTH 611 November 2000 EXECUTIVE SUMMARY "What the patient died of and what he is said to have died of are not always one and the same thing" Philip R, 1918. Inaugural address delivered on the institution of the chair of tuberculosis in the University of Edinburgh. Tuberculosis, declared a global emergency by the World Health Organisation in 1991, is a major infectious disease in the South African mining industry and deaths from tuberculosis (tB) exceed those due to mine accidents (Dr M A la Grange, Chamber of Mines). TB is a potentially curable disease and misdiagnosis has important implications for the individual, spread of TB in the community and compensation in terms of the Occupational Diseases in Mines and Works Act (ODMWA). Improved management can only occur if the diagnosis is correctly established, targeting areas for intervention. The National Centre for Occupational Health (NCOH) examines the lungs of deceased mineworkers in terms of ODMWA and is thus in a unique position to assist with strategies for improving the accurate and timeous diagnosis of pulmonary TB (PTB). The objectives of the study were to correlate the ante- and postmortem diagnoses of PTB, review medical data from a representative group of mine medical services to assess current clinical practice, and identify possible reasons for discordant diagnoses and strategies for improving clinical practice. There were 1858 autopsies performed during 1999 (excluding cases from Anglo Gold which did not participate in the study) of which 350 were study cases with a clinical diagnosis of PTB as a major factor in the cause of death and/or an autopsy diagnosis of PTB. Clinicians correctly ascribed PTB as the cause of death in 27% of cases, failed to diagnose PTB in 44% and incorrectly ascribed PTB as the cause of death in 29%. Poor clinico-pathological correlation is not unique to the mine medical services but also occurs in medical centres in America, Britain etc. Clinical practice was assessed by reviewing medical records from 8 different medical centres representing gold, coal and platinum mining commodities. Of the 187 patients whose records were reviewed, 76% were known to be HIV infected and of those who had had CD4+ cell count measurements, 90% had advanced AIDS. Autopsies showed lungs with extensive TB even though surveillance chest radiographs taken only months prior to death were normal. In patients in whom the clinical diagnosis of PTB was not made, important factors influencing the missed diagnosis of TB were the presence of miliary TB, the simultaneous presence of a second lung disease such as bacterial pneumonia and omission of accurate laboratory diagnostic tests such as sputum smears and culture for TB bacilli. About half of the cases, in whom the clinicians had correctly diagnosed TB, presented with advanced disease and had had a rapidly terminal course. In this group and in the undiagnosed group, there were missed `windows of opportunity' for the clinicians to have made an earlier diagnosis as many patients had attended the mine clinics and/or hospitals in the preceding three months. Cases were identified with extensive TB at autopsy who had been on prolonged treatment for TB. These patients (and especially those who also had previous TB) are at risk 2 of being drug resistant; drug susceptibility testing had not been performed for the majority of them. Of the patients for whom clinicians incorrectly ascribed PTB as a cause of death, 72% had been treated for TB for over 30 days. They appear to have responded to TB treatment and sequential development of other diseases, many of which would have been amenable to treatment if diagnosed, accounted for the discrepancies in ante- and postmortem diagnoses. About 250 health care workers attended the clinico-pathological conferences held to disseminate the study findings, present illustrative cases and discuss best practice clinical strategies, as the study progressed. A wide range of health care workers attended and the doctors appear to have subsequently incorporated at least some of the suggestions made into their practices as indicated in their responses to the evaluation questionnaire distributed to them . The considerable effort made to reduce fatalities due to mine accidents must be duplicated to reduce deaths due to a disease which, in theory at least, could be eradicated with the application of present knowledge. IMPORTANT RECOMMENDATIONS INCLUDE: More frequent medical surveillance for groups of employees at high risk for TB Improving the skills of nurses both with regard to case finding and monitoring of patients while on treatment for TB Actively excluding TB in all patients admitted to hospital with respiratory signs and symptoms, including use of sputum culture for TB, even if patients show some response to treatment for bacterial pneumonia A training course on the interpretation of chest radiographs Empirical treatment for suspected miliary TB while awaiting culture results All employees found unfit for continued employment to be actively investigated for TB before leaving the mines. Special attention to be paid to men with advanced AIDS Deterioration in a patient's condition should not be ascribed to progressive HIV infection without considering the possibility of TB Testing for drug susceptibility in all previously treated patients and those who fail to respond to treatment The NCOH should continue to provide autopsy reports if requested by the clinician, to enable them to undertake reviews of their performance 3 Acknowledgements This research project was funded by the Safety in Mines Research Advisory Committee (SIMRAC) of the Mines Health and Safety Council. Guidance, stimulation and intellectual support was provided by Dr Mary Ross throughout the project. Dr David Rees, Professor of Occupational Health and Head of the National Centre for Occupational Health enabled the researchers to devote considerable time and effort to this project and assisted them with valuable suggestions. We are deeply appreciative of the unceasing diligence and cooperation of the laboratory and mortuary staff, clerical assistants and fellow pathologists at the NCOH. Most importantly we express debt and gratitude to the many consultants listed below: - Dr Lucille Blumberg was responsible for presentations on laboratory techniques at numerous seminars and provided intellectual stimulation throughout - Dr David Griffiths allowed us to review hospital records of his patients and hosted a seminar at the Duff Scott hospital - Dr Mark Hopley contributed clinical expertise and willingly shared his knowledge and experience obtained at mine and the Chris Hani Baragwanath hospitals. He also provided valuable input into the discussion - Dr Lettie La Grange presented industry perspectives at the seminar hosted by Gold Fields Ltd. - Dr Stewart Shearer assisted throughout providing much data, access to Gold Fields hospitals and most importantly with support, advice and suggestions - Dr Jim Phillips arranged and administered financial matters with the WITS Health Consortium - Dr Beau Dees arranged a seminar and invited all the doctors in his organization to attend - Dr Jana Viljoen and Ms Ermien le Roux assisted in case reviews and provided us with innovative and practical ideas on patient management - Dr Dries Burger organized a seminar and provided clinical material for the study - Dr Berthus Smith assisted us with clinical material and enthusiastically supported this project - Prof Neil White who guided us with the analysis of the data - Dr Noel Pharoah who organized a seminar and provided us with clinical material for the study To the many persons who have made valuable suggestions, important to this study, we gratefully acknowledge our debt. We, however, remain responsible for all inaccuracies or errors in this report. 4 GLOSSARY Table of contents 14 1. INTRODUCTION 1.1 Background to the study 1.2 Objectives 17 17 2. METHODS 2.1 Study setting 2.2 Study population and Selection of study cases 2.3 Autopsy methods 2.4 Review of clinical records 2.5 Analysis of data 2.6 Ethics approval 17 18 18 18 18 18 3. RESULTS 3.1 Study subjects 3.2 Medical record review 3.2.1 Age 3.2.2 Place of Death 3.2.3 HIV infection 19 23 23 23 24 3.3 PTB CLINICALLY NEGATIVE : AUTOPSY POSITIVE PATIENTS 3.3.1 Case finding 25 3.3.1.1 Surveillance chest radiographs 25 3.3.1.2 Attendance at mine health facilities in the 3 months preceding death or the terminal hospital admission 25 5 3.3.2 Management during the terminal hospital admission 3.3.2.1 Investigations for PTB 3.3.2.2 Chest radiographs 3.3.2.3 Sputum examination 3.3.2.4 Clinical management 3.3.2.5 Previous TB 26 26 27 28 28 28 3.3.3 Autopsy findings 3.3.3.1 Correlation of pathology, radiology and clinical assessment for those whodied in hospital 28 30 3.4 PTB CLINICALLY POSITIVE : AUTOPSY POSITIVE PATIENTS 3.4.1 Case finding 30 3.4.1.1 Surveillance radiographs 30 3.4.1.2 Attendance at mine health facilities in the 3 months preceding death 30 3.4.2 Management 3.4.2.1 Management of newly diagnosed patients during their terminal hospital admission 3.4.2.2 Management of patients on TB treatment for longer than 30 days 3.4.2.3 Miscellaneous cases 3.4.3 Autopsy findings 32 32 33 34 35 3.5 Comparison of Clinically negative:autopsy positive and Clinically positive:autopsy positive groups 35 3.5.1 Comparison of features which may have influenced the diagnosis of TB 35 6 3.6 PTB CLINICALLY POSITIVE : AUTOPSY NEGATIVE PATIENTS 3.6.1 Patients on treatment for TB for longer than 30 days 3.6.2 Patients on treatment for TB for less than 30 days 36 36 4. DISCUSSION 4.1 Introduction to discussion 4.2 The natural history of TB 4.3 The burden of TB due to HIV 4.4 Case finding 4.4.1 Surveillance Programs 4.4.2 Passive case finding 4.4.3 Frequency of missed TB and diagnostic delay 4.4.4 The importance of undiagnosed PTB and diagnostic delay 38 38 39 40 40 40 40 41 4.5 Management of patients with suspected PTB 42 4.5.1 Diagnostic tests 42 4.5.2 Sputum smear for TB bacilli 42 4.5.2.1 Sputum smear negativity in HIV infected PTB patients 42 4.5.2.2 False negative sputum smears 43 4.5.3 Sensitivity of sputum smear versus sputum culture 4.5.4 New diagnostic techniques 44 44 7 4.6. Management of smearnegative PTB 4.6.1 Chest Radiographs 4.6.2 Trial of antibiotics 4.6.3 Extra-pulmonary tuberculosis 4.6.3.1 Pleural involvement 4.6.3.2 Pericardial effusion/constriction 4.6.3.3 Lymph nodes 4.6.3.4 Blood and bone marrow 4.6.3.5 Liver 4.6.3.6 Central Nervous System 4.6.3.7 Genitourinary tract 45 45 45 46 46 46 46 46 47 47 47 4.7 Miliary tuberculosis 4.8 Other lung diseases inpatients with tuberculosis 4.9 Advanced AIDS 4.10 Management of patients while on treatment for pulmonary tuberculosis 4.10.1 Directly ObservedTreatment Strategy (DOTS) 4.10.2 Failure to improve and deterioration while on treatment 4.11 Multi-drug Resistance 4.12 Risk factors for death from PTB 4.12.1 HIV infection 4.12.2 Silicosis 4.12.3 Other factors including quality of medical service 4.13 Limitations of the study 47 47 47 48 48 48 48 49 49 49 50 50 8 5. CONCLUSION 6. REFERENCES 7. TECHNOLOGY TRANSFER 7.1 Clinico-pathological conferences 7.2 Hand-out for medical staff 7.3 Chamber of Mines 7.4 Performance review on individual cases 8. EVALUATION OF THE STUDY 8.1 Surveillance 8.2 Diagnosis 8.3 Treatment 8.4 Autopsy 9. RECOMMENDATIONS 9.1 Introduction 9.2 Active and passive case finding 9.3 Sputum smear examination for TB bacilli 9.4 Sputum culture for TB bacilli 9.5 Additional diagnostic tests 9.6 Chest radiographs 9.7 Miliary TB 9.8 Drug Resistance 9.9 Management while on TB treatment 9.10 Advanced AIDS and medical incapacity 50 51 58 58 59 59 60 60 60 60 61 61 61 61 61 62 62 62 62 62 9 9.11 Recurrent TB 9.12 Performance review 10. APPENDICES Appendix 1 - Clinical & autopsy data capture sheet Appendix 2 - Evaluation questionnaire Appendix 3 - Letter sent to doctors for autopsy reports LIST OF TABLES TABLE 1 Study subjects as a proportion of autopsies done at NCOH by ethnic group and commodity: January - December 1999 TABLE 2 Distribution of 350 study subjects by clinico-pathological correlation, ethnic group and commodity TABLE 3 Place of death by clinico-pathological category TABLE 4 Attendance at mine health facilities in the 3 months preceding death or the terminal hospital admission PTB Clinically negative: autopsy positive patients TABLE 5 Investigations for PTB during the terminal hospital admission according to signs and symptoms of respiratory disease PTB Clinically negative: autopsy positive patients TABLE 6 Chest radiographs of patients who died in hospital PTB Clinically negative: autopsy positive patients TABLE 7 Sputum smear examination of the patients with signs and Symptoms of respiratory disease who died in hospital PTB Clinically negative: autopsy positive patients TABLE 8 Autopsy findings in PTB clinically negative: autopsy positive patients 62 63 64 72 75 19 20 24 25 27 27 28 29 10 TABLE 9 Attendance at mine health facilities in the 3 months preceding death by patients in whom PTB was diagnosed during their terminal hospital admission PTB Clinically positive: autopsy positive patients 31 TABLE 10 Characteristics of patients diagnosed during their terminal hospital admission PTB Clinically positive: autopsy positive patients 32 TABLE 11 Treatment duration, drug susceptibility and history of previous TB in patients on TB treatment for longer than 30 days PTB Clinically positive: autopsy positive patients 34 TABLE 12 Autopsy findings in PTB clinically positive: autopsy positive patients 35 TABLE 13 Comparison of features in diagnosed and undiagnosed TB patients who died in hospital 36 TABLE 14 Autopsy findings in PTB clinically positive: autopsy negative patients 37 TABLE 15 Clinical features of 182 HIV infected patients according to CD4+ count 43 LIST OF FIGURES FIGURE 1 Distribution of 350 study subjects by clinico-pathological correlation and commodity mined FIGURE 2 Distribution of 250 cases with TB at autopsy by clinico-pathological correlation; 100 cases where the clinical diagnosis of TB was not confirmed at autopsy are excluded FIGURE 3 Distribution of autopsies done at the NCOH and reviewed for this study FIGURE 4 HIV status in 187 cases 21 22 23 24 FIGURE 5 Attendance at mine health facilities in the 3 months preceding death or the terminal hospital admission. PTB Clinically negative: autopsy positive patients 26 11 FIGURE 6 Attendance at mine health facilities in the 3 months preceding death by patients in whom PTB was diagnosed during their terminal hospital admission PTB Clinically positive: autopsy positive patients 31 FIGURE 7 Drug susceptibility status for patients on TB treatment for longer than 30 days PTB Clinically positive: autopsy positive patients 33 FIGURE 8 Rates of PTB at autopsy 1975-1998 (NCOH pathology database) 39 LIST OF CASE HISTORIES AND PHOTOGRAPHS OF LUNGS (By place in text - actual photographs appended at end of report) CASE 1 - Previous hospital admission for pneumonia At autopsy: Miliary TB CASE 2 - Previous attendance for chronic disease at medical outpatients At autopsy: PTB CASE 3 - Previous attendance at primary clinic for respiratory symptoms At autopsy: Miliary TB CASE 4 - Admission with diagnosis of advanced AIDS: TB not investigated At autopsy: PTB CASE 5 - Fine miliary TB At autopsy: Miliary TB CASE 6 - Multiple respiratory diseases: At autopsy: PTB and Pneumocystis carinii pneumonia CASE 7 - Multiple respiratory diseases: At autopsy: PTB, Kaposi's sarcoma and Bronchopneumonia CASE 8 - Multiple respiratory diseases: At autopsy: Miliary TB and nocardia with cavitation CASE 9 - Known multi-drug resistant TB At autopsy: PTB with hemorrhage and silicosis CASE 10 - Patient at high risk for multi-drug resistant TB; drug susceptibility not done At autopsy: PTB and TB lymphadenitis 12 CASE 11 - Patient at risk for multi-drug resistant TB with sputum not assessed at end of TB treatment At autopsy: PTB with cavitation and pleural TB CASE 12 - Patient with multiple recurrent episodes of TB known to still not have drug resistance At autopsy: PTB with cavitation CASE 13 - Risk of transmission of undiagnosed TB to the community: Patient who died on the mine At autopsy: PTB with cavitation CASE 14 - Risk of transmission of undiagnosed TB to the community: Patient who died off the mine At autopsy: Miliary TB with marked dust deposition CASE 15 - Risk of transmission of undiagnosed TB to the community: Nosocomial risk At autopsy: Miliary TB and caseous TB CASE 16 - Empirically treated for recurrent TB for 26 days At autopsy: Aspergillus & Pneumocystis carinii pneumonia CASE 17 - Treated for smear positive TB for 183 days At autopsy: Cryptococcus and pneumonia CASE 18 - Treated for smear positive TB for 84 days At autopsy: Kaposi's sarcoma and Cryptococcal pneumonia CASE 19 - Empirically treated for TB for 148 days At autopsy: Pneumocystis carinii pneumonia and Kaposi's sarcoma CASE 20 - Empirically treated for TB for 100 days At autopsy: Extensive malignant tumour of unknown primary origin CASE 21 - Treated for smear positive TB for 62 days At autopsy: Bacterial pneumonia 13 GLOSSARY A Acquired Immuno-deficiency Syndrome (AIDS) A variety of secondary diseases caused by primary infection with the HIV Aspergillus A genus of fungi, several species of which cause disease in immune compromised patients B Bronchiectasis Chronic dilatation of the bronchi marked by fetid breath and coughing C Case Fatality Rate The proportion of cases of a specified condition which are fatal as a result of that condition within a specified time period. Culture Propagation of micro-organisms or living cells in special media conducive to their growth, e.g. Bactec Middlebrook used to culture Mycobacterium tuberculosis CSF Cerebrospinal fluid Cytomegalovirus One of a group of highly host-specific herpes viruses that infect man D Discordant Disagreement E Embolus A clot which obstructs the circulation Encephalitis Inflammation of the brain Emphysema A pathological accumulation of air in tissues or organs applied especially to a condition of the lungs Empirical Based on experience H Haemoptysis The spitting of blood Human Immuno-deficiency virus (HIV) The retrovirus responsible for AIDS K Kaposi's sarcoma Tumour made up of embryonic connective tissue often highly malignant 14 L Lymphocytic interstitial pneumonitis Pertaining to lymphocytes infiltrating the lungs Lymphoma Neoplastic disorder of lymphoid tissue including Hodgkins' disease M Medical station Clinic situated on a mine Meningitis Inflammation of the meninges surrounding the brain Metastatic carcinoma Malignant tumour which has spread from one organ to another which is distant from it N NCOH National Centre for Occupational Health Nocardia A fungus of the genus of actinomycetes. Nocardia asteroides produces pulmonary infections in man resembling tuberculosis Non-tuberculous mycobacteria (NTM) Organisms belonging to the genus Mycobacterium that do not cause TB Nosocomial Disease acquired in health care facilities or from medical treatment O ODMWA Occupational Diseases in Mines and Works Act (Act 78 of 1973) Opportunistic infection Micro-organism which does not ordinarily cause disease but which under certain circumstances (e.g. impaired immune responses) becomes pathogenic P PATHAUT Pathology Automation System. Computerized database at the Pathology division of the NCOH Pericarditis Inflammation of the pericardium surrounding the heart Pleural effusion Collection of fluid in the pleural space surrounding the lungs Pneumocystis A genus of fungi causing Pneumocystis carinii pneumonia Pneumonia Inflammation of the lungs with solidification of the air spaces Pulmonary oedema Fluid in the lungs Pyuria Presence of pus in the urine indicative of urinary tract infection 15 S Sensitivity The ability of a test to correctly identify those who have the disease under study Specificity The ability of a test to correctly identify those who do not have the disease under study Septicaemia Systemic disease associated with the presence of pathogenic organisms in the blood Silicosis Pneumoconiosis due to the inhalation of dust containing silica Stain Substance used in colouring tissues or micro-organisms for microscopical study, e.g. ZiehlNeelsen, Haematoxylin and Eosin Surveillance Ongoing monitoring usually aimed at early detection of disease T Tuberculosis (TB) Specific disease caused by the presence of Mycobacterium tuberculosis organisms Miliary TB TB Characterized by the formation of widespread lesions resembling millet seeds. The disease spreads widely to involve extra-pulmonary organs such as the liver, kidney etc. Multidrug resistant TB (MDR) Organisms resistant to rifampicin and isoniazid Single Drug resistant TB (SDR) Organisms resistant to any one drug on the standard treatment regimen 16 1. INTRODUCTION 1.1 Background to the study Pulmonary tuberculosis (PTB), declared a global emergency by the World Health Organisation in 1991, is a major infectious disease in the South African mining industry (Leon, 1995). Patients who are timeously diagnosed have an excellent response to treatment and yet, despite comprehensive TB control programs in the mining industry, deaths from TB exceed those due to mine accidents (La Grange, 2000). TB is a potentially curable disease and failure to diagnose it accurately and timeously has important implications for the individual, spread of PTB in the community and compensation in terms of the Occupational Diseases in Mines and Works Act (ODMW Act). However, improved management can only occur if the diagnosis is correctly established to target areas for intervention. Unsuspected TB as a cause of death has been described in the American, European and African medical literature in both general and HIV infected populations. These studies have emphasised the importance of autopsies for recognising TB that has not been clinically suspected and diagnostic discrepancies have been observed in over half the cases (d'Arminio Monforte, 1996; Wilkes, 1988). Data from SIMRAC project GEN 509 (Surveillance of respiratory diseases across the mining industry using the autopsy database) showed that during 1997 there were 379 cases of PTB diagnosed at autopsy, most of which were very extensive. However, the clinicians had correctly ascribed TB as the cause of death in only 31% of these cases. The National Centre for Occupational Health (NCOH) examines the lungs of deceased mineworkers, with an autopsy rate of around 80% for men dying while in employment. The NCOH is thus in a unique position to assist with strategies for improving the accurate diagnosis of PTB. 1.2 Objectives 1. Correlation of the ante- and postmortem diagnoses of PTB on a representative sample of miners in South Africa 2. Review of medical data to assess current clinical practice and identify possible reasons for discordant diagnoses 3. Identify strategies for improving clinical practice 2. METHODS 2.1 Study setting The study was undertaken on South African gold, coal and platinum mines. 17 2.2 Study population and Selection of study cases The study population comprised all men who died and had an autopsy examination of their lungs between January and December 1999, in terms of the ODMW Act. The study subjects comprised men with a clinical diagnosis of PTB (i.e. PTB was mentioned on death certificate as a factor in the cause of death) and / or an autopsy diagnosis of PTB. They were selected from the autopsy database using the programs written for a previous SIMRAC project (GEN509: Surveillance of respiratory diseases across the mining industry using the autopsy database). 2.3 Autopsy Methods Briefly, the autopsy methods are as follows: lungs are removed locally at the mines, placed in formalin and sent to the NCOH in Johannesburg for pathological examination. Tissue sections are routinely stained with hematoxylin, eosin and alcian-blue (for Pneumocystis carinii). All the study subjects also had a Ziehl-Neelsen (for acid fast bacilli) and Grocott stain (for Cryptococcus, other fungi and nocardia). Autopsy reports and microscopic slides of tissue sections from the lungs of all the study subjects were reviewed to confirm the pathological findings, prior to clinical record review. Bacterial pneumonia was defined as the presence of consolidation with polymorphonuclear leukocytes in the bronchioles and alveoli. The diagnosis of TB was made in the presence of granulomatous inflammation with or without acid fast bacilli, other causes of granulomatous inflammation having been excluded on special stains for fungi. TB was also diagnosed if no granulomata were identified but there was extensive necrosis with nuclear debris and large numbers of acid fast bacilli on ZiehlNeelsen stains (the pattern of non-reactive TB) 2.4 Review of clinical records Current clinical practice was assessed by a review of the patients' medical records. Data pertaining to hospital admissions, diagnostic tests, TB history and primary clinic visits were collected by the study members at regular visits to the mine hospitals. A single data capture sheet for autopsy and clinical data was developed (Appendix 1) 2.5 Analysis of data Autopsies from Anglo Gold were excluded from all the analyses. Study subjects were divided into three groups: 1) patients with a diagnosis of PTB at autopsy only; 2) patients with both a clinical and autopsy diagnosis of PTB; 3) patients with a clinical diagnosis of PTB which was not confirmed at autopsy. The clinical and autopsy data were analysed to identify possible reasons for discordant diagnoses. 2.6 Ethics approval Ethics approval was obtained from the University of the Witwatersrand Committee for Research on Human Subjects. Ethics approval was not obtained from Anglo Gold Health Service (Pty) Ltd Medical Research Ethics Committee. The issues which they raised were discussed at a meeting with Prof. Cleaton-Jones (chairperson of the WITS ethics committee) 18 and Dr Ross (Simpross) and subsequently by the WITS Committee for Research on Human Subjects. Assurance was given by the committee that the study could proceed with the medical centres which had agreed to participate and ethical approval was confirmed. 3. RESULTS 3.1 Study subjects During 1999, there were 1858 autopsy examinations of the lungs of miners performed at NCOH (excluding Anglo Gold). There were 350 study subjects and Table 1 shows the distribution of the study population and subjects by ethnic group and commodity mined. TABLE 1 STUDY SUBJECTS AS A PROPORTION OF AUTOPSIES DONE AT NCOH BY ETHNIC GROUP AND COMMODITY JANUARY - DECEMBER 1999 Ethnic group and commodity Black men Gold Coal Platinum Other* Unknown Total Study subjects / Autopsies at NCOH N% 243/791 26/83 47/173 14/68 1/17 331/1132 31 31 27 21 6 29 White men Gold Coal Platinum Other* Unknown Total 6/452 2/58 0/38 3/106 1/22 12/676 1 3 0 3 5 2 Coloured men Asbestos Other* Total Unknown 5/25 2/4 7/29 0/21 20 50 24 0 Total 350/1858 19 * Other includes copper, diamond etc. 19 The 350 study patients were grouped according to clinico-pathological correlation as: 1. PTB clinically negative : autopsy positive 2. PTB clinically positive : autopsy positive 3. PTB clinically positive : autopsy negative 155 cases (44%) 95 cases (27%) 100 cases (29%) PTB was correctly clinically ascribed according to autopsy findings in 27% of the study subjects. The distribution of the study subjects by clinico-pathological correlation, ethnic group and commodity mined is shown in Table 2 and Fig 1. TABLE 2 DISTRIBUTION OF 350 STUDY SUBJECTS BY CLINICOPATHOLOGICAL CORRELATION, ETHNIC GROUP AND COMMODITY Clinically negative : Clinically positive : Clinically positive : Total autopsy positive autopsy positive autopsy negative Ethnic group Black White Coloured Total n=155 N 142 10 3 155 44% % 92 6 2 100 n=95 N 91 2 2 95 27% % 96 2 2 100 n=100 N 98 0 2 100 29% % 98 0 2 100 n=35 0 N% 331 95 12 3 72 350 100 Commodity Gold 102 66 68 Coal 16 10 7 Platinum 23 15 14 Other 11 70 Unknown 3 26 Total 155 100 95 72 79 75 15 10 00 66 100 100 79 249 71 5 28 8 10 47 13 0 11 3 6 15 4 100 350 100 20 FIGURE 1 DISTRIBUTION OF 350 STUDY SUBJECTS BY CLINICOPATHOLOGICAL CORRELATION AND COMMODITY MINED Gold (n=249) Clinically negative; autopsy positive (44%) Clinically positive; autopsy positive (27%) Clinically positive; autopsy negative (29%) Coal (n=28) Platinum (n=47) Other & unknown (n=26) 21 Of all the cases where PTB was found at autopsy , PTB was correctly clinically diagnosed in 38% (95/250) of cases. Figure 2 shows the distribution of these 250 cases; the 100 cases where the clinical diagnosis of PTB was not confirmed are excluded. FIGURE 2 DISTRIBUTION OF 250 CASES WITH PTB AT AUTOPSY BY CLINICO-PATHOLOGICAL CORRELATION; 100 CASES WHERE CLINICAL DIAGNOSIS OF PTB WAS NOT CONFIRMED ARE EXCLUDED All cases with PTB at autopsy (250) 38% ^ coox Clinically negative; autopsy positive ((62%) Clinically positive; autopsy positive (38%) Gold (n=170) Coal (n=23) Platinum (n=37) Other & unknown (n=20) 22 3.2 Medical record review Eight mine medical centres (Leslie Williams, Gold Fields West, Duff Scott, Harmony, St Helena, SASOL-Secunda, ERPM and Amplats), which accounted for (81%) of all the study subjects were selected for medical record review. 65% (187/290) of the medical records of these patients were adequate for statistical analysis. The distribution of adequate medical records (from all 350 study cases) reviewed by clinico-pathological category and commodity is shown in Figure 3. FIGURE 3 DISTRIBUTION OF AUTOPSIES DONE AT THE NCOH AND REVIEWED FOR THIS STUDY THE 187 CASES WHERE MEDICAL RECORDS WERE ADEQUATE FOR STATISTICAL ANALYSIS WERE USED FOR THE REST OF THE RESULTS SECTION 3.2.1 Age The mean age of cases was 41.3 years (SD 7.1), median 41 and range 26-58. 3.2.2 Place of Death The study subjects included men who died in a mine hospital, as well as those dying elsewhere such as mine hostels, provincial hospitals and at home. The place of death of the study subjects by clinico-pathological category is shown in Table 3. 23 TABLE 3 PLACE OF DEATH BY CLINICO-PATHOLOGICAL CATEGORY (N=18 6*) Place of death Clinically negative: Clinically positive: Clinically positive: autopsy positive autopsy positive Autopsy negative N% N% N% Mine hospital 53 70 51 80 35 76 On mine 16 21 8 12 11 24 Off mine 79 58 00 TOTAL 76 100 64 100 46 100 * excluded is 1 case where the place of death could not be ascertained 3.2.3 HIV infection 76% (143/187) of the men were known to be HIV infected. CD4+ counts were known in a minority of the cases who were HIV infected (37/143) (Figure 4). There were no cases with a count greater than 500 cells/pL, and 90% had a count of <200 cells/pL. No patients were on anti-retroviral therapy nor were any on TB chemoprophylaxis. FIGURE 4 HIV STATUS IN 187 CASES CD4+ cells (cells/pL) (37 cases) 24 3.3 PTB CLINICALLY NEGATIVE:AUTOPSY POSITIVE There were 77 medical records in this category which were adequate for statistical analysis. 3.3.1 Case finding 3.3.1.1 Surveillance chest radiographs 27 (35.1%) patients were known (we did not specifically access the annual medical surveillance records) to have had a surveillance chest radiograph taken within the year preceding death, and all were assessed as having no active TB. 3.3.1.2 Attendance at mine health facilities in the 3 months preceding death or the terminal hospital admission 64% of patients (48/75) had attended the mine health facilities at least once in the 3 months preceding death, excluding a primary clinic visit that resulted in a hospital admission. Most patients (51; 68%) died in a mine hospital and of these, 61% had attended the medical facilities within the three months preceding their terminal admission (Table 4 and Fig 5). At a majority of the visits to the health facilities (26/48; 54%), the patients had respiratory symptoms and / or signs. Several patients were attending the mine health facilities monthly for chronic conditions such as diabetes and hypertension. Of the patients who died outside a mine hospital, 71% (17/24) had also attended the health facilities in the 3 months prior to death. TABLE 4 ATTENDANCE AT MINE HEALTH FACILITIES IN THE 3 MONTHS PRECEDING DEATH PTB: clinically negative : autopsy positive patients; n=75* Attendance at mine health facility Medical station (% with respiratory disease) Died in Mine hospital N=51* (68%) % 21 (64) Died outside Mine hospital N=24** (32%) % 21 (40) Total % 21 (56) Hospital (% with respiratory disease) 18 (78) 33 (63) 23 (71) Med Stat & Hosp (% with respiratory disease) 18 (78) 13 (33) 16 (67) Surveillance (% with respiratory disease) 4 (0) 4 (0) 4 (0) Total attendances (% with respiratory disease) 61 (68) 71 * 2 patients where data was not available are excluded ** 1 patient where place of death could not be ascertained is included (47) 64 (60) 25 FIGURE 5 ATTENDANCE AT MINE HEALTH FACILITIES IN THE 3 MONTHS PRECEDING DEATH OR THE TERMINAL HOSPITAL ADMISSION PTB: CLINICALLY NEGATIVE: AUTOPSY POSITIVE (Attendance at occupational health centre for surveillance examination is not shown (4%) 64% 21% 23% 16% Respiratory Respiratory Respiratory disease (56%) disease (71%) disease (67%) Respiratory disease (60%) Medical station Hospital admission Medical station+ No attendance Hospital Total previous attendences Case histories and photographs of lungs illustrating previous attendance at mine health facilities Case 1 - Previous hospital admission for pneumonia Case 2 - Previous attendance for chronic disease at medical outpatients Case 3 - Previous attendance at primary clinic for respiratory symptoms 3.3.2 Management during the terminal hospital admission 3.3.2.1 Investigations for PTB The 53 patients who died in a mine hospital were grouped according to the presence or absence of clinical signs and symptoms of respiratory disease, and investigations which may have led to the diagnosis of PTB were evaluated. Patients who were clinically assessed as having respiratory signs and symptoms were more likely to have chest radiographs and sputum smears examined for TB (Table 5). Duration of hospital stay was similar in both groups. No cultures for TB were requested. 26 TABLE 5 INVESTIGATIONS FOR PTB DURING THE TERMINAL HOSPITAL ADMISSION ACCORDING TO SIGNS AND SYMPTOMS OF RESPIRATORY DISEASE PTB: Clinically negative : Autopsy positive patients; n=53* Investigations Requested Chest radiograph Sputum smears for TB Sputum culture for TB Hospital stay mean days (sd) * 7 patients with focal TB are included. Respiratory signs & symptoms Present Absent n=33 (62%) % 88 61 0 16.7(9.4) n=20 (38%) % 55 5 0 17.2(12.4) 3.3.2.2 Chest radiographs Table 6 shows the number of chest radiographs requested, as well as the interpretation of the radiograph where this was recorded by the clinician in the medical record. The most frequent assessment of the radiographs were normal, pneumonia and possible TB, however, in these latter cases, TB was not mentioned on the death certificate TABLE 6 CHEST RADIOGRAPHS OF PATIENTS WHO DIED IN HOSPITAL PTB Clinically negative: autopsy positive patients; n=53 Respiratory signs & symptoms Present Absent N= 33 n=20 Chest radiograph: Requested 29 11 Taken 28 9 Reading recorded 26 7 Reading: Clear 6 7 Pneumonia 5 Inactive TB 3 Query TB 5 Other* 7 *includes comments such as interstitial infiltrate, oedema etc. 27 3.3.2.3 Sputum examination 61% of the patients admitted to hospital with clinical signs and symptoms of respiratory disease had at least one sputum sent for smear examination for TB (Table 7). In 39% of the patients no sputum was requested, these patients survived at least one day in hospital. Sputum could not be obtained in 2 mentally confused patients. TABLE 7 SPUTUM SMEAR EXAMINATION OF THE PATIENTS WITH SIGNS AND SYMPTOMS OF RESPIRATORY DISEASE WHO DIED IN HOSPITAL PTB: Clinically negative : Autopsy positive patients; n=33 Number of specimens sent * Sputum negative Result not available Sputum positive 1 2 3 3+ 2** 2 12 3 18 1 1*** * for one patient data on the number of smears sent were missing ** one patient died the same day, one became confused *** patient with hepato-renal failure; TB was not mentioned on the death certificate 3.3.2.4 Clinical management 58% of the hospitalized patients with signs and/or symptoms of respiratory disease were clinically assessed and managed as having non-specific pneumonia. 88% of them also had a diagnosis of AIDS. Of those without respiratory signs and/or symptoms, 90% had `AIDS', in 40% of whom this was the only clinical assessment. The remaining 60% had a variety of clinical disorders including meningitis, septicemia, diarrhea, pancreatic pseudocyst, Kaposi's sarcoma and renal failure. Of the two patients without AIDS, 1 had encephalitis and 1 renal failure. 3.3.2.5 Previous PTB A history of previous TB was present in 16%. 3.3.3 Autopsy findings The autopsy findings are shown in Table 8. Miliary TB was the predominant pathological pattern, being present in 57% of cases. 27% of the patients had PTB together with at least one other additional pathology, of which 76% were infectious with non-specific pneumonias predominating. 28 TABLE 8 AUTOPSY FINDINGS IN PTB CLINICALLY NEGATIVE : AUTOPSY POSITIVE PATIENTS n=77 Pathology Number of patients PTB pattern: Focal Miliary Extensive bronchopneumonic Fibrocaseous and 7 44 26 PTB and pericardial TB PTB and pleural TB 2 1 PTB and another lung disease: Infective: Non-specific Pneumonia Pneumocystis carinii Nocardia Cytomegalovirus Aspergillus 21* 16 10 3 1 1 1 Non-infective: Kaposi's sarcoma 1 Silicosis 6 Embolus 2 Emphysema 1 Bronchiectasis 1 Pulmonary oedema 1 Pleural exudate 1 * 21 patients, some had more than one additional lung disorder Case histories and photographs of lungs illustrating autopsy features which made a clinical diagnosis of TB difficult Case 5 - Fine miliary TB Case 6 - Multiple respiratory diseases: at autopsy: TB + Pneumocystis carinii pneumonia Case 7 - Multiple respiratory diseases: at autopsy: TB + bronchopneumonia + Kaposi's sarcoma Case 8 - Multiple respiratory diseases: at autopsy: Miliary TB + nocardia with cavitation 29 3.3.3.1 Correlation of pathology, radiology and clinical assessment for those who died in hospital Of those patients who were clinically assessed as having no evidence of respiratory signs or symptoms, 71% (5/7) had miliary PTB at autopsy, 1 had extensive pneumonic type PTB (he died after 38 days in hospital and was being managed as Kaposi's sarcoma of the palate) and one had focal PTB. None of these patients had another respiratory disease at autopsy. Of the patients with respiratory signs and symptoms, 69% had miliary PTB at autopsy, 15% had focal PTB and the rest extensive fibrocaseous and bronchopneumonic type PTB. Miliary PTB alone was present in 38% and miliary PTB together with another pathology was present in 61%, this was predominantly non-specific pneumonia (44%). 3.4 PTB CLINICALLY POSITIVE : AUTOPSY POSITIVE There were 64 medical records which were adequate for statistical analysis in this category. In 48%, the diagnosis of PTB was made during their terminal hospital admission. In 52%, the diagnosis had been previously made, they either died during a readmission to the mine hospital or elsewhere while on treatment for PTB. 3.4.1 Case finding 3.4.1.1 Surveillance radiographs Data pertaining to this were scanty in the hospital bed letters. Four patients were recorded as having had a surveillance radiograph in the year preceding death but in the rest, this data could not be ascertained. 3.4.1.2 Attendance at mine health facilities in the 3 months preceding death Of the 31 patients in this category who were diagnosed with PTB during their terminal hospital admission, 39% had attended the mine health facilities in the 3 months preceding death (Table 9 and Fig 6). The majority of the previous attendances (75%) were for respiratory conditions. The rest of the patients had been receiving treatment for TB at the medical stations. 30 TABLE 9 ATTENDANCE AT MINE HEALTH FACILITIES IN THE 3 MONTHS PRECEDING DEATH BY PATIENTS IN WHOM PTB WAS DIAGNOSED DURING THEIR TERMINAL HOSPITAL ADMISSION PTB: Clinically positive : Autopsy positive (n=31)* Attendance at mine health facility Medical station (% with respiratory disease) Died in mine hospital N=31 (84.2%) % 32 (70) Hospital admission (% with respiratory disease) 7 (100) Total attendances (% with respiratory disease) 39 (75) * 8 people who died before treatment started are included FIGURE 6 ATTENDANCE AT MINE HEALTH FACILITIES IN THE 3 MONTHS PRECEDING DEATH BY PATIENTS IN WHOM PTB WAS DIAGNOSED DURING THEIR TERMINAL HOPSITAL ADMISSION PTB: Clinically positive: autopsy positive 61% 32% 39% Respiratory disease (70%) Medical station ____ 7% Respiratory (100%) t---------------------------------------- ----------------- --i-- Hospital admission No attendance Respiratory disease (75%) Total previous attendances 31 3.4.2 Management 3.4.2.1 Management of newly diagnosed patients during their terminal hospital admission The diagnosis was made by chest radiograph in 42% (Table 10), positive sputum smear in 39% and by other means in a few (one had a positive culture which was sent on a previous admission, 1 had no x-ray but was diagnosed because of haemoptysis, one following surgery for a TB caecal mass, and in 3 patients we could not establish how the diagnosis was made). 65% died within 10 days of admission, and 26% died before treatment was started. Diagnostic delay was much lower in the sputum smear positive cases: (One outlier of 46 days is excluded) 21/11 = 1.9 days versus 92/15 = 6.1 days for the other cases TABLE 10 CHARACTERISTICS OF PATIENTS DIAGNOSED DURING THEIR TERMINAL HOSPITAL ADMISSION PTB: Clinically positive : Autopsy posi tive n=31 TB treatment Diagnostic delay Length of Method of diagnosis duration (days) hospital stay 01 1 x-ray 02 2 x-ray 02 2 Empiric (haemoptysis) 08 8 x-ray 03 3 x-ray 04 6 Smear+ 0 Unknown 5 Couldn't establish 0 Unknown 6 Couldn't establish 15 6 x-ray 11 2 x-ray 13 4 Smear+ 15 6 x-ray 1 10 11 x-ray 12 3 x-ray 18 9 x-ray 25 7 Smear+ 21 3 Smear+ 33 6 x-ray 53 8 Previous culture now + 53 8 Smear+ 6 10 16 Couldn't establish 72 9 Smear+ 14 46 60 Smear+ 18 18 36 Caecal TB (Biopsy) 19 14 33 x-ray 26 3 29 Smear+ 29 0 29 Smear+ 32 10 42 x-ray 51 0 51 Smear+ 57 0 57 Smear+ 32 81 0 81 Smear+ 3.4.2.2 Management of patients on TB treatment for longer than 30 days There were 27 patients who had received treatment for TB for more than 30 days, 85% of whom had extensive TB at autopsy and most of whom had been treated for longer than 100 days (Table 11). Of those cases treated for more than 30 days, 2 (7%) were known to be fully drug susceptible, 6 (22%) were known multi-drug resistant TB (MDR) and in 34% a sputum had not been sent for culture (Fig 7). FIGURE 7 DRUG SUSCEPTIBILITY STATUS FOR PATIENTS ON TB TREATMENT FOR LONGER THAN 30 DAYS PTB: Clinically positive : Autopsy positive n=27 Known MDR (22%) Known sensitive (7%) Culture sent, no result (15%) Culture not sent (34%) Unknown culture (22%) Case histories and photographs of lungs illustrating: Case 9 - Known MdR TB Case 10 - Patient at high risk for MDR, drug susceptibility not done Case 11 - Patient at risk for MDR TB with sputum not assessed at end of previous episode of TB treatment Case 12 - Patient with multiple recurrent episodes of TB known to still not have drug resistance 33 TABLE 11 TREATMENT DURATION, DRUG SUSCEPTIBILITY AND HISTORY OF PREVIOUS TB IN PATIENTS ON TB TREATMENT FOR LONGER THAN 30 DAYS PTB>: Clinically positive: autopsy positive; n=27 Treatment days Culture status MDR status Previous TB 32 Done, result n/a Unknown Yes 36 Done Unknown No 51 No culture Unknown Yes 57 No culture Unknown Yes 70 Done MDR Unknown 72 Done Sensitive Yes 81 No culture Unknown No 90 Unknown Unknown Yes 96 Unknown Unknown No 116 Done MDR Unknown 120 No culture Unknown No 120 Done Sensitive Yes 129 No culture Unknown Yes 141 Done, result n/a Unknown No 150 No culture Unknown Yes 155 Unknown Unknown Unknown 166 Unknown Unknown Unknown 172 Unknown Unknown Unknown 175 Unknown Unknown Yes 210 Done, result n/a Unknown Yes 211 No culture Unknown Yes 236 Done MDR Unknown 500 Done MDR Unknown 619 Done MDR Chronic TB 720 No culture Unknown Unknown 900 Done MDR Unknown 900 No Culture Unknown Unknown * Focal TB 3.4.2.3 Miscellaneous cases There were an additional 8 cases who did not fit into either of the preceding groups. *2 men died in the rural areas (Lesotho, Transkei), having left the mines several months previously with no mine history of TB *2 patients refused all medical treatment, both had a clinical diagnosis of TB *3 patients were brought in dead, the duration of treatment for TB could not be established in 2, one had been treated for 10 days.* *1 patient who was on treatment for TB for 30 days, was readmitted with advanced AIDS 34 and was being processed for medical discharge when he died. 3.4.3 Autopsy findings The autopsy findings are shown in Table 12. Miliary TB was present in 17% of patients, all but one of whom were newly diagnosed. 33% of the patients had PTB plus another disorder. TABLE 12 AUTOPSY FINDINGS IN PTB CLINICALLY POSITIVE : AUTOPSY POSITIVE PATIENTS (N=64) Pathology Number of patients PTB pattern: Focal Miliary Extensive bronchopneumonic and fibrocaseous 5 11 48 PTB and pleural TB 2 PTB and another lung disease Infective: Non-specific pneumonia Cryptococcus 21 11 8 3 Non-infective Lymphoma Interstitial pneumonitis Silicosis Embolus Emphysema 1 1 6 1 1 3.5 Comparison of Clinically negative:autopsy positive and Clinically positive:autopsy positive groups 3.5.1 Comparison of features which may have influenced the diagnosis of TB Table 13 shows that both miliary TB and the simultaneous presence of another additional lung disease were significantly (p<0.05) more frequent in patients in whom clinicians failed to diagnose TB antemortem, than they were in patients in whom TB was correctly diagnosed. On the other hand, a history of previous TB was significantly (P<0.05) less frequent in clinically undiagnosed patients. 35 TABLE 13 COMPARISON OF FEATURES IN DIAGNOSED AND UNDIAGNOSED TB PATIENTS WHO DIED IN HOSPITAL Autopsy finding Miliary PTB Additional lung disease Clinically negative: autopsy positive (n=33) Yes No 23 10 14 19 Clinically positive: autopsy positive (n=31) Yes No 10 21 6 25 X2=8.9 P=0.003 X2=7.5 P=0.006 Case histories and photographs of the lungs illustrating the risk of transmission of undiagnosed TB to the community Case 13 - Patient who died on the mine Case 14 - Patient who died off the mine Case 15 - Nosocomial risk 3.6 PTB CLINICALLY POSITIVE : AUTOPSY NEGATIVE Patients in this category were those in whom the clinicians had recorded PTB as a major factor in the cause of death but TB was not present at autopsy. There were 46 medical records adequate for analysis in this category. 3.6.1 Patient on treated for TB for longer than 30 days 72% of patients for whom TB was clinically incorrectly ascribed as the cause of death, had been treated for longer than 30 days. The initial diagnosis of PTB was bacteriologically confirmed in 51%, was empiric in 40% and in the rest, the mode of diagnosis could not be ascertained. Most (72%) showed an initial clinical response and had been discharged from hospital only to deteriorate subsequently. 27% of these patients were clinically assessed as having predominantly nervous system disease and in 2 patients, Cryptococcal meningitis was diagnosed. In 27%, the clinical cause of death was ascribed to respiratory failure and the clinical differential diagnosis included multi-drug resistant TB, Pneumocystis carinii and non-specific bacterial pneumonia. For some of the remaining patients, their deterioration was ascribed to progressive advanced AIDS. Nevertheless, PTB was included on the death certificate in all of these patients as a major factor in the cause of death. 3.6.2 Patient on treatment for TB for less than 30 days 22% of patients in this category had been treated for 30 days or less. In 7%, neither treatment duration or mode of diagnosis could be accurately ascertained. 36 A similar spectrum of lung disease was present at autopsy for patients treated for less than 30 days as well as for those treated for more than 30 days (Table 14). Infections predominated of which non-specific pneumonia was most frequent, followed by Cryptococcal and Pneumocystis carinii pneumonia. TABLE 14 AUTOPSY FINDINGS IN THE PTB CLINICALLY POSITIVE: AUTOPSY NEGATIVE PATIENTS Pathology Number of patients PTB 0 PTB plus another lung disease* Infective: Non-specific Pneumonia Cryptococcal pneumonia Pneumocystis carinii Aspergillus 16 10 8 1 Non-infective: Kaposi's sarcoma 3 Lymphocytic interstitial pneumonitis 2 Silicosis 8 Embolus 1 Emphysema 1 Pulmonary oedema 3 Metastatic cancer 3 * Some patients had more than one lung disease Case histories & photographs of lungs illustrating patients who died while on TB treatment with no PTB found at autopsy Case 16 - Empirically treated for recurrent TB for 26 days At autopsy: Aspergillus & Pneumocystis carinii pneumonia Case 17 - Treated for smear positive TB for 183 days At autopsy: Cryptococcus and pneumonia Case 18 - Treated for smear positive TB for 84 days At autopsy: Kaposi's sarcoma and cryptococcal pneumonia Case 19 - Empirically treated for TB for 148 days At autopsy: Pneumocystis carinii pneumonia and Kaposi's sarcoma Case 20 - Empirically treated for TB for 100 days At autopsy: Extensive malignant tumour of unknown primary origin Case 21 - Treated for smear positive TB for 62 days At autopsy: Bacterial pneumonia 37 4. DISCUSSION "Hic locus est ubi mors gaudet succerrere vitae: this is the place where death delights to help the living" anon 4.1 Introduction In this study of 350 South African miners who came to autopsy during 1999, we found that clinicians failed to diagnose PTB as the cause of death in 44% of cases, correctly ascribed PTB as the cause of death in 27%, and incorrectly ascribed PTB as the cause of death in 29%. We acknowledge that the study involved mainly failures in the TB control programmes, and realise that around 90% of TB patients are successfully treated (Murray, 1999a; Churchyard, 2000a). Nevertheless, even a few undiagnosed PTB cases represent a considerable public health risk and, in evaluating possible reasons for discordant diagnoses, areas which might be amenable to improved clinical management were identified. Poor clinico-pathological correlation is not unique to the mine medical services, but also occurs even in developed countries with very well resourced medical care. Numerous clinico-pathological correlation studies have shown how important autopsy is in quality control, medical education and research (Nemetz, 1987; Scottolini, 1983; Cameron, 1981; Goldman, 1983). Clinically important diagnoses are missed, despite improved medical knowledge, experience, and diagnostic tools, and previous studies have emphasised the importance of autopsies for recognising disorders that have not been clinically suspected. In both general and HIV-infected populations, infectious and other diseases are frequently missed, and diagnostic discrepancies have been observed in up to 75% of cases. (Cameron, 1981a&b; Hui, 1984 ; Wilkes, 1988; Klatt, 1988). Only a limited number of autopsy studies relating to HIV infected patients have been reported from Africa, and few of these have included clinical correlation (Lucas, 1991; Lucas, 1993; Rana, 1997; Nelson, 1993; Abouya, 1992; Murray, 1999a) Unsuspected TB as a cause of death has been described in both AIDS (d'Arminio Monforte, 1996; Flora, 1990) and general populations (Bobrowitz, 1982; Edlin, 1978; Enarson, 1978). In one large general autopsy series, TB was clinically diagnosed in only 50% of the cases in which it was judged to be the main diagnosis at autopsy (Naalsund, 1994). 4.2 The natural history of TB In order to evaluate the aspects identified in this study which might lead to a reduction in missed, delayed and misdiagnosis of PTB, the natural history of PTB is briefly outlined: Exposure ^ Outcome ^ Infection ^ Disease ^ Diagnosis ^ Treatment ^ cure treatment failure including multi-drug resistance recurrence death 38 Infection occurs when susceptible persons are exposed to infectious patients, not all of whom have detectable TB bacilli in their sputum. To break the chain of transmission, the cornerstone of all TB programmes is early case detection and successful treatment. The factors responsible for progression from TB infection to disease are not all known but include conditions which impair immunity such as co-existent HIV infection, alcoholism and silica dust exposure (Murray, 1996). The control of these disorders is outside the scope of this study, but clearly a reduction in them would impact on the incidence of TB. 4.3 The burden of TB due to HIV There is a 10% life time incidence of developing TB disease in an HIV negative person who is infected with TB bacilli versus a 50% life time incidence of TB disease in an HIV infected person (Narain, 1992). Not only does HIV infection increase susceptibility to TB infection but it also results in reactivation of TB and rapid progression of infection to active TB disease. (Chaisson, 1987; Daley, 1992; Small, 1993). The profound impact which HIV has had on TB in Africa (De Cock, 1992; Nunn, 1994), has not spared the mining industry. In this study, 76% of cases were known to be HIV infected. As the rate of HIV infection increased during the 1990's, so did deaths in miners from TB and this is reflected in the autopsies performed at NCOH: FIGURE 8 RATES OF PTB AT AUTOPSY 1975 - 1998 (NCOH PATHOLOGY DATABASE) Rate/1000 160 140 120 100 80 60 40 20 ir /tso t-- ir /s /s t-- i r--i--r o> t-- /s eo t-- t-- ir <0 eo t-- ir to eo t-- ir /s eo t-- i r--i---- r o> eo ot>-- t-- t-- ir ot>o t-- ir ot>o t-- 1 /s Oi t-- Year 39 4.4 Case finding 4.4.1 Surveillance programs The routine medical surveillance of miners includes annual medical examinations and chest radiography for the early detection of PTB. However in this study, autopsies showed lungs with advanced disease even though surveillance radiographs taken only months prior to death were normal. This demonstrates that TB in HIV infected persons may have a rapid course whether from new infection, re-infection or reactivation. In this study, 64% of the patients who were correctly clinically diagnosed with PTB presented with extensive disease and had a rapidly terminal course, dying within 10 days of hospital admission. Many of the clinicians who participated in the study believe than at annual surveillance examination is no longer sufficient. Two SIMRAC projects (GEN 524 and HEALTH 705) are currently investigating various other methods of screening for improved early detection of PTB. 4.4.2 Passive case finding The role of the primary health nurse is considered to be of great importance in all TB programs (South African Tuberculosis Control Program, 2000). The nurse is usually the first health care worker whom the patient contacts and thus clinical acumen, awareness and interest of nursing staff can contribute to early diagnosis. This study noted instances where patients were being seen regularly at the clinics by nurses (e.g. for dressing of wounds) and who were then admitted to hospital and died within days with advanced PTB. Doctors in wards may not always consider TB in their differential diagnosis. Initiatives such as recording of weight and involvement of mine workers' unions have been successful at one centre. Most nurses whom the study team encountered during the course of this study were unaware of research projects undertaken by SIMRAC. 4.4.3 Frequency or missed TB and diagnostic delay 64% of miners with clinically undiagnosed PTB and 39% of those in whom TB was diagnosed shortly before death had attended the mine health care facilities on at least one occasion within 3 months of death. These figures exclude a primary clinic visit that resulted in a hospital admission, as well as the terminal hospital admission. At a majority of these prior attendances, respiratory symptoms and signs were present. Health service delay in diagnosis occurred at both clinics and in hospital. Missed `windows of opportunity' to have made a timeous diagnosis have been described in many other settings (Marrero, 2000; Salaniponi, 2000; Taylor, 2000). The study data did not enable ascertainment of patient delay i.e. time elapsed from the onset of symptoms to medical consultation, but several studies have shown that health system delays may be longer than patient delays (Stean, 1998; Lawn, 1997; Lawn, 1998; Aoki, 1985). 40 4.4.4 The importance of undiagnosed PTB and diagnostic delay For the individual patient, delayed or missed diagnosis of PTB may result in disability or death. Unrecognized TB may be even more dangerous in HIV infected people because untreated TB may increase viral replication (Nakata, 1997) and accelerate the progression of HIV/AIDS (Whalen, 1995; Perneger, 1995). Undiagnosed and untreated PTB also poses a substantial threat to public health resulting in transmission to health care workers, family, friends and co-workers. Nosocomial transmission is important especially, but not only, with regard to HIV infected contacts. In this study, patients with clinically undiagnosed TB spent a total of 907 days in hospital before dying, and even patients who were diagnosed with TB during their terminal admission had spent a total of 361 days in hospital before TB treatment was started. This suggests a substantial risk to health care workers and other patients. A study from Malawi showed a higher incidence of TB in nurses in medical and TB wards as opposed to other hospital departments (Harries, 1997). Nosocomial outbreaks of TB have been well described in the USA (MMWR, 1991). A recent outbreak of MDR-TB in a South African hospital resulted in the deaths of 6 HIV infected women, with a mean survival of 43 days (Sacks, 1999). In a survey in Baltimore in the early 1960s, 44 per cent of cases of TB first recognised at death were considered to have been communicable (Simpson, 1965). More recently, it has been estimated that an untreated patient with sputum smear-positive TB may infect between 10 and 14 people every year (Murray, 1990). Where diagnosis is delayed or missed, the pulmonary disease may progress to become smear positive. In addition, patients with smear negative but culture positive PTB are also responsible for transmission: they accounted for 17% of all TB transmission in San Fransisco (Behr, 1999). The situation may be even worse in the mining industry, given the high background of HIV infection as HIV infection increases susceptibility to TB infection. A molecular epidemiology study of PTB in South African miners showed that despite a high cure rate, ongoing transmission of TB (rather than reactivation of latent infection) accounted for at least 50% of the TB cases - higher than in any other study (Godfrey-Faussett, 2000). It was suggested that improved active case finding and shortening delays in the diagnostic process were among the measures needed to interrupt transmission of TB. Thus patients with undiagnosed PTB or in whom the diagnosis is delayed, represent a major public health problem and may be one of the reasons why the TB rate continues to escalate on the mines. A recent study from Cuba illustrates how an intervention which reduced delay in diagnosis attributable to the health care system from 56.9 days to 14.2 days contributed to a reduction in the incidence of TB (Marrero, 2000). 41 4.5 Management of patients with suspected PTB 4.5.1 Diagnostic tests In this study, reasons for failing to make the diagnosis of PTB in hospitalised patients with respiratory signs and symptoms included omission of laboratory tests such as sputum smears and culture, as well as mistaking radiographic or clinical signs and symptoms of PTB for those of pneumonia and other conditions. Similar reasons for failing to diagnose TB accurately and timeously have been described in other settings for patients with and without HIV infection, and management errors have been noted in around half of the patients (Bobrowitz, 1982; Katz, 1985; Flora, 1990; Kramer, 1990). In the subjects of this study, two other factors contributed to the difficulty in clinical diagnosis: the high frequency of miliary PTB and the simultaneous presence of an additional lung disease. At autopsy, both miliary TB and the simultaneous presence of another additional lung disease were significantly more frequent in patients in whom clinicians failed to diagnose TB antemortem, than they were in patients in whom TB was correctly diagnosed. 4.5.2 Sputum smear for TB bacilli Sputum smear examination for TB bacilli is a cornerstone of TB diagnosis: it is rapid, simple and cheap and detects those patients who are most infectious. South African gold miners are at risk for disease due to non-tuberculous Mycobacteria, M. kansassi in particular (Cowie, 1990; Corbett, 1999). Nevertheless, a prospective study of miners showed that the predictive value of a positive smear being Mycobacterium tuberculosis and not a non-tuberculous mycobacterium, was 91% (Sonnenberg, submitted). 4.5.2.1 Sputum smear negativity in HIV infected PTB patients In our study, even patients with extensive PTB at autopsy had been sputum smear negative. HIV infection is associated with an increased prevalence of smear negative PTB and up to 60% of HIV infected patients may be smear negative (Klein, 1989 ; Elliott, 1993). In a South African study, 23% of HIV infected patients were unable to produce any sputum and the overall yield of sputum smears was 43% (Hudson, 2000). The rate of sputum smear negativity is related to the degree of immunosuppression as shown in Table 15. 42 TABLE 15 CLINICAL FEATURES OF 182 HIV INFECTED PATIENTS ACCORDING TO CD4+ COUNT CHARACTERISTIC POSITIVE SPUTUM SMEAR CHEST RADIOGRAPH Atypical CD4 categories >500 (n=27) 200-500 (n=66) <200 (n=89) n (%) 24 (88.9) 43 (65.2) 59 (66.3) n (%) 9 (33.3) 9 (14.1) 50 (56.2) P VALUE 0.079 0.001 CHEST RADIOGRAPH Cavitation n (%) 14 (51.9) 30 (46.9) 17 (19.1) 0.001 CHEST RADIOGRAPH No/Minimal change n (%) Moderate change n (%) Extensive change n (%) DRUG RESISTANCE None SDR MDR n (%) n (%) n (%) From Murray, 2000a 5 (18.5) 13 (48.1) 9 (33.3) 15 (23.4) 29 (45.3) 20 (31.3) 32 (36.0) 40 (44.9) 17 (19.1) 0.015 23 (88.5) 3 (11.5) 0 ( 0) 59 (90.8) 6 ( 9.2) 0 ( 0) 74 (85.1) 19 (10.7) 3 ( 1.7) 0.150 4.5.2.2 False negative sputum smears Our study found that negative sputum smears were associated with diagnostic delays, even in those patients who were correctly clinically diagnosed as having PTB during their terminal hospital admission (1.7 days to make the diagnosis in smear positive patients vs 6.1 days in smear negative patients), a finding which has been noted elsewhere (Kramer, 1990). Thus every effort should be made to increase the yield of sputum smear specimens. False negative results, rather than genuinely smear negative PTB disease, may arise from a number of correctable reasons: inadequate numbers of specimens: three high quality sputum specimens are required to reliably detect smear positive PTB. A study from Malawi showed that examination of three sputum smear specimens detected 21% more cases than would have been detected if only one specimen had been sent to the laboratory (Harries, 1996). inadequate quantity (Warren, 2000) and quality of specimens: specimen quality can be improved by physiotherapy and sputum induction (Anderson, 1995). poor laboratory technique: in our study some of the laboratories did not participate in a quality control scheme, and the quality of the sputum specimen was not always 43 commented on in the laboratory report. Nearly 1/3 of sputum specimens defined as smear negative in a local laboratory in Tanzania were found to be smear positive in a reference laboratory (Chum, 1996). In the laboratory, the use of techniques such as fluorochromestained smears and homogenisation and concentration of sputum increases the diagnostic yield. 4.5.3 Sensitivity of sputum smear versus sputum culture for TB bacilli The yield from sputa is increased dramatically if the sputum is submitted for culture. However, in this study clinicians sometimes omitted to send sputa for culture, even at centres which, according to their questionnaire responses, were routinely doing cultures. This omission may in part reflect the ethos of the South African National Tuberculosis Control Program (South African Tuberculosis Control Program, 2000) which de-emphasises sputum culture as a tool for the diagnosis of TB. The consequences of omitting sputum culture examination for the management of TB were stressed at the clinico-pathological meetings held during the course of the study, and the mine medical services appear to have subsequently tightened up on their practice. Under optimal conditions, about 10,000 TB bacilli per ml are required for detection by smear, versus around 500 viable bacilli per ml for culture. Under operative conditions smear sensitivity for TB ranges from 40 to 65%, using culture as the gold standard (Toman, 1981). Procedures need to put in place to ensure that culture result are collected and acted upon. Thus in both HIV and non HIV patients, if the diagnosis of PTB relies on smear microscopy alone, a good number of patients will be missed, many of whom will be a source of infection in the community and in whom diagnosis will be delayed until the disease is advanced. We acknowledge that cost of culture is a consideration. However, in the interests of public health and also because PTB is a scheduled occupational disease, these additional costs are justifiable in the mining industry. Indeed, there have been cogent arguments for the wider availability of culture for the diagnosis and management of PTB even in resource-poor countries (Heifets, 1999). 4.5.4 New diagnostic techniques Because of the lower sensitivity of sputum smears and the delay in cultures (2-4 weeks for a result), a variety of new technologies have been developed for the more rapid and sensitive detection of PTB. The appropriate utilisation of these was a lively source of debate at the clinico-pathological meetings. It was hoped that the polymerase chain reaction (PCR) technique, which can be performed on sputum smear specimens, would provide a more sensitive diagnosis than smears stained with conventional methods and a more rapid diagnosis of TB than sputum culture. However, it has become clear that PCR, which is an expensive test, is no more sensitive than properly performed smears stained by routine methods and there are significant rates of false-positive results (Heifets, 2000) Rapid serological tests for antigen and antibody detection are not recommended in South Africa. They have not been adequately evaluated in high prevalence 44 TB settings, false-negative results are common in HIV infected persons, and antibody tests cannot distinguish between active TB and mere infection (Weyer, 1999). Sputum culture examination is still considered to be the gold standard for laboratory diagnosis. 4.6. Management of smear negative PTB Although TB may be missed: "Won't Get Fooled Again" (by Tuberculosis)" (Ashkin, 1999) and the reasons for this failure sometimes are obvious in retrospect (Tattevin, 1999), management and diagnostic problems arise in patients with negative sputum smears. Clinical decision making is even more complicated in HIV/TB settings because of the increased incidence of smear negative PTB, atypical chest radiographs and because HIV co infection broadens the differential diagnosis and likelihood of co-existing respiratory conditions. Numerous algorithms for diagnosing smear negative PTB, with and without resort to culture, have been developed based on clinical symptoms, response to antibiotic trials and chest radiographs (Colebunders, 2000; Hudson, 2000; Elliott, 1992; Wilkinson, 2000). In trying to outline an approach to the problem of a patient with negative smears, the patient's clinical features should direct further investigations and action. 4.6.1 Chest radiographs This study found at autopsy, a high frequency of miliary TB, additional diseases and atypical TB with pneumonic type consolidation in patients in whom TB had not been clinically diagnosed. Over-reliance on chest radiographic findings may not improve diagnostic accuracy It is well known that the chest radiograph in HIV infected patients with PTB is often atypical with less apical disease and more basal infiltrates (Abouya, 1995; Pozniak, 1995; Pitchenik, 1985). Atypical radiographs occur more frequently as CD4+ counts decrease (see Table 15), and positive smears and cultures are even seen in some patients with normal chest radiographs (Murray, 1999a; Post, 1995). All the doctors who participated in this study indicated, in response to a questionnaire, that they would like formal training in interpreting radiographs. The proposed new project to research, develop and evaluate such a training program (SIMHEALTH 803) is awaited. 4.6.2 Trial of antibiotics Bacterial pneumonia is the main differential diagnosis in both HIV infected and non-infected patients and patients in this study frequently had a trial of antibiotics. However, antibiotics trials may be a source of multiple errors: PTB patients may show a partial response either because of successful treatment of a superimposed bacterial infection, or because of fluctuations in TB disease Non-TB patients may not respond because of a non-infective condition e.g. Kaposi's sarcoma, or because the antibiotic used is ineffective for example against Pneumocystis carinii, Nocardia or Cryptococcus Non-TB patients may respond to TB therapy because of the broad antibacterial effect of rifampicin 45 The adoption of a policy of following all patients with pulmonary infiltrates to radiological resolution may help. A patient whose radiograph does not resolve completely following antibiotic treatment for pneumonia, should undergo further investigation. 4.6.3 Extra-pulmonary TB TB may not be limited to the respiratory system. A search for extra-pulmonary involvement may often confirm the diagnosis. This is particularly true of patients with concomitant HIV infection. 4.6.3.1 Pleural involvement Rupture of a sub-pleural caseous focus into the pleural space elicits an immune response culminating in a pleural effusion. HIV co-infection doubles the probability of a patient developing a tuberculous effusion. Either biopsy or culture can confirm the diagnosis. HIV infection and the degree of immune suppression alter the yield from pleural fluid culture. In a retrospective study, pleural fluid cultures were shown to be positive for TB in 32% of HIV negative patients, this figure increased to 72% for those HIV positive patients with low CD4 counts (Hopley, 2000a). The system used to culture the pleural fluid may also affect the yield. In a prospective study of 35 HIV sero-positive patients with tuberculous pleural effusions, the standard laboratory method cultured TB from 40% of the patients. The BACTEC lytic Myco/F system had a significantly higher yield of 83% (Hopley, 2000b). 4.6.3.2 Pericardial effusion / constriction Involvement of the pericardium, when it occurs, is easily demonstrated by echocardiography. Culture and biopsy are not often undertaken due to the invasive nature of the sampling techniques. 4.6.3.3 Lymph nodes Many HIV infected PTB patients with negative smears have lymphadenopathy and, in these patients, fine-needle lymph node aspirates have a high yield for TB bacilli (Bem, 1993; Pithie, 1992). Direct staining of aspirated material is often positive for TB bacilli. A South African study found that lymph node aspiration was the most cost-effective diagnostic test in smear negative PTB (Hudson, 2000). In HIV persons with TB, lymph nodes may be diagnostic even when nodes are symmetrically enlarged, in contrast with tuberculous lymphadenitis in HIV negative patients (Bem, 1997; Hudson, 2000). 4.6.3.4 Blood and bone marrow Both blood culture and bone marrow biopsy may be helpful. The BACTEC lytic Myco/F system was developed specifically to culture Mycobacteria from blood and has the advantage of identifying non-tuberculous mycobacteria (Pettifer C, M.Med report submitted to WITS University, 2000). 46 4.6.3.5 Liver Liver biopsy will often confirm a diagnosis of TB in patients with evidence of hepatic infiltration (raised alkaline phosphatase and gamma-GT). 4.6.3.6 Central nervous system There should be a low threshold of clinical suspicion for performing a lumbar puncture. In patients with changes in their CSF, empiric therapy should be started if TB is suspected. 4.6.3.7 Genitourinary tract The genitourinary tract is frequently involved in patients with disseminated TB. This is true even in the absence of pyuria and urine cultures for TB may be positive in up to 77% of patients (Shafer, 1991). 4.7 Miliary TB The presentation of miliary TB is frequently subtle and non-specific. Symptoms often reported are fever, weight loss and malaise; cough may not be present and an altered mental status is often found (Prout, 1980; Kim, 1990). Up to 30% of patients have normal chest radiographs (Al-Jahdali, 2000) and doctors may fail to consider the diagnosis. There is a high mortality, often associated with diagnostic delays. If the sputum is negative for TB, blood and urine cultures may be useful. Liver needle biopsy and lymph node aspirates are also sensitive diagnostic tests (Al-Jahdali, 2000; Maartens, 1990; Monie, 1983; Kim, 1990). 4.8 Other lung diseases in patients with TB In this study, there was a high rate of other lung diseases occurring simultaneously with PTB at autopsy and this complicated clinical decision making. Non-specific bacterial pneumonia was most frequent, followed by Cryptoccocal and Pneumocystis carinii pneumonias. HIV co-infection broadens the differential diagnosis of respiratory conditions to include diseases such as pulmonary Kaposi's sarcoma, lymphoma, Nocardia (Miller, 1996). All these conditions must be added to diseases long-known to enter the differential diagnoses, such as carcinoma and silicosis. 4.9 Advanced AIDS About 70% of people with HIV will have at least one respiratory episode in the course of their disease. If fever, weight loss and malaise are mistakenly ascribed to progressive HIV infection alone, the possibility of TB may be overlooked and not investigated. In this study, most patients were HIV infected with advanced AIDS. Men who retire on grounds of ill-health have an exit medical examination which always includes a chest radiograph as laid down in the ODMW Act. The problem surrounding further investigation and treatment of TB in these men is clearly an important one both for the patient, his family and the community. A system to ensure continuation of care is urgently required, possibly through The Employment Bureau for Africa (TEBA). Efforts should also be made to ensure 47 that the-lungs of deceased ex-miners are sent to the NCOH to ensure that compensation of occupational disease, if present, is paid to their families. 4.10 Management of patients while on treatment for PTB 4.10.1 Directly observed treatment strategy (DOTS) Once diagnosed, the quality of treatment affects outcome. Compliance is a central issue to which DOTS is the recognized key. Nurses have an important role to play, not only in ensuring compliance, but also in the early recognition of clinical deterioration such as may be due to adverse drug reaction or, in HIV infected patients, the sequential development of another opportunistic disease. 4.10.2 Failure to improve and deterioration while on treatment We found that in 29% of the study subjects, the clinicians had recorded PTB as a major factor in the cause of death but TB was not present at autopsy. These patients were all on TB treatment. 72% of them had been treated for longer than 30 days. Most of them had clinically improved and been discharged from hospital, only to deteriorate subsequently and die. They appear to have responded to treatment for TB and sequential development of other diseases accounted for many of the discrepancies between pre-mortem and post-mortem diagnoses. Those in whom the initial diagnosis of TB was not laboratory confirmed may have had TB misdiagnosed from the start (e.g. cancer was found at autopsy) or the diagnosis of TB may have been correct and they also developed a second disease. At autopsy, non-specific pneumonia was most frequent, followed by Cryptococcal and Pneumocystis carinii pneumonia. Mortality among HIV infected TB patients is rarely due to TB after the first month of treatment, when death from other infections occurs more frequently. A study of South African miners was the first to provide autopsy data to support the contention that much of the excess mortality of HIV infected patients who die while on treatment for tuberculosis is due to non tuberculosis AIDS related conditions (De Cock, 1992; Nunn, 1992). Autopsy examination showed that early mortality (within one month of diagnosis of PTB) was due to TB while late deaths were most commonly due to other infection. In another autopsy study of 119 deaths in HIV infected South African miners, 47 patients were on treatment for PTB at the time of death. Of the 34 patients who had been treated for more than 30 days, only 3 had extensive TB at autopsy (Murray, 1999b) Deterioration in a patient who has received treatment for PTB for more than 30 days should thus prompt an aggressive search for reasons, including additional infections, non-compliance with treatment and drug resistance. If TB was diagnosed empirically, then it should be considered whether or not TB is the correct diagnosis. 4.11 Multi-drug Resistance In this study, few patients were known to have died from MDR-TB. It seems unlikely that MDR was a factor in those patients who had never been previously treated for TB. Two recent studies of TB drug resistance in South African gold miners showed that the rate of primary 48 MDR was less than 1%, and was not associated with HIV infection (Murray, 2000a; Churchyard, 2000b). However, the most powerful predictor of MDR organisms is a history of treatment for TB and patients who have previously undergone therapy should be presumed to harbour drug resistant organisms until proven otherwise (Iseman, 1993). Regardless of a history of previous TB, MDR also becomes a possibility in any patient who still has extensive TB disease after 30 days of treatment. In a prospective study of gold miners with PTB, acquired multidrug resistance was 18.1%: 6.5% for recurrent disease and 33.9% in treatment failure cases (Murray, 2000a). We found that many of the study subjects who were at risk for MDR TB had not had a sputum specimen sent for drug susceptibility testing. The emergence of MDR due to doctors' errors in the treatment of PTB has been described in two recent studies from America, where up to 3.9 `management errors' per patient were documented (Mahmoudi, 1993; Rao, 2000). 4.12 Risk factors for death from PTB 4.12.1 HIV infection This study found that most deaths occurred in patients known to be HIV infected: 76% were known to be HIV infected and, of those who had had CD4+ counts, 90% were profoundly immunocompromised (CD4+ count <200). Although those HIV positive patients on treatment for PTB who survive respond as well to treatment as do HIV negative patients, even if they have advanced immunosuppression, HIV positive patients have a higher mortality during treatment for PTB. The high mortality rate in HIV positive patients with tuberculosis is well known (Nunn, 1992; Wilkinson, 1996; Small, 1991; Churchyard, 2000a). In a prospective study of South African miners, mortality in HIV positive patients was 26 times that in HIV non-infected patients. (13.7% vs 0.5%). The overall fatality rate was 7.4% (Murray, 1999a). Most of the excess mortality is, as has been discussed, due to non-tuberculous AIDS related conditions. However, HIV infected patients are also more likely to die of TB. Despite a similar radiological severity of disease at presentation, 5/49 HIV positive patients with extensive disease died of autopsy proven tuberculosis in the first month, compared with 0/46 in HIV negative patients (Murray, 1999a). The last-mentioned study also showed that the degree of immunosuppression is the strongest predictor of survival in HIV infected TB patients while they are on treatment for TB. In patients with a CD4+ lymphocyte count of less than 200, the case fatality rate was 22.1%, compared to 7.7% in those with a count of between 200 and 500. There were no deaths among patients with a normal CD4+ count. 4.12.2 Silicosis Some studies (Churchyard, 2000a; Ng, 1992) but not others (Murray, personal communication) have shown that silicosis is associated with an increased TB case fatality rate. 49 4.12.3 Other factors including quality of medical service In addition to miliary TB, the severity of TB disease on chest radiographs, increasing age and MDR are well documented factors associated with death (Reider, 1999). It has also been shown that the TB case fatality may vary depending on the expertise of the medical doctor (Borgdorff, 1998). The mine medical service in our study with the least proportion of cases of PTB which were clinically undiagnosed (23%) has several features which may have been a factor: for decades, the senior management has considered TB to be a major problem requiring adequate funding. This resulted in the appointment of a dedicated doctor experienced in both the clinical management and epidemiology of TB to head this program. Computer programs were installed, laboratories upgraded and research projects undertaken on a regular basis. A study in 1994 highlighting the problem of undiagnosed TB resulted in many improvements, including better adherence to local protocols. Yet, even this at this medical service, the study showed that in some instances routine tasks had not been performed. 4.13 Limitations of study We acknowledge that the clinical data in this retrospective study was not complete. However, the proportion of medical records reviewed from the selected eight medical centres (65%), is comparable to a landmark autopsy study in which 63% of clinical records were reviewed (Wilkes, 1988). The autopsy rate in miners is around 85%, which is much higher than the 50% in most of the studies showing the value of autopsy (Wilkes, 1988; Cameron, 1981a; Lucas, 1993). The inconsistency with which different clinicians may have recorded their clinical actions is unavoidable in a retrospective study such as ours. We were unable to perform cultures at autopsy and, although the pathologic features were not those of Mycobacterium intracellulare, we could not definitively exclude the possibility that other mycobacteria such as M kansassii may have been present. However, miners with advanced AIDS do not have an increased incidence of non-tuberculous mycobacteria when compared with miners who are not HIV infected (Sonnenberg, 2000). 5. CONCLUSION We retrospectively reviewed the findings of miners who clinically were assessed as having PTB as a major factor in the cause of death and/or in whom PTB was present at autopsy. Most patients' were HIV infected. We showed that PTB was accurately ascribed as the cause of death by clinicians in only 27% of cases. 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TECHNOLOGY TRANSFER "Keep doing what you've always done and you'll get what you always got" Dixie Snider 7.1 Clinico-pathological conferences Clinico-pathological conferences were held to disseminate the study findings, present illustrative cases, and discuss best practice clinical strategies. A wide range of mine health care workers attended the conferences which were held at different centres, as the study progressed. The study findings were illustrated by showing macroscopic and microscopic photographs of the lungs and comparing autopsy findings with the clinical history obtained from record review. In the presentations, individual mines and patients were not identified. However, each participating doctor received a file containing laminated photographic illustrations of her/his cases as well as a summary of the findings of the study to date. Seven conferences were held: October 1999 at Leslie Williams Hospital for the West Rand mines November 1999 at Duff Scott Hospital for their doctors, nurses and laboratory staff February 2000 at Afrox Occupational Health for their doctors and nurses March 2000 at St Helena Hospital for the Gold Fields, Duff Scott and Harmony Free State centres health care workers April 2000 at Fochville for the West Rand mines' medical station staffs' annual meeting. May 2000 at Rustenburg for the platinum mines health care workers May 2000 at Secunda for the coal mines health care workers. Invited speakers: Dr Mark Hopley from Chris Hani - Baragwanath Hospital: an approach to the management of sputum-smear negative patients with respiratory disease. Dr Lucille Blumberg from the South African Institute for Medical Research: laboratory aspects of TB management. Dr La Grange from the Chamber of Mines: the problems of TB in the mining industry. Dr Mary Ross from SIMPROSS: an overview of SIMRAC research. The meetings were attended by about 250 people. Medical doctors (these included surgeons and radiologists), laboratory staff, clerks, nurses from the primary clinics as well as hospital wards, radiographers and students attended. Positive and enthusiastic feedback was received including comments like: "It is the first time we have ever had a participatory report back from a SIMRAC project". 58 7.2 Hand-out for medical staff A hand out which will include a summary of the study findings, selected references, and illustrative cases for distribution to health care workers will be compiled. This will be submitted to SIMRAC. It is anticipated that this will provide data to assist clinicians with the process of performance review of individual cases in the future. 7.3 Chamber of Mines The findings have been reported to the TB Committee tasked with development of a new policy document for the industry. 7.4 Performance review on individual cases The process of feedback on individual cases which was initiated during the study will become part of the routine autopsy service. With few exceptions, doctors indicated that they found this useful and have used the opportunity to initiate the process of performance review. Deciding when current diagnostic and management strategies are no longer good enough and need to be changed is a key issue. Self-assessment of one's own performance has been shown to be one of the most effective and efficient ways of achieving this (Sackett, 1991). A crucial step in initiating performance review is feedback to clinicians on what they are actually doing, compared with a confirmatory gold standard. Autopsy findings are such a `gold standard'. Performance review is time consuming, and the process should concentrate on crucial items in the history, physical examination and tests ordered which are key determinants of outcome. In setting up performance review one will also have to begin by improving the documentation in clinical records and consider the introduction of standard protocols. The findings of this study suggest that elements the review should cover include previous visits to the medical facilities, radiographs, with particular emphasis on miliary TB, and sputum for TB culture. This will form part of the hand out (see above). It is also important to be aware that `bad' outcomes may be the result of factors beyond the clinician's control (such as financial constraints) so that spurious conclusions about clinical performance are not drawn. Performance review is a lot of work - there is evidence it does actually improve subsequent performance (Sackett, 1991) - but, for the process to be successful, it requires time and it is too early to determine the success of this SIMRAC project with regard to TB management in the mining industry. 59 8. EVALUATION OF THE STUDY To evaluate the study, a questionnaire (Appendix 2) together with a personal letter (Appendix 3) was sent to selected mine health care workers. The selection of respondents was based on attendance at the clinico-pathological conferences, personal involvement in TB programs, and mine commodity. Fifteen questionnaires were sent and 12 replies were received from gold, platinum and coal mining groups. Most knew of health related SIMRAC projects and would like to receive these reports. All felt that this study was interesting and useful and would participate in future research projects initiated by SIMRAC. 8.1 Surveillance Several medical officers thought that the frequency of radiographic surveillance should be increased, particularly in the high risk groups of HIV infected persons and those with previous TB. Low dose digital radiographs were mentioned. All believed that nurses involved in primary health care should play an active role in the early detection of TB and should be encouraged to obtain sputa for TB bacilli examination. However, there was no consensus whether nurses should order chest radiographs or sent sputa for TB cultures. All but one thought that a formal training program for nurses should be introduced. 8.2 Diagnosis All mines have a formal TB control program based on the national guidelines, and one mentioned that the proposed Chamber of Mines guidelines would be adopted. The need for formal training in the interpretation of chest radiographs was felt and copies of the ILO radiographs on occupational chest disease were requested by most respondents. SIMHEALTH has responded by commissioning a project to research, develop and evaluate a training package for chest radiograph interpretation. The poor sensitivity of sputum smears for TB was recognised and most centres stated that cultures were routinely performed for all patients admitted for TB investigation. Financial constraints and laboratory overload were the reasons why others do cultures only on selected patients. Patients retired on grounds of ill-health were all required to undergo chest radiographs and to have a clinical examination. Difficulties were encountered in doing further investigations as most patients wanted to leave the mine as soon as possible. Treatment for suspected TB was often started prior to discharge. 8.3 Treatment Patients who failed to improve on TB treatment were all reinvestigated and cultures routinely performed. All believed that MDR cases should be treated at a dedicated centre. 8.4 Autopsy All but one would like to receive autopsy reports on their cases together with regular summaries of industry data. 60 9. RECOMMENDATIONS 9.1 Introduction The optimum management of TB on the mines requires measures that are additional to the national guidelines. The following recommendations are intended to supplement, not replace, the national guidelines. While some of the recommendations have financial implications, these additional costs are justifiable in the mining industry in the interests of public health and also because PTB is a scheduled occupational disease. The Chamber of Mines initiative to recommend practice standards for the management of PTB on mines, which incorporates many findings of this study, is strongly supported. 9.2 Active & passive case finding Cases with advanced TB had surveillance chest radiographs interpreted as normal performed during the year preceding death. Groups at high risk for TB, such as those with previous TB, HIV infection and high silica dust exposure should be identified and examined at more frequent intervals. The results from two current SIMRAC projects which are evaluating methods to improve surveillance for TB are awaited. Many patients with either undiagnosed TB or delayed diagnosis of TB had recently attended mine primary clinics and hospitals. The role of nurses in the primary health care setting should be strengthened and in many centres nurses should be enabled to request investigations for TB, including sputum smear examinations. Formal training programs in TB control are recommended for nurses. For patients admitted to hospital with respiratory signs and symptoms, TB should be actively excluded (see below) in all, even if they show some response to treatment for bacterial pneumonia. 9.3 Sputum smear examination for TB bacilli The poor sensitivity of sputum smear examination for TB bacilli is well known and even multiple tests will only result in positive results in around 60% of cases. Laboratories should be formally accredited, report on sputum quality and volume, and have a quality control program in place. 9.4 Sputum cultures for TB bacilli Sputum cultures for TB are the gold standard for the laboratory diagnosis of TB and should be routinely performed on all cases admitted for investigation of respiratory disease. 9.5 Additional diagnostic tests Expensive tests for the diagnosis of TB such as PCR are not recommended. Other tests such as fine needle aspiration of lymph nodes and culture of pleural fluid and blood in Bactec (Myco-F) media are recommended in sputum-smear negative patients suspect for TB. 61 9.6 Chest radiographs Chest radiographs should be routinely performed on all patients admitted to hospital, especially to the medical wards. Difficulties in interpretation of x-rays were common, and a training course on the interpretation of chest radiographs which was requested by many medical officers is recommended. 9.7 Miliary TB Many cases died from miliary TB and most were undiagnosed in life. Chest radiographs read as `clear' should be carefully scrutinised. The difficulties in making this diagnosis are acknowledged. Specimens from extra-pulmonary organs such as lymph nodes are often helpful in making the diagnosis of TB. Empirical treatment (whilst awaiting culture results) is advised when the diagnosis is suspected. 9.8 Drug Resistance The prevalence of drug resistance is unknown in several centres, and failures on prolonged treatment for TB suggest that this may be a problem. All re-treatment cases and treatment failures must have drug susceptibility tests performed, as in the national guidelines. Regional specialized centres should be established (for industry cases) for those cases with multi-drug resistant TB. 9.9 Management while on TB treatment Patients who have been on TB treatment for longer than 30 days, and in whom drug resistance has been excluded, seldom die of TB. Many treatable conditions such as bacterial and Pneumocystis carinii pneumonia contributed to the mortality in this study. The DOTS program provides the treatment supervisor an ideal opportunity to monitor the general well-being of the patient, and guidelines on when to re-investigate patients who deteriorate while on treatment for TB should be made. In addition to the presence of TB bacilli in sputum smears, patients with clinical features such as failure to gain weight and pyrexia should be actively investigated to exclude drug resistance as well as the development of other diseases. 9.10 Advanced AIDS and medical incapacity Patients who leave mine employment due to ill-health should be actively investigated for TB before termination. Cases of advanced AIDS require special attention as they are particularly susceptible to TB. Ideally, the intensive phase of treatment for TB should be given on the mine before discharge. A system to ensure continuation of care should be established, perhaps through the TEBA regional offices. 9.11 Recurrent TB Cure following treatment of the first episode of TB should be established by sputum culture as several cases of `recurrent' TB were identified within months of treatment completion. 62 9.12 Performance review The unique South African law (ODMWA) allows clinicians access to autopsy results on all their cases and a mechanism is now in place to ensure this will occur, if requested by the doctor. Only clinicians can institute change in their programs but performance review using autopsies as the gold standard will enable them to measure both positive and negative outcomes in their institution and to measure their performance against industry norms. This study has established a baseline against which performance improvement can be evaluated. 63 APPENDIX 1 CLINICAL AND AUTOPSY DATA CAPTURE SHEET HOSPITAL ADMISSION MEDICAL STATION TB DATA LABORATORY DATA XRAY: MX LP P NO STUDY NO BUREAU NO 1. DEMOGRAPHIC DATA SURNAME FIRST NAMES COMPANY NO INDUSTRY NO ID NO MINE HOSPITAL HOSP NO AGE YEARS SERVICE DEATH DATE DEATH PLACE in hospital casualty bid other 64 2. PATHAUT DATA CATEGORY: Cl+Path+ Cl-Path+ Cl+Path- Clinical Data: Cause Of Death: Clin Other Pathology Data: TB: Yes No AFB: Pos Neg Path Other Severity: Focal Moderate Marked X-rays Submitted With Organs Yes No 65 3 HOSPITAL RECORDS ADMITTED Yes No HOSPITAL WARD TB Medical Surg Trauma ADMISSION DATE DEATH DATE DURATION OF HOSP STAY CLIN CAUSE OF DEATH: CHEST DISEASE Main finding Mild Moderate Secondary finding Marked Admission Xray: Yes No Xray Reading Yes No Absent Q Chest Diagnosis: 66 Chest Lab Investigations TB: Smear: Yes No No. Of times Culture: Yes No No. Of times Results: Pos Neg N.A. Results: Pos Neg N.A. Drug Resistance: Yes No Sensitive MDR Other chest lab investigations: Treatment in hospital TB Continues with previous treatment Starts in hospital Date TB rx started No of days rx < 30 days > 30 days Other chest related rx OTHER IMPORTANT CLINICAL FINDINGS HIV Pos Neg Unk CD4 count Date Date 67 4. TB HISTORY Previous TB Yes No Date rx stopped If on Treatment on Admission: How was TB diagnosed: Empiric Smear Culture Drug Resistance: Not done Done Sensitive MDR 68 5. SURVEILLANCE MX Date < 1 year of death Reading > 1 year death 69 6. MEDICAL STATION VISITS IN YEAR PRECEDING DEATH Dates: Reason 1. 2 3 4. 5. 6. 7. 8. 9. 10. 11. 12. no of visits _ Tb investigated No Yes smear results cultures results No chest related visits If yes: Date 70 7. CASE SUMMARY 1 TB RX duration TB Extensive Focal CATEGORY 1 CLIN+PATH+: rx < 30 days: extensive ie late presentation rx> 30 days : drug resist / poor compliance CATEGORY 2 CLIN- PATH +: Rx usually < 30 days / fulminant course: Sputum sent for TB yes / no Sputum not sent died too soon / comatose // x-rays: Not done / not read as TB TB not considered CATEGORY 3 CL+ PM-: >30 DAYS: TB confirmed microbiologically (smear/culture) & patient recovered // TB not confirmed (query wrong clinical diagnosis) <30 DAYS: Incorrect clinical diagnosis: 1. Failure to present early e.g. Coughing is not considered to be a disease symptom 2. Primary health care workers do not investigate patients with early symptoms 3. Surveillance program failed MMX's not taken / Not read correctly/ Not acted on 4. Admitted to hospital with extensive, fulminant disease and dies even though on TB treatment 5. Admitted to hospital with extensive, fulminant disease and dies before can be adequately investigated (Inadequate diagnostic procedures) 6. Clinical error in judgement e.g. Acute infections such as pneumonia or meningitis dominate the clinical features also e.g. Inadequate diagnostic procedures e.g. non-TB disease dominates e.g. diabetes, cardiac failure 7. MDR organisms; not detected as no culture and sensitivity tests are performed 8. Autopsy lesions focal and diagnostic procedure may have failed to detect them 9. Subclinical course of disease with few clinical symptoms 71 APPENDIX 2 EVALUATION QUESTIONNAIRE Monday, November 06, 2000 14h30 Date: Mine/hospital: STATUS OF RESPONDENT/S * Are you involved in the design, implementation and/or evaluation of the TB program in your hospital. * Did you attend a clinico-pathological seminar on the correlation between ante and post mortem diagnosis of TB * Did you read the hand-out * Please supply your position in the hospital EARLY RECOGNITION OF DISEASE Surveillance * Most surveillance x-rays were normal - even in patients with advanced disease on * presentation- would you alter your surveillance programme in any way Medical Station Prior to hospital admission many patients had visited mine clinics on several occasions where they were seen by nurses for example for diabetes management, surgical dressings. * Is there a role for primary health care nurses in the early detection of TB What decision making is the nurse currently allowed, and would you like her to be able to do the following on men she suspect of having PTB: * Bring to attention of doctor * Send for sputum smear / culture * Order chest x-ray * Education of the health care worker in TB - is there any formal programme / do you think such a programme would be useful DIAGNOSIS Protocol Most centres we visited did not have a TB protocol, particularly so for the investigation of suspected cases. * Do you have a formal written protocol / informal protocol / follow National guidelines Radiology * Most but not all centres had as standard practice to take a chest x-ray on admission to medical wards - what is / was your practice (eg also before general anaesthetic) * Many x-rays were incorrectly interpreted as being normal eg with miliary TB at autopsy. Do the medical officers have any formal training in x-ray reading? Do you have access to a radiologist? * Previous x-rays for comparison: are they readily available? Are they routinely examined * At one centre the ILO x-rays were prominently and permanently displayed. Would this assist you and other responsible for reading and interpreting x-rays? Do you have the ILO x-rays - do you use them - would it be helpful to have them * Would you like x-ray training - in what form Sputum Many centres relied on sputum smear for the diagnosis of TB and did not do cultures: * Did the finding that sputa smear tests alone are such poor tests/lack sensitivity for the diagnosis of TB surprise you * Has your laboratory been instructed to report on the quality of the sputum specimen (5mls early morning significantly increases the yield) 72 * If you did not routinely do cultures previously for diagnosis of TB are you now doing cultures (if not why not eg costs) * Will you continue to put sputum smear negative patients onto treatment without sending a culture. * Do you regularly follow the SANTBP guidelines for sputum culture ie cases with recurrent TB and treatment failure * Will you continue to use other more expensive diagnostic tests such as PCR / TB antibodies * If patients are put onto treatment for empiric TB - are any special steps taken - do you keep them under the personal care of the medical officer, are they managed in the general TB programme * Many patients in the study had been previously admitted with pneumonia - if the x-ray does not resolve (by 6 weeks) what steps do you take * Will the finding that the TB yield of pleural fluid, gland aspirate and blood be significantly improved when material is directly inoculated into bactec/myco-f bottles at the bedside change your practice * Many patients with pulmonary disease admitted to hospital for other reasons were not investigated - how can this be rectified ADVANCED AIDS * Many patients with advanced aids had undiagnosed TB (and are a danger to others) - should a programme be instituted to ensure that TB is investigated in these patients prior to medical discharge: actively exclude TB on smear / culture; is the exit sufficient and do you have time to read it ON TREATMENT The study found that many patients who had been on treatment for >30 days had undiagnosed / uninvestigated bacterial pneumonia and / or PCP.* * How will this assist you in managing TB cases who deteriorate while on treatment for TB. * What observations should the nurse administering Dots make and when should the patient be referred to the doctor for investigation e.g. loss of weight, pyrexia, haemoptysis ? * An isolated case of non-compliance while on Dots was noted: how can Dots be improved and do you think that compliance testing should be part of your programme? If so urine colour only / drug tests. MULTI-DRUG RESISTANCE * Many cases that died of TB having been treated for longer than 30 days had MDR - in the others drug testing had not been done - will this encourage you to perform cultures more frequently: as per national guidelines; on all patients, recurrences only, treatment failures. * Should MDR TB be treated at a dedicated centre BARRIERS TO IMPROVED CLINICAL PRACTICE IN MANAGING TB What barriers exist in your practice which detract from performance * Financial : laboratory costs / staff (e.g. 1 day in hospital vs cost of culture) * Motivation: fatigue and burnout * Knowledge: NB access to `experts' e.g. laboratory person such as Lucille Blumberg, Prof. Solomon for x-rays * Experience: high staff turnover (doctors and other health care workers) 73 AUTOPSIES * The study found that around 50% of cases of TB were undiagnosed - did this surprise you, did you think that this applied to your centre * Did the autopsy details of miners' influence you in reassessing your TB programme and assist in performance review? * What use did you make of the photo hand outs - e.g. general education / bed letter review Would you like to: * be supplied with autopsy reports concerning all TB cases - with/without photos * receive autopsy results on interesting or unusual cases only * receive autopsy data on a named patient basis, requested by you What use will you make of this - be specific * receive regular summaries of industry data e.g. autopsy prevalence of TB, concordance between clinical and pathologic diagnosis How can we improve the number of autopsies on * miners in service * ex-miners COMMENTS ON STUDY / SIMRAC * How can we disseminate the findings of the study to doctors who mainly treat white miners and ex-miners and mine doctors in isolated regions? * Would you agree to participate in future SIMRAC projects * What comments, criticisms or suggestions/ recommendations (where to from here) would you like us to report on in the final SIMRAC report * Are you aware of other SIMHEALTH projects - name them * Get some feedback on Lucille / Mark * Has the study motivated you to improve the management of TB: * Did you fine the study: * Not interesting and not useful * Interesting but of little practical use * Interesting and useful 74 APPENDIX 3 - LETTER SENT TO DOCTORS FOR AUTOPSY REPORTS NATIONAL CENTRE FOR OCCUPATIONAL HEALTH Tel: 011 720 5734 Fax: 011 720 6103 Email: murraj@health.gov.za To: Dr....... Title..... Hospital Tel....... Fax...... Email ... Date: CONFIDENTIAL You may be interested in the findings of the autopsy on the below mentioned deceased worker. Name: Mine: Co No: MBOD No: Date of death: Industry No: Pathology No: Organs received: Clinical history received: The autopsy of the cardio-respiratory organs showed: If you would like further details please contact me. Please remember that the findings in no way mean that compensation is guaranteed Yours sincerely Dr J Murray Senior Pathologist signed on computer 75