I. Bastian

Recommendations on the management of smear-negative pulmonary tuberculosis (TB) are still based on the behaviour of this disease in populations unaffected by the human immunodeficiency virus (HIV). Studies prior to the HIV epidemic estimated that there were 1.22 cases of smear-negative and extra-pulmonary TB for each smear-positive case. Patients with smear-negative pulmonary TB were found to be less infectious and to have a lower mortality, but a significant proportion (50%-71%) progressed to active disease justifying treatment. Moreover, a wide variety of regimens also proved effective in the treatment of smear-negative disease in HIV-negative patients. The advent of HIV has changed many of these parameters. Countries affected by both HIV and TB have experienced a disproportionate increase in smear-negative disease. While apparently remaining less infectious than smear-positive cases, HIV-positive patients with smear-negative pulmonary TB are generally more immunocompromised, have more adverse drug reactions, and suffer higher mortality rates on treatment. Clinical decision-making has also been complicated because HIV co-infection broadens the differential diagnoses of smear-negative pulmonary TB to include diseases such as Pneumocystis carinii pneumonia (PCP), pulmonary Kaposi's sarcoma, and Gram-negative bacteraemia. Our approach to smear-negative pulmonary TB must therefore adapt to these changed parameters. Management algorithms based on several features (clinical symptoms, response to antibiotic trials, smear investigations, and chest radiography) have been developed to improve case detection. These algorithms must be validated in each locale because their performance will vary depending on numerous local factors such as the regional prevalence of PCP. Alternative methods of specimen collection, such as sputum induction, and processing must be evaluated. National tuberculosis programmes should also consider extending the use of rifampicin-based short-course chemotherapy (SCC) to new patients with smear-negative disease. This latter intervention, and the much-needed establishment of additional microscopy and culture facilities, will depend on increased financial and technical support from the international community.

The objectives of this study were to investigate the origin of highly discordant rifampin (rifampicin) (RMP) drug susceptibility test results obtained for Mycobacterium tuberculosis strains during proficiency testing. Nine Supra-National Tuberculosis Reference Laboratories tested the RMP susceptibilities of 19 selected M. tuberculosis strains, using standard culture-based methods. The strains were classified as definitely resistant (R) (n = 6) or susceptible (S) (n = 2) or probably resistant (PR) (n = 8) or susceptible (PS) (n = 3) based on rpoB mutations and treatment outcome. All methods yielded a susceptible result for the two S and three PS strains lacking an rpoB mutation and a resistant result for one R strain with a Ser531Leu mutation and one PR strain with a double mutation. Although the remaining 12 R and PR strains had rpoB mutations (four Asp516Tyr, three Leu511Pro, two Leu533Pro, one each His526Leu/Ser, and one Ile572Phe), they were all susceptible by the radiometric Bactec 460TB or Bactec 960 MGIT methods. In contrast, only one was susceptible by the proportion method on Löwenstein-Jensen medium and two on Middlebrook 7H10 agar. Low-level but probably clinically relevant RMP resistance linked to specific rpoB mutations is easily missed by standard growth-based methods, particularly the automated broth-based systems. Further studies are required to confirm these findings, to determine the frequency of these low-level-resistant isolates, and to identify technical improvements that may identify such strains.

The line probe assay (LiPA), a rapid molecular method for detecting rifampicin resistance (RMPr) in Mycobacterium tuberculosis, correctly identified all 145 rifampicin-sensitive (RMPs) and 262 (98.5%) of 266 RMPr strains among 411 isolates collected from diverse countries. If used as a marker of multidrug-resistant tuberculosis (MDR-TB), detection of RMPr by LiPA would have detected 236 of the 240 MDR strains in this study but would have wrongly suggested the presence of MDR in 26 RMP-monoresistant isolates (sensitivity 98.3%, specificity 84.8%). Hence, the reliability of using LiPA (or any other rapid RMPr-detection method) as a surrogate marker of MDR-TB largely depends on the prevalence of RMP-monoresistance in the study population. This approach must therefore be validated in each local situation.

SETTING: Individualised regimens based on drug susceptibility test results, generally used to treat multidrug-resistant tuberculosis (MDR-TB), require often unavailable expertise and resources. OBJECTIVE: To evaluate a standardised regimen based on the susceptibility profiles of locally prevalent MDR-TB strains. DESIGN: The activities of a successful DOTS programme in Bangladesh were complemented by offering treatment with a standardised 21-month regimen to patients with laboratory-confirmed MDR-TB disease. The regimen contained kanamycin, ofloxacin, prothionamide, pyrazinamide, ethambutol, isoniazid and clofazimine. Clinical and bacteriological progress was monitored quarterly until treatment completion, then 6 monthly for 2 years. RESULTS: The status at the end of treatment of this cohort of 58 documented MDR-TB patients was as follows: eight (14%) deaths, seven (12%) defaults, three (5%) failures and 40 (69%) cures. One bacteriologically-confirmed relapse was recognised. Frequent and sometimes serious side effects proved to be the main problem, suggesting the need for a better tolerated but equally effective regimen. CONCLUSION: A standardised approach may provide a reasonable alternative to individualised treatment of MDR-TB in resource-poor settings. However, DOTS-plus programmes in resource-poor settings may confront significant difficulties in the enrolment, diagnosis and management of MDR-TB patients.

BACKGROUND: Racial differences occur in the incidence of systemic lupus erythematosus (SLE). It has been suggested that SLE occurs at a higher prevalence and with greater severity in Aboriginal Australians, but because of the small, widely distributed population base, this has not been well documented. AIMS: To confirm and document the clinical impression of an increased prevalence and severity of systemic lupus erythematosus (SLE) in Aboriginal Australians, and to identify prognostic indicators. METHODS: Top End Northern Territory (NT) Aborigines with SLE on 1 January 1984 or diagnosed thereafter were followed until 1 January 1991. Epidemiological, clinical and serological data were collected. RESULTS: Prevalence on 1 January 1991 estimated at 1:1900, at least twice the estimated prevalence in non-Aboriginal Australians. High frequencies of renal disease (62% with proteinuria > 0.5 g/day) and autoantibodies to the Sm antigen (29%) were identified, contributing to the high mortality. Five year survival rate was 60%, with 67% of deaths resulting from infection. CONCLUSIONS: There is a high prevalence of SLE in NT Aborigines. In view of probable under-recognition of mild cases the true prevalence is likely to be even higher. Although morbidity and mortality may have been overestimated for the same reason, both were found to be high. Improved living conditions and health care delivery may improve prognosis.