Performance-related allowances within the Malawi National Tuberculosis Control Programme.

SETTING: National Tuberculosis (TB) Control Programme (NTP), Malawi. OBJECTIVES: To determine the feasibility and effectiveness of performance-related allowances for NTP personnel working at central and regional levels in Malawi. In particular, to determine 1) whether programme staff can complete 6-monthly self-assessment forms related to the tasks they are expected to perform during that period, and 2) whether the NTP can achieve four key programme targets related to case finding, treatment outcome and the sending of sputum specimens for drug resistance monitoring. DESIGN: A descriptive study. RESULTS: For January to June 2003, 25 personnel completed self-assessment forms, and in all cases individual performance was judged satisfactory. For July to December 2003, 21 personnel completed self-assessment forms, and in 20 cases individual performance was judged satisfactory. In the first quarter of 2003, only one target was achieved for the country, and NTP personnel were awarded one quarter of the performance payment. In the third quarter, two targets were achieved and NTP personnel were awarded one half of the performance payment. CONCLUSION: It is feasible to implement performance-related payments for NTP personnel. Ways to routinely introduce such a system for NTP and other staff in the health sector urgently need to be explored.

Infection and morbidity in patients with tuberculosis in Nairobi, Kenya.

OBJECTIVE: To examine the role of acute infection as a cause of morbidity in patients with tuberculosis. DESIGN: Cross-sectional documentation of predefined acute morbid events. SETTING: Infectious Diseases Hospital, Nairobi, Kenya. PATIENTS: Adults (> or = 15 years), inpatients and outpatients with a diagnosis of tuberculosis presenting with one or more of a series of clinical features. A new event was defined as one occurring at least 1 week after the initial event. INTERVENTIONS: Patients' treatment was modified depending on the results of laboratory investigations. MAIN OUTCOME MEASURES: There were 642 events from 398 patients, 235 HIV-positive patients had 438 events and 163 HIV-negative patients had 204 events (P < 0.0001). Forty-two out of the 235 (18%) HIV-positive patients were bacteraemic compared with nine out of the 163 (6%) HIV-negative patients (P = 0.0003). The most common isolates from blood were Salmonella typhimurium and Streptococcus pneumoniae. RESULTS: Faecal specimens were obtained more commonly from HIV-positive patients (P < 0.001), and often contained bacterial pathogens. CONCLUSIONS: Many of the causes of morbidity in patients with tuberculosis and HIV are not due to tuberculosis or antituberculous therapy, and will not be identified without microbiological investigation.

PIP: Tuberculosis (TB) is a common complication of HIV in Africa. A 1988-89 study further confirmed that considerable morbidity and mortality from acute bacterial infection occurred in HIV patients. It has also been found that anti-TB therapy seems to be as effective in HIV-positive as in HIV-negative TB patients. This paper reports on the level and nature of infectious morbidity suffered by HIV-positive patients receiving treatment for TB. The assessment is based upon a sample of inpatients and outpatients at the Infectious Diseases Hospital in Nairobi. Patients were aged 15 years and older, with a TB diagnosis presenting with 1 or more of a series of clinical features. 642 morbid events were seen in 398 patients: 235 HIV-positive patients had 438 event and 163 HIV-negative patients had 204 events. 18% of the HIV-positive patients versus 6% of the HIV-negative patients were bacteremic. Salmonella typhimurium and Streptococcus pneumoniae were most commonly isolated from sera, while fecal specimens were obtained more commonly from HIV-positive patients and often contained bacterial pathogens. The authors conclude that many causes of morbidity in patients with TB and HIV are not due to TB or anti-TB therapy and will not be identified without microbiological investigation. These results suggest that even with effective anti-TB chemotherapy HIV-positive patients will remain or become unwell.

The impact of HIV on infectiousness of pulmonary tuberculosis: a community study in Zambia.

OBJECTIVE: To examine the impact of HIV on infectiousness of pulmonary tuberculosis (TB). DESIGN: A cross-sectional tuberculin survey carried out among household contacts of HIV-1-positive and negative patients with bacteriologically confirmed pulmonary TB. Contacts were also examined for active TB. SETTING: Index cases were recruited from patients attending the University Teaching Hospital in Lusaka, Zambia and household contacts were examined during visits to their homes within Lusaka. PATIENTS, PARTICIPANTS: A total of 207 contacts of 43 HIV-positive patients, and 141 contacts of 28 HIV-negative patients with pulmonary TB were examined. MAIN OUTCOME MEASURES: Proportion of contacts of HIV-positive and negative index cases with a positive tuberculin response (diameter of induration > or = 5 mm to a dose of 2 tuberculin units). RESULTS: Fifty-two per cent of contacts of HIV-positive pulmonary TB patients had a positive tuberculin response compared with 71% of contacts of HIV-negative patients (odds ratio, 0.43; 95% CI, 0.26-0.72; P < 0.001). This difference persisted after allowing for between-household variations in the tuberculin response. Tuberculin response in the contact was related to age of contact, intimacy with the index case and crowding in the household. However, the effect of HIV status of the index case was not confounded by these variables. Tuberculin response in the contact was also related to the number of bacilli seen in the sputum smear of the index case which partially explained the effect of HIV status of the index case. Active TB was diagnosed in 4% of contacts of HIV-positive and 3% of contacts of HIV-negative cases, respectively (P = 0.8). CONCLUSIONS: HIV-positive patients with pulmonary TB may be less infectious than their HIV-negative counterparts and this may partly be explained by lower bacillary load in the sputum.

PIP: Between April and December 1989, the chest clinic of the University Teaching Hospital in Lusaka, Zambia, confirmed pulmonary tuberculosis (TB) in 141 adults, 95 (67%) of whom were HIV-1 seropositive. Health workers made home visits to 71 of the index cases (43 HIV-1 positive and 28 HIV-1 negative) to learn whether the 348 household members would also develop TB, thus allowing researchers to determine the effect of HIV on infectiousness of TB. Contacts of HIV-1 positive patients developed TB at a lower rate than did those of HIV-1 negative patients (52% vs. 71%; odds ratio [OR] = 0.43; p .001). This difference continued even after controlling for between-household variations, indicating that confounding variables did not account for the difference. Age of contact, intimacy with the index case, and crowding in the household were associated with the tuberculin response in the contact, but they did not confound the effect of HIV status. Tuberculin response in the contact was associated with the number of bacilli in the sputum smear (crude OR = 3.13; p = .013, and adjusted OR =1.84; p = .28), suggesting that the number of bacilli somewhat explained the difference in infectiousness between HIV-1 positive and HIV-1 negative patients. 12 contacts (8 of HIV-positive cases and 4 of HIV-negative cases) developed active TB after the TB diagnosis in the index case. These findings clearly demonstrated that infection with Mycobacterium tuberculosis was less likely in household members of HIV-1 positive cases than in those of HIV-1 negative cases. The lower bacillary load in the sputum in HIV- 1 cases may have accounted somewhat for the lower infectiousness of pulmonary TB.

Isoniazid preventive therapy for tuberculosis in HIV-1-infected adults: results of a randomized controlled trial.

OBJECTIVES: To determine the efficacy of isoniazid 300 mg daily for 6 months in the prevention of tuberculosis in HIV-1-infected adults and to determine whether tuberculosis preventive therapy prolongs survival in HIV-1-infected adults. DESIGN AND SETTING: Randomized, double-blind, placebo-controlled trial in Nairobi, Kenya. SUBJECTS: Six hundred and eighty-four HIV-1-infected adults. MAIN OUTCOME MEASURES: Development of tuberculosis and death. RESULTS: Three hundred and forty-two subjects received isoniazid and 342 received placebo. The median CD4 lymphocyte counts at enrolment were 322 and 346 x 10(6)/l in the isoniazid and placebo groups, respectively. The overall median follow-up from enrolment was 1.83 years (range, 0-3.4 years). The incidence of tuberculosis in the isoniazid group was 4.29 per 100 person-years (PY) of observation [95% confidence interval (CI) 2.78-6.33] and 3.86 per 100 PY of observation (95% CI, 2.45-5.79) in the placebo group, giving an adjusted rate ratio for isoniazid versus placebo of 0.92 (95% CI, 0.49-1.71). The adjusted rate ratio for tuberculosis for isoniazid versus placebo for tuberculin skin test (TST)-positive subjects was 0.60 (95% CI, 0.23-1.60) and for the TST-negative subjects, 1.23 (95% CI, 0.55-2.76). The overall adjusted mortality rate ratio for isoniazid versus placebo was 1.18 (95% CI, 0.79-1.75). Stratifying by TST reactivity gave an adjusted mortality rate ratio in those who were TST-positive of 0.33 (95% CI, 0.09-1.23) and for TST-negative subjects, 1.39 (95% CI, 0.90-2.12). CONCLUSIONS: Overall there was no statistically significant protective effect of daily isoniazid for 6 months in the prevention of tuberculosis. In the TST-positive subjects, where reactivation is likely to be the more important pathogenetic mechanism, there was some protection and some reduction in mortality, although this was not statistically significant. The small number of individuals in this subgroup made the power to detect a statistically significant difference in this subgroup low. Other influences that may have diluted the efficacy of isoniazid include a high rate of transmission of new infection and rapid progression to disease or insufficient duration of isoniazid in subjects with relatively advanced immunosuppression. The rate of drug resistance observed in subjects who received isoniazid and subsequently developed tuberculosis was low.

Resistance to trimethoprim-sulfamethoxazole in the treatment of Pneumocystis carinii pneumonia. Implication of folinic acid.

Pneumocystis carinii pneumonia is a well-known complication of immunosuppression in renal transplant recipients. Treatment is generally with trimethoprim-sulfamethoxazole (TMP-SMZ). A case of Pneumocystis pneumonia failed to respond to TMP-SMZ until concomitant administration of folinic acid was stopped. Physicians should be alerted to the possibility that folinic acid may impair the efficacy of TMP-SMZ in Pneumocystis carinii infection.

Long-term outcome in patients registered with tuberculosis in Zomba, Malawi: mortality at 7 years according to initial HIV status and type of TB.

SETTING: Zomba Central Hospital, Malawi. OBJECTIVES: To determine the outcome of all adult patients who were registered for tuberculosis (TB) treatment 7 years previously according to initial human immunodeficiency virus (HIV) status and type of TB. DESIGN: A retrospective cohort study of adult patients registered for TB treatment between July and December 1995. Follow-up at patients' homes was performed at the end of treatment, at 32 months and at 84 months (7 years) from the time of TB registration. FINDINGS: Eight hundred and twenty-seven TB patients were registered: 793 had concordant HIV test results, of whom 612 (77%) were HIV-positive. At 7 years, 136 (17%) patients were alive, 539 (65%) had died and 152 (18%) were lost to follow-up. The death rate for all TB patients was 23.7 per 100 person-years of observation. HIV-positive patients had higher death rates than HIV-negative patients (hazard ratio [HR] 2.2, 95% confidence interval [95%CI] 1.7-2.8). Death rates in smear-negative pulmonary TB patients (HR 2.1, 95%CI 1.7-2.6) and in patients with extra-pulmonary TB (HR 1.7, 95% CI 1.3-2.0) were higher than in patients with smear-positive PTB. CONCLUSIONS: There was a high mortality rate in TB patients during and after anti-tuberculosis treatment. Adjunctive treatments to reduce death rates are urgently needed.

Costs and benefits of improving tuberculosis control: the case of Thailand.

The study evaluates the economic costs and benefits of improving tuberculosis control interventions in Thailand. Provider costs are determined on the basis of marginal treatment costs for varying case numbers and estimates of the cost of required infrastructure changes. Indirect costs are calculated as income lost due to morbidity and premature mortality. An epidemiological model is used to calculate case numbers and mortality under current control conditions and a scenario of improved control. An improved control strategy initially leads to a higher number of detected cases. For longer projection periods, the epidemiological impact of curing a higher proportion of infectious sources results in lower case numbers than those expected without programme improvement. Model simulations show a reduction of total annual case numbers through improved control measures by an average 45% after a simulation period of 20 years. The corresponding societal savings in form of reduced indirect costs from the disease are U.S.$2.4 billion. Reductions in direct provider costs can be expected as a result of decreased numbers of detected cases for longer evaluation periods, as well as a lower proportion of multi-drug-resistant cases. The mean value of predicted savings is U.S.$8.3 million. Since this value is likely to be higher than the required investment in improved infrastructure, net savings can be expected. The result of an uncertainty analysis shows a wide range of potential additional costs or net savings with respect to direct provider costs. Indirect cost calculations show net savings for all parameter values.

Mycobacterial infections and AIDS.

PIP: In the West, 1 of the most common opportunistic bacterial infections in AIDS patients is Mycobacterium avium-intracellulare (MAI). Physicians have diagnosed it in 15-20% of AIDS patients before they died, and it was identified in 50% of dead AIDS patients. Only 2 cases have been diagnosed in Africa. Before AIDS began afflicting the human population, dissemination of MAI was rare, but in AIDS patients the degree of dissemination is widespread and has been found, at least, in the spleen, lymph nodes, lung, liver, and gastrointestinal (GI) tract. The portal of entry in MAI infections has not been clearly identified, but some evidence suggests that in AIDS patients the disseminated infection enters through the GI tract. Response to antibiotic treatment for MAI in AIDS patients is poor. Other nontuberculous mycobacteria, such as M. kansasii and 1 case of M. leprae, have also been found in association with AIDS. In the United States, tuberculosis is often associated with AIDS, especially if the cases are black, of foreign origin (particularly from Haiti), or had a history of intravenous drug abuse. Tuberculosis in AIDS patients is more likely to be lymphatic and disseminated than pulmonary. 1 study revealed that 30% of AIDS cases with tuberculosis had pulmonary tuberculosis compared with 80% of those with only tuberculosis. Further, pericardial disease commonly accompanies tuberculosis in AIDS patients. The treatment for tuberculosis in AIDS patients is standard antituberculous drugs. It appears that, at least in the case of tuberculosis, HIV infection causes reactivation of latent infections 1st acquired in childhood. Further research on the association of mycobacterial infection and AIDS will lead to a greater understanding of the immune defense system in all types of patients.^ieng

Tropical respiratory medicine. 2. Impact of human immunodeficiency virus on tuberculosis in developing countries.

PIP: Mycobacterium tuberculosis is present in approximately 50% of 15-49 year olds in the developing world, while infection in Europe and North America is limited largely to the elderly and some disadvantaged groups. The authors concentrate upon the interaction of HIV infection and tuberculosis (TB) in developing countries with a particular focus upon research data from sub-Saharan Africa. They discuss HIV infection and predisposition for TB, epidemiological determinants of the TB-HIV interaction, HIV-2 and TB, the impact of HIV on TB treatment services, treatment regimes, and prevention. They note that HIV greatly increases a person's risk of contracting TB by reactivation or recent infection or both, and that HIV-associated TB is not more infectious. The efficacy of most diagnostic procedures is compromised by HIV and anti-TB drug resistance is associated with HIV infection in industrialized countries. TB responds well to optimal treatment, but death from other causes during treatment and recurrence of TB are common with the suboptimal regimens applied in most developing countries. Thiacetazone should be removed from treatment regimens because of its high incidence of toxicity. A need also exists to determine the duration of anti-TB treatment needed for HIV-infected patients. More effective drugs are needed, while short-course chemotherapy needs to be made available where it is currently in short supply or unavailable. The authors also recommend adherence to International Union against Tuberculosis and Lung Disease program guidelines.^ieng

Agranulocytosis associated with carbamazepine, and a positive reaction with anti-lymphoid leukaemia antiserum during recovery.

Carbamazepine is a valuable drug in the treatment of trigeminal neuralgia and temporal lobe epilepsy. Rarely agranulocytosis has been described associated with its use but in this further non-fatal case a new finding of a positive reaction with anti-lymphoid leukaemia anti-serum was seen during the recovery phase. A brief review of 18 cases in the literature is provided and it is noted that 94% of reported cases are over the age of 45 years. The significance of the haematological finding is discussed.

Obstructive sodium-losing nephropathy--a case report and review.

The third case in the literature of sodium-losing renal disease due to obstruction is presented. The experimental evidence and limited clinical experience is reviewed which suggests that the sodium loss is due to an inappropriate response in the adaptive processes that are initiated by the loss of functioning nephrons. The immediate treatment is by replacement of sodium but in the long term the condition may be reversed by very cautious reduction in sodium intake. Definitive treatment may be indicated where obstruction is the cause and consequently this should be sought in all cases of salt-losing renal disease.

Quantitative bacillary response to treatment in HIV-associated pulmonary tuberculosis.

A group of 122 patients with culture-proven pulmonary tuberculosis were recruited to examine the concentrations of Mycobacterium tuberculosis in sputum and the relationship to HIV-1 antibody status. They were followed for up to 28 days from the start of antituberculous chemotherapy to assess the early bacillary response to two chemotherapeutic regimens. Of 67 treated with streptomycin, thiacetazone, and isoniazid 17 were HIV positive, and subsequently 55, of whom 20 were HIV positive, were treated with streptomycin, rifampin, isoniazid, and pyrazinamide. The mean initial concentration of M. tuberculosis in the sputum of the HIV-negative patients was significantly higher than in HIV-positive patients (6.95 and 6.34 log colony-forming units respectively; p = 0.019). The HIV-positive patients had less radiologic evidence of disease and significantly fewer zones of lung affected with cavities. The response to treatment was similar, but with HIV-positive patients more likely to become culture negative by 28 days. The differences that exist between HIV-positive and HIV-negative patients are minor, and standard regimens are at least as effective in HIV-positive patients in the first month of treatment.

Effects of almitrine on the regional distribution of ventilation and perfusion in chronic bronchitis.

A double-blind, placebo-controlled, crossover study of the effects on regional lung function of oral almitrine bismesylate at a dose of 3 mg X kg-1, was carried out in six patients with severe chronic airflow obstruction. Oxygen saturation (SaO2) was measured by ear-lobe oximetry and ventilation (VE) by inductance plethysmography. Radionuclide ventilation images of the lungs were obtained using krypton-81m by inhalation and perfusion images using both krypton-81m, by i.v. infusion, and technetium-99m human serum albumin macro-aggregates. The images of ventilation, blood flow and VA/Q ratios were analysed in several ways to see if distributional changes explained the improvement in oxygen saturation. SaO2 improved by 6% and VE was 19% greater after almitrine than after placebo. There was no significant change in the distribution of ventilation, perfusion or VA/Q between any of 10 horizontal slices through the left lung. The average position of ventilation distribution was shifted towards the top of the lung compared to placebo (p less than 0.05). No significant changes in distribution of perfusion were observed. We conclude that almitrine is not associated with any change in the inter-regional distribution of perfusion, but may have a slight effect on the distribution of ventilation.

The impact of human immunodeficiency virus on response to treatment and recurrence rate in patients treated for tuberculosis: two-year follow-up of a cohort in Lusaka, Zambia.

To examine the effect of HIV on response to treatment and recurrence rate in patients with tuberculosis (TB), we have followed 239 previously untreated, adult, TB patients in a prospective cohort study in Lusaka, Zambia. One hundred and seventy-four (73%) were HIV-1 antibody positive. Patients with sputum smear positive, miliary, or meningeal TB were prescribed 2 months daily streptomycin, thiacetazone, isoniazid, rifampicin, pyrazinamide followed by 6 months thiacetazone and isoniazid; others, 2 months streptomycin, thiacetazone and isoniazid followed by 10 months thiacetazone and isoniazid. Thirty-five per cent of HIV-positive (HIV+ve) and 9% of HIV-negative (HIV-ve) patients were known to have died before the scheduled end of treatment. Surviving HIV+ve patients showed weight gain and improvement in symptoms and laboratory and radiological findings similar to HIV-ve patients. The risk of cutaneous drug reaction was 17% (95% CI: 12-25%) in HIV+ve, and 4% (1-13%) in HIV-ve patients. Severe rashes were attributed to thiacetazone. Recurrence of active TB was examined among 64 HIV+ve and 37 HIV-ve patients who successfully completed treatment, with mean follow-up after the end of treatment of 13.5 and 16.8 months, respectively. The rate of recurrence was 22/100 person years (pyr) for HIV+ve patients and 6/100 pyr for HIV-ve patients, giving a recurrence rate ratio of 4.0 (95% CI 1.2-13.8, P = 0.03).

PIP: In 1989, researchers followed 239 newly diagnosed adult patients with tuberculosis (TB), never previously treated for TB, for two years to examine the response to TB treatment among patients with and without HIV infection and the TB recurrence rate. They were patients in the medical wards and the chest clinic outpatients' department of the University Teaching Hospital in Lusaka, Zambia. 174 (73%) tested positive for HIV. HIV-positive patients were more likely than HIV-negative patients to have extrapulmonary and both pulmonary and extrapulmonary TB (35% and 26% for both, respectively vs. 17% and 12%, respectively; p 0.001). They were less likely to have positive sputum tests than HIV-negative patients (36% vs. 57% for smear; p = 0.005 and 39% vs. 55% for culture; p = 0.03). HIV-positive patients were more likely to receive standard TB therapy (62% vs. 37%), while HIV-negative patients were more likely to receive short course therapy (62% vs. 37%; p = 0.001). HIV-positive patients were more likely than HIV-negative patients to die before completion of treatment (35% vs. 9%). Surviving HIV-positive patients gained weight and experienced improvement in symptoms at the same rate as did surviving HIV-negative patients. They also had similar laboratory and radiological findings. HIV-positive patients had a higher risk of cutaneous drug reaction than HIV-negative patients (17% vs. 4%; hazard ratio = 5.1; p = 0.03). One HIV-positive patient with a rash died. Thiacetazone was responsible for the rashes. Among the HIV-positive and HIV-negative patients who successfully completed treatment, the active TB recurrence rate was greatest for HIV-positive patients (22 vs. 6/100 person years; rate ratio = 4; p = 0.03). Yet, all but one of the HIV-positive cases with recurrent TB responded well to TB treatment. High recurrence rates pose renewed potential sources of infection and a high cost of renewed treatment.

The impact of human immunodeficiency virus on presentation and diagnosis of tuberculosis in a cohort study in Zambia.

Two hundred and forty-nine patients with tuberculosis were recruited to a cohort study to investigate the interaction between tuberculosis and HIV in Lusaka, Zambia; findings at presentation are presented here. One hundred and eighty-two (73%; 95% confidence interval 67-79%) of the cases were HIV-1 antibody positive. The diagnosis of tuberculosis was confirmed by microscopy for acid-alcohol fast bacilli, culture of Mycobacterium tuberculosis, or histology in 74% of all cases. HIV negative and positive cases differed in site of disease: among HIV negative patients 72% had pulmonary disease alone, 16% extrapulmonary disease alone and 12% had both, whereas among HIV positive patients 40% had pulmonary disease alone, 34% extrapulmonary disease alone and 26% both (P < 0.001). HIV negative and positive cases were compared with regard to outcome of diagnostic procedures: 55% of HIV negative cases could be diagnosed at enrollment by sputum smear, but only 35% of HIV positive cases (P < 0.01). Among pulmonary cases confirmed by sputum culture, 76% of HIV negative patients had a positive sputum smear, compared with 57% of HIV positive patients (P = 0.09). Pleural and pericardial disease were difficult to confirm, but culture of pleural fluid was positive in 12/46 HIV positive patients, compared with 0/11 HIV negative patients. Lymph node disease was readily confirmed by biopsy. The tuberculin test was positive in only 30/110 (27%) of HIV positive cases, but in 21/38 (55%) of HIV negative cases (P < 0.01). Mycobacterium tuberculosis was cultured in 57% of HIV negative cases and 54% of HIV positive cases; no atypical mycobacteria were isolated. Initial resistance to isoniazid was present in isolates from 5% of cases with a positive culture.