Philip C. Hopewell

An outbreak of tuberculosis with accelerated progression among persons infected with the human immunodeficiency virus. An analysis using restriction-fragment-length polymorphisms.

BACKGROUND Tuberculosis typically develops from a reactivation of latent infection. Clinical tuberculosis may also arise from a primary infection, and this is thought to be more likely in persons infected with the human immunodeficiency virus (HIV). However, the relative importance of these two pathogenetic mechanisms in this population is unclear. METHODS Between December 1990 and April 1991, tuberculosis was diagnosed in 12 residents of a housing facility for HIV-infected persons. In the preceding six months, two patients being treated for tuberculosis had been admitted to the facility. We investigated this outbreak using standard procedures plus analysis of the cultured organisms with restriction-fragment-length polymorphisms (RFLPs). RESULTS Organisms isolated from all 11 of the culture-positive residents had similar RFLP patterns, whereas the isolates from the 2 patients treated for tuberculosis in the previous six months were different strains. This implicated the first of the 12 patients with tuberculosis as the source of this outbreak. Among the 30 residents exposed to possible infection, active tuberculosis developed in 11 (37 percent), and 4 others (13 percent) had newly positive tuberculin skin tests. Of 28 staff members with possible exposure, at least 6 had positive tuberculin-test reactions, but none had tuberculosis. CONCLUSIONS Newly acquired tuberculous infection in HIV-infected patients can spread readily and progress rapidly to active disease. There should be heightened surveillance for tuberculosis in facilities where HIV-infected persons live, and investigation of contacts must be undertaken promptly and be focused more broadly than is usual.

Pulmonary Complications of the Acquired Immunodeficiency Syndrome: Report of a National Heart, Lung, and Blood Institute Workshop

Under the sponsorship of the Division of Lung Diseases of the National Heart, Lung, and Blood Institute, a two-day workshop on the pulmonary complications of the acquired immunodeficiency syndrome ...

Bacterial Pneumonia in Persons Infected with the Human Immunodeficiency Virus

BACKGROUND Patients with human immunodeficiency virus (HIV) infection are at increased risk for bacterial pneumonia in addition to opportunistic infection. However, the risk factors for bacterial pneumonia and its incidence in this population are not well defined. METHODS In a multicenter, prospective, observational study, we monitored 1130 HIV-positive and 167 HIV-negative participating adults for up to 64 months for pulmonary disease. The HIV-positive group comprised 814 homosexual or bisexual men, 261 injection-drug users, and 55 female partners of HIV-infected men. RESULTS There were 237 episodes of bacterial pneumonia among the HIV-positive participants (rate, 5.5 per 100 person-years), as compared with 6 episodes among the HIV-negative participants (rate, 0.9 per 100 person-years; P < 0.001). The rate of bacterial pneumonia increased with decreasing CD4 lymphocyte counts (2.3, 6.8, and 10.8 episodes per 100 person-years in the strata with more than 500, 200 to 500, and fewer than 200 cells per cubic millimeter, respectively; P < or = 0.022 for each comparison). Injection-drug users had a higher rate of bacterial pneumonia than did homosexual or bisexual men or female partners. In the stratum with the fewest CD4 lymphocytes, cigarette smoking was associated with an increased rate of pneumonia. Mortality was almost four times higher among participants with an episode of pneumonia than among the others. Prophylaxis with trimethoprim-sulfamethoxazole was associated with a 67 percent reduction in confirmed episodes of bacterial pneumonia (P = 0.007). CONCLUSIONS Bacterial pneumonia is more frequent in HIV-positive persons than in seronegative controls, and the risk is highest among those with CD4 lymphocyte counts below 200 per cubic millimeter and among injection-drug users.

Fluorescence versus conventional sputum smear microscopy for tuberculosis: a systematic review

Most of the worlds tuberculosis cases occur in low-income and middle-income countries, where sputum microscopy with a conventional light microscope is the primary method for diagnosing pulmonary tuberculosis. A major shortcoming of conventional microscopy is its relatively low sensitivity compared with culture, especially in patients co-infected with HIV. In high-income countries, fluorescence microscopy rather than conventional microscopy is the standard diagnostic method. Fluorescence microscopy is credited with increased sensitivity and lower work effort, but there is concern that specificity may be lower. We did a systematic review to summarise the accuracy of fluorescence microscopy compared with conventional microscopy. By searching many databases and contacting experts, we identified 45 relevant studies. Sensitivity, specificity, and incremental yield were the outcomes of interest. The results suggest that, overall, fluorescence microscopy is more sensitive than conventional microscopy, and has similar specificity. There is insufficient evidence to determine the value of fluorescence microscopy in HIV-infected individuals. The results of this review provide a point of reference, quantifying the potential benefit of fluorescence microscopy, with which the increased cost and technical complexity of the method can be compared to determine the possible value of the method under programme conditions.

Exogenous Reinfection with Multidrug-Resistant Mycobacterium tuberculosis in Patients with Advanced HIV Infection

BACKGROUND In the United States there have been recent outbreaks of multidrug-resistant tuberculosis. These outbreaks have primarily involved persons infected with the human immunodeficiency virus (HIV). METHODS We collected clinical information on 17 patients seen at a New York City hospital who had repeatedly positive cultures for Mycobacterium tuberculosis. Analysis of restriction-fragment--length polymorphisms (RFLPs) was performed on serial isolates of M. tuberculosis obtained from these patients. RESULTS Six patients had isolates that remained drug-susceptible, and the RFLP patterns of these isolates did not change over time. Eleven patients had isolates that became resistant to antimicrobial agents. The RFLP patterns of the isolates from six of these patients remained essentially unchanged (two strains showed one additional band) despite the development of drug resistance. In five other patients, however, the RFLP patterns of the isolates changed dramatically at the time that drug resistance was detected. The change in the RFLP pattern of the isolate from one patient appeared to be the result of contamination during processing in the laboratory. In the remaining four patients, all of whom had advanced HIV disease, the clinical and microbiologic evidence was consistent with the presence of active tuberculosis caused by a new strain of M. tuberculosis. CONCLUSIONS Resistance to antituberculous drugs can develop not only in the strain that caused the initial disease, but also as a result of reinfection with a new strain of M. tuberculosis that is drug-resistant. Exogenous reinfection with multidrug-resistant M. tuberculosis can occur either during therapy for the original infection or after therapy has been completed.

International Standards for Tuberculosis Care

Part of the reason for failing to bring about a more rapid reduction in tuberculosis incidence worldwide is the lack of effective involvement of all practitioners-public and private-in the provision of high quality tuberculosis care. While health-care providers who are part of national tuberculosis programmes have been trained and are expected to have adopted proper diagnosis, treatment, and public-health practices, the same is not likely to be true for non-programme providers. Studies of the performance of the private sector conducted in several different parts of the world suggest that poor quality care is common. The basic principles of care for people with, or suspected of having, tuberculosis are the same worldwide: a diagnosis should be established promptly; standardised treatment regimens should be used with appropriate treatment support and supervision; response to treatment should be monitored; and essential public-health responsibilities must be carried out. Prompt and accurate diagnosis, and effective treatment are essential for good patient care and tuberculosis control. All providers who undertake evaluation and treatment of patients with tuberculosis must recognise that not only are they delivering care to an individual, but they are also assuming an important public-health function. The International Standards for Tuberculosis Care (ISTC) describe a widely endorsed level of care that all practitioners should seek to achieve in managing individuals who have, or are suspected of having, tuberculosis. The document is intended to engage all care providers in delivering high quality care for patients of all ages, including those with smear-positive, smear-negative, and extra-pulmonary tuberculosis, tuberculosis caused by drug-resistant Mycobacterium tuberculosis complex, and tuberculosis combined with HIV infection.

Treatment of Tuberculosis in Patients with Advanced Human Immunodeficiency Virus Infection

BACKGROUND AND METHODS Infection with the human immunodeficiency virus (HIV) increases the risk of tuberculosis and may interfere with the effectiveness of antituberculosis chemotherapy. To examine the outcomes in patients with both diagnoses, we conducted a retrospective study of all 132 patients listed in both the acquired immunodeficiency syndrome (AIDS) and tuberculosis case registries in San Francisco from 1981 through 1988. RESULTS At the time of the diagnosis of tuberculosis, 78 patients (59 percent) did not yet have a diagnosis of AIDS, 18 patients (14 percent) were given a concomitant diagnosis of AIDS (as determined by the presence of an AIDS-defining disease other than tuberculosis), and the remaining 36 patients (27 percent) already had AIDS. The manifestations of tuberculosis were entirely pulmonary in 50 patients (38 percent), entirely extrapulmonary in 40 patients (30 percent), and both pulmonary and extrapulmonary in 42 patients (32 percent). The treatment regimens were as follows: isoniazid and rifampin supplemented by ethambutol for the first two months, 52 patients; isoniazid and rifampin supplemented by pyrazinamide and ethambutol for the first two months, 39 patients; isoniazid and rifampin, 13 patients; isoniazid and rifampin supplemented by pyrazinamide for the first two months, 4 patients; and other drug regimens, 17 patients. The intended duration of treatment for patients whose regimen included pyrazinamide was six months, and for patients who did not receive pyrazinamide, nine months. Seven patients received no treatment because tuberculosis was first diagnosed after death. Sputum samples became clear of acid-fast organisms after a median of 10 weeks of therapy. Abnormalities on all chest radiographs taken after three months of treatment were stable or improved except for those of patients who had new nontuberculous infections. The only treatment failure occurred in a man infected with multiple drug-resistant organisms who did not comply with therapy. Adverse drug reactions occurred in 23 patients (18 percent). For all 125 treated patients, median survival was 16 months from the diagnosis of tuberculosis. Tuberculosis was a major contributor to death in 5 of the 7 untreated patients and 8 of the 125 treated patients. Three of 58 patients who completed therapy had a relapse (5 percent); compliance was poor in all 3. CONCLUSIONS Tuberculosis causes substantial mortality in patients with advanced HIV infection. In patients who comply with the regimen, conventional therapy results in rapid sterilization of sputum, radiographic improvement, and low rates of relapse.

Sputum processing methods to improve the sensitivity of smear microscopy for tuberculosis: a systematic review

In low-income and middle-income countries, direct (unconcentrated) sputum smear microscopy is the primary method for diagnosing pulmonary tuberculosis. The method is fast, inexpensive, and specific for Mycobacterium tuberculosis in high incidence areas. The main limitations of direct microscopy are its relatively low sensitivity, especially in individuals co-infected with HIV, and variable quality of the test in programme conditions. Thus, there is a need to identify methods to improve the sensitivity of microscopy. Physical and chemical sputum processing methods, including centrifugation, sedimentation, and bleach, have been studied and found to show promise. We did a systematic review to assess the ability of different processing methods to improve the sensitivity of microscopy. By searching many sources, we identified 83 studies. Overall, by comparison with direct smears, the results suggested that centrifugation with any of several chemical methods (including bleach) is more sensitive, that overnight sedimentation preceded by chemical processing is more sensitive, and that specificity is similar. There were insufficient data to determine the value of sputum processing methods in patients with HIV infection. Operational studies are needed to determine whether the increased sensitivity provided by processing methods is sufficient to offset their increased cost, complexity, and potential biohazards, and to examine their feasibility.

Bronchoalveolar Lavage and Transbronchial Biopsy for the Diagnosis of Pulmonary Infections in the Acquired Immunodeficiency Syndrome

The efficacy of bronchoalveolar lavage and transbronchial biopsy in diagnosing lung infection was determined in 276 fiberoptic bronchoscopic examinations done on 171 patients with known or suspected acquired immunodeficiency syndrome. Of 173 pathogens (Pneumocystis carinii, cytomegalovirus, Mycobacterium avium-intracellulare, Cryptococcus neoformans, M. tuberculosis, Coccidioides immitis, and Histoplasma capsulatum) identified during the initial evaluation or in the subsequent month, the initial bronchoscopic examination detected 166 (96%). Bronchoalveolar lavage and transbronchial biopsy had sensitivities of 86% and 87%, respectively. When bronchoscopy included both bronchoalveolar lavage and transbronchial biopsy, the yield for all pathogens was 98% and the sensitivity for P. carinii infections was 100%. Follow-up for at least 3 weeks after examination failed to detect any additional false-negative results. Fiberoptic bronchoscopy is extremely accurate for the detection of pathogens in patients with the acquired immunodeficiency syndrome, especially when bronchoalveolar lavage and transbronchial biopsy are combined. In patients at high risk of complications from transbronchial biopsy, bronchoalveolar lavage is sufficiently accurate to be used alone.

The intrinsic transmission dynamics of tuberculosis epidemics.

In developed countries the major tuberculosis epidemics declined long before the disease became curable in the 1940s. We present a theoretical framework for assessing the intrinsic transmission dynamics of tuberculosis. We demonstrate that it takes one to several hundred years for a tuberculosis epidemic to rise, fall and reach a stable endemic level. Our results suggest that some of the decline of tuberculosis is simply due to the natural behaviour of an epidemic. Although other factors must also have contributed to the decline, these Causal factors were constrained to operate within the slow response time dictated by the intrinsic dynamics.