Surgery as an Adjunctive Treatment for Multidrug-Resistant Tuberculosis: An Individual Patient Data Metaanalysis.

BACKGROUND: Medical treatment for multidrug-resistant (MDR)-tuberculosis is complex, toxic, and associated with poor outcomes. Surgical lung resection may be used as an adjunct to medical therapy, with the intent of reducing bacterial burden and improving cure rates. We conducted an individual patient data metaanalysis to evaluate the effectiveness of surgery as adjunctive therapy for MDR-tuberculosis. METHODS: Individual patient data, was obtained from the authors of 26 cohort studies, identified from 3 systematic reviews of MDR-tuberculosis treatment. Data included the clinical characteristics and medical and surgical therapy of each patient. Primary analyses compared treatment success (cure and completion) to a combined outcome of failure, relapse, or death. The effects of all forms of resection surgery, pneumonectomy, and partial lung resection were evaluated. RESULTS: A total of 4238 patients from 18 surgical studies and 2193 patients from 8 nonsurgical studies were included. Pulmonary resection surgery was performed on 478 patients. Partial lung resection surgery was associated with improved treatment success (adjusted odds ratio [aOR], 3.0; 95% confidence interval [CI], 1.5-5.9; I(2)R, 11.8%), but pneumonectomy was not (aOR, 1.1; 95% CI, .6-2.3; I(2)R, 13.2%). Treatment success was more likely when surgery was performed after culture conversion than before conversion (aOR, 2.6; 95% CI, 0.9-7.1; I(2)R, 0.2%). CONCLUSIONS: Partial lung resection, but not pneumonectomy, was associated with improved treatment success among patients with MDR-tuberculosis. Although improved outcomes may reflect patient selection, partial lung resection surgery after culture conversion may improve treatment outcomes in patients who receive optimal medical therapy.

Drug resistance beyond extensively drug-resistant tuberculosis: individual patient data meta-analysis.

The broadest pattern of tuberculosis (TB) drug resistance for which a consensus definition exists is extensively drug-resistant (XDR)-TB. It is not known if additional drug resistance portends worsened patient outcomes. This study compares treatment outcomes of XDR-TB patients with and without additional resistance in order to explore the need for a new definition. Individual patient data on XDR-TB outcomes were included in a meta-analysis comparing outcomes between XDR alone and three nonmutually exclusive XDR-TB patient groups: XDR plus resistance to all the second-line injectables (sli) and capreomycin and kanamycin/amikacin (XDR+2sli) XDR plus resistance to second-line injectables and to more than one group 4 drug, i.e. ethionamide/protionamide, cycloserine/terizidone or para-aminosalicylic acid (XDR+sliG4) and XDR+sliG4 plus resistance to ethambutol and/or pyrazinamide (XDR+sliG4EZ). Of 405 XDR-TB cases, 301 were XDR alone, 68 XDR+2sli, 48 XDR+sliG4 and 42 XDR+sliG4EZ. In multivariate analysis, the odds of cure were significantly lower in XDR+2sli (adjusted OR 0.4, 95% CI 0.2-0.8) compared to XDR alone, while odds of failure and death were higher in all XDR patients with additional resistance (adjusted OR 2.6-2.8). Patients with additional resistance beyond XDR-TB showed poorer outcomes. Limitations in availability, accuracy and reproducibility of current drug susceptibility testing methods preclude the adoption of a useful definition beyond the one currently used for XDR-TB.

Drug-resistant tuberculosis in Shanghai, China, 2000-2006: prevalence, trends and risk factors.

SETTING: During 2000-2006, a regional anti-tuberculosis drug resistance surveillance study was conducted in Shanghai, China. OBJECTIVE: To determine the prevalence, trends and risk factors for drug-resistant tuberculosis (TB) in Shanghai, China. DESIGN: A retrospective study of all pulmonary TB patients reported in Shanghai during 2000-2006 was conducted. RESULTS: Of 8419 pulmonary TB patients, 16.6% had resistance to any first-line anti-tuberculosis drug and 4.0% had multidrug resistance (MDR). The percentage of TB patients with resistance to any first-line anti-tuberculosis drug and MDR significantly increased during 2000-2003 (P=0.01 and P<0.01, respectively). After improvements in the TB control programme in 2004, the increasing trend in drug resistance was contained. Age 30-59 years, being an urban migrant and residence in an urban area of Shanghai were independently associated with resistance to any first-line drug and MDR in new cases, while age 30-59 years and being an urban migrant were independently associated with resistance to any first-line drug and MDR in previously treated cases. CONCLUSIONS: Drug-resistant TB and MDR-TB pose a challenge for TB control in Shanghai. Improved case management, including DOTS and appropriate treatment regimens, should be sustained to prevent further transmission and development of drug-resistant TB in this setting.

Gender differentials of pulmonary tuberculosis transmission and reactivation in an endemic area.

BACKGROUND: In most low income countries there are twice as many cases of tuberculosis (TB) reported among men than among women, a difference commonly attributed to biological and epidemiological characteristics as well as socioeconomic and cultural barriers in access to health care. The World Health Organization has encouraged gender specific comparisons in TB rates to determine whether women with TB are less likely than men with TB to be diagnosed, reported, and treated. A study was undertaken to identify gender based differences in patients with pulmonary TB and to use this information to improve TB control efforts. METHODS: Individuals with a cough for more than 2 weeks in southern Mexico were screened from March 1995 to April 2003. Clinical and mycobacteriological information (isolation, identification, drug susceptibility testing and IS6110 based genotyping, and spoligotyping) was collected from those with bacteriologically confirmed pulmonary TB. Patients were treated in accordance with official norms and followed to ascertain treatment outcome, retreatment, and vital status. RESULTS: 623 patients with pulmonary TB were enrolled. The male:female incidence rate ratio for overall, reactivated, and recently transmitted disease was 1.58 (95% CI 1.34 to 1.86), 1.64 (95% CI 1.36 to 1.98), and 1.41 (95% CI 1.01 to 1.96), respectively. Men were more likely than women to default from treatment (adjusted OR 3.30, 95% CI 1.46 to 7.43), to be retreated (hazard ratio (HR) 3.15, 95% CI 1.38 to 7.22), and to die from TB (HR 2.23, 95% CI 1.25 to 3.99). CONCLUSIONS: Higher rates of transmitted and reactivated disease and poorer treatment outcomes among men are indicators of gender differentials in the diagnosis and treatment of pulmonary TB, and suggest specific strategies in endemic settings.

The private-public divide: impact of conflicting perceptions between the private and public health care sectors in India.

SETTING: India's private health care sector manages half the nation's tuberculosis (TB) patients, accounting for an estimated sixth of global TB cases. While several studies have demonstrated private physicians' dubious diagnosis and treatment styles and lack of cooperation with public physicians, very little is still known about the private sector. OBJECTIVES: Using a detailed questionnaire to randomly survey private and public practitioners in Ahmedebad, Gujarat, India, we quantified perceptions held by each sector. STUDY DESIGN: Cross-sectional survey of private and public physicians. RESULTS: Significant conflicts in perception were found regarding interpretation of general facts, attitudes towards each sector, and effectiveness and social implications of DOTS. We also found that such differences in perception were likely to result in mistrust, differing views on reform propositions, conflicting mindsets about social agendas, and unwillingness to cooperate. CONCLUSION: Our data suggest that reconciliation is attainable by obtaining and distributing unbiased, evidence-based information and exposing physicians to both private and public health care sectors in a professional setting.

Transmission of Mycobacterium tuberculosis to contacts of HIV-infected tuberculosis patients.

We assessed the infectiousness of human immunodeficiency virus (HIV)-seropositive and HIV-seronegative individuals with pulmonary tuberculosis (TB) in a prospective cohort study. We enrolled, evaluated, and followed 104 close contacts of HIV-seropositive pulmonary TB patients and 256 close contacts of HIV-seronegative pulmonary TB patients using a standardized questionnaire, symptom review, chest radiograph, HIV serology, and tuberculin skin testing (TST). Contacts were followed for > or = 12 mo. TB infection at enrollment was 27% (28/104) among contacts of HIV-seropositive TB patients and 35% (90/256) among contacts of HIV-seronegative TB patients (odds ratio [OR] = 0.68, 95% confidence interval [CI] 0.41 to 1.12; p = 0.130). TST conversion occurred in 21% (42/ 204) of subjects; 8% (5/63) of contacts of HIV-seropositive index cases and 26% (37/141) of contacts of HIV-seronegative index cases (OR = 0.24, 95% CI 0.09 to 0.65; p = 0.003). TB was diagnosed in nine contacts; eight were contacts of HIV-seronegative index cases. HIV seropositivity in the index case was independently associated with a lower risk of TB infection among contacts, even among household contacts younger than 15 yr of age. Contacts of HIV-seropositive persons with pulmonary TB were less likely to have a positive TST response at 1 yr of follow-up than contacts of HIV-seronegative persons.

Survey of mycobacteriology laboratory practices in an urban area with hyperendemic pulmonary tuberculosis.

SETTING: Rio de Janeiro, Brazil, where 10210 cases of tuberculosis (TB) were reported in 1997, 86.2% of them with pulmonary TB. OBJECTIVE: To assess laboratory resources, practices, biosafety measures and training needs relative to the volume of work required for the TB control program and implementation of directly observed therapy, short course (DOTS). DESIGN: A cross-sectional survey of laboratories that receive funds from the public sector and work with mycobacteria, using a structured questionnaire and onsite visits to collect data. The main outcome measure of interest was processing > or = 20 specimens per week. RESULTS: More than half (56.5%) of the laboratories reported performing < 20 specimens per week, a level at which it is difficult to maintain proficiency in mycobacteriologic techniques. The demand for sputum smear microscopy was not met. Working conditions such as shared laboratory and air space, inadequate ventilation, accidents with biological specimens, and inadequate disposal of biological waste present risks of TB transmission to laboratory workers and other staff. CONCLUSION: Training and supervising laboratory workers in good technique and biosafety practices and providing the necessary organization, resources and working conditions will strengthen TB control and facilitate implementation of DOTS. Several simple interventions are proposed.

HIV testing among tuberculosis patients in the era of antiretroviral therapy: a population-based study in Brazil.

SETTING: Rio de Janeiro, Brazil, a city with 29862 cases of tuberculosis (TB) reported between January 1995 and June 1998. OBJECTIVES: To evaluate the counseling and testing practices for human immunodeficiency virus (HIV) infection among TB patients, and to identify the patient characteristics associated with HIV screening as antiretroviral therapy was introduced. DESIGN: Cross-sectional study of patients with TB who were reported to the health department and who initiated anti-TB treatment. The main outcome measure was screened versus not screened for HIV. RESULTS: The proportion of TB patients who received HIV screening increased from January 1995 through June 1998 (P < 0.001). Among young adults aged 20-49 years with TB, the independent predictors of HIV screening were a diagnosis of both pulmonary and extrapulmonary TB (odds ratio [OR] = 2.4, 95% confidence interval [CI] 2.1-2.8); TB meningitis (OR = 13.5, 95%CI 6.5-31.5); disseminated TB (OR = 8.2, 95%CI 5.3-12.9); lymphatic TB (OR = 5.6, 95%CI 4.7-6.6); and male sex (OR = 1.4, 95%CI 1.3-1.6). Patients with newly diagnosed TB who were women, lived in a low income neighborhood (OR = 0.7, 95%CI, 0.6-0.7), and sought TB treatment in their own residential neighborhood (OR = 0.3, 95%CI 0.3-0.4) were less likely to receive HIV counseling and testing. CONCLUSION: Health care providers in Rio de Janeiro selectively offered HIV counseling and testing to persons they perceived to be at risk for HIV and those with advanced stages of TB. HIV counseling and testing should be expanded and offered to all TB patients.

Medical students at risk of nosocomial transmission of Mycobacterium tuberculosis.

SETTING: University and teaching hospital in Rio de Janeiro, Brazil, a city with a high prevalence of tuberculosis (TB). OBJECTIVE: To determine whether medical students are at increased risk of nosocomial transmission of Mycobacterium tuberculosis relative to other university students. DESIGN: A cross-sectional study of medical and chemical engineering students in different levels of their training programmes. Information about socio-demographic characteristics, BCG vaccination history, and potential exposures to TB were obtained using a standardised questionnaire. Tuberculin skin testing (TST) was used to determine the prevalence of infection with TB. RESULTS: Medical students have an increasing prevalence of TST positivity as they advance in their training programme to increasing levels of study (4.6%, 7.8%, 16.2%, respectively, P < 0.001), but chemical engineering students do not (4.2%, 4.3%, 4.4%, respectively, P = 0.913). The risks are greatest during the years of clinical training, when medical students have increased contact with patients. CONCLUSIONS: Medical students in this setting may be at increased risk of M. tuberculosis infection, relative to chemical engineering students. A programme of routine tuberculin skin testing is needed, combined with interventions to reduce the risk of nosocomial transmission in the workplace.

Predictive value of the acid fast smear for detection of Mycobacterium tuberculosis in respiratory specimens in a reference center of HIV/AIDS in Rio de Janeiro, Brazil.

In order to evaluate the predictive value of acid fast bacilii (AFB) smear for the diagnosis of Mycobacterium tuberculosis in respiratory specimens in a setting with a high prevalence of AIDS and an unknown prevalence of nontuberculous mycobacteria (NTM), we retrospectively examined specimens cultured for mycobacteria between 1 September 1993 and 30 September 1994 and medical records of patients with positive culture in a General Hospital, AIDS reference in Rio de Janeiro, Brazil. Seventy three per cent (1517/2077) of samples were respiratory specimens and mycobacteria were recovered from 20.6% (313/1517) of these. M. tuberculosis was identified in 94.2% (295/313) and NTM in 5.8% (18/313). The yield of positive AFB smear and of positive culture was 6.1% (93/1517) and 20.6% (313/1517), respectively. The positive predictive value (PPV) of AFB for M. tuberculosis was 98.4% in expectorated sputum and 96.4% in bronchoalveolar lavage. Forty four percent (130/295) of specimens with positive culture for M. tuberculosis and 66.7% (12/18) for NTM were from patients HIV positive. The conclusion was that in our study population, the PPV of AFB for M. tuberculosis in respiratory specimens was high and the prevalence of NTM was low despite the high prevalence of HIV positive.

The epidemiology of tuberculosis diagnosed after death in San Francisco, 1986-1995.

SETTING: San Francisco, California. OBJECTIVES: To identify the characteristics of persons in whom tuberculosis was diagnosed after death, and determine whether secondary cases of tuberculosis resulted from them. DESIGN: Retrospective review of all cases of tuberculosis reported in San Francisco from 1986 through 1995, combined with a prospective evaluation of the molecular epidemiology of tuberculosis. RESULTS: Four per cent of the reported 3102 tuberculosis cases were diagnosed after death. The rate of tuberculosis cases diagnosed after death was 1.63 per 100000 population. Age 43 years or older, male sex, white race, and birth in the United States were characteristics independently associated with a diagnosis of tuberculosis after death. During 1993-1995, injecting drug use was also independently associated with a diagnosis of tuberculosis after death (odds ratio 9.24, 95% confidence interval 1.77-39.38). Cases of tuberculosis diagnosed after death do not appear to be significant sources of undetected tuberculosis transmission causing new secondary tuberculosis cases in the community. CONCLUSIONS: Health care providers in San Francisco, and probably other urban areas, should maintain a high index of suspicion for tuberculosis in ageing, white, US-born males, and injecting drug users.

Preventing tuberculosis among HIV-infected persons: a survey of physicians' knowledge and practices.

BACKGROUND: Guidelines exist for screening, diagnosing, and preventing tuberculosis (TB) among HIV-infected persons, but their application and utility are unknown. METHODS: We conducted a survey of knowledge and practices among 1,300 physicians in the San Francisco Bay area to assess their practices towards TB among HIV-infected persons. RESULTS: Of 630 respondents, 350 (56%) provided care for HIV-infected persons. Thirty-four percent of the respondents had seen the most recent guidelines for preventing tuberculosis among HIV-infected persons; 65% routinely provide information to HIV-infected patients about the risks of exposure to Mycobacterium tuberculosis; 39% provide annual tuberculin skin testing (TST) to HIV-infected patients without a history of a positive test; 86% knew that >/=5-mm induration is considered a positive TST result in HIV-infected persons; and 47% provide a 12-month regimen of chemoprophylaxis for HIV-infected persons who have a positive TST but not active tuberculosis. Physician specialty and experience with HIV-infected persons were not strongly correlated; experience was a better predictor of correct knowledge and practices. CONCLUSIONS: Many physicians were not aware of the standards of care for preventing tuberculosis among HIV-infected patients, even in a geographic area with a high prevalence of M. tuberculosis and HIV.

Differences in contributing factors to tuberculosis incidence in U.S. -born and foreign-born persons.

To determine the factors contributing to tuberculosis incidence in the U.S.-born and foreign-born populations in San Francisco, California, and to assess the effectiveness of tuberculosis control efforts in these populations, we performed a population-based molecular epidemiologic study using 367 patients with strains of Mycobacterium tuberculosis recently introduced into the city. IS6110-based and PGRS-based restriction fragment length polymorphism (RFLP) analyses were performed on M. tuberculosis isolates. Patients whose isolates had identical RFLP patterns were considered a cluster. Review of public health and medical records, plus patient interviews, were used to determine the likelihood of transmission between clustered patients. None of the 252 foreign-born cases was recently infected (within 2 yr) in the city. Nineteen (17%) of 115 U. S.-born cases occurred after recent infection in the city; only two were infected by a foreign-born patient. Disease from recent infection in the city involved either a source or a secondary case with human immunodeficiency virus (HIV) infection, homelessness, or drug abuse. Failure to identify contacts accounted for the majority of secondary cases. In San Francisco, disease from recent transmission of M. tuberculosis has been virtually eliminated from the foreign-born but not from the U.S.-born population. An intensification of contact tracing and screening activities among HIV-infected, homeless, and drug-abusing persons is needed to further control tuberculosis in the U.S.-born population. Elimination of tuberculosis in both the foreign-born and the U.S. -born populations will require widespread use of preventive therapy.

Epidemiology and clinical consequences of drug-resistant tuberculosis in a Guatemalan hospital.

STUDY OBJECTIVE: To determine the epidemiology and clinical consequences of drug-resistant TB in Guatemala. DESIGN: A prospective study conducted for 12 months. SETTING: A thoracic referral hospital in western Guatemala. PATIENTS: Three hundred and seventy-six patients with confirmed TB. RESULTS: Of 376 confirmed cases, 335 (89%) were culture-positive. Tests of drug sensitivities to four first-line antituberculous drugs were performed in 172 (51%) of the culture-positive cases. Fifty-one patients (30%) were resistant to at least one antimicrobial agent, and 26 (15%) were resistant to at least two drugs. In a multivariate model of clinically available patient characteristics, only cavitary disease (odds ratio=2.1; 95% confidence interval, 1.1-6.6) and a history of taking anti-TB medication for >2 weeks (OR=3.0; 95% CI, 1.5-10.3) were independent predictors of resistance to two or more anti-TB agents. Resistance to two or more anti-TB drugs was the single independent predictor of treatment failure (OR=6.4; 95% CI, 2.3-17.8). Twenty-four of 172 patients (14%) who denied having received prior anti-TB therapy were infected with resistant organisms, suggesting ongoing transmission of drug-resistant strains. Although 84% (69 of 82 cases) of patients with fully susceptible organisms and 89% (17 of 19 cases) with singly resistant organisms were cured, only 45% of patients (10 of 22 cases) infected with organisms resistant to two or more agents were successfully treated. CONCLUSIONS: At this sentinel site for complicated TB, a substantial subset of cases who are infected with drug-resistant bacteria cannot be easily identified or treated.

Tuberculosis among immigrants and refugees.

BACKGROUND: Overseas screening of immigrants and refugees applying for a visa to the United States identifies foreign-born individuals who are at high risk for tuberculosis (TB) or who have active TB. The system's effectiveness relies on further medical evaluation and follow-up of foreign-born individuals after their arrival in the United States. METHODS: Retrospective cohort study of 893 immigrants and refugees who arrived in the United States from July 1, 1992, through December 31, 1993, with a destination of San Francisco, Calif, and a referral for further medical evaluation. MAIN OUTCOME MEASURES: Time to report to the local health department after arrival and the yield of active and preventable cases of TB from follow-up medical evaluations. RESULTS: Median time from arrival in the United States to seeking care in San Francisco was 9 days (range, 1-920 days). Of 745 immigrants and refugees (83.4%) who sought further medical evaluation, 51 (6.9%) had active TB and 296 (39.7%) were candidates for preventive therapy. Being a refugee was an independent predictor of failure to seek further medical evaluation in the United States. Class B-1 disease status based on overseas TB screening (odds ratio, 3.5; 95% confidence interval, 2.0-6.2) and being from mainland China (odds ratio, 4.4; 95% confidence interval, 1.9-9.9) were independent predictors of TB diagnosed in San Francisco. CONCLUSIONS: Timely, adequate medical evaluation and follow-up care of immigrants and refugees has a relatively high yield and should be a high priority for TB prevention and control programs.

Toxicity and pharmacology of extracts from dorid nudibranches.

1. Aqueous extracts of digestive glands of specimens of the dorid nudibranchs Cadlina flavomaculata, Doriopsilla albopunctata, Anisodoris nobilis, Archidoris montereyenis, and A. odhneri were lethal when injected into shore crabs and when injected intraperitoneally into mice. 2. Aqueous extracts of the degestive glands of Doriopsilla albopunctata and of Anisodoris nobilis were shown by bioassay (guinea pig ileum)and by chemical determination to contain histamine. The amount present was far too small to account for the toxicity of the glands. 3. Extracts of the digestive glands of Anisodoris nobilis were fractionated by column chromatography on Biogel P-2 to yield an active fraction designated "dorid toxin". This produces lethargy and bradycardia in mice. In anesthetized rats it produces sustained (60 min or more) bradycardia and hypotension. On isolated hearts, especially spontaneously beating guinea pig atria, it has negative inotropic and chronotropic effects. 4. Dorid toxin has a molecular weight under 8000. It is heat stable and is not destroyed by trypsin, chymotrypsin or Pronase. It is therefore unlikely that it is a polypeptide.