Kenneth G. Castro

Transmission of Human Immunodeficiency Virus Type 1 from a Seronegative Organ and Tissue Donor

BACKGROUND Since 1985, donors of organs or tissues for transplantation in the United States have been screened for human immunodeficiency virus type 1 (HIV-1), and more than 60,000 organs and 1 million tissues have been transplanted. We describe a case of transmission of HIV-1 by transplantation of organs and tissues procured between the time the donor became infected and the appearance of antibodies. The donor was a 22-year-old man who died 32 hours after a gunshot wound; he had no known risk factors for HIV-1 infection and was seronegative. METHODS We reviewed the processing and distribution of all the transplanted organs and tissues, reviewed the medical histories of the donor and HIV-1-infected recipients, tested stored donor lymphocytes for HIV-1 by viral culture and the polymerase chain reaction, and tested stored serum samples from four organ recipients for HIV-1 antigen and antibody. RESULTS HIV-1 was detected in cultured lymphocytes from the donor. Of 58 tissues and organs obtained from the donor, 52 could be accounted for by the hospitals that received them. Of the 48 identified recipients, 41 were tested for HIV-1 antibody. All four recipients of organs and all three recipients of unprocessed fresh-frozen bone were infected with HIV-1. However, 34 recipients of other tissues--2 receiving corneas, 3 receiving lyophilized soft tissue, 25 receiving ethanol-treated bone, 3 receiving dura mater treated with gamma radiation, and 1 receiving marrow-evacuated, fresh-frozen bone--tested negative for HIV-1 antibody. Despite immunosuppressive chemotherapy, HIV-1 antibody appeared between 26 and 54 days after transplantation in the three organ recipients who survived more than four weeks. CONCLUSIONS Although rare, transmission of HIV-1 by seronegative organ and tissue donors can occur. Improvements in the methods used to screen donors for HIV-1, advances in techniques of virus inactivation, prompt reporting of HIV infection in recipients, and accurate accounting of distributed allografts would help to reduce further this already exceedingly low risk.

Tuberculosis control and elimination 2010–50: cure, care, and social development

Rapid expansion of the standardised approach to tuberculosis diagnosis and treatment that is recommended by WHO allowed more than 36 million people to be cured between 1995 and 2008, averting up to 6 million deaths. Yet tuberculosis remains a severe global public health threat. There are more than 9 million new cases every year worldwide, and the incidence rate is falling at less than 1% per year. Although the overall target related to the Millennium Development Goals of halting and beginning to reverse the epidemic might have already been reached in 2004, the more important long-term elimination target set for 2050 will not be met with present strategies and instruments. Several key challenges persist. Many vulnerable people do not have access to affordable services of sufficient quality. Technologies for diagnosis, treatment, and prevention are old and inadequate. Multidrug-resistant tuberculosis is a serious threat in many settings. HIV/AIDS continues to fuel the tuberculosis epidemic, especially in Africa. Furthermore, other risk factors and underlying social determinants help to maintain tuberculosis in the community. Acceleration of the decline towards elimination of this disease will need invigorated actions in four broad areas: continued scale-up of early diagnosis and proper treatment for all forms of tuberculosis in line with the Stop TB Strategy; development and enforcement of bold health-system policies; establishment of links with the broader development agenda; and promotion and intensification of research towards innovations.

HIV Infection and Multidrug-Resistant Tuberculosis—The Perfect Storm

BACKGROUND Multidrug-resistant (MDR) tuberculosis (TB) has emerged as a global epidemic, with ~425,000 new cases estimated to occur annually. The global human immunodeficiency virus (HIV) infection epidemic has caused explosive increases in TB incidence and may be contributing to increases in MDR-TB prevalence. METHODS We reviewed published studies and available surveillance data evaluating links between HIV infection and MDR-TB to quantify convergence of these 2 epidemics, evaluate the consequences, and determine essential steps to address these epidemics. RESULTS Institutional outbreaks of MDR-TB have primarily affected HIV-infected persons. Delayed diagnosis, inadequate initial treatment, and prolonged infectiousness led to extraordinary attack rates and case-fatality rates among HIV-infected persons. Whether this sequence occurs in communities is less clear. MDR-TB appears not to cause infection or disease more readily than drug-susceptible TB in HIV-infected persons. HIV infection may lead to malabsorption of anti-TB drugs and acquired rifamycin resistance. HIV-infected patients with MDR-TB have unacceptably high mortality; both antiretroviral and antimycobacterial treatment are necessary. Simultaneous treatment requires 6-10 different drugs. In HIV-prevalent countries, TB programs struggle with increased caseloads, which increase the risk of acquired MDR-TB. Surveillance data suggest that HIV infection and MDR-TB may converge in several countries. CONCLUSIONS Institutional outbreaks, overwhelmed public health programs, and complex clinical management issues may contribute to the convergence of the MDR-TB and HIV infection epidemics. To forestall disastrous consequences, infection control, rapid case detection, effective treatment, and expanded program capacity are needed urgently.

Transmission of Multidrug-Resistant Mycobacterium tuberculosis during a Long Airplane Flight

BACKGROUND In April 1994, a passenger with infectious multi-drug resistant tuberculosis traveled on commercial-airline flights from Honolulu to Chicago and from Chicago to Baltimore and returned one month later. We sought to determine whether she had infected any of her contacts on this extensive trip. METHODS Passengers and crew were identified from airline records and were notified of their exposure, asked to complete a questionnaire, and screened by tuberculin skin tests. RESULTS Of the 925 people on the airplanes, 802 (86.7 percent) responded. All 11 contacts with positive tuberculin skin tests who were on the April flights and 2 of 3 contacts with positive tests who were on the Baltimore-to-Chicago flight in May had other risk factors for tuberculosis. More contacts on the final, 8.75-hour flight from Chicago to Honolulu had positive skin tests than those on the other three flights (6 percent, as compared with 2.3, 3.8, and 2.8 percent). Of 15 contacts with positive tests on the May flight from Chicago to Honolulu, 6 (4 with skin-test conversion) had no other risk factors; all 6 had sat in the same section of the plane as the index patient (P=0.001). Passengers seated within two rows of the index patient were more likely to have positive tuberculin skin tests than those in the rest of the section (4 of 13, or 30.8 percent, vs. 2 of 55, or 3.6 percent; rate ratio, 8.5; 95 percent confidence interval, 1.7 to 41.3; P=0.01). CONCLUSIONS The transmission of Mycobacterium tuberculosis that we describe aboard a commercial aircraft involved a highly infectious passenger, a long flight, and close proximity of contacts to the index patient.

Interpretation of Restriction Fragment Length Polymorphism Analysis of Mycobacterium tuberculosis Isolates from a State with a Large Rural Population

Epidemiologic relatedness of Mycobacterium tuberculosis isolates from Arkansas residents diagnosed with tuberculosis in 1992-1993 was assessed using IS6110- and pTBN12-based restriction fragment length polymorphism (RFLP) and epidemiologic investigation. Patients with isolates having similar IS6110 patterns had medical records reviewed and were interviewed to identify epidemiologic links. Complete RFLP analyses were obtained for isolates of 235 patients; 78 (33%) matched the pattern of > or = 1 other isolate, forming 24 clusters. Epidemiologic connections were found for 33 (42%) of 78 patients in 11 clusters. Transmission of M. tuberculosis likely occurred many years in the past for 5 patients in 2 clusters. Of clusters based only on IS6110 analyses, those with > or = 6 IS6110 copies had both a significantly greater proportion of isolates that matched by pTBN12 analysis and patients with epidemiologic connections, indicating IS6110 patterns with few bands lack strain specificity. Secondary RFLP analysis increased specificity, but most clustered patients still did not appear to be epidemiologically related. RFLP clustering in rural areas may not represent recent transmission.

Towards universal access to HIV prevention, treatment, care, and support: the role of tuberculosis/HIV collaboration

Tuberculosis is the oldest of the worlds current pandemics and causes 8.9 million new cases and 1.7 million deaths annually. The disease is among the most common causes of morbidity and mortality in people living with HIV. However, tuberculosis is more than just part of the global HIV problem; well-resourced tuberculosis programmes are an important part of the solution to scaling-up towards universal access to comprehensive HIV prevention, diagnosis, care, and support. This article reviews the impact of the interactions between tuberculosis and HIV in resource-limited settings; outlines the recommended programmatic and clinical responses to the dual epidemics, highlighting the role of tuberculosis/HIV collaboration in increasing access to prevention, diagnostic, and treatment services; and reviews progress in the global response to the epidemic of HIV-related tuberculosis.

HIV-1 Seroconversion in Patients with and without Genital Ulcer Disease: A Prospective Study

Since the beginning of the acquired immunodeficiency syndrome (AIDS) epidemic, two predominant and distinct epidemiologic patterns of human immunodeficiency virus (HIV-1) transmission have been reported. In North America and Western Europe, although heterosexual transmission has been increasing [1], men exposed to HIV-1 through sexual contact with other men and injection drug users (users of illicit drugs) are the predominant groups at risk for development of AIDS [2]. The second pattern, prevalent in Africa and parts of Asia and the Caribbean, is predominantly characterized by heterosexual transmission, with a nearly equal male-to-female ratio of patients [3, 4]. The reasons for these different patterns of transmission have not been fully identified, but studies have addressed the possibility that the presence of genital ulcers, especially chancroid, has enhanced heterosexual transmission [5, 6]. Sexually transmitted diseases that result in a disrupted genital epithelium, such as syphilis, chancroid, and herpes, have been associated with heterosexual transmission of HIV-1 using retrospective studies in the United States [7-10] and both retrospective [11] and prospective studies in sub-Saharan Africa [12, 13]. In New York City, an ongoing epidemic of genital ulcer disease has occurred in communities where HIV-1 infection related to injection drug use is well documented [10, 14]. The number of cases of primary and secondary syphilis reported to the New York City Department of Health increased from 2157 in 1985 to 4231 in 1990. The number of reported cases of chancroid increased from 1323 in 1985 to 2277 in 1989. Consequently, a prospective study of HIV-1 seroconversion was initiated to further characterize the relation between genital ulcer disease and HIV-1 transmission in primarily heterosexual persons in the United States. Methods Study Population This study was done in 1 of the 12 inner-city, sexually transmitted disease clinics operated by the New York City Department of Health. The study site is located in an area of New York City where the cumulative incidence of AIDS in adults through 1990 was 1 per 100 persons (New York City AIDS Case Surveillance data) and illicit drug use, including crack (smokable freebase cocaine) use, is common. In 1990, this clinic provided care to 14 243 persons: 9589 (67%) were men and 4654 were women. Primary or secondary syphilis was diagnosed in 226 patients, and 113 were found to have chancroid. From 1988 to 1989, the HIV-1 prevalence in this clinic was 7.8%, estimated by a serosurvey that was done without using patient identifiers (Weisfuse I. Personal communication). Study Population Recruitment into the study consisted of two phases. In the first phase, all of the approximately 28 000 persons attending the clinic for diagnosis or treatment of a sexually transmitted disease during the study period were asked to participate in a study of the prevalence of HIV-1 infection and associated risk factors. Those who agreed (n = 2893) received HIV-1 pretest counseling and were given a return appointment to receive test results and post-test counseling. Those with a diagnosis of genital ulcer were recruited more intensively. Thus, approximately 700 (24%) of the 2893 participants recruited into phase 1 had genital ulcers. These 700 participants with genital ulcer disease represented more than 80% of all patients seen in the clinic with ulcers during the study period. Study interviewers administered standardized questionnaires in either English or Spanish. Information on demographic characteristics, socioeconomic status, and risk behavior associated with HIV-1 transmission was collected, as previously described [14]. Of the 2543 participants who were HIV negative, 1679 returned for post-test counseling 3 weeks after initial study enrollment and were asked to participate in the prospective component (or phase 2) of the study. For those who agreed, an additional questionnaire was administered to identify potential HIV-1-related high-risk behavior during three periods of interest: the 6 months before the initial clinic visit, the 10 days before the symptom developed that resulted in the clinic visit, and the period while the symptoms were present. The questioning focused on intravenous drug use and the number of sexual contacts and the type of sexual activities with intravenous drug users, homosexual or bisexual men, prostitutes, and others. The regularity of condom use was determined using the following scale: always, usually (>50%), sometimes (approximately 50%), rarely (<50%), and never. Anonymous HIV-1 testing was available for patients who did not want to participate in the study or who did not have a sexually transmitted disease. At the time of enrollment in phase 2, participants were asked to return to the clinic for a third time, approximately 3 months after the initial clinic visit. For the participants who returned for the final follow-up visit, a repeated serum sample for HIV-1 testing was obtained, and a questionnaire similar to that described above was administered to identify high-risk behavior for the period between the two HIV-1 antibody tests. Informed consent was obtained for both phases of the study, and the study was approved by the institutional review boards of the New York City Department of Health and the Centers for Disease Control and Prevention. Laboratory Methods Patients with a genital ulcer had the following diagnostic tests: syphilis serology, dark-field examination of ulcer exudate for Treponema pallidum, Gram stain of ulcer exudate, microbiologic culture for Haemophilus ducreyi using blood and chocolate media, and Tzanck smear for herpes virus. Testing for syphilis was done using the rapid plasma reagin card test (Hynson, Wescott, and Dunning; Baltimore, Maryland) and the microhemagglutination assay for T. pallidum (Fujirebio Inc., Tokyo, Japan, and Ames Division, Miles Laboratory, Elkhart, Indiana). Haemophilus ducreyi was isolated using previously described methods [15]. Antibody testing for HIV-1 was done by an enzyme-linked immunosorbent assay (DuPont, Wilmington, Delaware), followed by a confirmatory Western blot analysis of all reactive samples using reagents prepared by the Laboratory of Retrovirology and Immunobiology of the New York City Department of Health [16]. Diagnosis of Genital Ulcer Disease Primary syphilis was diagnosed when a genital ulcer was present and the ulcer exudate was dark-field positive, the rapid plasma reagin card test was positive, or the patient had recent contact with a person known to have syphilis. A diagnosis of chancroid was made when a positive culture occurred for H. ducreyi, if Gram stain of the ulcer exudate showed pleomorphic gram-negative rods, or if clinical findings suggested chancroid (tender or multiple ulcers, painful inguinal adenitis) with a negative dark-field examination as well as a negative syphilis serologic test result and a negative Tzanck smear. Genital herpes was diagnosed when the lesions were vesicular or recurrent or an ulcer had a positive Tzanck smear. In the absence of, or with negative, microbiologic and serologic data, the clinical diagnosis was made by the supervising physician in the clinic and not by study personnel. Statistical Analysis Analysis was done using the SAS statistical software system, version 6.06 (SAS Institute, Inc., Cary, North Carolina). The strength of the association between individual categorical variables or continuous variables grouped categorically and HIV-1 seroconversion was evaluated by the relative risk, and 95% direct precision-based CIs were obtained. Statistical relations were tested by the chi-square test or the Fisher exact test (two-tailed). Differences between continuous variables were analyzed by the Student t-test (two-tailed), the Wilcoxon rank-sum test, or the median test. The SAS LOGIST procedure was used to fit the multiple logistic regression model to the single binary outcome variable (HIV seroconversion or no seroconversion). The adjusted odds ratios obtained in this model approximated the adjusted relative risk. Measurement of Risk Index For heterosexual men, a summary measure was constructed of the risk for HIV-1 transmission attributable to a combination of the probability of encountering and the frequency of exposure to an HIV-1-infected partner. The sexual risk index was generated for the period from 6 months before the clinic visit through the second HIV test. Indices were computed by taking the sum of the products of the number of sexual contacts with partners in each of four risk groups (prostitutes, female intravenous drug users, women with chancroid, and women with no risk) and the estimated HIV-1 seroprevalence among the members of that group. Prevalence estimates for risk groups were determined from among our own study participants during phase 1, unblinded risk-factor serosurvey because sexual contacts were likely to occur in the local geographic area. The overall seroprevalence for the 644 women with no risk in phase 1 was 6%, for the 88 injection drug users it was 44%, for the 167 female prostitutes it was 29%, and for the 26 women with chancroid it was 19%. Using these values, risk indices were generated for four groups of male study participants: those with chancroid who did and did not seroconvert and those without chancroid who did and did not seroconvert. The risk indices were scaled proportionately from 0 to 100 for graphic presentation. Statistical comparisons were done between the Sexual Risk Index medians of the patients with chancroid and those without chancroid who seroconverted; between those without chancroid who seroconverted and those without chancroid who did not seroconvert; and between patients with chancroid who seroconverted and all patients who did not seroconvert using the median test. Results Of the 2543 seronegative persons identified in the cross-sectional component (phase 1) of the study, 1679 (62%) r

Extensively Drug-Resistant Tuberculosis in the United States, 1993-2007

CONTEXT Worldwide emergence of extensively drug-resistant tuberculosis (XDR-TB) has raised global public health concern, given the limited therapy options and high mortality. OBJECTIVES To describe the epidemiology of XDR-TB in the United States and to identify unique characteristics of XDR-TB cases compared with multidrug-resistant TB (MDR-TB) and drug-susceptible TB cases. DESIGN, SETTING, AND PATIENTS Descriptive analysis of US TB cases reported from 1993 to 2007. Extensively drug-resistant TB was defined as resistance to isoniazid, a rifamycin, a fluoroquinolone, and at least 1 of amikacin, kanamycin, or capreomycin based on drug susceptibility test results from initial and follow-up specimens. MAIN OUTCOME MEASURES Extensively drug-resistant TB case counts and trends, risk factors for XDR-TB, and overall survival. RESULTS A total of 83 cases of XDR-TB were reported in the United States from 1993 to 2007. The number of XDR-TB cases declined from 18 (0.07% of 25 107 TB cases) in 1993 to 2 (0.02% of 13 293 TB cases) in 2007, reported to date. Among those with known human immunodeficiency virus (HIV) test results, 31 (53%) were HIV-positive. Compared with MDR-TB cases, XDR-TB cases were more likely to have disseminated TB disease (prevalence ratio [PR], 2.06; 95% confidence interval [CI], 1.19-3.58), less likely to convert to a negative sputum culture (PR, 0.55; 95% CI, 0.33-0.94), and had a prolonged infectious period (median time to culture conversion, 183 days vs 93 days for MDR-TB; P < .001). Twenty-six XDR-TB cases (35%) died during treatment, of whom 21 (81%) were known to be HIV-infected. Mortality was higher among XDR-TB cases than among MDR-TB cases (PR, 1.82; 95% CI, 1.10-3.02) and drug-susceptible TB cases (PR, 6.10; 95% CI, 3.65-10.20). CONCLUSION Although the number of US XDR-TB cases has declined since 1993, coinciding with improved TB and HIV/AIDS control, cases continue to be reported each year.

A Nosocomial Outbreak of Multidrug-Resistant Tuberculosis

Nosocomial outbreaks of tuberculosis have affected recommendations for infection control practices in hospitals in the United States [1-8]. Administrative and environmental measures and respiratory protection for health care workers have been recommended [9, 10]. Evidence suggests that adherence to these guidelines may be effective in preventing nosocomial transmission of Mycobacterium tuberculosis [11-13]. Of the 34 cases of multidrug-resistant tuberculosis (resistant to at least isoniazid and rifampin) that were reported to the Chicago Department of Health from January 1994 through April 1995, 6 occurred in patients with AIDS who had been admitted to one floor of one hospital. Because nosocomial transmission of multidrug-resistant tuberculosis was suspected, an investigation was initiated. Methods Potential outbreak cases-cases of tuberculosis in persons whose isolates were resistant to at least isoniazid and rifampin-were identified by matching the names of patients and health care workers at the hospital to state and local tuberculosis registries and by reviewing laboratory records and death certificates. We performed DNA fingerprinting of M. tuberculosis isolates using IS6110 and pTBN12 probes [14, 15]. Medical records were reviewed for patients who were admitted to the outbreak floor when a patient whose sputum smears were positive for acid-fast bacilli was present. Patients who died within 30 days of exposure were excluded. Private providers of patients who may have been exposed to M. tuberculosis were contacted by telephone or by mail. All were advised to screen their patients for tuberculous disease and infection by tuberculin skin tests and symptom checks. A positive result on a tuberculin skin test was defined as induration of 5 mm or more, and an increase in induration of at least 5 mm was considered a skin test conversion. Severely immunocompromised patients (CD4+ T-lymphocyte count < 50 cells/mL) who did not receive skin testing were assumed to be anergic [16]. To assess exposure of health care workers to M. tuberculosis, we reviewed work schedules, chart signatures, and patient assignments. Results of testing for fit of respirators with high-efficiency particulate air (HEPA) filters and results of annual tuberculin skin tests were obtained from employee records. Health care workers also completed a form about infection control practices and exposure to M. tuberculosis. Acid-fast bacilli isolation rooms (that is, rooms in which the air pressure is negative in relation to the hallway and that have 6 air changes per hour) were installed in December 1994. The design of the ventilation system on the outbreak floor was reviewed, and smoke tube testing was done to assess the direction of air flow. Data analysis was conducted using Epi Info, version 6 [17]. Categorical variables were compared using the chi-square test, and relative risks with 95% CIs were derived. Continuous variables were compared using the Wilcoxon rank-sum test. Results Seven persons had outbreak cases of tuberculosis: six patients already known and one health care worker identified during the investigation. All of these persons had AIDS. All of their M. tuberculosis isolates were resistant to isoniazid and rifampin and had identical DNA fingerprints. Two generations of nosocomial transmission were identified (Figure 1). Case-patient 1 was admitted to the hospital with a diagnosis of tuberculosis; was placed in a private room; and began receiving therapy with isoniazid, rifampin, pyrazinamide, and ethambutol. From the time this patient was admitted, persons entering the patients room were required to use HEPA-filter respirators. Case-patient 1 refused to remain in the room and was the source of infection for case-patient 2, who was hospitalized at the same time across the hallway. Figure 1. Timeline demonstrating two chains of nosocomial transmission of tuberculous organisms between August 1994 and September 1995 in a hospital in Chicago. Case-patient 2 was readmitted to the hospital 10 weeks later with fever, sinus pressure, and cough. Because the chest radiograph at admission was normal, tuberculosis was not initially suspected. A sputum smear obtained 3 days after admission was positive (3+) for acid-fast bacilli. Treatment with isoniazid, rifampin, and ethambutol was started, and persons entering the patients room were required to use HEPA-filter respirators. It was reported that the door to the patients room was malfunctioning and failed to remain closed. Case-patient 2 remained in his room and yet was the source of infection for case-patients 3, 4, 5, and 6, who were hospitalized on the same ward. Transmission to case-patient 6, who was restricted to bed rest, occurred during this patients short 23-hour hospitalization. Case-patient 7, the health care worker, drew blood from case-patient 2 before case-patient 2 received a diagnosis of tuberculosis and occasionally worked on the outbreak floor while case-patients 1 and 2 were present. For case-patients 2, 3, 4, 5, 6, and 7, no exposure to M. tuberculosis other than that which occurred in the hospital was identified. Case-patients 1 and 2 were never in an acid-fast bacilli isolation room while they were infectious because no such rooms were available until December 1994. Case-patients 4, 5, 6, and 7 were all placed in acid-fast bacilli isolation rooms when tuberculosis was suspected; case-patient 3 did not have sputum samples smear-positive for acid-fast bacilli. Smoke tube testing done in April 1995 revealed that the rooms occupied by case-patients 1 and 2 while these patients were infectious had air pressure that was positive in relation to the hallway. The acid-fast bacilli isolation rooms had air pressure that was negative in relation to the hallway. Ultraviolet germicidal irradiation was not used in the hospital. The outbreak floor was composed of two separate wings with a central nursing station. Of the 169 patients on the floor, 5 had tuberculosis (case-patients 2, 3, 4, 5, and 6). Of the 164 patients who did not have tuberculosis, 71 (43%) had AIDS. Fifty-three of the 164 patients died before completing screening; none (including 37 patients with AIDS) received a diagnosis of tuberculosis. Of the remaining 111 patients, 5 had positive results on tuberculin skin testing, 34 had negative results, 5 had previously had positive results, 27 were anergic, and 40 had unknown test results. All 5 patients with positive test results had other risk factors for M. tuberculosis infection (for example, foreign birth). All 5 patients were on the same ward as case-patients 1 or 2 while these patients were infectious. No evidence of transmission among patients who did not have AIDS or patients exposed only to case-patients 3, 4, 5, or 6 was identified. Twenty-six patients with AIDS (all of whom were known or presumed to be anergic) were exposed to case-patients 1 or 2. At the time of exposure, case-patients had lower CD4+ T-lymphocyte counts than non-case-patients and were more likely to be ambulatory (Table 1). Table 1. Risk Factors for Nosocomial Transmission of Mycobacterium tuberculosis among Patients and Staff Of the 104 exposed health care workers, 17 who had previously had positive results on skin tests and 13 who had resigned from the hospital were excluded from analysis. Of the remaining 74, 11 (15%) had tuberculin skin test conversions (6 nurses, 4 housestaff physicians, and 1 ward secretary) and 4 had positive skin test results, but no baseline test results. None had any other identified exposure to tuberculosis. The remaining 59 (80%) had negative results on skin testing at least 12 weeks after exposure. Except for case-patient 7, no health care worker developed tuberculosis. Case-patient 2 was the source of most of the episodes of transmission to health care workers. While case-patient 2 was hospitalized with infectious tuberculosis, health care workers with skin test conversions worked more days on the floor than did health care workers with negative test results. Health care workers who had conversion were no more likely to have provided direct care to a case-patient, including case-patient 2, than were workers with negative test results (Table 1). Forty-two (57%) of 74 exposed health care workers responded to questions about infection control practices. Those with negative test results were no more likely than those with skin test conversion to report always wearing a HEPA-filter respirator when entering the room of a patient with tuberculosis (25 of 29 workers compared with 4 of 5 workers; 8 workers did not recall whether they used HEPA-filter respirators). The results of respirator-fit testing before exposure were available for 68 health care workers; 62, including 80% of those with skin test conversions, passed this testing. Discussion This investigation provides evidence of nosocomial transmission of multidrug-resistant M. tuberculosis, including 1) exposure of case-patients who had secondary cases of tuberculosis to a source case-patient on the same floor of the hospital; 2) consistency of incubation periods with those of previous nosocomial outbreaks among patients with AIDS [1-3]; 3) isolates with matching patterns of drug susceptibility and DNA fingerprints; 4) lack of any other identified exposure to tuberculosis; and 5) exposure of all health care workers with skin test conversion to a case-patient who was not in an acid-fast bacilli isolation room. Several factors may have contributed to the transmission of M. tuberculosis, but the evidence for the role of insufficient environmental controls is most compelling. Case-patients 1 and 2 were both infectious, and the flow of contaminated air from their rooms (which had air pressure that was positive in relation to the hallway) facilitated the spread of infectious droplet nuclei throughout the outbreak floor. Organisms were transmitted to health care workers who did not directly care for a patient with infectious

Is operational research delivering the goods? The journey to success in low-income countries

Operational research in low-income countries has a key role in filling the gap between what we know from research and what we do with that knowledge-the so-called know-do gap, or implementation gap. Planned research that does not tangibly affect policies and practices is ineffective and wasteful, especially in settings where resources are scarce and disease burden is high. Clear parameters are urgently needed to measure and judge the success of operational research. We define operational research and its relation with policy and practice, identify why operational research might fail to affect policy and practice, and offer possible solutions to address these shortcomings. We also propose measures of success for operational research. Adoption and use of these measures could help to ensure that operational research better changes policy and practice and improves health-care delivery and disease programmes.