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.

WHO guidelines for the programmatic management of drug-resistant tuberculosis: 2011 update.

The production of guidelines for the management of drug-resistant tuberculosis (TB) fits the mandate of the World Health Organization (WHO) to support countries in the reinforcement of patient care. WHO commissioned external reviews to summarise evidence on priority questions regarding case-finding, treatment regimens for multidrug-resistant TB (MDR-TB), monitoring the response to MDR-TB treatment, and models of care. A multidisciplinary expert panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to develop recommendations. The recommendations support the wider use of rapid drug susceptibility testing for isoniazid and rifampicin or rifampicin alone using molecular techniques. Monitoring by sputum culture is important for early detection of failure during treatment. Regimens lasting ≥ 20 months and containing pyrazinamide, a fluoroquinolone, a second-line injectable drug, ethionamide (or prothionamide), and either cycloserine or p-aminosalicylic acid are recommended. The guidelines promote the early use of antiretroviral agents for TB patients with HIV on second-line drug regimens. Systems that primarily employ ambulatory models of care are recommended over others based mainly on hospitalisation. Scientific and medical associations should promote the recommendations among practitioners and public health decision makers involved in MDR-TB care. Controlled trials are needed to improve the quality of existing evidence, particularly on the optimal composition and duration of MDR-TB treatment regimens.

Treatment outcome of multidrug/extensively drug-resistant tuberculosis in Latvia, 2000-2004.

In the present study, we characterised drug-resistance patterns, compared treatment outcome between extensively and nonextensively drug-resistant tuberculosis (non-XDR-TB) cases, and assessed risk factors for poor outcome in a high-prevalence country that screens all TB patients for first-line anti-TB drug resistance. We reviewed drug susceptibility test results among all pulmonary TB cases in Latvia diagnosed from 2000-2004, as well as demographic and clinical characteristics, drug-resistance patterns, and treatment outcomes. During the 5-yr period, 1,027 multidrug-resistant tuberculosis (MDR-TB) cases initiated treatment. Among all cases, the proportion that experienced an outcome of cure or completion increased from 66.2 to 70.2% (p = 0.06 for linear trend). Among the 48 (4.7%) XDR-TB cases, 18 (38%) were cured, four (8%) died, three (6%) defaulted, and treatment failed in 23 (48%). In proportional-hazards analysis, characteristics significantly associated with poor outcome included XDR-TB, being retired, presence of bilateral cavitation, and previous MDR-TB treatment history for those aged ≥55 yrs. Overall, treatment success among all MDR-TB cases increased over time. Strategies to prevent transmission of XDR-TB and to further improve treatment outcome are crucial for the future of TB control in Latvia.

Adjunctive resectional lung surgery for extensively drug-resistant tuberculosis.

Extensively drug-resistant (XDR) tuberculosis (TB) poses significant management challenges as there are limited pharmacological treatment options for cure. Adjunctive resectional lung surgery decreases case-fatality rates for some patients with multidrug-resistant tuberculosis (MDR-TB), but its use has not been well documented for patients with XDR-TB. We describe 17 XDR-TB patients treated with surgery as part of their case management in Latvia during 1999-2005. One patient had no previous TB treatment history, 10 were previously treated for drug-susceptible TB and six were previously treated for MDR-TB. Mycobacterium tuberculosis isolates from the 17 patients were resistant to a mean of 9.2 drugs. Due to failure of pharmacological therapy, one due to a large cavity and one due to pulmonary haemorrhage, 15 patients were treated with surgery. Despite failure of pharmacological treatment in 15 out of 17 patients, eight (47%) were cured with adjunctive surgical treatment. Surgery should be explored as a possible treatment option for patients with XDR-TB.

Inclusion of information on risk factors, socio-economic status and health seeking in a tuberculosis prevalence survey.

Data on socio-economic status, exposure to risk factors for tuberculosis (TB) and previous health-seeking for TB may be included in a TB prevalence survey to gain better knowledge about the distribution of TB in the population as well as a better understanding of what factors are driving the TB epidemic in a given setting. This article provides an overview of how such additional information may be collected. The article highlights the need to carefully consider the risk of jeopardising the quality of the overall survey by overburdening it with additional data collection, and concludes that additional time and resources for planning, training, logistics and supervision are required to safeguard quality. The article also discusses special considerations regarding sampling, sample size and data interpretation when including such information in a TB prevalence survey.

Why we need pre-exposure prophylaxis: incident HIV and syphilis among men, and transgender women, who have sex with men, Bangkok, Thailand, 2005-2015.

We describe incident human immunodeficiency virus (HIV) and syphilis trends in men who have sex with men (MSM) and transgender women (TGW) presenting for HIV voluntary counseling and testing (VCT) services and sexually transmitted infection (STI) management at the Silom Community Clinic, Bangkok, Thailand. Clients underwent rapid HIV testing and syphilis rapid plasma reagin (RPR) testing. For incidence analysis, we included clients with >1 follow-up visit. Initial negative HIV with subsequent positive HIV defined incident HIV infection; incident syphilis infection was defined as negative RPR followed by positive RPR (titer ≥1:8) and confirmatory anti- Treponema pallidum antibodies. Calculation of incidence using Poisson regression assumed a uniform probability distribution throughout the seroconversion interval. From 15 September 2005 to 31 December 2015, we tested 10,158 clients for HIV and 10,324 for syphilis. Overall, 7109 clients tested HIV-seronegative and contributed 7157 person-years (PY). Three-hundred forty-seven incident HIV infections resulted in an incidence rate of 4.8 per 100 PY (95% confidence interval [CI] 4.4-5.4). We found an inverted U-shape trend of HIV incidence over time with a peak of 6.4 per 100 PY in quarter 2/2011 ( p < 0.01) (Poisson with RCS function, p = 0.001). Overall, 8713 clients tested seronegative for syphilis and contributed 8623 PY. The incidence of syphilis infection was 4.4 per 100 PY (95% CI 3.9-4.8). Despite an apparent decline in HIV incidence among MSM and TGW attending VCT services, syphilis incidence rose and remained high. Evaluating temporal trends of HIV and syphilis incidence provides an opportunity to evaluate epidemic trajectories and target limited program funding. We recommend focused HIV and STI prevention interventions for MSM in Bangkok.

Treatment outcome and follow-up of multidrug-resistant tuberculosis patients, West Coast/Winelands, South Africa, 1992-2002.

SETTING: Brooklyn Chest Hospital, Western Cape, South Africa. OBJECTIVE: To evaluate the treatment outcome and 2- and 5-year follow-up of patients treated for multidrug-resistant tuberculosis (MDR-TB) with individualized regimens. DESIGN: Retrospective cohort study of all MDR-TB patients starting treatment during 1992-2002. Patients were evaluated every 6 months for 2 years after treatment and at 5 years when possible. RESULTS: Over 11 years, 491 (66%) of 747 MDR-TB patients received treatment with two or more second-line drugs; 239 (49%) were cured or completed treatment, 68 (14%) died, 144 (29%) defaulted from treatment, 27 (5%) failed, 10 (2%) transferred out and 3 (<1%) remained on treatment. Only 176 (36%) were tested for human immunodeficiency virus and 15 were positive. The proportion with a successful MDR-TB treatment outcome declined over time, while the proportion who defaulted remained stable. Among 410 patients who had not transferred out or died, 281 (69%) had 2-year data available: 185 (66%) were cured or completed treatment, 32 (11%) were retreated for TB and 64 (23%) died. CONCLUSIONS: Under program conditions in the West Coast/Winelands District, default rates were high and treatment success rates low. Outreach strategies for MDR-TB treatment should only be implemented if adequate resources are committed to the program.

Tuberculosis prevalence surveys: rationale and cost.

This article is the first of the educational series 'Assessing tuberculosis (TB) prevalence through population-based surveys'. The series will give overall guidance in conducting cross-sectional surveys of pulmonary TB (PTB) disease. TB prevalence surveys are most valuable in areas where notification data obtained through routine surveillance are of unproven accuracy or incomplete, and in areas with an estimated prevalence of bacteriologically confirmed TB of more than 100 per 100,000 population. To embark on a TB prevalence survey requires commitment from the national TB programme, compliance in the study population, plus availability of trained staff and financial resources. The primary objective of TB prevalence surveys is to determine the prevalence of PTB in the general population aged >or=15 years. Limitations of TB prevalence surveys are their inability to assess regional or geographic differences in prevalence of TB, estimate the burden of childhood TB or estimate the prevalence of extra-pulmonary TB. The cost of a prevalence survey is typically US$ 4-15 per person surveyed, and up to US$ 25 per person with radiographic screening. A survey of 50,000 people, of limited precision, would typically cost US$ 200,000-1,250,000.

Treatment outcome cohort analysis in an integrated DOTS and DOTS-Plus TB program in Latvia.

International guidelines for treatment outcome analysis of tuberculosis cases have been published and are widely used. They do not, however, fully address the incorporation of multidrug-resistant tuberculosis (MDR-TB) cases. Here we present an approach to cohort analysis of treatment outcomes for all registered TB cases, including MDR-TB cases. We analyzed all new pulmonary smear- and/or culture-positive cases registered in Latvia during 2002. Analysis of treatment outcomes at 24 months after initial case registration showed overall treatment success at 84%. This approach to outcome analysis is possible only for settings where MDR-TB treatment is established.

Risk factors associated with default from multidrug-resistant tuberculosis treatment, South Africa, 1999-2001.

SETTING: Multidrug-resistant tuberculosis (MDR-TB) treatment centers in five provinces, South Africa. OBJECTIVES: To estimate the mortality and evaluate risk factors associated with default from MDR-TB treatment. DESIGN: Using registries and a standardized questionnaire, we conducted a case-control study among patients diagnosed and treated for MDR-TB. Cases were defined as patients who began MDR-TB treatment between 1 October 1999 and 30 September 2001 and defaulted from treatment for more than 2 months; controls were defined as patients who began MDR-TB treatment during the same time and were cured, completed or failed. RESULTS: After initial identification and reclassification, 269 cases and 401 controls were confirmed eligible for interview. Further investigation revealed that 74 (27%) cases and 44 (10%) controls had died. Among 96 cases located who consented and were interviewed, 70% had defaulted after receiving at least 6 months of treatment. In a multivariate model, the strongest individual risk factors for default included reporting smoking marijuana or mandrax during treatment, and having an unsatisfactory opinion about the attitude of health care workers. CONCLUSION: Mortality among MDR-TB defaulters was high. Interventions to reduce default from MDR-TB treatment should center on substance abuse treatment, patient education and support and improving provider-patient relationships.

Emporiatrics: diarrhea in travelers.

The degree of discomfort and inconvenience caused by travelers' diarrhea highlights the need to prepare the international traveler thoroughly. In addition to observing food and water precautions, most travelers should carry antibiotics and antimotility agents to be started if diarrhea occurs. Used judiciously, these precautions may prevent an unplanned tour of bathrooms and outhouses in foreign countries.

Postdischarge surveillance for nosocomial wound infection: a brief review and commentary.

Escalating medical care costs during the last decade have resulted in shorter hospital stays and higher volumes of outpatients surgical procedures. As a result, the proportion of nosocomial surgical wound infections manifesting after discharge will increase. We performed a literature review to assess the current state of the art of postdischarge surveillance for nosocomial wound infection. From 20% to 70% of postoperative surgical site infections do not become apparent until after the patient's discharge, resulting in serious underreporting of true rates. Infections in outpatients are not being identified efficiently. Institutions using self-reporting methods report a low validity for these methods. The Centers for Disease Control and the Joint Commission for the Accreditation of Healthcare Organizations currently have no strong guidelines on the subject. Since valid postdischarge surveillance may become a necessity for a quality infection control program, new national recommendations are needed.

Prevalence of Treponema pallidum seropositivity and herpes simplex virus type 2 infection in a cohort of men who have sex with men, Bangkok, Thailand, 2006-2010.

We report prevalence of Treponema pallidum (TP) seropositivity and herpes simplex virus type 2 (HSV-2) infection and risk factors associated with their prevalence in a cohort of men who have sex with men (MSM) in Bangkok, Thailand. Between April 2006 and March 2010 we enrolled Thai MSM into a cohort study based at the Silom Community Clinic, with baseline behavioural data and laboratory testing for sexually transmitted infections (STIs). Logistic regression was used to analyse risk factors associated with the prevalence of TP seropositivity and HSV-2 infection. From a total of 1544 enrolled men (mean age 26 years) TP, HSV-2 and HIV seropositive rates were 4.4%, 20.7% and 21.6%, respectively. After multivariable analysis, participating in group sex, reporting paying for sex, reporting sex with a casual partner in a park and being HSV-2 seropositive were associated with TP prevalence. Age ≥30 years, having less than a high school education, past use of recreational drugs, meeting casual sexual partners at a public venue (sauna) and TP seropositivity were associated with HSV-2 infection. The significant baseline prevalence of TP seropositivity and HSV-2 infection in this cohort demonstrates the need for screening and treatment of these STIs and targeted prevention interventions in Thai MSM in Bangkok.

Implementation of the INNO-LiPA Rif. TB® line-probe assay in rapid detection of multidrug-resistant tuberculosis in Latvia.

SETTING: In Latvia, 11% of tuberculosis (TB) patients have multidrug-resistant TB (MDR-TB). The INNO-LiPA Rif.TB ® line-probe assay (LPA) detects rifampin (RMP) resistance and may accelerate the time to effective MDRTB treatment. OBJECTIVE: To determine the impact of LPA on time to diagnosis, initiation of treatment, sputum culture conversion and treatment outcome. DESIGN: From October 2004 to September 2006, we performed LPA and drug susceptibility testing (DST) using BACTEC and Löwenstein-Jensen (LJ) media among all individuals at risk for MDR-TB compared to a 2003 cohort of 48 MDR-TB patients detected by BACTEC. RESULTS: In a total of 107 sputum smear-positive individuals at risk for MDR-TB, Mycobacterium tuberculosis was isolated from 85; 23 were RMP-resistant on LJ compared to 22 on LPA (96% sensitivity). There was a significant difference in the mean time between specimen collection and LPA result (10.0 days) and BACTEC DST result (17.0 days, P = 0.0005) in the LPA cohort. The LPA cohort achieved culture conversion a median of 105 days after treatment initiation vs. a median of 88.5 days (P = 0.54) in the BACTEC cohort. There was no difference in the proportion achieving culture conversion (P = 0.54) or in treatment outcome ( P = 0.65). CONCLUSION: LPA accelerated empiric treatment, but did not reduce the time to culture conversion or improve the rate of culture conversion or treatment outcome.

Adverse events related to multidrug-resistant tuberculosis treatment, Latvia, 2000-2004.

SETTING: Latvia has one of the highest rates of multidrug-resistant tuberculosis (MDR-TB) globally. Clinical management of MDR-TB requires lengthy multidrug regimens that often cause adverse events. DESIGN: We retrospectively reviewed records of patients who began MDR-TB treatment between 2000 and 2004. Treatment-related adverse events and factors associated with experiencing adverse events were evaluated. We also examined the frequency of and reasons for changing drug regimens. RESULTS: Among 1027 cases, 807 (79%) experienced at least one adverse event, with a median of three events per case. The most commonly reported events were nausea (58%), vomiting (39%) and abdominal pain (24%). More serious events, such as psychiatric episodes (13%), hepatitis (9%) and renal failure (4%), were relatively frequent. A change in drug dose due to an adverse event occurred in 201 (20%) cases, while 661 (64%) had at least one drug discontinued temporarily or permanently. Being older, female, having bilateral lung cavities and a greater number of TB symptoms at baseline were associated with an increased number of events. CONCLUSION: Adverse events were prevalent among MDR-TB cases treated in Latvia, with over two thirds requiring discontinuation of at least one drug. MDR-TB patients who are female, older or have severe TB disease should be closely monitored for treatment-related adverse events.

Refugee trauma versus torture trauma: a retrospective controlled cohort study of Tibetan refugees.

A retrospective cohort study of 35 refugee Tibetan nuns and lay students who were arrested and tortured in Tibet matched with 35 controls who were not arrested or tortured was carried out in India. Subjects were administered the Hopkins Checklist-25, evaluating anxiety symptoms, effective disturbances, somatic complaints, and social impairment. The prevalence of symptom scores in the clinical range for both cohorts was 41.4% for anxiety symptoms and 14.3% for depressive symptoms. The torture survivors had a statistically significant higher proportion of elevated anxiety scores than did the nontortured cohort (54.3% vs. 28.6%, p = .05). This was not true for elevated depressive scores. The results suggest that torture has long-term consequences on mental health over and above the effects of being uprooted, fleeing one's country, and living in exile as a refugee, though the additional effects were small. Political commitment, social support in exile, and prior knowledge of and preparedness for confinement and torture in the imprisoned cohort served to foster resilience against psychological sequelae. The contribution of Buddhist spirituality plays an active role in the development of protective coping mechanisms among Tibetan refugees.

Probable locally acquired mosquito-transmitted malaria in Georgia, 1999.

In July 1999, the Centers for Disease Control and Prevention received notification of a case of malaria in a 32-year-old female native of Colquitt County, Georgia, who had no history of travel into an area where malaria transmission is endemic. An epidemiological investigation confirmed the absence of risk factors, such as blood transfusion, organ transplantation, malariotherapy, needle sharing, or past malaria infection. Active case finding revealed no other infected persons in Colquitt County. Light trapping and larvae-dipping failed to identify adult or larval anophelines; however, Colquitt County is known to be inhabited by Anopheles quadrimaculatus, a competent malaria vector. The patient's home was located near housing used by seasonal migrant workers from regions of southern Mexico and Central America where malaria is endemic, one of whom may have been the infection source. The occurrence of malaria in this patient with no risk factors, except for proximity to potentially gametocytemic hosts, suggests that this illness probably was acquired through the bite of an Anopheles species mosquito.

Malaria surveillance--United States, 1998.

PROBLEM/CONDITION: Human malaria is caused by one or more of four species of intraerythrocytic protozoa of the genus Plasmodium (i.e., P. falciparum, P. vivax, P. ovale, or P. malariae). The protozoa are transmitted by the bite of an infective female Anopheles species mosquito. The majority of malaria infections in the United States occur among persons who have traveled to areas with endemic transmission. Cases occasionally occur that are acquired through exposure to infected blood products, by congenital transmission, or by local mosquitoborne transmission. Malaria surveillance is conducted to identify episodes of local transmission and to guide prevention recommendations for travelers. REPORTING PERIOD: Cases with an onset of symptoms during 1998. DESCRIPTION OF SYSTEM: Malaria cases confirmed by blood smear are reported to local and state health departments by health-care providers and laboratory staff members. Case investigations are conducted by local and state health departments, and reports are sent to CDC through the National Malaria Surveillance System (NMSS). This report uses NMSS data. RESULTS: CDC received reports of 1,227 cases of malaria with onsets of symptoms in 1998, among persons in the United States and its territories. This number represents a decrease of 20.5% from the 1,544 cases reported during 1997. P. falciparum, P. vivax, P. malariae, and P. ovale were identified in 42.8%, 37.8%, 3.5%, and 2.1% of cases, respectively. More than one species was present in seven patients (0.6% of total). The infecting species was not determined in 162 (13.2%) cases. Compared with reported cases in 1997, reported malaria cases acquired in Africa increased by 1.3% (n = 706); those acquired in Asia decreased by 52.1% (n = 239); and those acquired in the Americas decreased by 6.5% (n = 229). Of 636 U.S. civilians who acquired malaria abroad, 126 (19.8%) reportedly had followed a chemoprophylactic drug regimen recommended by CDC for the area to which they had traveled. Five persons became infected in the United States. One case was congenitally acquired; one was acquired by blood transfusion; and three were isolated cases that could not be epidemiologically linked to another case. Four deaths were attributed to malaria. INTERPRETATION: The 20.5% decrease in malaria cases during 1998 compared with 1997 resulted primarily from decreases in P. vivax cases acquired in Asia among non-U.S. civilians. This decrease could have resulted from local changes in disease transmission, decreased immigration from the region, decreased travel to the region, incomplete reporting from state and local health departments, or increased use of effective antimalarial chemoprophylaxis. In a majority of reported cases, U.S. civilians who acquired infection abroad had not taken an appropriate chemoprophylaxis regimen for the country where they acquired malaria. PUBLIC HEALTH ACTIONS TAKEN: Additional information was obtained from state and local health departments and clinics concerning the four fatal cases and the five infections acquired in the United States. Persons traveling to a malarious area should take a recommended chemoprophylaxis regimen and use personal protection measures to prevent mosquito bites. Any person who has been to a malarious area and subsequently develops fever or influenza-like symptoms should seek medical care immediately; the investigation should include a blood smear for malaria. Malaria infections can be fatal if not diagnosed and treated promptly. Current recommendations concerning prevention and treatment of malaria can be obtained from CDC.