Max R. O'Donnell

High Incidence of Hospital Admissions with Multidrug Resistant and Extensively Drug Resistant Tuberculosis among South African Health Care Workers

BACKGROUND Nosocomial transmission has been described in extensively drug-resistant tuberculosis (XDR-TB) and HIV co-infected patients in South Africa. However, little is known about the rates of drug-resistant tuberculosis among health care workers in countries with high tuberculosis and HIV burden. OBJECTIVE To estimate rates of multidrug-resistant tuberculosis (MDR-TB) and XDR-TB hospitalizations among health care workers in KwaZulu-Natal, South Africa. DESIGN Retrospective study of patients with drug-resistant tuberculosis who were admitted from 2003 to 2008 for the initiation of drug-resistant tuberculosis therapy. SETTING A public tuberculosis referral hospital in KwaZulu-Natal, South Africa. PARTICIPANTS 231 health care workers and 4151 non-health care workers admitted for initiation of MDR-TB or XDR-TB treatment. MEASUREMENTS Hospital admission rates and hospital admission incidence rate ratios. RESULTS Estimated incidence of MDR-TB hospitalization was 64.8 per 100,000 health care workers versus 11.9 per 100,000 non-health care workers (incidence rate ratio, 5.46 [95% CI, 4.75 to 6.28]). Estimated incidence of XDR-TB hospitalizations was 7.2 per 100,000 health care workers versus 1.1 per 100,000 non-health care workers (incidence rate ratio, 6.69 [CI, 4.38 to 10.20]). A higher percentage of health care workers than non-health care workers with MDR-TB or XDR-TB were women (78% vs. 47%; P < 0.001), and health care workers were less likely to report previous tuberculosis treatment (41% vs. 92%; P < 0.001). HIV infection did not differ between health care workers and non-health care workers (55% vs. 57%); however, among HIV-infected patients, a higher percentage of health care workers were receiving antiretroviral medications (63% vs. 47%; P < 0.001). LIMITATION The study had an observational retrospective design, is subject to referral bias, and had no information on type of health care work or duration of occupational exposure to tuberculosis. CONCLUSION Health care workers in this HIV-endemic area were substantially more likely to be hospitalized with either MDR-TB or XDR-TB than were non-health care workers. The increased risk may be explained by occupational exposure, underlining the urgent need for tuberculosis infection-control programs.

Revisiting Rates of Reactivation Tuberculosis: A Population-based Approach

RATIONALE Reactivation tuberculosis (TB) occurs as a result of reactivation of latent TB infection (LTBI), and was reported to occur in the United States at a rate of 0.10 to 0.16 cases per 100 person-years in the 1950s; it has not been measured since. OBJECTIVES To calculate the rate of reactivation TB in a U.S. community. METHODS A population-based tuberculin skin test survey for LTBI was performed in western Palm Beach County, Florida, from 1998 to 2000 along with a cluster analysis of TB case isolates in the same area from 1997 to 2001. Reactivation (unclustered) TB was presumed to have arisen from the population with LTBI. MEASUREMENTS AND MAIN RESULTS The rate of reactivation TB among persons with LTBI without HIV infection was 0.040 cases per 100 person-years (95% confidence interval [CI], 0.024-0.067) using the n method and 0.058 cases per 100 person-years (95% CI, 0.038-0.089) using the n-1 method. HIV infection was the strongest risk factor for reactivation (rate ratio [RR], 57; 95% CI, 27-120; P < 0.001). Among persons without HIV infection, reactivation was increased among those older than 50 years (RR, 3.8; 95% CI, 1.3-11) and among those born in the United States (RR, 3.2; 95% CI, 1.1-9.3). CONCLUSIONS Rates of reactivation TB in this area have declined substantially since the 1950s. The greatest part of this decline may be attributed to the disappearance of old, healed TB in the population. If similar declines are seen in other areas of the United States, the cost-effectiveness of screening and treatment of LTBI may be substantially less than previously estimated.

Systematic review of clofazimine for the treatment of drug-resistant tuberculosis

The increased incidence of drug-resistant tuberculosis has created an urgent necessity for the development of new and effective anti-tuberculosis drugs and for alternative therapeutic regimens. Clofazimine (CFZ) is a fat-soluble riminophenazine dye used in the treatment of leprosy worldwide. CFZ has also been used as a Group 5 drug in the treatment of tuberculosis (TB). A large cohort study from Bangladesh published in 2010 described a treatment regimen for multidrug-resistant tuberculosis (MDR-TB) including CFZ as being highly effective against MDR-TB. We searched multiple databases for studies published through February 2012 that reported use of CFZ in MDR- and extensively drug-resistant TB (XDR-TB) treatment regimens. We identified nine observational studies (6 MDR-TB and 3 XDR-TB) including patients with drug-resistant TB treated with CFZ. Overall, 65% (95% confidence interval [95%CI] 54-76) of the patients experienced favorable outcomes, defined as either cure or treatment completion. Using random effects meta-analysis, 65% (95%CI 52-79) of those with MDR-TB and 66% (95%CI 42-89) of those with XDR-TB experienced favorable treatment outcomes. High-quality prospective cohort studies and clinical trials examining the effect of CFZ as part of drug-resistant TB treatment regimens are needed.

Malnutrition associated with unfavorable outcome and death among South African MDR-TB and HIV co-infected children.

SETTING Pediatric multidrug-resistant tuberculosis (MDR-TB) is complicated by difficult diagnosis, complex treatment, and high mortality. In South Africa, these challenges are amplified by human immunodeficiency virus (HIV) co-infection; however, evidence on treatment outcomes among co-infected children is limited. OBJECTIVE Using conventional and new pediatric definitions, to describe treatment outcomes and identify risk factors for unfavorable outcome and mortality in children aged <15 years with MDR-TB or extensively drug-resistant TB (XDR-TB) in KwaZulu-Natal, South Africa. DESIGN Retrospective cohort study in a regional TB referral hospital. RESULTS From January 2009 to June 2010, 84 children (median age 8 years, IQR 4-12) with MDR-TB (n = 78) or XDR-TB (n = 6) initiated treatment. Sixty-four (77%) were HIV-positive and 62 (97%) received antiretroviral therapy. Sixty-six (79%) achieved favorable treatment outcomes. Overall mortality was 11% (n = 9) at 18 months after initiation of treatment. Malnutrition (aOR 27.4, 95%CI 2.7-278.7) and severe radiographic findings (aOR 4.68, 95%CI 1.01-21.9) were associated with unfavorable outcome. New pediatric outcome definitions increased the proportion classified as cured. CONCLUSION It is possible to successfully treat pediatric MDR-TB-HIV even in resource-poor settings. Malnutrition is a marker for severe TB-HIV disease, and is a potential target for future interventions in these patients.

Dual skin tests with Mycobacterium avium sensitin and PPD to detect misdiagnosis of latent tuberculosis infection.

BACKGROUND A positive tuberculin skin test (TST) may indicate cross-reacting immunity to non-tuberculous mycobacteria (NTM) and not latent tuberculosis infection (LTBI). OBJECTIVES To assess misclassification of LTBI, as assessed by skin testing with Mycobacterium avium sensitin (MaS), and to determine how this misclassification affects the analysis of risk factors for LTBI. METHODS In a population-based survey, participants underwent skin testing with M. tuberculosis purified protein derivative (PPD) and MaS. A PPD-dominant skin test was a reaction that was ≥ 3 mm larger than the MaS reaction; a MaS-dominant skin test was a reaction that was ≥ 3 mm larger than the PPD reaction. RESULTS Of 447 randomly selected persons, 135 (30%) had a positive PPD test. Of these, 21 (16%) were MaS- dominant, and were therefore attributable to NTM and misclassified as LTBI. PPD reactions of 5-14 mm were more likely to be misclassified than those ≥ 15 mm (OR = 5.0, 95%CI 1.9-13.2). Adjusting for misclassification had only a small impact on the analysis of risk factors for LTBI. CONCLUSIONS A substantial number of individuals who are diagnosed with LTBI are actually sensitized to NTM. Using dual skin testing would reduce misdiagnosis and prevent unnecessary treatment.

Elucidating the role of clofazimine for the treatment of tuberculosis

Clofazimine (CFZ), a riminophenazine and a key component of the treatment regimen for lepromatous leprosy, has been rehabilitated clinically for the treatment of multidrug-resistant tuberculosis (MDR-TB). Observational studies and a randomized control trial suggest efficacy in the treatment of MDR-TB and the potential for treatment shortening. Animal and translational research have shown mixed results. In this article, we review key clinical, animal, and translational data to better understand the potential role of CFZ in the treatment of MDR-TB and in shortening anti-tuberculosis treatment.

Acceptance of interferon-gamma release assay by a high-risk urban cohort.

BACKGROUND QuantiFERON ® -TB Gold (QFT-G), an interferon-gamma release assay, is approved for the diagnosis of latent tuberculosis infection (LTBI). It is unknown if patients at high risk for LTBI will more readily accept LTBI treatment based on tuberculosis skin testing (TST) or QFT-G. METHODS Prospectively enrolled participants were interviewed, were read an informational paragraph on QFT-G, completed a questionnaire and were tested with QFT-G. RESULTS A total of 230 consecutive participants with a history of hepatitis C virus infection and active or past illicit drug use were enrolled and underwent QFT-G testing: 77% had recent TST, 82% were human immuno- deficiency virus co-infected, 87% had a history of injection drug use, and 52% a history of homelessness. Of the 230 participants, 148 (64%) stated a preference for TST compared to QFT-G. The majority would take treatment based on either test (68%). A minority of patients (20%) stated a willingness to take LTBI treatment based on TST alone. Black race was associated with a willingness to take treatment based on TST (OR 2.72, 95%CI 1.05-7.10). CONCLUSIONS Patients at high risk for LTBI were found to prefer TST to QFT-G. Most would accept treatment based on either test, and a subset stated unwillingness to take treatment based on QFT-G results. Outreach and education should accompany QFT-G roll-out in high-risk urban populations.

Sustained reduction in tuberculosis incidence following a community-based participatory intervention.

BACKGROUND Rates of latent tuberculosis infection (LTBI) and tuberculosis (TB) disease are elevated in the rural southeastern United States and among US- and foreign-born Black residents. To prevent TB and reduce TB transmission, community-based strategies are essential. OBJECTIVE To describe a community-based participatory intervention for improving the detection and treatment of LTBI and TB and reducing TB incidence. DESIGN In rural Florida, we carried out a community educational TB campaign from 1997 to 2000, including presentations at community events, a media campaign and working with local community groups to develop culturally appropriate prevention messages. The campaign was implemented concurrently with a population-based LTBI survey. RESULTS The annual TB incidence rate in the intervention area decreased from 81 per 100 000 in 1994-1997, to 42/ 100 000 in 1998-2001, and to 25/100 000 in 2002-2005 (P = 0.001). This decrease was not observed in communities where the intervention was not implemented. There was no decrease in the TB incidence rate ratio between Blacks and non-Blacks in either region during the study period. CONCLUSIONS We conclude that community participation in LTBI screening and TB education was associated with a substantial reduction in TB rates. Although the TB incidence rate ratio did not decrease between Blacks and non-Blacks, TB incidence fell in all racial groups.