Lauren A. Lambert

National Survey to Measure Rates of Liver Injury, Hospitalization, and Death Associated with Rifampin and Pyrazinamide for Latent Tuberculosis Infection

BACKGROUND Cases of severe and fatal liver injury were reported after a 2-month course of rifampin-pyrazinamide therapy was recommended in 2000 as an alternative to isoniazid for treatment of latent tuberculosis infection. We estimated rates of rifampin-pyrazinamide-associated liver injury and compared these with historical rates for isoniazid. METHODS We conducted a survey of state and city tuberculosis programs and other health care settings in the United States where rifampin-pyrazinamide was prescribed. The number of rifampin-pyrazinamide therapy initiations was collected, as well as the number of occurrences of (1) asymptomatic aspartate aminotransferase serum concentration >5 times the upper limit of normal, (2) symptomatic hepatitis (in which the patient was not hospitalized), (3) hospitalization for liver injury, (4) death with liver injury, and (5) treatment completion. We also searched a national pharmacy claims database (Verispan). Rates of these events were calculated. RESULTS Among 139 programs, 110 (79%) responded; 87 (79%) had initiated rifampin-pyrazinamide therapy for a total of 8087 patients between January 2000 and June 2002. Rates per 1000 rifampin-pyrazinamide therapy initiations during this period were 25.6 (95% confidence interval [CI], 22.3-29.3) for asymptomatic aspartate aminotransferase level >5 times the upper limit of normal and 18.7 (95% CI, 15.9-21.9) for hepatitis. Seven fatalities and 23 hospitalizations occurred, with rates of 0.9 (95% CI, 0.4-1.9) and 2.8 (95% CI, 1.8-4.3) per 1000 rifampin-pyrazinamide therapy initiations, respectively. Of 8087 patients, 64% completed rifampin-pyrazinamide therapy. The Verispan search revealed 1 rifampin-pyrazinamide-associated hospitalization (2.9 hospitalizations per 1000 rifampin-pyrazinamide therapy initiations; 95% CI, 0.1-18.4) and no deaths. Articles on the use of isoniazid therapy for latent tuberculosis infection that were published after 1990 reported fatality rates of 0.0-0.3 deaths per 1000 persons. CONCLUSIONS Rates of liver injury, hospitalization, and death associated with rifampin-pyrazinamide therapy exceed rates reported for isoniazid therapy. Because earlier randomized trials of rifampin-pyrazinamide lacked adequate statistical power to detect fatal events, the Centers for Disease Control and Prevention recommends that rifampin-pyrazinamide generally should not be used for treatment of latent tuberculosis infection.

Severe or Fatal Liver Injury in 50 Patients in the United States Taking Rifampin and Pyrazinamide for Latent Tuberculosis Infection

BACKGROUND Severe liver injuries were attributed to the rifampin and pyrazinamide (RZ) regimen after it was recommended for treating latent tuberculosis infection. Implicating RZ as the likeliest cause required excluding alternative causes. METHODS US health departments reported data on patients who died or were hospitalized for liver disease within 1 month after taking RZ for latent tuberculosis infection from October 1998 through March 2004. The circumstances were investigated on site for each case. Illness characteristics, reasons for RZ treatment, doses and frequency of administration of pyrazinamide, monitoring during treatment, and causes of liver injury were determined. RESULTS Liver injury was attributable to RZ use for all 50 patients reported, 12 of whom died. For 47 patients, RZ was the likeliest cause of liver injury. The median patient age was 44 years (range, 17-73 years). Thirty-two patients (64%) were male. Seven (16%) of 43 patients tested had hepatitis C virus antibodies, 1 (2%) of 45 had chronic hepatitis B, 3 (14%) of 22 had positive results of HIV serologic tests, 34 (71%) of 48 had alcohol use noted, and 33 (66%) of 50 were taking additional hepatotoxic medications. Six patients, 2 of whom died, had no predictors for liver disease. Patients who died were older (median age, 52 vs. 42 years; P=.08) and took a greater number of other medications (median number of medications, 4 vs. 2; P=.05) than did those who recovered, but these 2 factors were correlated (P<.01). Thirty-one patients (62%) were monitored according to guidelines, 9 of whom died. CONCLUSIONS RZ was the likeliest cause of most of these liver injuries, some of which were fatal in spite of monitoring. Fatality was predicted by age or use of other medications, but none of the cofactors showed promise as a reliable clinical predictor of severe liver injury.

Tuberculosis Infection in the United States: Prevalence Estimates from the National Health and Nutrition Examination Survey, 2011-2012

Background Reexamining the prevalence of persons infected with tuberculosis (TB) is important to determine trends over time. In 2011–2012 a TB component was included in the National Health and Nutrition Examination Survey (NHANES) to estimate the reservoir of persons infected with TB. Methods Civilian, noninstitutionalized U.S. population survey participants aged 6 years and older were interviewed regarding their TB history and eligibility for the tuberculin skin test (TST) and interferon gamma release assay (IGRA) blood test. Once eligibility was confirmed, both tests were conducted. Prevalence and numbers of TST positive (10 mm or greater), IGRA positive, and both TST and IGRA positive were calculated by adjusting for the complex survey design after applying corrections for item nonresponse and digit preference in TST induration measurements. To examine TST positivity over time, data from NHANES 1999–2000 were reanalyzed using the same statistical methods. The TST was performed using Tubersol, a commercially available purified protein derivative (PPD), rather than PPD-S, which was the antigen used in NHANES 1999–2000. Prior patient history of TB vaccination was not collected in this study nor were patients examined for the presence of a Bacillus of Calmette and Guerin (BCG) vaccine scar. Results For NHANES 2011–2012, TST and IGRA results were available for 6,128 (78.4%) and 7,107 (90.9%) eligible participants, respectively. There was no significant difference between the percentage of the U.S. population that was TST positive in 2011–2012 (4.7% [95% CI 3.4–6.3]; 13,276,000 persons) compared with 1999–2000 (4.3%; 3.5–5.3). In 2011–2012 the percentage that was IGRA positive was 5.0% (4.2–5.8) and double TST and IGRA positivity was 2.1% (1.5–2.8). The point estimate of IGRA positivity prevalence in foreign-born persons (15.9%; 13.5–18.7) was lower than for TST (20.5%; 16.1–25.8) in 2011–2012. The point estimate of IGRA positivity prevalence in U.S.-born persons (2.8%; 2.0–3.8) was higher than for TST (1.5%; 0.9–2.6). Conclusions No statistically significant decline in the overall estimated prevalence of TST positivity was detected from 1999–2000 to 2011–2012. The prevalence of TB infection, whether measured by TST or IGRA, remains lower among persons born in the United States compared with foreign-born persons.

Costs of implementing and maintaining a tuberculin skin test program in hospitals and health departments

OBJECTIVE To determine (1) the annual costs of implementing and maintaining tuberculin skin test (TST) programs at participating study sites, (2) the cost of the TST program per healthcare worker (HCW), and (3) the outcomes of the TST programs, including the proportion of HCWs with a documented TST conversion and the proportion who accepted and completed treatment for latent TB infection, before and after the implementation of staffTRAK-TB software (Centers for Disease Control and Prevention, Atlanta, GA). DESIGN Cost analysis in which costs for salaries, training, supplies, radiography, and data analysis were collected for two 12-month periods (before and after the implementation of staffTRAK-TB). SETTING Four hospitals (two university and two city) and two health departments (one small county and one big city). RESULTS The annual cost of implementing and maintaining a TST program ranged from dollars 66,564 to dollars 332,728 for hospitals and dollars 92,886 to dollars 291,248 for health departments. The cost of the TST program per HCW ranged from dollars 41 to dollars 362 for hospitals and dollars 176 to dollars 264 for health departments. CONCLUSIONS Costs associated with implementing and maintaining a TST program varied widely among the participating study sites, both before and after the implementation of staffTRAK-TB. Compliance with the TB infection control guidelines of the Centers for Disease Control and Prevention may require a substantial investment in personnel time, effort, and commitment.

Potential nosocomial exposure to Mycobacterium tuberculosis from a bronchoscope.

OBJECTIVE To investigate a possible nosocomial outbreak of tuberculosis (TB). DESIGN Retrospective cohort study. SETTING Community hospital. METHODS We reviewed medical records, hospital infection control measures, and potential locations of nosocomial exposure. We examined the results of acid-fast bacilli (AFB) smears, cultures, and drug susceptibility testing, and performed a DNA fingerprint analysis. We observed laboratory specimen processing procedures and bronchoscope disinfection procedures. We also reviewed bronchoscopy records. RESULTS In October 2000, three patients had bronchoscopy specimen cultures that were positive for Mycobacterium tuberculosis. Of the three, only one had clinical signs and symptoms consistent with TB and positive AFB sputum smears. The other two did not have signs and symptoms consistent with TB and had no known exposure to individuals with infectious TB. The three M. tuberculosis isolates had matching DNA fingerprints. No evidence of laboratory cross-contamination was identified. The three culture-positive specimens of M. tuberculosis were collected with the same bronchoscope within 9 days. This bronchoscope was inadequately cleaned and disinfected between patients, and the automated reprocessor used was not approved for use with the hospital bronchoscope. CONCLUSIONS One of the bronchoscopes at this hospital was contaminated with M. tuberculosis during bronchoscopy of an AFB-smear-positive patient. Subsequent specimen contamination likely occurred because the bronchoscope had been inadequately cleaned and disinfected. Patients who subsequently underwent bronchoscopy were also potentially exposed to M. tuberculosis from this bronchoscope.

Investigation of Healthcare-Associated Transmission of Mycobacterium tuberculosis among Patients with Malignancies at Three Hospitals and at a Residential Facility

Immunocompromised patients have an increased risk of experiencing progression of latent Mycobacterium tuberculosis infection (LTBI) to active tuberculosis (TB) disease. In January 2002, 2 patients with leukemia (Patients 1 and 2) developed pulmonary TB after recent exposure at 3 hospitals (Hospital A, Hospital B, and Hospital C) and at a residential facility for patients with cancer. Neither was known to have LTBI. Within 1 year, 3 other patients with malignancy and TB disease had been identified at these facilities, prompting an investigation of healthcare facility–associated transmission of M. tuberculosis.

A survey of latent tuberculosis infection among laboratory healthcare workers in New York City

OBJECTIVE To determine the prevalence of positive tuberculin skin tests (TSTs), incidence of TST conversion, risk factors for positive TSTs, and history of active TB among HCWs in microbiology laboratories in New York City. DESIGN Two-year survey from May 1999 to June 2001. SETTING Nineteen microbiology laboratories. RESULTS During the first year, interviews were conducted with 345 laboratory HCWs (mean, 18 HCWs per site; range, 2 to 51) to assess the prevalence of positive TSTs, but 3 (1%) could not recall their result and were excluded from further analyses. The mean age of the remaining 342 HCWs was 48 years; 68% (n = 233) were female, 54% (n = 183) received bacille Calmette-Guerin (BCG) vaccination, and 71% (n = 244) were foreign born. The prevalence of a positive TST was 57% (n = 196), but only 20% (n = 39) of the HCWs received isoniazid. The incidence of TST conversion in the second year of the study was 1% (1 of 108). Multivariate analysis identified age (odds ratio [OR] per year, 1.05; 95% confidence interval [CI95], 1.02-1.08), foreign birth (OR, 3.80; CI95, 1.98-7.28), BCG immunization (OR, 4.89; CI95, 2.72-8.80), and employment in a mycobacteriology laboratory (OR, 2.14; CI95, 1.25-3.68) as risk factors for a positive TST. Only one HCW had been treated for active TB. CONCLUSIONS The prevalence of positive TSTs was high among laboratory HCWs, but the TST conversion rate was low. Higher rates of treatment for latent TB infection are desirable.

Tuberculosis among healthcare workers, United States, 1995-2007.

OBJECTIVE We examined surveillance data to describe the epidemiology of tuberculosis (TB) among healthcare workers (HCWs) in the United States during the period 1995-2007. DESIGN Cross-sectional descriptive analysis of existing surveillance data. SETTING AND PARTICIPANTS TB cases reported to the Centers for Disease Control and Prevention from the 50 states and the District of Columbia from 1995 through 2007. RESULTS Of the 200,744 reported TB cases in persons 18 years of age or older, 6,049 (3%) occurred in individuals who were classified as HCWs. HCWs with TB were more likely than other adults with TB to be women (unadjusted odds ratio [95% confidence interval], 4.1 [3.8-4.3]), be foreign born (1.3 [1.3-1.4]), have extrapulmonary TB (1.6 [1.5-1.7]), and complete TB treatment (2.5 [2.3-2.8]). CONCLUSIONS Healthcare institutions may benefit from intensifying TB screening of HCWs upon hire, especially persons from countries with a high incidence of TB, and encouraging treatment for latent TB infection among HCWs to prevent progression to TB disease.

Characteristics of multidrug-resistant tuberculosis in Namibia

BackgroundTo describe the epidemiology and possible risk factors for the development of multidrug-resistant tuberculosis (MDR-TB) in Namibia.MethodsUsing medical records and patient questionnaires, we conducted a case-control study among patients diagnosed with TB between January 2007 and March 2009. Cases were defined as patients with laboratory-confirmed MDR-TB; controls had laboratory-confirmed drug-susceptible TB or were being treated with WHO Category I or Category II treatment regimens.ResultsWe enrolled 117 MDR-TB cases and 251 TB controls, of which 100% and 2% were laboratory-confirmed, respectively. Among cases, 97% (113/117) had been treated for TB before the current episode compared with 46% (115/251) of controls (odds ratio [OR] 28.7, 95% confidence interval [CI] 10.3–80.5). Cases were significantly more likely to have been previously hospitalized (OR 1.9, 95% CI 1.1–3.5) and to have had a household member with MDR-TB (OR 5.1, 95% CI 2.1–12.5). These associations remained significant when separately controlled for being currently hospitalized or HIV-infection.ConclusionsMDR-TB was associated with previous treatment for TB, previous hospitalization, and having had a household member with MDR-TB, suggesting that TB control practices have been inadequate. Strengthening basic TB control practices, including expanding laboratory confirmation, directly observed therapy, and infection control, are critical to the prevention of MDR-TB.

Public health response to a multidrug-resistant tuberculosis outbreak among Guatemalans in Tennessee, 2007.

Background: In June 2007, the Tennessee Department of Health notified the Centers for Disease Control and Prevention of four multidrug-resistant tuberculosis (MDR TB) cases in individuals of Guatemalan descent, and requested onsite epidemiologic assistance to investigate this outbreak. Methods: A case was defined as either culture-confirmed MDR TB with a drug-susceptibility pattern closely resembling that of the index case, or a clinical diagnosis of active TB disease and corroborated contact with a person with culture-confirmed MDR TB. Medical records were reviewed, and patients and their contacts were interviewed. Results: Five secondary TB cases were associated with the index case. Of 369 contacts of the index case, 189 (51%) were evaluated. Of those, 97 (51%) had positive tuberculin skin test (TST) results, 79 (81%) began therapy for latent TB infection (LTBI), and 38 (48%) completed LTBI therapy. Conclusion: Despite consistent follow up by public health officials, a low proportion of patients diagnosed with LTBI completed therapy. Clinicians and public health practitioners who serve immigrant communities should be vigilant for MDR TB.