John A. Jereb

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.

Interferon-γ release assays: new diagnostic tests for Mycobacterium tuberculosis infection, and their use in children

Purpose of review The testing and treatment of children at risk for Mycobacterium tuberculosis infection represents an important public health priority in the United States. Until recently, diagnosis has relied upon the tuberculin skin test (TST). New interferon-γ release assays (IGRAs) offer improvements over TST, but these tests have not been studied in children until recently. Recent findings Evidence regarding IGRA performance in children is accumulating rapidly. Overall, the findings demonstrate performance of IGRAs equivalent or superior to that of the TST. However, IGRAs have biological limitations similar to TST and some technical problems of their own, and critical gaps in our knowledge remain. Summary Current evidence supports usage of IGRAs in children aged 5 years or older. IGRAs are preferred over TST when specificity is paramount or wherein patients might fail to return for TST reading. Evidence for use in children aged less than 5 years is insufficient at this time: the sensitivity is poorly defined, and TST is preferred for testing these children. Future IGRA research should focus on children aged less than 5 years for informing expanded usage in this vulnerable population.

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.

Unintended consequences: mandatory tuberculin skin testing and severe isoniazid hepatotoxicity.

After mandatory school-enrollment tuberculin skin testing, a 4-year-old girl who was at low risk for Mycobacterium tuberculosis infection had severe isoniazid hepatotoxicity that was managed with a liver transplant. Although severe isoniazid hepatotoxicity is very uncommon in children, this case emphasizes the need to limit skin testing to persons who have a risk factor for infection and to educate parents on how to monitor for adverse effects during treatment.

New Guidelines About Latent Tuberculosis Infection in Children and Adolescents: A Welcome Advancement

In a supplement to this month’s issue of Pediatrics , comprehensive new guidelines are being published on finding and treating latent tuberculosis infection (LTBI) in children and adolescents.1 The collaborative group responsible for the guidelines is composed of health professionals from US health departments, the National Tuberculosis Model Centers, academic institutions, and the Centers for Disease Control and Prevention. With these guidelines, pediatricians have a single comprehensive reference about preventing tuberculosis (TB) in their patients. The guidelines are founded on a paradigm that is evolving with the TB epidemiology for US children and adolescents. Although TB rates have been declining overall since 1992, infections and cases have become even more concentrated among high-risk groups such as children born outside the United States. Thus, these guidelines recommend that children should be screened for risk factors for TB and LTBI and tested with the tuberculin skin test only if at least 1 risk factor is present. These guidelines discourage the use of administrative or mandated tuberculin skin tests for entry to child care, school, or summer camp, because these they are likely to consume limited resources but yield very little in finding current cases or preventing future ones. For these settings and most others, testing should be undertaken only if (1) preceded by screening for risk factors as described in the guidelines and (2) coupled to systems that start children who have LTBI on treatment and help them to complete it. The authors of … Reprint requests to (L.J.N.) Division of TB Elimination, Centers for Disease Control and Prevention, 1600 Clifton Rd, MS E-10, Atlanta, GA 30333. E-mail: lnelson{at}cdc.gov

Comparison of Sensitivities to Two Commercially Available Tuberculin Skin Test Reagents in Persons with Recent Tuberculosis

Discrepancies have been reported between results obtained with tuberculin skin tests (TSTs) performed with use of different reagents. We compared TST results and determined the sensitivities of the two commercially available TSTs in 51 human immunodeficiency virus-negative persons with culture-confirmed active tuberculosis. Simultaneous TSTs were done with use of the Mantoux method and 5-tuberculin unit purified protein derivative (PPD) tuberculin preparations from single lots of Aplisol and Tubersol. Aplisol skin test reactions ranged from 5 mm to 26 mm (median, 16.0 mm), and Tubersol reactions ranged from 7 mm to 23 mm (median, 15.0 mm). The mean difference in paired reaction sizes for the two reagents was 0.58 mm and was not statistically different from zero (P value, 0.26). The difference in reaction sizes was < or =2 mm in 55% and > or =5 mm in 18% of patients. With a cutoff of either 5 mm or 10 mm to define a positive reaction, all results were concordant, with sensitivity of 100% and 96%, respectively. We found indistinguishable reaction size distributions and median TST results for the two commercially available PPD TST reagents, Aplisol and Tubersol, in a population with recent culture-proven tuberculosis.

Pandemic influenza: implications for programs controlling for HIV infection, tuberculosis, and chronic viral hepatitis.

Among vulnerable populations during an influenza pandemic are persons with or at risk for HIV infection, tuberculosis, or chronic viral hepatitis. HIV-infected persons have higher rates of hospitalization, prolonged illness, and increased mortality from influenza compared with the general population. Persons with tuberculosis and chronic viral hepatitis may also be at increased risk of morbidity and mortality from influenza because of altered immunity and chronic illness. These populations also face social and structural barriers that will be exacerbated by a pandemic. Existing infrastructure should be expanded and pandemic planning should include preparations to reduce the risks for these populations.

High Rate of Treatment Completion in Program Settings With 12-Dose Weekly Isoniazid and Rifapentine for Latent Mycobacterium tuberculosis Infection

Background Randomized controlled trials have demonstrated that the newest latent tuberculosis (LTBI) regimen, 12 weekly doses of directly observed isoniazid and rifapentine (3HP), is as efficacious as 9 months of isoniazid, with a greater completion rate (82% vs 69%); however, 3HP has not been assessed in routine healthcare settings. Methods Observational cohort of LTBI patients receiving 3HP through 16 US programs was used to assess treatment completion, adverse drug reactions, and factors associated with treatment discontinuation. Results Of 3288 patients eligible to complete 3HP, 2867 (87.2%) completed treatment. Children aged 2-17 years had the highest completion rate (94.5% [155/164]). Patients reporting homelessness had a completion rate of 81.2% (147/181). In univariable analyses, discontinuation was lowest among children (relative risk [RR], 0.44 [95% confidence interval {CI}, .23-.85]; P = .014), and highest in persons aged ≥65 years (RR, 1.72 [95% CI, 1.25-2.35]; P < .001). In multivariable analyses, discontinuation was lowest among contacts of patients with tuberculosis (TB) disease (adjusted RR [ARR], 0.68 [95% CI, .52-.89]; P = .005) and students (ARR, 0.45 [95% CI, .21-.98]; P = .044), and highest with incarceration (ARR, 1.43 [95% CI, 1.08-1.89]; P = .013) and homelessness (ARR, 1.72 [95% CI, 1.25-2.39]; P = .001). Adverse drug reactions were reported by 1174 (35.7%) patients, of whom 891 (76.0%) completed treatment. Conclusions Completion of 3HP in routine healthcare settings was greater overall than rates reported from clinical trials, and greater than historically observed using other regimens among reportedly nonadherent populations. Widespread use of 3HP for LTBI treatment could accelerate elimination of TB disease in the United States.

Possible Airborne Person-to-Person Transmission of Mycobacterium bovis — Nebraska 2014–2015

Mycobacterium bovis, one of several mycobacteria of the M. tuberculosis complex, is a global zoonotic pathogen that primarily infects cattle. Humans become infected by consuming unpasteurized dairy products from infected cows; possible person-to-person airborne transmission has also been reported. In April 2014, a man in Nebraska who was born in Mexico was determined to have extensive pulmonary tuberculosis (TB) caused by M. bovis after experiencing approximately 3 months of cough and fever. Four months later, a U.S.-born Hispanic girl from a nearby town who had been ill for 4-5 months was also determined to have pulmonary TB caused by M. bovis. The only social connection between the two patients was attendance at the same church, and no common dietary exposure was identified. Both patients had pulmonary cavities on radiography and acid-fast bacilli (AFB) on sputum-smear microscopy, indicators of being contagious. Whole-genome sequencing results of the isolates were nearly indistinguishable. Initial examination of 181 contacts determined that 39 (22%) had latent infection: 10 (42%) of 24 who had close exposure to either patient, 28 (28%) of 100 who were exposed to one or both patients in church, and one (2%) of 57 exposed to the second patient at a school. Latent infection was diagnosed in six contacts on follow-up examination, 2 months after an initial negative test result, for an overall latent infection rate of 25%. No infected contacts recalled consuming unpasteurized dairy products, and none had active TB disease at the initial or secondary examination. Persons who have M. bovis TB should be asked about consumption of unpasteurized dairy products, and contact investigations should follow the same guidance as for M. tuberculosis TB.

Do we have evidence for policy changes in the treatment of children with latent tuberculosis infection

For more than 50 years, isoniazid has been prescribed to prevent the progression of latent tuberculosis infection (LTBI) to overt TB disease.1,2 Treating LTBI benefits the individual by preventing TB disease, and it benefits public health by diminishing the pool of infection that could become contagious TB disease in the future.3 In this issue of Pediatrics , Finnell et al4 point to rising Mycobacterium tuberculosis drug-resistance rates globally and question the standard regimen of 9 months of isoniazid treatment. From a cost/benefit analysis, they conclude that rifampin should replace isoniazid for treating LTBI in immigrant children from countries where the likelihood of being infected with isoniazid-resistant M tuberculosis exceeds 11%. An estimated 586 000 US children aged 1 to 14 years have LTBI, 70% of whom were born overseas.5 The worldwide epidemic of drug-resistant TB warrants consideration of alternative treatment regimens. For a proposed strategy to be effective, treatment should be efficacious, safe, acceptable to the patient, and cost-effective. Isoniazid fulfills these criteria. Cost/benefit models for treating LTBI are sensitive to several variables: (1) the proportion of … Address correspondence to John A. Jereb, MD, Centers for Disease Control and Prevention, 1600 Clifton Rd, MS E-10, Atlanta, GA 30333. E-mail: jxj4{at}cdc.gov