Thomas R. Navin

Sulfa or sulfone prophylaxis and geographic region predict mutations in the Pneumocystis carinii dihydropteroate synthase gene.

To determine factors associated with mutations in the Pneumocystis carinii dihydropteroate synthase (DHPS) gene, a prospective study of human immunodeficiency virus (HIV)-infected patients with confirmed P. carinii pneumonia was conducted in Atlanta, Seattle, and San Francisco. Clinical information was obtained from patient interview and chart abstraction. DHPS genotype was determined from DNA sequencing. Overall, 76 (68.5%) of 111 patients had a mutant DHPS genotype, including 22 (81.5%) of 27 patients from San Francisco. In multivariate analysis, sulfa or sulfone prophylaxis and study site were independent predictors of a mutant genotype. Fourteen (53.8%) of 26 patients who were newly diagnosed with HIV infection and had never taken prophylaxis had a mutant genotype. The significance of geographic location as a risk factor for mutant genotype and the high proportion of mutant genotypes among persons never prescribed prophylaxis, including those newly diagnosed with HIV infection, provide indirect evidence that these mutations are transmitted from person to person either directly or through a common environmental source.

Effect of mutations in Pneumocystis carinii dihydropteroate synthase gene on outcome of P carinii pneumonia in patients with HIV-1: a prospective study

BACKGROUND Investigators have reported that patients infected with Pneumocystis carinii containing mutations in the DHPS (dihydropteroate synthase) gene have a worse outcome than those infected with P carinii containing wild-type DHPS. We investigated patients with HIV-1 infection and P carinii pneumonia to determine if DHPS mutations were associated with poor outcomes in these patients. METHODS We compared presence of mutations at the DHPS locus with survival and response of patients to co-trimoxazole or other drugs. FINDINGS For patients initially given co-trimoxazole, nine (14%) of 66 with DHPS mutant died, compared with nine (25%) of 36 with wild type (risk ratio50.55 [95% CI=0.24-1.25]; p=0.15). Ten (15%) of 66 patients with a DHPS mutant did not respond to treatment, compared with 13 (36%) of 36 patients with the wild type (0.42 [0.20-0.86]; p=0.02). For patients aged 40 years or older, four (14%) of 29 with the mutant and nine (56%) of 16 with the wild type died (0.25 [0.09-0.67]; p=0.005). INTERPRETATION These results, by contrast with those of previous studies, suggest that patients with wild-type P carinii do not have a better outcome than patients with the mutant when given co-trimoxazole. Our results suggest that presence of a DHPS mutation should be only one of several criteria guiding the choice of initial drug treatment of P carinii pneumonia in patients with HIV-1 infection.

Human Tuberculosis due to Mycobacterium bovis in the United States, 1995-2005

BACKGROUND Understanding the epidemiology of human Mycobacterium bovis tuberculosis (TB) in the United States is imperative; this disease can be foodborne or airborne, and current US control strategies are focused on TB due to Mycobacterium tuberculosis and airborne transmission. The National TB Genotyping Services work has allowed systematic identification of M. tuberculosis-complex isolates and enabled the first US-wide study of M. bovis TB. METHODS Results of spacer oligonucleotide and mycobacterial interspersed repetitive units typing were linked to corresponding national surveillance data for TB cases reported for the period 2004-2005 and select cases for the period 1995-2003. We also used National TB Genotyping Service data to evaluate the traditional antituberculous drug resistance-based case definition of M. bovis TB. RESULTS Isolates from 165 (1.4%) of 11,860 linked cases were identified as M. bovis. Patients who were not born in the United States, Hispanic patients, patients <15 years of age, patients reported to be HIV infected, and patients with extrapulmonary disease each had increased adjusted odds of having M. bovis versus M. tuberculosis TB. Most US-born, Hispanic patients with TB due to M. bovis (29 [90.6%] of 32) had extrapulmonary disease, and their overall median age was 9.5 years. The National TB Genotyping Services data indicated that the pyrazinamide-based case definitions sensitivity was 82.5% (95% confidence interval; 75.3%-87.9%) and that data identified 14 errors in pyrazinamide-susceptibility testing or reporting. CONCLUSIONS The prevalence of extrapulmonary disease in the young, US-born Hispanic population suggests recent transmission of M. bovis, possibly related to foodborne exposure. Because of its significantly different epidemiologic profile, compared with that of M. tuberculosis TB, we recommend routine surveillance of M. bovis TB. Routine surveillance and an improved understanding of M. bovis TB transmission dynamics would help direct the development of additional control measures.

Declining CD4+ T-lymphocyte counts are associated with increased risk of enteric parasitosis and chronic diarrhea: results of a 3-year longitudinal study.

From January 1991 through September 1994, we observed people who were infected with HIV to assess the impact of enteric parasite-associated diarrhea. Respondents answered comprehensive questionnaires covering clinical and epidemiologic information and provided stool specimens monthly, which were examined unstained as well as stained with trichrome, chromotrope 2R, and with Kinyoun carbol-fuchsin, and with indirect immunofluorescence for Cryptosporidium. In all, 602 participants, who were interviewed, provided stool specimens at 3254 monthly visits. Parasites were associated with 50 of 354 (14.1%) acute diarrheal episodes (lasting < or = 28 days) and with 97 of 279 (34.8%) chronic episodes (lasting > 28 days). A parasite was associated with 31 of 222 (14.0%) episodes that occurred when CD4+ counts were > or = 200 cells/microl and with 150 of 566 (26.5%) episodes that occurred when CD4+ counts were < 200 cells/microl. The most commonly identified parasite was C. parvum, which was associated with 18 of 354 (5.1%) acute episodes and 36 (12.9%) of the 279 chronic episodes of diarrhea. In this patient population, enteric protozoan parasites were commonly associated with illness, particularly as immunosuppression worsened, and were more likely to be associated with chronic rather than acute diarrhea.

Risk Factors for Primary Pneumocystis carinii Pneumonia in Human Immunodeficiency Virus—Infected Adolescents and Adults in the United States: Reassessment of Indications for Chemoprophylaxis

Risk factors for the development of a first episode of Pneumocystis carinii pneumonia (PCP) were investigated in the Adult and Adolescent Spectrum of Disease Project, a medical record review study involving longitudinal follow-up of human immunodeficiency virus-infected adults in 9 US cities. Risk factors included decreasing CD4 lymphocyte count and history of AIDS-defining illness, non-P. carinii pneumonia, oral thrush, or unexplained fever for > or = 2 days; PCP prophylaxis was protective. PCP incidence/100 person-years of observation among persons not prescribed PCP prophylaxis was higher in those with CD4 lymphocyte counts < 250 cells/microL or CD4 cell percent < 14% (8.3; 95% confidence interval [CI], 7.7-9.0) than in persons with CD4 cell counts < 200 or history of thrush or fever, which constitute current criteria for prophylaxis against PCP (5.9; 95% CI, 5.5-6.4). Because of increased efficiency in capturing persons at highest risk, CD4 cell count < 250 or CD4 cell percent < 14% should be considered as criteria for prophylaxis against first episodes of PCP.

Cryptosporidium: Its biology and potential for environmental transmission

Protozoans of the genus Cryptosporidium are small (2 to 6 μm, depending on life cycle stage) coccidian parasites that reside within the microvillous region of the mucosal epithelium of man and a variety of animals. Infections with Cryptosporidium spp. were considered rare in animals, and in man they were thought to be the result of a little‐known opportunistic pathogen outside its normal host range. Our concept of Cryptosporidium has changed within the past 4 years to that of a significant and widespread cause of diarrheal illness in several animal species, especially calves and humans. In immunocompetent humans, this protozoan may produce a mild to severe diarrheal illness lasting from several days to more than 1 month. In immune‐deficient persons, especially those with the acquired immune deficiency syndrome (AIDS), cryptosporidiosis usually presents a prolonged, life‐threatening, cholera‐like illness. Treatment of cryptosporidiosis, especially in immune‐deficient persons, has been for the most part uns...

Estimated Rate of Reactivation of Latent Tuberculosis Infection in the United States, Overall and by Population Subgroup

We estimated the rate of reactivation tuberculosis (TB) in the United States, overall and by population subgroup, using data on TB cases and Mycobacterium tuberculosis isolate genotyping reported to the Centers for Disease Control and Prevention during 2006-2008. The rate of reactivation TB was defined as the number of non-genotypically clustered TB cases divided by the number of person-years at risk for reactivation due to prevalent latent TB infection (LTBI). LTBI was ascertained from tuberculin skin tests given during the 1999-2000 National Health and Nutrition Examination Survey. Clustering of TB cases was determined using TB genotyping data collected by the Centers for Disease Control and Prevention and analyzed via spatial scan statistic. Of the 39,920 TB cases reported during 2006-2008, 79.7% were attributed to reactivation. The overall rate of reactivation TB among persons with LTBI was estimated as 0.084 (95% confidence interval (CI): 0.083, 0.085) cases per 100 person-years. Rates among persons with and without human immunodeficiency virus coinfection were 1.82 (95% CI: 1.74, 1.89) and 0.073 (95% CI: 0.070, 0.075) cases per 100 person-years, respectively. The rate of reactivation TB among persons with LTBI was higher among foreign-born persons (0.098 cases/100 person-years; 95% CI: 0.096, 0.10) than among persons born in the United States (0.082 cases/100 person-years; 95% CI: 0.080, 0.083). Differences in rates of TB reactivation across subgroups support current recommendations for targeted testing and treatment of LTBI.

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.

Using Genotyping and Geospatial Scanning to Estimate Recent Mycobacterium tuberculosis Transmission, United States

These tools may enable direction of resources to populations with high transmission rates.

Tuberculosis genotyping information management system: enhancing tuberculosis surveillance in the United States.

Molecular characterization of Mycobacterium tuberculosis complex isolates (genotyping) can be used by public health programs to more readily identify tuberculosis (TB) transmission. The Centers for Disease Control and Preventions National Tuberculosis Genotyping Service has offered M. tuberculosis genotyping for every culture-confirmed case in the United States since 2004. The TB Genotyping Information Management System (TB GIMS), launched in March 2010, is a secure online database containing genotype results linked with case characteristics from the national TB registry for state and local TB programs to access, manage and analyze these data. As of September 2011, TB GIMS contains genotype results for 89% of all culture-positive TB cases for 2010. Over 400 users can generate local and national reports and maps using TB GIMS. Automated alerts on geospatially concentrated cases with matching genotypes that may represent outbreaks are also generated by TB GIMS. TB genotyping results are available to enhance national TB surveillance and apply genotyping results to conduct TB control activities in the United States.