Cost-effectiveness of a 12-dose regimen for treating latent tuberculous infection in the United States.

SETTING: A large randomized controlled trial recently showed that for treating latent tuberculous infection (LTBI) in persons at high risk of progression to tuberculosis (TB) disease, a 12-dose regimen of weekly rifapentine plus isoniazid (3HP) administered as directly observed treatment (DOT) can be as effective as 9 months of daily self-administered isoniazid (9H). OBJECTIVES: To assess the cost-effectiveness of 3HP compared to 9H. DESIGN: A computational model was designed to simulate individuals with LTBI treated with 9H or 3HP. Costs and health outcomes were estimated to determine the incremental costs per active TB case prevented and per quality-adjusted life year (QALY) gained by 3HP compared to 9H. RESULTS: Over a 20-year period, treatment of LTBI with 3HP rather than 9H resulted in 5.2 fewer cases of TB and 25 fewer lost QALYs per 1000 individuals treated. From the health system and societal perspectives, 3HP would cost respectively US$21,525 and $4294 more per TB case prevented, and respectively $4565 and $911 more per QALY gained. CONCLUSIONS: 3HP may be a cost-effective alternative to 9H, particularly if the cost of rifapentine decreases, the effectiveness of 3HP can be maintained without DOT, and 3HP treatment is limited to those with a high risk of progression to TB disease.

Association between Mycobacterium tuberculosis lineage and time to sputum culture conversion.

SETTING: Mycobacterium tuberculosis comprises four principal genetic lineages: one evolutionarily ancestral (Indo-Oceanic) and three modern. Whether response to tuberculosis (TB) treatment differs among the lineages is unknown. OBJECTIVE: To examine the association between M. tuberculosis lineage and time to sputum culture conversion in response to standard first-line drug therapy. DESIGN: We conducted an exploratory retrospective cohort analysis of time to sputum culture conversion among pulmonary tuberculosis (PTB) cases reported in the United States from 2004 to 2007. RESULTS: The analysis included 13,170 PTB cases with no documented resistance to first-line drugs who received a standard four-drug treatment regimen. Among cases with baseline positive sputum smear results, relative to cases with Euro-American lineage, cases with Indo-Oceanic lineage had higher adjusted hazards of sputum culture conversion (aHR 1.32, 95%CI 1.20-1.45), whereas cases with East-African-Indian or East-Asian lineage did not differ (aHR 1.05, 95%CI 0.88-1.25 and aHR 0.99, 95%CI 0.91-1.07, respectively). Among cases with baseline negative sputum smear results, time to sputum culture conversion did not differ by lineage. CONCLUSION: Although these results are exploratory, they suggest that the eradication of viable bacteria may occur sooner among cases with Indo-Oceanic lineage than among those with one of the three modern lineages. Prospective studies of time to sputum culture conversion by lineage are required.

Requirements for the clinical evaluation of new anti-tuberculosis agents in children.

The ultimate goal of evidence-based drug treatment is to produce a desired pharmacological response in a predictable manner and also to minimise adverse effects. This goal requires not only an increased awareness of the need to provide specific dosing recommendations aimed at specific patient groups, but also the implementation of a consistent integrative approach to recognise all factors contributing to the within- and between-subject variability in drug disposition and response. The assessment of new anti-tuberculosis agents and regimens in children requires a specific programme of investigation, and should be included early in human drug evaluation programmes. Appreciation of this principle is an important step forward towards the full integration of children into the tuberculosis research agenda and control programmes. The development of anti-tuberculosis drug formulations and regimens tailored to the requirements of children needs to consider physiological age-related differences for pharmacokinetics and toxicity between adults and children. Research based on these principles will create an evidence base that will inform the appropriate treatment of children with novel agents and regimens and will also inform future research, including the use of chemoprophylaxis and treatment-shortening strategies in children.

Lessons from a randomised clinical trial for multidrug-resistant tuberculosis.

BACKGROUND: The treatment of multidrug-resistant tuberculosis (MDR-TB) is currently based upon expert opinion and findings from case series, rather than upon randomised clinical trials (RCTs). OBJECTIVE: To describe the challenges encountered during an RCT for the treatment of MDR-TB. METHODS: Tuberculosis Trials Consortium Study 30 was a pilot, Phase I/II, double-blind, placebo-controlled, RCT of the safety and tolerability of 16 weeks of daily, low-dose linezolid treatment for MDR-TB. RESULTS: A total of 36 patients, 56% of the target of 64 patients, consented to participate, for an average of 0.69 enrolments per week. Of the 36 patients enrolled, only 25 (69%) completed at least 90 doses of study treatment. Among the 12 (33%) patients who did not complete all 112 doses of the study treatment, the median time to study withdrawal was 15 days (range 0-92). After the study, we discovered discordance between treatment assignment and study drug for at least 9 (25%) of the 36 patients. CONCLUSIONS: Recruitment and retention in this MDR-TB clinical trial posed substantial challenges, suggesting the need for a large, multidisciplinary group of study staff to support the participants. Withdrawal tended to occur early in study treatment. The discrepancy in assigned study medication reflects the need for stronger administrative controls for study drugs.

Cryptosporidium parvum-specific antibody responses among children residing in Milwaukee during the 1993 waterborne outbreak.

A major gastroenteritis outbreak among >400,000 residents of Milwaukee, Wisconsin, in April 1993 was attributed to Cryptosporidium parvum oocysts in drinking water. Plasma specimens obtained from children (6 months to 12 years old) for routine blood lead level surveillance March-May 1993 were assayed by ELISA for levels of IgG antibody against the immunodominant Triton-17 and 27-kDa C. parvum antigens. Over a 5-week period, the seroprevalence for antibodies to the 2 antigens increased from 15% to 82% and from 17% to 87%, respectively, in samples from children living in southern ZIP code areas (n=218), whereas smaller increases (20% to 43% and 22% to 46%, respectively) were noted among samples from children living in northern ZIP code areas (n=335; P<.0001). The results demonstrate that C. parvum infection was much more widespread than previously appreciated and confirm that infection was associated with residence in the area served by the southern water treatment plant.

Ebola hemorrhagic fever, Kikwit, Democratic Republic of the Congo, 1995: risk factors for patients without a reported exposure.

In 1995, 316 people became ill with Ebola hemorrhagic fever (EHF) in Kikwit, Democratic Republic of the Congo. The exposure source was not reported for 55 patients (17%) at the start of this investigation, and it remained unknown for 12 patients after extensive epidemiologic evaluation. Both admission to a hospital and visiting a person with fever and bleeding were risk factors associated with infection. Nineteen patients appeared to have been exposed while visiting someone with suspected EHF, although they did not provide care. Fourteen of the 19 reported touching the patient with suspected EHF; 5 reported that they had no physical contact. Although close contact while caring for an infected person was probably the major route of transmission in this and previous EHF outbreaks, the virus may have been transmitted by touch, droplet, airborne particle, or fomite; thus, expansion of the use of barrier techniques to include casual contacts might prevent or mitigate future epidemics.

Multinational outbreak of Salmonella enterica serotype Newport infections due to contaminated alfalfa sprouts.

CONTEXT: In December 1995, reported Salmonella enterica serotype Newport (SN) infections increased sharply in Oregon and British Columbia but not elsewhere in North America. Similar unexplained increases had been noted in 6 other states in the fall of 1995. OBJECTIVE: To determine the source of the outbreak(s). DESIGN: Case-control studies, environmental investigations, bacterial subtyping, and surveillance information review. SETTINGS: Oregon and British Columbia communities (winter 1995-1996) and Georgia, Oklahoma, Pennsylvania, Vermont, Virginia, and West Virginia (fall 1995). PARTICIPANTS: Oregon and British Columbia residents with culture-confirmed SN infections and onset from December 1, 1995, through February 29, 1996, and healthy community controls. MAIN OUTCOME MEASURES: Odds ratio (OR) of illness associated with exposures; distribution patterns and culture of alfalfa seeds and sprouts; subtyping of SN isolates. RESULTS: We identified 133 cases in Oregon and British Columbia; 124 (93%) occurred in patients older than 18 years; 87 (65%) were female. Case patients were more likely than community control subjects to report having eaten alfalfa sprouts in the 5 days preceding illness (41% [17/41] vs 4% [3/75]; OR, 17.0; 95% confidence interval, 4.3-96.0). Case isolates shared a distinctive pulsed-field gel electrophoresis (PFGE) pattern. The SN was grown from seeds and alfalfa sprouts. The distribution of 1 seed lot to multiple growers corresponded to the distribution of cases. Distribution of a second seed lot from the same European wholesaler corresponded to the location of the fall outbreak, which was characterized by a similar demographic profile. The PFGE pattern of fall outbreak isolates and confiscated sprouts and seeds was indistinguishable from the Oregon and British Columbia outbreak and differed from background isolates. CONCLUSIONS: The SN-contaminated alfalfa seeds were distributed to multiple growers across North America in 1995 and resulted in a protracted international outbreak scattered over many months. Current sprouting methods are inadequate to protect consumers from such events. Alfalfa sprouts may be an elusive but important vehicle for salmonellosis and other enteric infections.

Wound botulism associated with black tar heroin among injecting drug users.

CONTEXT: Wound botulism (WB) is a potentially lethal, descending, flaccid, paralysis that results when spores of Clostridium botulinum germinate in a wound and elaborate neurotoxin. Since 1988, California has experienced a dramatic increase in WB associated with injecting "black tar" heroin (BTH), a dark, tarry form of the drug. OBJECTIVE: To identify risk factors for WB among injecting drug users (IDUs). DESIGN: Case-control study based on data from in-person and telephone interviews. PARTICIPANTS: Case patients (n=26) were IDUs who developed WB from January 1994 through February 1996. Controls (n=110) were IDUs newly enrolled in methadone detoxification programs in 4 counties. MAIN OUTCOME MEASURES: Factors associated with the development of WB. RESULTS: Among the 26 patients, the median age was 41.5 years, 15 (58%) were women, 14 (54%) were non-Hispanic white, 11 (42%) were Hispanic, and none were positive for the human immunodeficiency virus. Nearly all participants (96% of patients and 97% of controls) injected BTH, and the mean cumulative dose of BTH used per month was similar for patients and controls (27 g and 31 g, respectively; P=.6). Patients were more likely than controls to inject drugs subcutaneously or intramuscularly (92% vs 44%, P<.001) and used this route of drug administration more times per month (mean, 67 vs 24, P<.001), with a greater cumulative monthly dose of BTH (22.3 g vs 6.3 g, P<.001). A dose-response relationship was observed between the monthly cumulative dose of BTH injected subcutaneously or intramuscularly and the development of WB (chi2 for linear trend, 26.5; P<.001). In the final regression model, subcutaneous or intramuscular injection of BTH was the only behavior associated with WB among IDUs (odds ratio, 13.7; 95% confidence interval, 3.0-63.0). The risk for development of WB was not affected by cleaning the skin, cleaning injection paraphernalia, or sharing needles. CONCLUSIONS: Injection of BTH intramuscularly or subcutaneously is the primary risk factor for the development of WB. Physicians in the western United States, where BTH is widely used, should be aware of the potential for WB to occur among IDUs.

Genetic polymorphism among Cryptosporidium parvum isolates: evidence of two distinct human transmission cycles.

We report the results of molecular analysis of 39 isolates of Cryptosporidium parvum from human and bovine sources in nine human outbreaks and from bovine sources from a wide geographic distribution. All 39 isolates could be divided into either of two genotypes, on the basis of genetic polymorphism observed at the thrombospondin-related adhesion protein (TRAP-C2) locus. Genotype 1 was observed only in isolates from humans. Genotype 2, however, was seen in calf isolates and in isolates from a subset of human patients who reported direct exposure to infected cattle or consumed items thought to be contaminated with cattle faces. Furthermore, experimental infection studies showed that genotype 2 isolates were infective to mice or calves under routine laboratory conditions, whereas genotype 1 isolates were not. These results support the occurrence of two distinct transmission cycles of C. parvum in humans.

Recurrent chlamydial infections increase the risks of hospitalization for ectopic pregnancy and pelvic inflammatory disease.

OBJECTIVE: We examined whether the risks of hospitalization for ectopic pregnancy and pelvic inflammatory disease increase with increasing numbers of chlamydial infections. STUDY DESIGN: A retrospective cohort design was used to evaluate the risks of hospitalization for ectopic pregnancy or pelvic inflammatory among 11,000 Wisconsin women who had one or more chlamydial infections between 1985 and 1992. Logistic regression was used to evaluate the strength of association between recurrent infection and sequelae. RESULTS: After adjustment in multivariate analyses, we observed elevated risks of ectopic pregnancy among women who had two (odds ratio 2.1, 95% confidence interval 1.3 to 3.4) and three or more chlamydial infections (odds ratio 4.5, 95% confidence interval 1.8 to 5.3). These groups were also at increased risk for pelvic inflammatory (two infections: odds ratio 4.0, 95% confidence interval 1.6 to 9.9; three or more infections: odds ratio 6.4, 95% confidence interval 2.2 to 18.4). CONCLUSIONS: A unique prevention opportunity occurs at the diagnosis of any chlamydial infection because women with subsequent recurrences are at increased risk for reproductive sequelae.

Erythema migrans-like rash illness at a camp in North Carolina: a new tick-borne disease?

BACKGROUND: Borrelia burgdorferi, the causative agent of Lyme disease, has never been isolated from a patient thought to have acquired Lyme disease in any southeastern state. OBJECTIVE: To investigate 14 cases of an erythema migrans (EM)-like rash illness that occurred during 2 summers at an outdoor camp in central North Carolina in an effort to determine the etiologic, epidemiological, and clinical aspects of this illness. METHODS: Using active surveillance, we identified cases of clinically diagnosed EM in residents and staff of the camp. We collected clinical and demographic information; history of exposure to ticks; acute and convalescent serum antibodies to B. burgdorferi, Rickettsia rickettsii, and Ehrlichia chaffeensis; and cultures for spirochetes from biopsy specimens of skin lesions. Serum samples from a group of residents and staff who did not develop rashes were tested for the same antibodies. We speciated ticks removed from people and collected from vegetation. RESULTS: We identified 14 cases of EM-like rash illness during the 2 summers. Of the 14 case-patients, 10 had associated mild systemic symptoms and 1 had documented fever. All 14 case-patients had removed attached ticks, and 8 remembered having removed a tick from the site where the rash developed a median of 12 days earlier (range, 2-21 days). One tick removed from the site where a rash later developed was identified as Amblyomma americanum, the Lone Star tick; 97% of ticks collected from vegetation and 95% of ticks removed from people were A. americanum. No spirochetes were isolated from skin biopsy specimens. Paired serum samples from 13 case-patients did not show diagnostic antibody responses to B. burgdorferi or other tick-borne pathogens. CONCLUSIONS: This investigation suggests the existence of a new tick-associated rash illness. We suspect that the disease agent is carried by A. americanum ticks. In the southern United States, EM-like rash illness should no longer be considered definitive evidence of early Lyme disease.

Steaming oysters does not prevent Norwalk-like gastroenteritis.

OBJECTIVES: To determine whether steaming oysters prevents gastroenteritis caused by small round structured (Norwalk-like) viruses and to identify risk factors for illness. METHODS: The authors interviewed all 48 people who ate oysters at two church suppers that were followed by outbreaks of gastroenteritis from a Norwalk-like virus. Data were collected on demographics, clinical illness, number of oysters eaten, and the extent to which they were cooked. RESULTS: Among the 48 persons, the attack rate was 56%. The risk of illness increased with the number of oysters eaten (chi-square for trend = 5.7, P = 0.02). There was no decrease in attack rates among persons who ate oysters that were better done (chi-square for trend = 1.1, P = 0.29). CONCLUSIONS: In these outbreaks, the risk of illness increased with the number of oysters eaten. Steaming oysters did not appear to prevent illness, suggesting that steaming may not be adequate to inactivate small round structured viruses. Public health messages that have emphasized the role of raw shellfish in the transmission of enteric viruses should be altered to increase the public's awareness that eating steamed oysters may also pose health risks.

A massive outbreak in Milwaukee of cryptosporidium infection transmitted through the public water supply.

BACKGROUND: Early in the spring of 1993 there was a widespread outbreak of acute watery diarrhea among the residents of Milwaukee. METHODS: We investigated the two Milwaukee water-treatment plants, gathered data from clinical laboratories on the results of tests for enteric pathogens, and examined ice made during the time of the outbreak for cryptosporidium oocysts. We surveyed residents with confirmed cryptosporidium infection and a sample of those with acute watery diarrhea consistent with cryptosporidium infection. To estimate the magnitude of the outbreak, we also conducted a survey using randomly selected telephone numbers in Milwaukee and four surrounding counties. RESULTS: There were marked increases in the turbidity of treated water at the city's southern water-treatment plant from March 23 until April 9, when the plant was shut down. Cryptosporidium oocysts were identified in water from ice made in southern Milwaukee during these weeks. The rates of isolation of other enteric pathogens remained stable, but there was more than a 100-fold increase in the rate of isolation of cryptosporidium. The median duration of illness was 9 days (range, 1 to 55). The median maximal number of stools per day was 12 (range, 1 to 90). Among 285 people surveyed who had laboratory-confirmed cryptosporidiosis, the clinical manifestations included watery diarrhea (in 93 percent), abdominal cramps (in 84 percent), fever (in 57 percent), and vomiting (in 48 percent). We estimate that 403,000 people had watery diarrhea attributable to this outbreak. CONCLUSIONS: This massive outbreak of watery diarrhea was caused by cryptosporidium oocysts that passed through the filtration system of one of the city's water-treatment plants. Water-quality standards and the testing of patients for cryptosporidium were not adequate to detect this outbreak.

Trends in syphilis incidence in Wisconsin, 1985-1991.

Between 1985 and 1991, increases in early (infectious) syphilis occurred among Wisconsin residents (1.8 to 18.4 cases per 100,000 persons). Males represented 54% and females 46% of early syphilis cases. Increases in early syphilis morbidity occurred among both white residents (0.9 to 1.5 cases per 100,000 persons) and black residents (25.4 to 330.4 cases per 100,000 persons). The largest increases occurred in Milwaukee County; in 1990, 90% of the cases of early syphilis in Wisconsin occurred among residents of Milwaukee County. In 1990 and 1991, age-specific rates of early syphilis among Milwaukee County residents were highest in the 20- to 24-year-old age group. Increases in early syphilis are likely to be due to increased participation in high risk behaviors. Between 1985 and 1991, congenital syphilis increased among all Wisconsin infants (1.4 to 38.9 cases per 100,000 live births), white infants (0 to 3.3 cases per 100,000 live births), and black infants (20.8 to 326.0 cases per 100,000 live births). Of the 28 mothers giving birth in Wisconsin in 1990 to infants meeting CDC criteria for congenital syphilis, 22 (79%) attended at least one prenatal care visit (mean, four visits; range, 1-10 visits). Of the mothers who attended at least one prenatal care visit, only 11 (50%) were tested for syphilis during their first prenatal visit, and 5 (23%) were not tested until the time of delivery. Inadequate prenatal screening for syphilis contributed to the increase in congenital syphilis.

Multiple false-positive serologic tests for HIV, HTLV-1, and hepatitis C following influenza vaccination, 1991.

OBJECTIVE: (1) To assess factors associated with the occurrence of multiple false-positive viral enzyme-linked immunosorbent assays (ELISAs) for human immunodeficiency virus (HIV), human T-cell lymphotrophic virus type 1 (HTLV-1), and hepatitis C virus (HCV) among individual blood donors and (2) to determine the frequency and time course of this phenomenon. DESIGN: Case-control study. SETTING: A regional blood center. PARTICIPANTS: Blood donors found to have multiple false-positive viral ELISAs (case donors) and randomly selected seronegative controls (control donors) who donated between October 31, 1991, and December 15, 1991. An additional random sample of 262 donation records was reviewed to calculate the proportion of donors who received influenza vaccine. MAIN OUTCOME MEASURES: Multiple false-positive viral ELISAs, receipt of influenza vaccination formulated for the 1991-1992 influenza season, and follow-up ELISA results on serum samples obtained from case donors. RESULTS: Among 17,941 donors, 10 case donors were identified. Nine of the 10 case donors received influenza vaccine, compared with three of 30 control donors (odds ratio [OR] = 81; 95% confidence interval [CI], 6 to 3670; P less than .001). Among nine case donors, the mean time between vaccination and blood donation was 26 days (range, 9 to 68 days). Follow-up ELISAs of serum samples from seven case donors obtained 52 to 130 days (mean, 75 days) after vaccination demonstrated reversion to HIV and HTLV-1 seronegativity in all but one specimen, with persistence of positive HCV ELISAs in four specimens. We estimate between 0.6% and 1.7% of blood donors who received influenza vaccine this season had multiple false-positive viral ELISAs. CONCLUSIONS: The occurrence of multiple false-positive viral ELISAs among blood donors was associated with influenza vaccination, but was infrequent among vaccinees. This phenomenon is of short duration for HIV and HTLV-1, but may persist longer for HCV. We recommend influenza vaccinees not be deferred from blood donation. Blood donors with multiple false-positive viral ELISAs should be considered for future reentry as blood donors.