An evaluation of computer-aided disproportionality analysis for post-marketing signal detection.

To understand the value of computer-aided disproportionality analysis (DA) in relation to current pharmacovigilance signal detection methods, four products were retrospectively evaluated by applying an empirical Bayes method to Merck's post-marketing safety database. Findings were compared with the prior detection of labeled post-marketing adverse events. Disproportionality ratios (empirical Bayes geometric mean lower 95% bounds for the posterior distribution (EBGM05)) were generated for product-event pairs. Overall (1993-2004 data, EBGM05> or =2, individual terms) results of signal detection using DA compared to standard methods were sensitivity, 31.1%; specificity, 95.3%; and positive predictive value, 19.9%. Using groupings of synonymous labeled terms, sensitivity improved (40.9%). More of the adverse events detected by both methods were detected earlier using DA and grouped (versus individual) terms. With 1939-2004 data, diagnostic properties were similar to those from 1993 to 2004. DA methods using Merck's safety database demonstrate sufficient sensitivity and specificity to be considered for use as an adjunct to conventional signal detection methods.

Varicella vaccine exposure during pregnancy: data from the first 5 years of the pregnancy registry.

OBJECTIVE: To assess the risks of congenital varicella syndrome and other birth defects in offspring of women who inadvertently received varicella vaccine during pregnancy or within 3 months of conception. METHODS: Pregnant women inadvertently exposed to varicella vaccine, reported voluntarily, were enrolled in the Pregnancy Registry for VARIVAX (Merck & Co., Inc., West Point, PA). The pregnancies were monitored and the outcomes ascertained from questionnaires completed voluntarily by the health care providers. The rates of congenital varicella syndrome and congenital anomalies were calculated for seronegative women prospectively reported to the registry. RESULTS: From March 17, 1995 through March 16, 2000, 362 pregnancy outcomes were identified from prospective reports. Ninety-two women were known to be seronegative to varicella, of whom 58 received their first dose of vaccine during the first or second trimester. No cases of congenital varicella syndrome were identified among 56 live births (rate 0%, 95% confidence interval [CI] 0, 15.6). Among all the prospective reports of live births, five congenital anomalies were reported. No specific pattern was identified in either the susceptible cohort or the sample population as a whole. CONCLUSION: No abnormal features have been reported that suggested the occurrence of congenital varicella syndrome or other birth defects related to vaccine exposure during pregnancy. Because of the small numbers, this study has limited precision, so continued surveillance is warranted. However, these results should provide some assurance to health care providers and women with inadvertent exposure before or during pregnancy.

The postmarketing safety profile of varicella vaccine.

The postmarketing safety profile of varicella vaccine was evaluated by analyzing selected adverse experience reports temporally associated with the administration of the vaccine. There were 7963 reports voluntarily submitted to Merck for an overall reporting rate of 5.0 per 10000 doses of vaccine distributed. A varicella zoster virus (VZV) identification program detected the presence of the Oka vaccine strain in three individuals with an immune deficiency - two with pneumonia and one with hepatitis - and in three instances of secondary transmission from vaccinees with vesicular lesions to susceptible household contacts. The Oka vaccine strain was present in 23 patients and wild-type VZV was present in 15 patients with herpes zoster. Vesicular rashes that occurred within 2 weeks of vaccination were more likely to contain the presence of wild-type VZV, while vesicular rashes that occurred more than 2 weeks post-vaccination were more likely to contain the Oka vaccine strain. Eleven patients were hospitalized with complications of breakthrough varicella infection.

Transmission of varicella-vaccine virus from a healthy 12-month-old child to his pregnant mother.

A 12-month-old healthy boy had approximately 30 vesicular skin lesions 24 days after receiving varicella vaccine. Sixteen days later his pregnant mother had 100 lesions. Varicella-vaccine virus was identified by polymerase chain reaction in the vesicular lesions of the mother. After an elective abortion, no virus was detected in the fetal tissue. This case documents transmission of varicella-vaccine virus from a healthy 12-month-old infant to his pregnant mother.

Risk factors for syphilis: cocaine use and prostitution.

In Philadelphia, a large increase in syphilis among minority group heterosexuals began in 1986 and preceded similar increases elsewhere in the United States. To determine reasons for this increase, we conducted a case-control study in the metropolitan sexually transmitted diseases clinic during 1987 and 1988. Cocaine use (odds ratio [OR] 3.1; 95% confidence interval [95% CI] = 1.5, 6.5 among men; OR 5.8; 95% CI = 1.5, 33 among women) and exchange of drugs for sex (OR 3.5; 95% CI = 1.4, 8.7 among men) were risk factors for syphilis. Although cocaine users reported more sexual partners and more frequently reported sex with prostitutes, cocaine use remained a risk factor after adjustment for these behaviors. These data suggest that sexual behavior or another factor, such as availability or utilization of health care, among cocaine users leads to increased risk of syphilis in this population. Increases in cocaine use may be partly responsible for recent increases in syphilis incidence in the United States.

Isoniazid prophylaxis in hepatitis B carriers.

Both tuberculosis and hepatitis B are endemic in southeast Asia and are common among refugees to the United States from that region. Isoniazid, used for the prophylactic treatment of tuberculosis, is a potentially hepatotoxic drug. Carriers of the hepatitis B virus are likely to have some degree of liver damage due to their chronic infection. We hypothesized that prophylactic treatment of carriers with isoniazid would cause greater liver damage, as measured by serum alanine aminotransferase (ALT) levels, than would such therapy of noncarriers. Cross-sectional and longitudinal studies of the southeast Asian refugee population in Philadelphia failed to support this hypothesis. Isoniazid did not cause greater hepatotoxicity in hepatitis B carriers than in noncarriers. Although carriers had higher ALT levels than noncarriers, both groups experienced transient ALT elevations during the first 2 months of isoniazid prophylactic therapy. Therefore, we concluded that chronic infection with hepatitis B virus is not a contraindication to the prophylactic use of isoniazid.

Characterization of yeast agglutinins in lavage fluid from lungs of rabbits.

Rabbits were challenged intratracheally with 10(8) Candida albicans or Torulopsis glabrata, and their lungs were lavaged 5, 60, and 120 min later. Initial lavage samples showed significant agglutination of yeasts, followed by the development of larger aggregates in association with alveolar macrophages. To investigate this early agglutination reaction, lungs of normal rabbits were lavaged with heparinized saline, and after alveolar macrophages were discarded, the cell-free lavage fluid was centrifuged at 25,000 g to recover a small, whitish, surface-active pellet (F fraction). The supernatant was concentrated 15-fold by vacuum dialysis (P fraction). When Candida species, T. glabrata, and Saccharomyces cerevisiae were incubated with the F fraction, serial colony counts decreased eight- to 20-fold with every yeast species tested except S. cerevisiae and Candida krusei. Decrease in colony counts was associated with yeast agglutination. The F fraction was further separated by ethanol-ether extraction, and yeast agglutination was seen only in the protein-rich fraction. Further separation of this protein-rich fraction by polyacrylamide gel electrophoresis yielded three bands, one of which, with a molecular size of about 10(4) daltons, agglutinated C. albicans. IgA in the P fraction also agglutinated C. albicans, although not as dramatically as the F fraction.

Summertime pneumonias in Philadelphia in 1976. An epidemiologic study.

Summertime pneumonias in Philadelphia during 1976 were studied epidemiologically, and the epidemiologic, clinical, and laboratory features of pneumonia cases serologically positive for Legionnaires' disease were compared with features of serologically negative cases. Both groups were similar in many respects, but in patients with Legionnaires' disease diarrhea and neurologic findings were significantly more frequent (P = 0.01 and P = 0.05 respectively). A diagnosis of Legionnaires' disease was also suggested by an elevated serum creatinine phosphokinase level (P = 0.02) and the presence of occult blood in the urine with fewer than six erythrocytes per highpower field. Abnormalities in renal function tests or liver function tests were commoner in patients with Legionnaires' disease (P = 0.05). Radiographic features, however, could not be used to separate pneumonia cases. The high frequency of extrapulmonary manifestations involving the gastrointestinal tract, the central nervous system, kidneys, and liver suggests that Legionnaires' disease is a multisystemic disorder possibly caused by a toxin-producing organism.

Legionnaires' disease: description of an epidemic of pneumonia.

An explosive, common-source outbreak of pneumonia caused by a previously unrecognized bacterium affected primarily persons attending an American Legion convention in Philadelphia in July, 1976. Twenty-nine of 182 cases were fatal. Spread of the bacterium appeared to be air borne. The source of the bacterium was not found, but epidemiologic analysis suggested that exposure may have occurred in the lobby of the headquarters hotel or in the area immediately surrounding the hotel. Person-to-person spread seemed not to have occurred. Many hotel employees appeared to be immune, suggesting that the agent may have been present in the vicinity, perhaps intermittently, for two or more years.

Comparison of media for direct isolation and transport of Shigellae from Fecal specimens.

Xylose-lysine-deoxycholate (XLD) agar, SS agar, and MacConkey agar for isolating shigellae from fecal specimens were compared. XLD agar was superior to both SS agar and MacConkey agar for isolating Shigella sonnei, and both XLD and SS agar were superior to MacConkey agar for isolating S. flexneri. Direct plating of the fecal specimens in the field resulted in a greater yield of shigellae as compared to transporting specimens to the laboratory either in holding media or enrichment broth. Buffered glycerol saline was superior to other transport media evaluated, yielding 83% of shigella isolates when plated within 48 hr as compared to direct plating. The combination of XLD agar and SS agar is recommended for direct isolation of shigellae, and, whenever possible, these solid media should be taken to the bedside and inoculated directly.

National influenza experience in the USA, 1968-69.

An extensive outbreak of Hong Kong influenza occurred in the USA during the autumn and early winter of 1968-69. Introduction and seeding of the virus occurred in September and early October as individuals returned from the Far East. Civilian outbreaks did not develop until late October and November. By 28 December, all States had experienced influenza outbreaks. Limited information concerning age- and sex-specific attack rates indicates that all age segments of the population were equally involved. Significant excess pneumonia-influenza mortality occurred in all 9 geographical areas of the country and followed influenza activity by several weeks. Influenza B activity was documented in 37 States during the winter.