Abatacept, Cenicriviroc, or Infliximab for Treatment of Adults Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial.

Importance: Immune dysregulation contributes to poorer outcomes in COVID-19. Objective: To investigate whether abatacept, cenicriviroc, or infliximab provides benefit when added to standard care for COVID-19 pneumonia. Design, Setting, and Participants: Randomized, double-masked, placebo-controlled clinical trial using a master protocol to investigate immunomodulators added to standard care for treatment of participants hospitalized with COVID-19 pneumonia. The results of 3 substudies are reported from 95 hospitals at 85 clinical research sites in the US and Latin America. Hospitalized patients 18 years or older with confirmed SARS-CoV-2 infection within 14 days and evidence of pulmonary involvement underwent randomization between October 2020 and December 2021. Interventions: Single infusion of abatacept (10 mg/kg; maximum dose, 1000 mg) or infliximab (5 mg/kg) or a 28-day oral course of cenicriviroc (300-mg loading dose followed by 150 mg twice per day). Main Outcomes and Measures: The primary outcome was time to recovery by day 28 evaluated using an 8-point ordinal scale (higher scores indicate better health). Recovery was defined as the first day the participant scored at least 6 on the ordinal scale. Results: Of the 1971 participants randomized across the 3 substudies, the mean (SD) age was 54.8 (14.6) years and 1218 (61.8%) were men. The primary end point of time to recovery from COVID-19 pneumonia was not significantly different for abatacept (recovery rate ratio [RRR], 1.12 [95% CI, 0.98-1.28]; P = .09), cenicriviroc (RRR, 1.01 [95% CI, 0.86-1.18]; P = .94), or infliximab (RRR, 1.12 [95% CI, 0.99-1.28]; P = .08) compared with placebo. All-cause 28-day mortality was 11.0% for abatacept vs 15.1% for placebo (odds ratio [OR], 0.62 [95% CI, 0.41-0.94]), 13.8% for cenicriviroc vs 11.9% for placebo (OR, 1.18 [95% CI 0.72-1.94]), and 10.1% for infliximab vs 14.5% for placebo (OR, 0.59 [95% CI, 0.39-0.90]). Safety outcomes were comparable between active treatment and placebo, including secondary infections, in all 3 substudies. Conclusions and Relevance: Time to recovery from COVID-19 pneumonia among hospitalized participants was not significantly different for abatacept, cenicriviroc, or infliximab vs placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT04593940.

Abatacept for Treatment of Adults Hospitalized with Moderate or Severe Covid-19.

Background: We investigated whether abatacept, a selective costimulation modulator, provides additional benefit when added to standard-of-care for patients hospitalized with Covid-19. Methods: We conducted a master protocol to investigate immunomodulators for potential benefit treating patients hospitalized with Covid-19 and report results for abatacept. Intravenous abatacept (one-time dose 10 mg/kg, maximum dose 1000 mg) plus standard of care (SOC) was compared with shared placebo plus SOC. Primary outcome was time-to-recovery by day 28. Key secondary endpoints included 28-day mortality. Results: Between October 16, 2020 and December 31, 2021, a total of 1019 participants received study treatment (509 abatacept; 510 shared placebo), constituting the modified intention-to-treat cohort. Participants had a mean age 54.8 (SD 14.6) years, 60.5% were male, 44.2% Hispanic/Latino and 13.7% Black. No statistically significant difference for the primary endpoint of time-to-recovery was found with a recovery-rate-ratio of 1.14 (95% CI 1.00-1.29; p=0.057) compared with placebo. We observed a substantial improvement in 28-day all-cause mortality with abatacept versus placebo (11.0% vs. 15.1%; odds ratio [OR] 0.62 [95% CI 0.41- 0.94]), leading to 38% lower odds of dying. Improvement in mortality occurred for participants requiring oxygen/noninvasive ventilation at randomization. Subgroup analysis identified the strongest effect in those with baseline C-reactive protein >75mg/L. We found no statistically significant differences in adverse events, with safety composite index slightly favoring abatacept. Rates of secondary infections were similar (16.1% for abatacept; 14.3% for placebo). Conclusions: Addition of single-dose intravenous abatacept to standard-of-care demonstrated no statistically significant change in time-to-recovery, but improved 28-day mortality. Trial registration: ClinicalTrials.gov ( NCT04593940 ).

Infliximab for Treatment of Adults Hospitalized with Moderate or Severe Covid-19.

Background: Immune dysregulation contributes to poorer outcomes in severe Covid-19. Immunomodulators targeting various pathways have improved outcomes. We investigated whether infliximab provides benefit over standard of care. Methods: We conducted a master protocol investigating immunomodulators for potential benefit in treatment of participants hospitalized with Covid-19 pneumonia. We report results for infliximab (single dose infusion) versus shared placebo both with standard of care. Primary outcome was time to recovery by day 29 (28 days after randomization). Key secondary endpoints included 14-day clinical status and 28-day mortality. Results: A total of 1033 participants received study drug (517 infliximab, 516 placebo). Mean age was 54.8 years, 60.3% were male, 48.6% Hispanic or Latino, and 14% Black. No statistically significant difference in the primary endpoint was seen with infliximab compared with placebo (recovery rate ratio 1.13, 95% CI 0.99-1.29; p=0.063). Median (IQR) time to recovery was 8 days (7, 9) for infliximab and 9 days (8, 10) for placebo. Participants assigned to infliximab were more likely to have an improved clinical status at day 14 (OR 1.32, 95% CI 1.05-1.66). Twenty-eight-day mortality was 10.1% with infliximab versus 14.5% with placebo, with 41% lower odds of dying in those receiving infliximab (OR 0.59, 95% CI 0.39-0.90). No differences in risk of serious adverse events including secondary infections. Conclusions: Infliximab did not demonstrate statistically significant improvement in time to recovery. It was associated with improved 14-day clinical status and substantial reduction in 28- day mortality compared with standard of care. Trial registration: ClinicalTrials.gov ( NCT04593940 ).

Randomized Trial of a Vaccine Regimen to Prevent Chronic HCV Infection.

BACKGROUND: A safe and effective vaccine to prevent chronic hepatitis C virus (HCV) infection is a critical component of efforts to eliminate the disease. METHODS: In this phase 1-2 randomized, double-blind, placebo-controlled trial, we evaluated a recombinant chimpanzee adenovirus 3 vector priming vaccination followed by a recombinant modified vaccinia Ankara boost; both vaccines encode HCV nonstructural proteins. Adults who were considered to be at risk for HCV infection on the basis of a history of recent injection drug use were randomly assigned (in a 1:1 ratio) to receive vaccine or placebo on days 0 and 56. Vaccine-related serious adverse events, severe local or systemic adverse events, and laboratory adverse events were the primary safety end points. The primary efficacy end point was chronic HCV infection, defined as persistent viremia for 6 months. RESULTS: A total of 548 participants underwent randomization, with 274 assigned to each group. There was no significant difference in the incidence of chronic HCV infection between the groups. In the per-protocol population, chronic HCV infection developed in 14 participants in each group (hazard ratio [vaccine vs. placebo], 1.53; 95% confidence interval [CI], 0.66 to 3.55; vaccine efficacy, -53%; 95% CI, -255 to 34). In the modified intention-to-treat population, chronic HCV infection developed in 19 participants in the vaccine group and 17 in placebo group (hazard ratio, 1.66; 95% CI, 0.79 to 3.50; vaccine efficacy, -66%; 95% CI, -250 to 21). The geometric mean peak HCV RNA level after infection differed between the vaccine group and the placebo group (152.51×103 IU per milliliter and 1804.93×103 IU per milliliter, respectively). T-cell responses to HCV were detected in 78% of the participants in the vaccine group. The percentages of participants with serious adverse events were similar in the two groups. CONCLUSIONS: In this trial, the HCV vaccine regimen did not cause serious adverse events, produced HCV-specific T-cell responses, and lowered the peak HCV RNA level, but it did not prevent chronic HCV infection. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT01436357.).

U.S. Maternal Mortality Within a Global Context: Historical Trends, Current State, and Future Directions.

In the United States, despite significant investment and the efforts of multiple maternal health stakeholders, maternal mortality (MM) has reemerged since 1987 and MM disparity has persisted since 1935. This article provides a review of the U.S. MM trajectory throughout its history up to its current state. From this longitudinal perspective, MM trends and themes are evaluated within a global context in an effort to understand the problems and contributing factors. This article describes domestic and worldwide strategies recommended by maternal health stakeholders to reduce MM.

Safety and immunogenicity of unadjuvanted subvirion monovalent inactivated influenza H3N2 variant (H3N2v) vaccine in children and adolescents.

OBJECTIVE: In response to the emergence of influenza viruses with pandemic potential, we evaluated a swine-origin influenza A/H3N2 variant (H3N2v) vaccine in children. STUDY DESIGN: This multicenter phase II open-label study assessed the safety and immunogenicity of two doses, 21 days apart, of investigational unadjuvanted subvirion monovalent inactivated H3N2v vaccine administered via intramuscular injection. Children 6-35 months of age received 7.5mcg or 15mcg of hemagglutinin (HA)/dose; children 3-17 years of age received 15mcg HA/dose. Safety and reactogenicity were assessed by measuring the occurrence of solicited injection site and systemic reactions in the 7 days after each vaccination; adverse events were assessed for 42 days and serious adverse events for 7 months after the first vaccination. Immunogenicity was evaluated by measuring hemagglutination inhibition (HAI) and neutralizing (Neut) antibodies to H3N2v prior to and 21 days after each vaccination. Cross-reactivity against seasonal H3N2 strains was evaluated. RESULTS: The H3N2v vaccine was well tolerated. Transient mild to moderate injection site tenderness, pain and erythema was observed, with the most commonly reported systemic reactogenicity being irritability in children 6-35 months, and headache and fatigue in children 9-17 years old. Children 6-35 months old, whether they received 7.5mcg or 15mcg/dose, had low HAI and Neut antibody responses after two doses compared to older children. Children under 9 years of age required two doses of vaccine to demonstrate a response, while 9-17 year olds responded well after one dose. Previous influenza vaccination and older age were associated with higher immune responses to H3N2v vaccine. Children 9-17 years of age also developed cross-reactive antibodies against recent seasonal H3N2 influenza viruses. CONCLUSION: The H3N2v vaccine was safe and immunogenic in children and adolescents. Age-related increases in immunogenicity against H3N2v and seasonal H3N2 viruses were observed, suggesting prior priming via infection and/or immunization. Clinical trial registry: The trial is registered with clinicaltrial.gov: NCT02100436.

Template protocol for clinical trials investigating vaccines--focus on safety elements.

This document is intended as a guide to the protocol development for trials of prophylactic vaccines. The template may serve phases I-IV clinical trials protocol development to include safety relevant information as required by the regulatory authorities and as deemed useful by the investigators. This document may also be helpful for future site strengthening efforts.

U.S. Postlicensure safety surveillance for adolescent and adult tetanus, diphtheria and acellular pertussis vaccines: 2005-2007.

BACKGROUND: Pre-licensure clinical trials for two U.S. licensed tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) vaccines did not reveal any major safety concerns. However, routine use in large adolescent and adult populations could reveal rare and potentially serious adverse events (AEs). METHODS: To characterize reported AEs following Tdap vaccination and identify potential safety concerns warranting further evaluation, we analyzed data from the Vaccine Adverse Event Reporting System (VAERS) and assessed the frequency and proportions of AEs and reporting rates (reports per 100,000 vaccine doses distributed). RESULTS: A total of 2090 reports (7% were serious; 55% listed Tdap alone) involving Tdap vaccines were submitted to VAERS May 2005-June 2007. The crude reporting rate was 10.2 per 100,000 vaccine doses distributed. The median age of vaccinees was 22 years, and the female to male ratio was about 2 to 1. The majority of reports described common local and systemic signs and symptoms, such as injection site reactions, fever, and headache. Rarely reported AEs included myopericarditis, demyelinating diseases of the central nervous system, Guillain-Barré Syndrome, syncope, encephalopathy/encephalitis, seizure, Bell's palsy, anaphylaxis, and thrombocytopenia. CONCLUSIONS: Because adolescents and adults were not routinely vaccinated against pertussis in the past, this surveillance summary provides important - and reassuring - information about the use of Tdap in these age groups. Although subject to the limitations of passive surveillance, the findings of this VAERS review support the pre-licensure clinical trial data with regard to the safety of the U.S. licensed Tdap vaccines. Continued monitoring of clinically significant AEs that are temporally associated with Tdap vaccination and further assessment of such events using controlled observational studies may provide additional information about the safety of these vaccines.

Safety assessment of recalled Haemophilus influenzae type b (Hib) conjugate vaccines--United States, 2007-2008.

PURPOSE: On 13 December 2007, Merck & Co., Inc. voluntarily recalled 1.2 million doses of Haemophilus influenzae type b (Hib) vaccines that had been distributed since April 2007 for concerns regarding potential Bacillus cereus contamination. Enhanced postrecall surveillance was conducted to detect vaccine-associated B. cereus infections. METHODS: We reviewed reports involving recalled Hib vaccines received by the Vaccine Adverse Event Reporting System (VAERS) during 1 April 2007-29 February 2008. For each reported death, autopsy review sought evidence of B. cereus infections. For each specified outcome, the proportional reporting ratios (PRRs) were calculated to compare the recalled Hib vaccines with the manufacturer's nonrecalled Hib vaccines in the VAERS databases. On 20 December 2007, we used the Epidemic Information Exchange (Epi-X) to solicit nongastrointestinal vaccine-associated B. cereus infections, and requested B. cereus isolates for genotyping to compare with the manufacturing facility isolate. RESULTS: VAERS received 75 reports involving recalled Hib vaccines; none described a confirmed B. cereus infection. Comparative analyses did not reveal disproportionate reporting of specified outcomes for recalled Hib vaccines. The Epi-X posting triggered one report of vaccine-associated B. cereus bacteremia from a child who received a nonrecalled Hib vaccine manufactured by Merck; the genotypes of isolates from the patient and the manufacturing facility differed. CONCLUSIONS: No evidence of vaccine-associated B. cereus infection had been found in recipients of recalled Hib vaccines. Conducting laboratory surveillance through Epi-X was feasible and may enhance public health response capacities for future vaccine safety emergencies.

Preventable mix-ups of tuberculin and vaccines: reports to the US Vaccine and Drug Safety Reporting Systems.

BACKGROUND: Errors involving the mix-up of tuberculin purified protein derivative (PPD) and vaccines leading to adverse reactions and unnecessary medical management have been reported previously. OBJECTIVES: To determine the frequency of PPD-vaccine mix-ups reported to the US Vaccine Adverse Event Reporting System (VAERS) and the Adverse Event Reporting System (AERS), characterize adverse events and clusters involving mix-ups and describe reported contributory factors. METHODS: We reviewed AERS reports from 1969 to 2005 and VAERS reports from 1990 to 2005. We defined a mix-up error event as an incident in which a single patient or a cluster of patients inadvertently received vaccine instead of a PPD product or received a PPD product instead of vaccine. We defined a cluster as inadvertent administration of PPD or vaccine products to more than one patient in the same facility within 1 month. RESULTS: Of 115 mix-up events identified, 101 involved inadvertent administration of vaccines instead of PPD. Product confusion involved PPD and multiple vaccines. The annual number of reported mix-ups increased from an average of one event per year in the early 1990s to an average of ten events per year in the early part of this decade. More than 240 adults and children were affected and the majority reported local injection site reactions. Four individuals were hospitalized (all recovered) after receiving the wrong products. Several patients were inappropriately started on tuberculosis prophylaxis as a result of a vaccine local reaction being interpreted as a positive tuberculin skin test. Reported potential contributory factors involved both system factors (e.g. similar packaging) and human errors (e.g. failure to read label before product administration). CONCLUSIONS: To prevent PPD-vaccine mix-ups, proper storage, handling and administration of vaccine and PPD products is necessary.

Elective termination of pregnancy after vaccination reported to the Vaccine Adverse Event Reporting System (VAERS): 1990-2006.

Generally, live-virus vaccines are contraindicated for pregnant women because of the theoretical risk of transmission of the vaccine virus to the fetus. Advisory groups recommend avoiding pregnancy in the immediate period after administration of such contraindicated vaccines (CVs) and stress benefit-to-risk evaluation for live or inactivated vaccines regarding pregnancy. Given the limited available data and theoretical risks associated particularly with live-virus vaccines, inadvertent immunization with CVs may lead to elective termination of pregnancy (ETP), despite advisory group statements that "vaccination is not ordinarily an indication to terminate the pregnancy." The Vaccine Adverse Event Reporting System (VAERS), a national passive surveillance system managed by the Food and Drug Administration (FDA) and Centers for Disease Control and Prevention (CDC), accepts reports of adverse events after vaccination. The objectives of this review were to describe reports of ETP in VAERS and characterize the circumstances of inadvertent administration of vaccines to pregnant women among ETP reports. We reviewed VAERS reports of ETP submitted from 1990 to 2006. Reports of ETP for reasons other than vaccination during or shortly before pregnancy, such as fetal abnormalities or deaths, were excluded. Of 80 ETP reports, 62 (78%) originated from the US; 79 (99%) were reported by manufacturers. Median age of vaccinees was 26 years (range: 13-43 years; 67 reports). Seventy-three vaccinees (91%) received a single vaccine; 65 (81%) received at least one live-virus vaccine. In 48 (60%) ETP reports, vaccinees were unaware of pregnancy at time of immunization. In 15 (19%) reports, vaccinees became pregnant within 3 months of vaccination; in 13 (16%) reports, vaccinees might have been pregnant before vaccination; in 4 (5%) reports, information was missing. All 80 reports of ETP involved vaccines for which possible effects on fetal development are unknown. However, no cases of vaccine-associated congenital rubella or varicella syndromes have been reported in the medical literature. Also, these syndromes have not been reported to varicella or rubella vaccine pregnancy registries. VAERS has the limitations of passive surveillance systems. Under-reporting of ETP in VAERS could be substantial. More attention may be needed to assess the likelihood of pregnancy when administering vaccines to women with child-bearing potential, and to inform women who learn they are pregnant shortly after being immunized of current information on risks. Quantifying the frequency of ETP related to CVs and the risk (if any) to the fetus of such vaccines can help to inform policy, practice, and individual decision making. Good quality information may be obtained from controlled observational studies.

Perinatal hepatitis B transmission and vaccination timing in a managed care cohort: assessment of the temporary delay in newborn hepatitis B vaccination due to thimerosal content.

BACKGROUND: From July to September 1999, due to a concern of toxicity from exposure to thimerosal-containing vaccines, the American Academy of Pediatrics and U.S. Public Health Service temporarily recommended delaying the administration of first dose of hepatitis B vaccine until the age of 2-6 months for infants born to hepatitis B surface antigen negative mothers. Our objectives were to determine whether the recommendation affected the rate of perinatal hepatitis B infection in a multistate managed care population; to describe neonatal and early childhood cases of hepatitis B infection and to evaluate a possible role of the recommendation; and to assess the timeliness, with respect to the U.S. childhood immunization schedule, of vaccinations during the first 2 years of life. METHODS: We identified 3 cohorts of infants born before (July 1998 to June 1999), during (July 1999 to September 1999) and after (October 1999 to September 2000) the recommendation period. We used automated claims data to identify possible neonatal and early childhood hepatitis B cases using specific ICD-9 diagnosis and CPT procedure codes and validated cases through medical record review. Using Health Plan Employer Data and Information Set (HEDIS) data, we calculated vaccination coverage for the first dose of hepatitis B vaccine at 3-month intervals from January 1999 to September 2000. RESULTS: The eligible populations in the "before," "during" and "after" cohorts were 29,347, 7791 and 29,215 infants, respectively. Of 41 possible hepatitis B cases identified in the 3 cohorts, we confirmed 1 case in the after cohort with medical record review. Despite receiving the first dose of hepatitis B vaccine and hepatitis B immunoglobulin within 12-24 hours of birth, the infant was diagnosed with laboratory-confirmed chronic hepatitis B at age of 9 months. An analysis of HEDIS data showed that vaccination coverage for the first dose of hepatitis B vaccine was 98% (January to March 1999) and 96% (April to June 1999) for the "before" cohort and 66% for the "during" cohort. For the "after" cohort the coverage was 72% (October to December 1999), 83% (January to March 2000), 91% (April to June 2000) and 95% (July to September 2000). CONCLUSIONS: This study did not identify any perinatal hepatitis B transmission among health plan enrollees associated with the 1999 recommendation. The recommendation did result in a delay of hepatitis B birth dose in the "during" cohort as intended for infants born to hepatitis B surface antigen negative mothers. Six months after the recommendation was rescinded there was still a delay in the timing of first dose of hepatitis B vaccine, but the timing had returned to the prerecommendation level after 9-12 months.

Adverse events reported following live, cold-adapted, intranasal influenza vaccine.

CONTEXT: In June 2003, the US Food and Drug Administration licensed a trivalent live, attenuated influenza vaccine (LAIV-T) for intranasal administration to healthy persons 5 to 49 years of age. Although prelicensure testing involved 20 228 vaccinees, clinical trials were not of sufficient size to detect rare adverse events reliably. OBJECTIVE: To identify adverse events reported following LAIV-T administration after licensure. DESIGN, SETTING, AND PARTICIPANTS: All adverse events reported to the US Vaccine Adverse Event Reporting System (VAERS) during the 2003-2004 and the 2004-2005 influenza seasons. MAIN OUTCOME MEASURES: Numbers and proportions of reported adverse events and reporting rates of adverse events per 100,000 vaccinees. RESULTS: Approximately 2,500,000 persons received LAIV-T during the first 2 postlicensure seasons. As of August 16, 2005, VAERS received 460 adverse event reports for vaccinations received from August 2003 through July 2005. No fatalities were reported. There were 7 reports of possible anaphylaxis, 2 reports of Guillain-Barré syndrome, 1 report of Bell palsy, and 8 reports of asthma exacerbation among individuals with a prior asthma history. Events in individuals for whom the vaccine was not indicated accounted for 73 reports (16%). CONCLUSIONS: Reports to VAERS in the first 2 seasons of LAIV-T use did not identify any unexpected serious risks with this vaccine when used according to approved indications. Like many vaccines and other medical products, LAIV-T may rarely cause anaphylaxis. Secondary transmission of the vaccine virus merits further investigation. Reports of asthma exacerbations in vaccinees with prior asthma history highlight the risks of vaccine use inconsistent with approved labeling.

Adverse events after inactivated influenza vaccination among children less than 2 years of age: analysis of reports from the vaccine adverse event reporting system, 1990-2003.

BACKGROUND: In April 2002, the Advisory Committee on Immunization Practices (ACIP) encouraged providers to vaccinate healthy 6- to 23-month-old infants and children with trivalent influenza vaccine (TIV). OBJECTIVES: To describe adverse events (AEs) reported to the Vaccine Adverse Event Reporting System (VAERS) after TIV vaccination among children <2 years of age and to compare reports before the ACIP guideline (January 1990 to June 2002) and after the ACIP guideline (July 2002 to June 2003). METHODS: VAERS is a passive vaccine safety surveillance system begun by the Food and Drug Administration and the Centers for Disease Control and Prevention in 1990. We reviewed reports to VAERS for children <2 years of age who received TIV, alone or in combination with other vaccines. Influenza seasons were defined as the period from July 1 of one year to June 30 of the following year. RESULTS: Between 1990 and 2003, VAERS received 166 TIV reports for children <2 years of age. There were 62 reports (37%) after administration of TIV alone and 104 reports (63%) after administration of TIV and > or =1 other vaccine. Approximately one third of reports (N = 61) were in the post-ACIP guideline period. The 4 most frequent AE coding terms were fever (N = 59, 35%), unspecified or urticarial rash (42, 25%), seizure (28, 17%), and injection site reaction (28, 17%). The median number of days from vaccination to symptom onset, the percentage of reports that represented serious AEs, and the gender distribution were similar in the pre-ACIP guideline and post-ACIP guideline periods. The percentage of reports describing an underlying medical condition for the subject decreased from 58% before the ACIP guideline to 37% after the ACIP guideline. Nineteen of 28 seizure reports (68%) described fever with the seizure within 2 days after vaccination. Seizure was the most frequent coding term (N = 10, 7 with fever) among 23 serious reports. The annual number of TIV-related VAERS reports for children <2 years of age increased in the post-ACIP guideline period, probably at least in part because of an increase in the number of vaccinees after the ACIP announcement. The safety profiles in the pre-ACIP guideline and post-ACIP guideline periods were similar. CONCLUSIONS: In October 2003, the ACIP recommended that all healthy children 6 to 23 months of age be vaccinated with TIV, starting in the 2004-2005 influenza season. This study provides generally reassuring, although limited, data regarding the safety of TIV among children in this age range. Continued surveillance for seizures and other clinically significant AEs is warranted and will continue.

Human health effects of sodium azide exposure: a literature review and analysis.

Sodium azide, used mainly as a preservative in aqueous laboratory reagents and biologic fluids and as a fuel in automobile airbag gas generants, has caused deaths for decades. Its exposure potential for the general population increases as the use of airbags increase. In order to characterize the known health effects of sodium azide in humans and the circumstances of their exposure, the authors conducted a systematic review of the literature from 1927 to 2002 on human exposure to sodium azide and its health effects. The most commonly reported health effect from azide exposure is hypotension, almost independent of route of exposure. Most industrial exposures are by inhalation. Most laboratory exposures or suicide attempts are by ingestion. Most of the reported cases involved persons working in laboratories. The time between exposure and detection of hypotension can predict outcome. Fatal doses occur with exposures of >or=700 mg (10 mg/kg). Nonlethal doses ranged from 0.3 to 150 mg (0.004 to 2 mg/kg). Onset of hypotension within minutes or in less than an hour is indicative of a pharmacological response and a benign course. Hypotension with late onset (>1 hour) constitutes an ominous sign for death. All individuals with hypotension for more than an hour died. Additional health effects included mild complaints of nausea, vomiting, diarrhea, headache, dizziness, temporary loss of vision, palpitation, dyspnea, or temporary loss of consciousness or mental status decrease. More severe symptoms and signs included marked decreased mental status, seizure, coma, arrhythmia, tachypnea, pulmonary edema, metabolic acidosis, and cardiorespiratory arrest. The signs and symptoms from lower exposures (<700 mg) are physiological responses at the vascular level and those at or above are toxicological responses at the metabolic level. There is no specific antidote for sodium azide intoxication. Recommended preventive measures for sodium azide exposure consist of education of people at high risk, such as laboratory workers, regarding its chemical properties and toxicity, better labeling of products containing sodium azide, and strict enforcement of laboratory regulations and access control.

Pediatric neurobehavioral diseases in Nevada counties with respect to perchlorate in drinking water: an ecological inquiry.

BACKGROUND: Contamination of drinking water with perchlorate, a known thyrotropic agent, has been demonstrated in areas in the western United States. The health consequences of that exposure have been studied, particularly in the State of Nevada. Previous studies in Nevada, comparing the area with perchlorate in the drinking water and the areas without perchlorate in the drinking water, have found no difference in neonatal thyroxine (T(4)) or thyrotropin (TSH) levels, or in the prevalences of thyroid diseases and thyroid cancer. This same study design has now been applied to the major neurobehavioral diseases of childhood (i.e., attention deficit-hyperactivity disorder (ADHD) and autism) and to school performance in order to determine whether those conditions are more frequent in the area with perchlorate-contaminated water. METHODS: Medical services data on ADHD and autism were obtained from the Nevada Medicaid system for the period of January 1, 1996, to December 31, 2000, with county of residence used as the basis for residential information. Analyses of fourth-grade school performance results for two recent time periods came from the state government. Perchlorate concentrations in drinking water had been determined by local water authorities. ADHD and autism rates for the area with perchlorate in the drinking water (Clark County) were calculated and compared with the rates for the other areas in the state, as were fourth-grade school performances. RESULTS: Analysis of the data from the Nevada Medicaid program shows that the rates for ADHD and for autism in the area where perchlorate was in the drinking water did not exceed the rates in those areas where there was no perchlorate contamination in the drinking water. Fourth-grade standardized test results for students in Clark County were not different from those of the remainder of the state. CONCLUSIONS: This ecological study of children in the exposure area did not find evidence of an increased risk of either ADHD or of autism caused by perchlorate contamination in the drinking water. Furthermore, no difference in overall fourth-grade school performance was observed. No evidence was found that children from the area with perchlorate in the drinking water (up to 24 microg/liter) had either an increase in pediatric neurobehavioral disease (ADHD and autism) or a decrease in fourth-grade academic performance. The limitations of this ecological study relate to diagnostic criteria and ascertainment of geographic and demographic differences and to data on individual residence and water consumption during pregnancy.