Assessing Residual Bias in Estimating Influenza Vaccine Effectiveness: Comparison of High-dose Versus Standard-dose Vaccines.

BACKGROUND: Estimating influenza vaccine effectiveness using an unvaccinated comparison group may result in biased effect estimates. OBJECTIVES: To explore the reduction of confounding bias in an active comparison of high-dose versus standard-dose influenza vaccines, as compared with vaccinated versus unvaccinated comparisons. METHODS: Using Medicare data from the United States end-stage renal disease program (2009-2013), we compared the risk of all-cause mortality among recipients of high-dose vaccine (HDV) versus standard-dose vaccine (SDV), HDV versus no vaccine, and SDV versus no vaccine. To quantify confounding bias, analyses were restricted to the preinfluenza season, when the protective effect of vaccination should not yet be observed. We estimated the standardized mortality ratio-weighted cumulative incidence functions using Kaplan-Meier methods and calculated risk ratios (RRs) and risk differences between groups. RESULTS: Among 350,921 eligible patients contributing 825,642 unique patient preinfluenza seasons, 0.8% received HDV, 70.5% received SDV, and 28.7% remained unvaccinated. Comparisons with unvaccinated patients yielded spurious decreases in mortality risk during the preinfluenza period, for HDV versus none [RR, 0.60; 95% confidence interval (CI), 0.51-0.70)] and SDV versus none (RR, 0.72; 95% CI, 0.70-0.75). The effect estimate was attenuated in the HDV versus SDV comparison (RR, 0.89; 95% CI, 0.77-1.03). Estimates on the absolute scale followed a similar pattern. CONCLUSIONS: The HDV versus SDV comparison yielded less-biased estimates of the all-cause mortality before influenza season compared to those with nonuser comparison groups. Vaccine effectiveness and safety researchers should consider the active comparator design to reduce bias due to differences in underlying health status between vaccinated and unvaccinated individuals.

Elevated blood lead and cadmium levels associated with chronic infections among non-smokers in a cross-sectional analysis of NHANES data.

BACKGROUND: Experimental animal studies, in vitro experiments, and clinical assessments have shown that metal toxicity can impair immune responses. We analyzed data from a United States representative National Health and Nutrition Examination Survey (NHANES) to explore associations between chronic infections and elevated blood concentrations of lead and cadmium among non-smoking NHANES participants. METHODS: NHANES data from 1999 to 2012 were examined and weighted to represent the United States population. Multivariable logistic regression was used to estimate adjusted odds ratios (AOR) and 95 % confidence intervals (CI) for heavy metal associations with seropositivity for Helicobacter pylori, Toxoplasma gondii, and Hepatitis B virus (HBV) infections. RESULTS: Available 2-year survey cycles for infection seroprevalence varied by pathogen, from 1 to 7 cycles. Available sample size, disease seroprevalence, and participant age range also varied by pathogen of interest. After controlling for demographic characteristics and general health condition, an elevated blood lead level above the survey population median was significantly associated with seropositivity for all three pathogens (AORs = 1.2-1.5). In addition, an elevated blood cadmium level above the median was significantly associated with HBV (AOR = 1.5; 95 % CI = 1.2-2.0) and H. pylori (AOR = 1.5; 95 % CI = 1.2-1.7) seropositivity. Age-specific analyses for H. pylori and T. gondii indicated stronger associations among children under 13 years of age, particularly for lead exposure and H. pylori seropositivity, and weaker associations among those over 35 years of age. CONCLUSIONS: The results of this cross-sectional human health survey suggest that the immunological effects of lead and cadmium toxicity may be associated with an increased susceptibility to chronic infections.

Evidence for subclinical H5N1 avian influenza infections among Nigerian poultry workers.

In recent years Nigeria has experienced sporadic incursions of highly pathogenic H5N1 avian influenza among poultry. In 2008, 316 poultry-exposed agricultural workers, and 54 age-group matched non-poultry exposed adults living in the Enugu or Ebonyi States of Nigeria were enrolled and then contacted monthly for 24 months to identify acute influenza-like-illnesses. Annual follow-up sera and questionnaire data were collected at 12 and 24 months. Participants reporting influenza-like illness completed additional questionnaires, and provided nasal and pharyngeal swabs and acute and convalescent sera. Swab and sera specimens were studied for evidence of influenza A virus infection. Sera were examined for elevated antibodies against 12 avian influenza viruses by microneutralization and 3 human viruses by hemagglutination inhibition. Four (3.2%) of the 124 acute influenza-like-illness investigations yielded molecular evidence of influenza, but virus could not be cultured. Serial serum samples from five poultry-exposed subjects had a ≥4-fold change in microneutralization titers against A/CK/Nigeria/07/1132123(H5N1), with three of those having titers ≥1:80 (maximum 1:1,280). Three of the five subjects (60%) reported a preceding influenza-like illness. Hemagglutination inhibition titers were ≥4-fold increases against one of the human viruses in 260 participants. While cross-reactivity from antibodies against other influenza viruses cannot be ruled out as a partial confounder, over the course of the 2-year follow-up, at least 3 of 316 (0.9%) poultry-exposed subjects had evidence for subclinical HPAI H5N1 infections. If these data represent true infections, it seems imperative to increase monitoring for avian influenza among Nigeria's poultry and poultry workers.

Swine influenza virus infections in man.

Because pigs are susceptible to both avian and human influenza viruses, genetic reassortment between avian, human, and/or swine influenza viruses in the pig host can lead to the generation of novel influenza A viruses (Ma et al. 2009). Since the first serological evidence of a swine influenza virus (SIV) infecting humans in 1958, sporadic cases have continued to occur. In recent years, case reports have been increasing, seemingly in concert with modern pig farming and the emergence of triple reassortant SIVs in swine. SIV infections in man generally are mild or subclinical, and often are not diagnosed; however, SIV infections can be quite serious in patients with underlying medical conditions. As of August 2010, 73 case reports of symptomatic human SIV infections have been documented in the medical literature or reported by health officials (excluding cases of the 2009 pandemic H1N1 influenza virus), of which 7 infections (10 %) resulted in death. While exposure to swine is often considered a risk factor for human SIV infections, 37 of 73 (51 %) reported cases had no known exposure to pigs; consequently, SIV may be crossing the species barrier via transmission routes yet to be acknowledged. In addition, human-to-human transmission was suspected in 10 of 34 (30 %) of the cases with epidemiological investigation. This chapter discusses the observations of illness and infections in humans, risk factors associated with infection, and methods for diagnosing human infections of SIV.

Drinking water source and human Toxoplasma gondii infection in the United States: a cross-sectional analysis of NHANES data.

BACKGROUND: Toxoplasma gondii imparts a considerable burden to public health. Human toxoplasmosis can be life-threatening in immunocompromised individuals, has been associated with psychiatric disorders, and can cause severe congenital pathologies, spontaneous abortion, or stillbirth. Environmental modes of transmission contributing to the incidence of human toxoplasmosis are poorly understood. We sought to examine National Health and Nutrition Examination Survey (NHANES) data for risk factors associated with T. gondii seroprevalence. METHODS: T. gondii serology results reported for Continuous NHANES survey years 1999-2004 and 2009-10 were examined. To explore associations with toxoplasmosis seropositivity, covariates of interest were selected a priori, including source and home treatment of tap water. Associations between potential risk factors and evidence of IgG antibodies against T. gondii were assessed using multivariable logistic regression. RESULTS: Among 23,030 participants with available T. gondii serology across 8 years of continuous NHANES survey data (1999-2004; 2009-2010), persons born outside the United States were significantly more likely to be seropositive, and seropositivity was inversely associated with years spent in the United States. Among US-born participants, participants with homes on well water (both those who used at-home water treatment devices and those who did not), as well as participants with public/private company-provided tap water who did not use at-home water treatment devices, were significantly more likely to be seropositive compared to participants who used home treatment devices on tap water provided by a private or public water company. A comparative subpopulation analysis revealed age-adjusted seroprevalence among US-born persons 12-49 yrs old significantly declined to 6.6% (95% CI, 5.2-8.0) (P <0.0001) in 2009-10, compared to previously published reports for NHANES data from 1988-1994 (14.1%) and 1999-2004 (9.0%). CONCLUSIONS: Data suggests that T. gondii infections continue to decline in the United States, but the overall infection rate remains substantial at nearly 7%. Despite the limitations in the Continuous NHANES cross-sectional survey, the association between well water use and T. gondii infection warrants further research.

Longitudinal Molecular and Serological Evidence of SARS-CoV-2 Infections and Vaccination Status: Community-Based Surveillance Study (CONTACT).

INTRODUCTION: This prospective, longitudinal, community-based study, EpidemiologiCal POpulatioN STudy of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Lake CounTy, Illinois (CONTACT), investigated coronavirus disease 2019 (COVID-19) immunity, occupational risks related to SARS-CoV-2 exposure, and long-term immunoglobulin G (IgG) seroconversion kinetics. METHODS: At baseline and follow up (3, 6, and 9 months), non-hospitalized adult participants provided nasal and blood serum specimens for molecular [reverse transcription polymerase chain reaction (RT-PCR)] and serological (IgG) testing (4 November 2020-30 October 2021). RESULTS: At baseline, 6.4% (65/1008) had evidence of current/prior SARS-CoV-2 infection. At 3, 6, and 9 months, positive PCR tests were obtained from 0.4% (3/781), 0.4% (3/733), and 0% (0/673) of participants, respectively. Positive IgG occurred at baseline and 3, 6, and 9 months in 4.5% (45/1008), 6.0% (48/799), 5.4% (39/733), and 2.8% (19/673) of participants, respectively. Of participants positive for IgG at baseline, 28 had a negative IgG test at a follow-up visit; of those 28, 21 had their first negative IgG test within 6 months. Participants were more likely to retain positive IgG if they were 18-29 years of age, were male, or had medium-high/high-risk occupations. A high vaccination rate (70% received ≥ 1 dose by 9 months) was observed. Influence of occupational status or characteristics on transmission and IgG, and COVID-19 vaccination trends, are shown. CONCLUSIONS: This study expands on prior studies assessing COVID-19 immunity and IgG seroconversion by including both RT-PCR and serologic testing and longitudinal follow-up of study participants. We observed decreased infection rates over the 9 month follow-up period as well as a decline in IgG persistency after 6 months. The findings from this community-based study regarding vaccinate rates, infection rates by PCR, and IgG persistency over time can help improve our understanding of COVID-19 immunity, occupational risks related to SARS-CoV-2 exposure, and the kinetics of long-term IgG seroconversion, which is important to help guide local and national mitigation strategies. CLINICAL TRIAL REGISTRATION: NCT04611230.

Serologic evidence of avian influenza virus infections among Nigerian agricultural workers.

Nigeria has had multiple incursions of highly pathogenic avian influenza A (HPAI) H5N1 virus into its poultry population since 2006. This study aimed to determine if Nigerians exposed to poultry had evidence of avian influenza virus transmission to man. Between 2008 and 2010, 316 adult farmers and open market workers and 54 age-group matched, non-animal exposed controls were enrolled in a prospective, population-based study of zoonotic influenza transmission in four towns in southeastern Nigeria. Questionnaire data and sera obtained at the time of enrollment were examined for evidence of previous infection with 10 avian influenza virus strains. Serologic studies on sera collected at the time of enrollment showed modest evidence of previous infection with three avian-origin influenza viruses (H5N1, H5N2, and H11N1) and one avian-like H9N2 influenza virus, with eight (2.4%) of animal-exposed subjects and two (3.7%) unexposed subjects having elevated microneutralization assay antibody titer levels (ranging from 1:10 to 1:80). Statistical analyses did not identify specific risk factors associated with the elevated antibody titers observed for these zoonotic influenza viruses. These data suggested only occasional virus transmission to humans in areas thought to have been enzootic for avian influenza virus. Prospective data from this cohort will help the authors to better understand the occurrence of zoonotic infections due to avian influenza viruses in Nigeria.

Real-world treatment patterns of rheumatoid arthritis in Brazil: analysis of DATASUS national administrative claims data for pharmacoepidemiology studies (2010-2020).

Our study assessed DATASUS as a potential source for pharmacoepidemiologic studies in rheumatoid arthritis (RA) in the Brazilian population focusing on treatment patterns and determinants of initiating or switching to a novel therapy. This was a descriptive database study of RA patients with at least one claim of RA and ≥ 2 claims of disease-modifying anti-rheumatic drug (DMARD); conventional synthetic (cs), biologic (b) or targeted synthetic (ts) DMARD with more than 6 months of follow-up from 01-Jan-2010 to 31-Dec-2020. Analyses were stratified for SUS-exclusive and SUS+ private user cohorts. We identified 250,251 patients with RA in DATASUS: mean age of 58.4 years, majority female (83%) and white (58%). 62% were SUS-exclusive and 38% SUS+ private. Most common bDMARDs were adalimumab and etanercept. Age (adjusted odds ratio 1.78 [50+]; 95% CI 1.57-2.01), SUS exclusive status (0.53; 0.47-0.59), distance to clinic [160+ km] (0.57; 0.45-0.72), and pre-index csDMARD claims (1.23; 1.08-1.41) were independent predictors of initiating a novel oral tsDMARD. Switching from bDMARD to tsDMARD, associations were similar, except for the direction of associations for SUS exclusive status (adjusted hazard ratio 1.10; 1.03-1.18), distance to clinic (1.18; 1.03-1.35), and number of previous bDMARD (0.15; 0.14-0.16). DATASUS is a source suitable for treatment-related analyses in RA reflecting the public health system in Brazil.

Factors Associated with Severe COVID-19 Among Patients with Rheumatoid Arthritis: A Large, Nationwide Electronic Health Record Cohort Study in the United States.

INTRODUCTION: To evaluate factors associated with severe coronavirus disease 2019 (COVID-19) among patients with rheumatoid arthritis (RA) in the US. METHODS: Adults with RA who had a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, based on molecular or antigen test or clinical diagnosis, were identified from the Optum® COVID-19 Electronic Health Record dataset (March 1, 2020-April 28, 2021). The primary outcome was the occurrence of severe COVID-19 (hospitalization or death) within 30 days from SARS-CoV-2 infection. Adjusted odds ratios (aOR) and 95% confidence intervals (CI) were estimated using multivariable logistic regression models to assess the association between severe COVID-19 and patient characteristics, including demographics, baseline comorbidities, and recent RA treatments. RESULTS: During the study period, 6769 SARS-CoV-2 infections were identified in patients with RA, among whom 1460 (22%) developed severe COVID-19. Multivariable logistic regression analysis showed that being older, male, and non-White and having diabetes and cardiovascular conditions are associated with greater odds of severe COVID-19. In addition, compared with no use, the adjusted odds of severe COVID-19 were lower with recent use of tumor necrosis factor inhibitors (aOR 0.60, 95% CI 0.41-0.86) and higher with recent use of corticosteroids (aOR 1.38, 95% CI 1.13-1.69) or rituximab (aOR 2.87, 95% CI 1.60-5.14), respectively. CONCLUSION: Nearly one in five patients with RA developed severe COVID-19 disease within 30 days after SARS-CoV-2 infection. In patients with RA, recent use of corticosteroids and rituximab were two factors associated with a greater risk of severe COVID-19 in addition to the risk factors among demographics and comorbidities previously identified in the general population.

Influenza A(H1N1)pdm09 virus among healthy show pigs, United States.

Within 5 months after the earliest detection of human influenza A(H1N1)pdm09 virus, we found molecular and culture evidence of the virus in healthy US show pigs. The mixing of humans and pigs at swine shows possibly could further the geographic and cross-species spread of influenza A viruses.

Risk of Severe COVID-19 Outcomes Among Patients with Immune-Mediated Inflammatory Diseases or Malignancies: A Retrospective Analysis of Real-World Data in the United States.

INTRODUCTION: There are concerns that patients in an immunocompromised state may be at risk for increased coronavirus disease 2019 (COVID-19) severity. The aim of this study was to describe the characteristics of patients with COVID-19 and immune-mediated inflammatory diseases (IMIDs) or malignancies and evaluate their risk of developing severe COVID-19. METHODS: Cases of COVID-19 (ICD-10 code U07.1 or U07.2, or positive polymerase chain reaction or antigen test) among patients with IMIDs or malignancies were identified in the US-based Optum® Electronic Health Records database between 1 February 2020 and 3 March 2021. Age- and sex-standardized risks of severe COVID-19 were calculated by condition of interest. The risks were further adjusted by multiple covariates, and 95% confidence intervals were estimated. RESULTS: A total of 499,772 patients with COVID-19 were identified (mean [SD] age, 46.9 [20.7] years; 57.0% female). Patients with hematologic cancers (adjusted risk ratio [aRR] 2.0, 1.8-2.1), solid tumors (aRR 1.1, 1.1-1.1), or rheumatoid arthritis (aRR 1.2, 1.1-1.3) had a significantly higher risk of severe COVID-19 compared to the general population of patients with COVID-19. Patients with systemic lupus erythematosus (aRR 1.1, 0.9-1.2), psoriasis (aRR 1.0, 0.7-1.2), ulcerative colitis (aRR 0.9, 0.8-1.1), Crohn's disease (aRR 0.9, 0.7-1.0), or ankylosing spondylitis (aRR 0.8, 0.5-1.0) showed a comparable risk of severe COVID-19. Patients with atopic dermatitis (aRR 0.8, 0.7-0.9) or psoriatic arthritis (aRR 0.8, 0.6-1.0) showed a lower risk of severe COVID-19. CONCLUSIONS: The risk of developing severe COVID-19 varied between the studied IMIDs and malignancies. Patients with hematologic cancers, solid tumors, or rheumatoid arthritis had significantly increased risk for severe COVID-19 compared to the general population. These findings highlight the need to protect and monitor immunocompromised patients such as those with IMIDs or malignancies as part of the strategy to control the pandemic worldwide.

EpidemiologiCal POpulatioN STudy of SARS-CoV-2 in Lake CounTy, Illinois (CONTACT): Methodology and Baseline Characteristics of a Community-Based Surveillance Study.

INTRODUCTION: EpidemiologiCal POpulatioN STudy of SARS-CoV-2 in Lake CounTy, Illinois (CONTACT) is an observational, epidemiological study with a 9-month longitudinal follow-up of nonhospitalized persons aged 18 years or older currently living or employed in Lake County, IL. We describe the study design and report baseline characteristics of the study participants, including the proportion of participants with acute or previous SARS-CoV-2 infection at enrollment. METHODS: At enrollment and subsequent timepoints, participants recruited through digital and paper-based advertising campaigns reported their occupational and school-based exposure, risk factors, and behaviors, and provided nasal and serum specimens. Stratified enrichment was used to enhance enrollment into medium- and higher-risk groups within four occupational risk groups for SARS-CoV-2 infection. RT-PCR and serologic (IgG) testing were conducted to detect acute or previous SARS-CoV-2 infection in participants, respectively. RESULTS: Between November 2020 and January 2021, 1008 participants (female 70.7%, mean age ± SD 51 ± 13.8 years) completed the questionnaire and diagnostic testing. Among participants, 41.8% (n = 421) were considered low risk, 24.6% (n = 248) were medium-to-low risk, 22.3% (n = 225) were medium-to-high risk, and 11.3% (n = 114) were high risk. Of 56 (5.6%) participants with evidence of acute or previous SARS-CoV-2 infection at baseline, 11 (19.6%) were RT-PCR-positive, 36 (64.3%) were IgG-seropositive, and 9 (16.1%) were positive by both assays. Participants who were adherent vs nonadherent to social distancing measures (odds ratio [95% CI] 0.8 [0.4-1.8]) were less likely, while those in higher vs lower occupational risk groups (2.0 [1.0-4.4]) were more likely to have evidence for acute or previous SARS-CoV-2 infection. CONCLUSION: In fall/winter 2020/21, 5.6% of adults in a Lake County convenience sample had evidence for acute or previous SARS-CoV-2 infection at baseline. Nonadherence to social distancing measures and high-risk professions were associated with SARS-CoV-2 infection. The study is ongoing and future analyses will assess infection status over time. CLINICAL TRIAL REGISTRATION: NCT04611230.

Evidence for subclinical avian influenza virus infections among rural Thai villagers.

BACKGROUND: Regions of Thailand reported sporadic outbreaks of A/H5N1 highly pathogenic avian influenza (HPAI) among poultry between 2004 and 2008. Kamphaeng Phet Province, in north-central Thailand had over 50 HPAI poultry outbreaks in 2004 alone, and 1 confirmed and 2 likely other human HPAI infections between 2004 and 2006. METHODS: In 2008, we enrolled a cohort of 800 rural Thai adults living in 8 sites within Kamphaeng Phet Province in a prospective study of zoonotic influenza transmission. We studied participants' sera with serologic assays against 16 avian, 2 swine, and 8 human influenza viruses. RESULTS: Among participants (mean age 49.6 years and 58% female) 65% reported lifetime poultry exposure of at least 30 consecutive minutes. Enrollees had elevated antibodies by microneutralization assay against 3 avian viruses: A/Hong Kong/1073/1999(H9N2), A/Thailand/676/2005(H5N1), and A/Thailand/384/2006(H5N1). Bivariate risk factor modeling demonstrated that male gender, lack of an indoor water source, and tobacco use were associated with elevated titers against avian H9N2 virus. Multivariate modeling suggested that increasing age, lack of an indoor water source, and chronic breathing problems were associated with infection with 1 or both HPAI H5N1 strains. Poultry exposure was not associated with positive serologic findings. CONCLUSIONS: These data suggest that people in rural central Thailand may have experienced subclinical avian influenza infections as a result of yet unidentified environmental exposures. Lack of an indoor water source may play a role in transmission.

High-dose influenza vaccine use among patients receiving hemodialysis in the United States, 2010-2013.

BACKGROUND: Standard influenza vaccines may be of limited benefit to patients with end-stage renal disease (ESRD). These patients may benefit from high-dose influenza vaccine, currently indicated for patients aged ≥65 years. Studies in other populations have demonstrated that high-dose vaccine elicits a stronger immunological response. We compared vaccine uptake in the United States and predictors of receipt for high-dose and standard influenza vaccines. METHODS: Using data from the United States Renal Data System (2010-2013), we conducted a cohort study of 421,482 adult patients on hemodialysis. We examined temporal trends in uptake of high-dose or standard trivalent influenza vaccine each influenza season, and used multivariate logistic regression to assess the association between individual-level variables (e.g., demographics, comorbidities) and facility-level variables (e.g., facility size and type) with vaccine receipt. RESULTS: The proportion of patients with ESRD who were vaccinated with any influenza vaccine increased from 68.3% in 2010 to 72.4% in 2013. High-dose vaccines were administered to 0.9% of patients during the study period, and 16.7% of high-dose vaccines were administered to patients <65 years of age. Among patients aged ≥65 years, older patients (>79 vs. 65-69 years: OR, 1.29; 95% CI, 1.19-1.41) and patients at hospital-based versus free-standing dialysis facilities (OR, 2.31; 95% CI, 2.13-2.45) were more likely to receive high-dose vaccine, while blacks (vs. whites [OR, 0.66; 95% CI, 0.61-0.71]) and patients with longer duration of ESRD (>9 vs. 0 years: OR, 0.66; 95% CI, 0.55-0.78) were less likely to receive the high-dose vaccine. CONCLUSIONS: While the overall influenza vaccination rate has increased, use of high-dose vaccine among patients with ESRD was very low. Being an older patient, living in the Midwest, and receiving care at hospital-based facilities were the strongest predictors of receiving high-dose vaccine.

Evaluating the Safety of Medication Exposures During Pregnancy: A Case Study of Study Designs and Data Sources in Multiple Sclerosis.

BACKGROUND: Regulatory agencies often request prospective, product-specific post-authorization pregnancy exposure registries to monitor safety during pregnancy, even though studies using existing health databases could also be employed. OBJECTIVES: Using multiple sclerosis (MS) as a case study, we evaluated various study designs and data sources previously used to study medication exposure in pregnancy. METHODS: We examined (1) strengths and limitations of study designs used for pregnancy safety studies in women exposed to MS-specific medications during pregnancy and (2) existing data sources used to conduct such studies in other disease areas. For the data sources identified, we contacted data custodians to determine the feasibility of assessing the risk of adverse outcomes in women with MS exposed to disease-modifying therapies (DMTs) during pregnancy. RESULTS: Of 43 MS-specific studies identified, most of which were prospective registries, very few, regardless of design and study population, produced timely and robust results for spontaneous abortions and major congenital malformations, considering study duration, achievement of target enrollment numbers, inclusion of internal comparators, and publication of results. Building on the successful use of existing healthcare databases to investigate drug safety during pregnancy in other disease areas, we identified 13 data sources that could be used to study intravenous DMT exposures in women with MS. CONCLUSIONS: Prospective, treatment-specific registries have generally failed to deliver robust information. For this reason, other study approaches, in particular cohort studies using existing healthcare databases, should be considered for evaluating the safety of drug exposure in pregnancy, including in MS.

No evidence for zoonotic transmission of H3N8 canine influenza virus among US adults occupationally exposed to dogs.

OBJECTIVES: The zoonotic potential of H3N8 canine influenza virus (CIV) has not been previously examined; yet considering the popularity of dogs as a companion animal and the zoonotic capabilities of other influenza viruses, the public health implications are great. This study aimed to determine the seroprevalence of antibodies against CIV among a US cohort. DESIGN: A cross-sectional seroepidemiological study was conducted between 2007 and 2010. SETTING: Recruitments primarily occurred in Iowa and Florida. Participants were enrolled at dog shows, or at their home or place of employment. SAMPLE: Three hundred and four adults occupationally exposed to dogs and 101 non-canine-exposed participants completed a questionnaire and provided a blood sample. MAIN OUTCOME MEASURES: Microneutralization and neuraminidase inhibition assays were performed to detect human sera antibodies against A/Canine/Iowa/13628/2005(H3N8). An enzyme-linked lectin assay (ELLA) was adapted to detect antibodies against a recombinant N8 neuraminidase protein from A/Equine/Pennsylvania/1/2007(H3N8). RESULTS: For all assays, no significant difference in detectable antibodies was observed when comparing the canine-exposed subjects to the non-canine-exposed subjects. CONCLUSION: While these results do not provide evidence for cross-species CIV transmission, influenza is predictably unpredictable. People frequently exposed to ill dogs should continually be monitored for novel zoonotic CIV infections.

Little evidence of avian or equine influenza virus infection among a cohort of Mongolian adults with animal exposures, 2010-2011.

Avian (AIV) and equine influenza virus (EIV) have been repeatedly shown to circulate among Mongolia's migrating birds or domestic horses. In 2009, 439 Mongolian adults, many with occupational exposure to animals, were enrolled in a prospective cohort study of zoonotic influenza transmission. Sera were drawn upon enrollment and again at 12 and 24 months. Participants were contacted monthly for 24 months and queried regarding episodes of acute influenza-like illnesses (ILI). Cohort members confirmed to have acute influenza A infections, permitted respiratory swab collections which were studied with rRT-PCR for influenza A. Serologic assays were performed against equine, avian, and human influenza viruses. Over the 2 yrs of follow-up, 100 ILI investigations in the cohort were conducted. Thirty-six ILI cases (36%) were identified as influenza A infections by rRT-PCR; none yielded evidence for AIV or EIV. Serological examination of 12 mo and 24 mo annual sera revealed 37 participants had detectable antibody titers (≥1∶10) against studied viruses during the course of study follow-up: 21 against A/Equine/Mongolia/01/2008(H3N8); 4 against an avian A/Teal/Hong Kong/w3129(H6N1), 11 against an avian-like A/Hong Kong/1073/1999(H9N2), and 1 against an avian A/Migrating duck/Hong Kong/MPD268/2007(H10N4) virus. However, all such titers were <1∶80 and none were statistically associated with avian or horse exposures. A number of subjects had evidence of seroconversion to zoonotic viruses, but the 4-fold titer changes were again not associated with avian or horse exposures. As elevated antibodies against seasonal influenza viruses were high during the study period, it seems likely that cross-reacting antibodies against seasonal human influenza viruses were a cause of the low-level seroreactivity against AIV or EIV. Despite the presence of AIV and EIV circulating among wild birds and horses in Mongolia, there was little evidence of AIV or EIV infection in this prospective study of Mongolians with animal exposures.

A prospective study of Romanian agriculture workers for zoonotic influenza infections.

BACKGROUND: In this prospective study we sought to examine seroepidemiological evidence for acute zoonotic influenza virus infection among Romanian agricultural workers. METHODS: Sera were drawn upon enrollment (2009) and again at 12 and 24 months from 312 adult agriculture workers and 51 age-group matched controls. Participants were contacted monthly for 24 months and queried regarding episodes of acute influenza-like illnesses (ILI). Cohort members meeting ILI criteria permitted respiratory swab collections as well as acute and convalescent serum collection. Serologic assays were performed against 9 avian, 3 swine, and 3 human influenza viruses. RESULTS: During the two-year follow-up, a total of 23 ILI events were reported. Two subjects' specimens were identified as influenza A by rRT-PCR. During the follow-up period, three individuals experienced elevated microneutralization antibody titers ≥1∶80 against three (one each) avian influenza viruses: A/Teal/Hong Kong/w312/97(H6N1), A/Hong Kong/1073/1999(H9N2), or A/Duck/Alberta/60/1976(H12N5). However, none of these participants met the criteria for poultry exposure. A number of subjects demonstrated four-fold increases over time in hemagglutination inhibition (HI) assay titers for at least one of the three swine influenza viruses (SIVs); however, it seems likely that two of these three responses were due to cross-reacting antibody against human influenza. Only elevated antibody titers against A/Swine/Flanders/1/1998(H3N2) lacked evidence for such confounding. In examining risk factors for elevated antibody against this SIV with multiple logistic regression, swine exposure (adjusted OR = 1.8, 95% CI 1.1-2.8) and tobacco use (adjusted OR = 1.8; 95% CI 1.1-2.9) were important predictors. CONCLUSIONS: While Romania has recently experienced multiple incursions of highly pathogenic avian influenza among domestic poultry, this cohort of Romanian agriculture workers had sparse evidence of avian influenza virus infections. In contrast, there was evidence, especially among the swine exposed participants, of infections with human and one swine H3N2 influenza virus.

High rate of A(H1N1)pdm09 infections among rural Thai villagers, 2009-2010.

BACKGROUND: Pandemic influenza A(H1N1)pdm09 emerged in Thailand in 2009. A prospective longitudinal adult cohort and household transmission study of influenza-like illness (ILI) was ongoing in rural Thailand at the time of emergence. Symptomatic and subclinical A(H1N1)pdm09 infection rates in the cohort and among household members were evaluated. METHODS: A cohort of 800 Thai adults underwent active community-based surveillance for ILI from 2008-2010. Acute respiratory samples from ILI episodes were tested for A(H1N1)pdm09 by qRT-PCR; acute and 60-day convalescent blood samples were tested by A(H1N1)pdm09 hemagglutination inhibition assay (HI). Enrollment, 12-month and 24-month follow-up blood samples were tested for A(H1N1)pdm09 seroconversion by HI. Household members of influenza A-infected cohort subjects with ILI were enrolled in household transmission investigations in which day 0 and 60 blood samples and acute respiratory samples were tested by either qRT-PCR or HI for A(H1N1)pdm09. Seroconversion between annual blood samples without A(H1N1)pdm09-positive ILI was considered as subclinical infection. RESULTS: The 2-yr cumulative incidence of A(H1N1)pdm09 infection in the cohort in 2009/2010 was 10.8% (84/781) with an annual incidence of 1.2% in 2009 and 9.7% in 2010; 83.3% of infections were subclinical (50% in 2009 and 85.9% in 2010). The 2-yr cumulative incidence was lowest (5%) in adults born ≤ 1957. The A(H1N1)pdm09 secondary attack rate among household contacts was 47.2% (17/36); 47.1% of these infections were subclinical. The highest A(H1N1)pdm09 secondary attack rate among household contacts (70.6%, 12/17) occurred among children born between 1990 and 2003. CONCLUSION: Subclinical A(H1N1)pdm09 infections in Thai adults occurred frequently and accounted for a greater proportion of all A(H1N1)pdm09 infections than previously estimated. The role of subclinical infections in A(H1N1)pdm09 transmission has important implications in formulating strategies to predict and prevent the spread of A(H1N1)pdm09 and other influenza virus strains.