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.

Venous thromboembolism risk is lower in patients with atopic dermatitis than other immune-mediated inflammatory diseases: A retrospective, observational, comparative cohort study using US claims data.

BACKGROUND: Certain immune-mediated inflammatory diseases (IMIDs) may increase patients' risk for venous thromboembolisms (VTEs), yet how atopic dermatitis (AD) influences VTE risk remains unclear. OBJECTIVE: Describe VTE incidence in patients with AD compared with other IMIDs and unaffected, AD-matched controls. METHODS: This retrospective, observational, comparative cohort study used Optum Clinformatics United States claims data (2010-2019) of adults with AD, rheumatoid arthritis (RA), Crohn's disease (CD), ulcerative colitis (UC), psoriasis (PsO), psoriatic arthritis (PsA), or ankylosing spondylitis (AS). Unaffected control patients were matched 1:1 with patients with AD. RESULTS: Of 2,061,222 patients with IMIDs, 1,098,633 had AD. Patients with AD had a higher VTE incidence (95% CI) than did unaffected, AD-matched controls (0.73 [0.72-0.74] versus 0.59 [0.58-0.60] cases/100 person-years). When controlling for baseline VTE risk factors, however, AD was not associated with increased VTE risk (HR 0.96 [0.90-1.02]). VTE risk was lower in patients with AD versus RA, UC, CD, AS, or PsA; VTE risk was similar to patients with PsO. LIMITATIONS: Disease activity and severity were not accounted for. CONCLUSION: AD did not increase VTE risk when accounting for underlying risk factors. AD was associated with lower VTE risk compared with several rheumatologic and gastrointestinal IMIDs.

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.

Prevalence and burden of atopic dermatitis involving the head, neck, face, and hand: A cross sectional study from the TARGET-DERM AD cohort.

BACKGROUND: Atopic dermatitis (AD) is severely burdensome, and there has been poor characterization of any differences in impact based on the area affected. OBJECTIVE: To estimate the prevalence and HRQoL impact of head/face/neck/hand (HFNH) involvement among patients with moderate-to-severe atopic dermatitis. METHODS: All TARGET-DERM AD registry patients with moderate/severe Investigator Global Assessment (vIGA-AD) were assessed using the Patient Oriented SCORing Atopic Dermatitis, Patient Oriented Eczema Measure (POEM) and the (Children's) Dermatology Life Quality Index ((C)DLQI). RESULTS: 541 participants met the criteria (75.0% adults) and 84% (N = 453) reported HFNH involvement. HFNH and non-HFNH involved participants had similar characteristics; 55.2% female and 46.9% White. Compared to the non-HFNH involved, the involved had severe vIGA-AD (28.5% vs 16.3%, P = .02) and higher median body surface area affected (15% vs 10%, P ≤ .01) and were twice as likely to have higher (C)DLQI and POEM scores. LIMITATIONS: This was an analysis of real-world and patient reported outcome data. CONCLUSION: Real-world HFNH involved AD patients were associated with significantly worse quality of life, POEM/(C)DLQI, and more severe disease. Detailed assessments of specific areas affected by AD are needed to personalize treatment.

Do Atopic Dermatitis Patient-Reported Outcomes Correlate With Validated Investigator Global Assessment? Insights From TARGET-AD Registry.

BACKGROUND: Research examining associations between the clinician-reported validated Investigator Global Assessment for AD (vIGA-AD) and patient-reported disease burden is sparse. This study aims to evaluate the relationship between vIGA-AD with patient-reported disease severity and quality of life (QoL). METHODS: A cross-sectional analysis was conducted using a September 2021 data cut from the TARGET-DERM AD study, a real-world, longitudinal cohort of children, adolescents, and adults with AD enrolled at 44 academic and community dermatology and allergy sites in the US. Clinical AD severity was measured using vIGA-AD while disease severity and QoL were assessed by the Patient Oriented Eczema Measure (POEM) and (Children's) Dermatology Life Quality Index (C/DLQI), respectively. Patient characteristics, clinical- and patient reported-outcomes were assessed by stratified POEM and C/DLQI categories using descriptive statistics. Associations with vIGA-AD were evaluated using unadjusted and adjusted ordinal logistic regression and linear regression models. RESULTS: The analysis cohort (n=1,888) primarily consisted of adults (57%), females (56%), and patients with private insurance (63%). Unadjusted analyses suggest that clinical AD severity was associated with age, with more adolescents and adults having moderate/severe vIGA-AD than pediatric patients. Clinical AD severity was also associated with disease severity, with greater POEM scores observed at greater vIGA-AD severity levels (r = 0.496 and 0.45 for adults and pediatrics, respectively). Clinical AD severity and QoL were positively correlated, with greater CDLQI/DLQI scores at greater vIGA-AD severity levels (r = 0.458 and 0.334 for DLQI and CDLQI, respectively). After adjusting for demographics and other risk factors, vIGA-AD continued to show significant associations with POEM and DLQI/CDLQI. Compared to patients with clear/almost clear disease, adults and pediatrics with moderate-to-severe AD were 8.19 and 5.78 times as likely to be in a more severe POEM category, respectively. Similarly, compared to patients with clear/almost clear disease, adults and pediatrics with moderate/severe AD were 6.69 and 3.74 times as likely to be in a more severe DLQI/CDLQI category. Adjusted linear regression analyses of DLQI in adults showed significant differences by vIGA-AD level, with mild AD and moderate/severe AD associated with a 2.26-point and 5.42-point greater DLQI relative to clear/almost clear AD. CONCLUSIONS: In this real-world study of patients with AD, greater clinician-reported disease severity is positively correlated with higher patient-reported disease severity and lower QoL. J Drugs Dermatol. 2023;22(4): doi:10.36849/JDD.7473 Access Supplementary Material here Citation: Guttman-Yassky E, Bar J, Rothenberg Lausell C, et al. Do atopic dermatitis patient-reported outcomes correlate with validated investigator global assessment? Insights from TARGET-AD registry. J Drugs Dermatol. 2023;22(4):344-355. doi:10.36849/JDD.7473.

A time-course prediction model of global COVID-19 mortality.

Introduction: The COVID-19 pandemic has caused over 6 million deaths worldwide and is a significant cause of mortality. Mortality dynamics vary significantly by country due to pathogen, host, social and environmental factors, in addition to vaccination and treatments. However, there is limited data on the relative contribution of different explanatory variables, which may explain changes in mortality over time. We, therefore, created a predictive model using orthogonal machine learning techniques to attempt to quantify the contribution of static and dynamic variables over time. Methods: A model was created using Partial Least Squares Regression trained on data from 2020 to rank order the significance and effect size of static variables on mortality per country. This model enables the prediction of mortality levels for countries based on demographics alone. Partial Least Squares Regression was then used to quantify how dynamic variables, including weather and non-pharmaceutical interventions, contributed to the overall mortality in 2020. Finally, mortality levels for the first 60 days of 2021 were predicted using rolling-window Elastic Net regression. Results: This model allowed prediction of deaths per day and quantification of the degree of influence of included variables, accounting for timing of occurrence or implementation. We found that the most parsimonious model could be reduced to six variables; three policy-related variables - COVID-19 testing policy, canceled public events policy, workplace closing policy; in addition to three environmental variables - maximum temperature per day, minimum temperature per day, and the dewpoint temperature per day. Conclusion: Country and population-level static and dynamic variables can be used to predict COVID-19 mortality, providing an example of how broad temporal data can inform a preparation and mitigation strategy for both COVID-19 and future pandemics and assist decision-makers by identifying population-level contributors, including interventions, that have the greatest influence in mitigating mortality, and optimizing the health and safety of populations.

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.

Predictors of Treatment Change Among Patients with Rheumatoid Arthritis Treated with TNF Inhibitors as First-Line Biologic Agent in the USA: A Cohort Study from Longitudinal Electronic Health Records.

BACKGROUND: Previous observational studies utilizing administrative claims data have largely been unable to consider clinical factors that may be related to patterns of drug use among patients with rheumatoid arthritis (RA). OBJECTIVE: To understand predictors of treatment changes following initiation of a tumor necrosis factor inhibitor (TNFi) using nation-wide electronic health record (EHR) data in the USA. METHODS: The Optum Immunology Condition EHR data (01/01/2011-09/30/2019) was used to identify a population of adult patients with RA initiating a TNFi as the first line biologic disease-modifying anti-rheumatic drug (DMARD). The primary outcome was any treatment change during the 1-year post-index period defined as cycling to a different TNFi or switching to non-TNFi biologic or targeted synthetic DMARDs. Secondary outcomes were the individual components of TNFi cycling and switching, examined separately. To identify predictors of DMARD treatment changes, we used a least absolute shrinkage and selection operator (LASSO) regression model. Model c-statistics and odds ratios (ORs, 95% confidence intervals (CIs)) of predictors were reported. RESULTS: We identified 24,871 patients with RA who initiated a TNFi. The mean age was 55.5 (± 13.7) years and 77.2% were female. Among the TNFi initiators, 22.2% experienced TNFi cycling or switching during the 1-year follow-up time. Predictors that are associated with higher likelihood of TNFi cycling or switching included female gender (OR: 1.26, 95% CI: 1.16-1.36) and glucocorticoid use (OR: 1.30, 95% CI: 1.21-1.40). In contrast, inflammatory bowel disease (OR: 0.62, 95% CI: 0.48-0.78), psoriasis (OR: 0.82, 95% CI: 0.70-0.95), recent use of methotrexate (OR: 0.89, 95% CI: 0.81-0.97), and vitamin D intake (OR: 0.92, 95% CI: 0.85-0.99) were negatively associated with TNFi cycling or switch. CONCLUSIONS: Gender, glucocorticoid use, inflammatory bowel disease, psoriasis, and vitamin D intake were identified as significant predictors of TNFi cycling or switching for TNFi initiators in the RA population. Predicting treatment change remains challenging even with large detailed EHR data. This study aimed to identify key determinants of treatment changes among patients with rheumatoid arthritis (RA) initiating a tumor necrosis factor inhibitor (TNFi) as their first-line biologic disease-modifying antirheumatic drug (DMARD) in routine care settings using a US nation-wide longitudinal electronic health record (EHR). Among 24,871 patients with RA who initiated a TNFi, 22.2% experienced TNFi cycling or switching during the 1-year follow-up time. Female patients and those who used glucocorticoids were more likely to experience TNFi cycling or switching, whereas inflammatory bowel disease, psoriasis, recent methotrexate use, and vitamin D intake were negatively associated with the outcome. However, predicting treatment change remains challenging even with larger detailed EHR data potentially due to unmeasured factors such as prescriber's preference or patient's belief in the medication.

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.

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.

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.

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.

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.

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.

Little evidence of subclinical avian influenza virus infections among rural villagers in Cambodia.

In 2008, 800 adults living within rural Kampong Cham Province, Cambodia were enrolled in a prospective cohort study of zoonotic influenza transmission. After enrollment, participants were contacted weekly for 24 months to identify acute influenza-like illnesses (ILI). Follow-up sera were collected at 12 and 24 months. A transmission substudy was also conducted among the family contacts of cohort members reporting ILI who were influenza A positive. Samples were assessed using serological or molecular techniques looking for evidence of infection with human and avian influenza viruses. Over 24 months, 438 ILI investigations among 284 cohort members were conducted. One cohort member was hospitalized with a H5N1 highly pathogenic avian influenza (HPAI) virus infection and withdrew from the study. Ninety-seven ILI cases (22.1%) were identified as influenza A virus infections by real-time RT-PCR; none yielded evidence for AIV. During the 2 years of follow-up, 21 participants (3.0%) had detectable antibody titers (≥ 1:10) against the studied AIVs: 1 against an avian-like A/Migratory duck/Hong Kong/MPS180/2003(H4N6), 3 against an avian-like A/Teal/Hong Kong/w312/97(H6N1), 9 (3 of which had detectible antibody titers at both 12- and 24-month follow-up) against an avian-like A/Hong Kong/1073/1999(H9N2), 6 (1 detected at both 12- and 24-month follow-up) against an avian-like A/Duck/Memphis/546/74(H11N9), and 2 against an avian-like A/Duck/Alberta/60/76(H12N5). With the exception of the one hospitalized cohort member with H5N1 infection, no other symptomatic avian influenza infections were detected among the cohort. Serological evidence for subclinical infections was sparse with only one subject showing a 4-fold rise in microneutralization titer over time against AvH12N5. In summary, despite conducting this closely monitored cohort study in a region enzootic for H5N1 HPAI, we were unable to detect subclinical avian influenza infections, suggesting either that these infections are rare or that our assays are insensitive at detecting them.

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.