Clinical and immunological outcomes of HIV-exposed uninfected and HIV-unexposed uninfected children in the first 24 months of life in Western Kenya.

BACKGROUND: Previous studies show increased morbidity in children who are HIV-exposed but uninfected (HEU) compared to children who are HIV-unexposed uninfected (HUU). We sought to evaluate the effects of prenatal HIV exposure on clinical and immunological outcomes in the first 24 months of life. METHODS: Eighty-five HEU and 168 HUU children from Kenya were followed from birth to 24 months. All mothers living with HIV received combination antiretroviral therapy. Children who were HEU received standard-of-care cotrimoxazole prophylaxis through 18 months. Episodes of acute illness were identified through a combination of active and passive follow up. Trajectories of plasma cytokines, vaccine-specific antibodies, and antimalarial antibodies were examined. RESULTS: Children who were HEU and children who were HUU had similar growth curves. Children who were HEU had lower rates of malaria (rate ratio 0.54, 95% CI 0.38, 0.77) and respiratory illness (rate ratio 0.80, 95% CI 0.68, 0.93). Trajectories of plasma cytokines and vaccine-specific antibodies were similar in children who were HEU and HUU. There were subtle differences in antimalarial antibody dynamics, in which children who were HEU had overall lower antibody levels against five of the 14 malaria antigens tested. CONCLUSIONS: Children who were HEU and born to optimally treated mothers living with HIV had similar growth characteristics and immune profiles compared to children who were HUU. Children who were HEU had reduced risk for malaria and respiratory illness, which may be secondary to cotrimoxazole prophylaxis.

Effect of Malaria Infection on Epstein-Barr Virus Persistence in Kenyan Children.

BACKGROUND: The 2 cofactors in the etiology of Burkitt lymphoma (BL) are Epstein-Barr virus (EBV) and repeated Plasmodium falciparum malaria infections. This study evaluated EBV loads in mucosal and systemic compartments of children with malaria and controls. Age was analyzed as a covariate because immunity to malaria in endemic regions is age dependent. METHODS: Children (2-10 years) with clinical malaria from Western Kenya and community controls without malaria were enrolled. Saliva and blood samples were collected, EBV viral load was assessed by quantitative polymerase chain reaction, and EpiTYPER MassARRAY was used to assess methylation of 3 different EBV genes. RESULTS: Regardless of the compartment, we detected EBV more frequently in malaria cases compared to controls, although the difference was not significant. When EBV was detected, there were no differences in viral load between cases and controls. However, EBV methylation was significantly lower in the malaria group compared to controls in both plasma and saliva (P < .05), indicating increased EBV lytic replication. In younger children before development of immunity to malaria, there was a significant effect of malaria on EBV load in peripheral blood mononuclear cells (P = .04). CONCLUSIONS: These data suggest that malaria can directly modulate EBV persistence in children, increasing their risk for BL.

Plasmodium falciparum Malaria Is Associated With Increased Kaposi Sarcoma-Associated Herpesvirus (KSHV) Seropositivity and Higher KSHV Antibody Breadth and Magnitude: Results of a Case-Control Study From Rural Uganda.

BACKGROUND: Previously, we showed that children with asymptomatic Plasmodium falciparum (Pf) malaria infection had higher Kaposi sarcoma-associated herpesvirus (KSHV) viral load, increased risk of KSHV seropositivity, and higher KSHV antibody levels. We hypothesize that clinical malaria has an even larger association with KSHV seropositivity. In the current study, we investigated the association between clinical malaria and KSHV seropositivity and antibody levels. METHODS: Between December 2020 and March 2022, sick children (aged 5-10 years) presenting at a clinic in Uganda were enrolled in a case-control study. Pf was detected using malaria rapid diagnostic tests (RDTs) and subsequently with quantitative real-time polymerase chain reaction (qPCR). Children with malaria were categorized into 2 groups: RDT+/PfPCR+ and RDT-/PfPCR+. RESULTS: The seropositivity of KSHV was 60% (47/78) among Pf-uninfected children, 79% (61/77) among children who were RDT-/PfPCR+ (odds ratio [OR], 2.41 [95% confidence interval {CI}, 1.15-5.02]), and 95% (141/149) in children who were RDT+/PfPCR+ (OR, 10.52 [95% CI, 4.17-26.58]; Ptrend < .001). Furthermore, RDT+/PfPCR+ children followed by RDT-/PfPCR+ children had higher KSHV IgG and IgM antibody levels and reacted to more KSHV antigens compared to uninfected children. CONCLUSIONS: Clinical malaria is associated with both increased KSHV seropositivity and antibody magnitude, suggesting that Pf is affecting KSHV immunity.

Epstein-Barr virus (EBV) antibody changes over time in a general population cohort in rural Uganda, 1992-2008.

BACKGROUND: Epstein-Barr virus (EBV) infection is ubiquitous and in sub-Saharan Africa, occurs early in life. In a population-based rural African cohort, we leveraged historical samples from the General Population Cohort (GPC) in Uganda to examine the epidemiology of infection with EBV over time, in the era of HIV. METHODS: We used 9024 serum samples collected from the GPC in 1992, 2000, 2008, from 7576 participants across the age range (0-99 years of age) and tested for anti-EBV immunoglobulin G (IgG) antibodies to EAd, VCA, and EBNA-1 using a multiplex bead-based assay. The related gammaherpesvirus, Kaposi's sarcoma-associated herpesvirus (KSHV) seropositivity was also determined by detection of anti-KSHV IgG antibodies to K8.1 or ORF73 measured by recombinant protein enzyme-linked immunosorbent assay. Data on sex, age, and HIV serostatus were also collected. EBV seropositivity was modeled with age (excluding those under one year, who may have had maternal antibodies), sex, HIV serostatus, and KSHV serostatus using generalized linear mixed effects models to produce beta estimates. RESULTS: More than 93% of children were EBV seropositive by one year of age. EBV seropositivity was significantly associated with KSHV seropositivity. Anti-EBNA-1 antibody levels decreased with increasing age and were lower on average in people living with HIV. In general, anti-EAd antibody levels increased with age, were higher in males and KSHV seropositive persons, but decreased over calendar time. Anti-VCA antibody levels increased with age and with calendar time and were higher in KSHV seropositive persons but lower in males. CONCLUSIONS: This is the first study to identify factors associated with EBV antibodies across the entire life-course in rural sub-Saharan Africa. Consistent with other studies, EBV was near ubiquitous in the population by age one year. Patterns of antibodies show changes by age, sex and calendar time, but no association with HIV was evident, suggesting no relationship between EBV sero-epidemiology and the spread of HIV in the population over time in Uganda.

Effects of Maternal HIV Infection on Early Kaposi Sarcoma-Associated Herpesvirus Seroconversion in a Kenyan Mother-Infant Cohort.

BACKGROUND: We identified whether maternal human immunodeficiency virus (HIV) infection during pregnancy affects transplacental transfer of Kaposi sarcoma-associated herpesvirus (KSHV)-specific antibodies and subsequent infant infection. METHODS: We followed pregnant Kenyan women through delivery and their infants until age 2 years. Children were classified as HIV-exposed uninfected (HEU) or HIV-unexposed uninfected (HUU) based on maternal HIV status. Maternal venous and cord blood at delivery and child venous blood every 6 months were tested for antibodies to 20 KSHV antigens by multiplex bead-based immunoassay. Multiple comparisons were adjusted using false discovery rate (FDR). RESULTS: Maternal HIV infection was significantly associated with decreased transplacental transfer of antibodies against all KSHV antigens and lower cord blood levels for 8 antigens at FDR P < .10. Neither birth to 6-month antibody level changes nor 6-month levels differed in HEU and HUU, except for ORF50. By age 24 months, 74% of children KSHV seroconverted but HEU and HUU did not differ in time to seroconversion nor 2-year seropositivity after adjustment for child malaria infection. CONCLUSIONS: Maternal HIV infection reduced a child's initial KSHV antibody levels but did not affect age of infection. Regardless of HIV exposure in utero, KSHV seroconversion in Kenyan children occurred early; associated factors must be identified.

Clinical and Immunological Outcomes of HIV-Exposed Uninfected and HIV-Unexposed Uninfected Children in the First 24 Months of Life in Western Kenya.

Background: Previous studies show increased morbidity in children who are HIV-exposed but uninfected (HEU) compared to children who are HIV-unexposed uninfected (HUU). We sought to evaluate the effects of prenatal HIV exposure on clinical and immunological outcomes in the first 24 months of life. Methods: Eighty-five HEU and 168 HUU children from Kenya were followed from birth to 24 months. All mothers with HIV received combination antiretroviral therapy. HEU children received standard-of-care cotrimoxazole prophylaxis through 18 months. Episodes of acute illness were identified through a combination of active and passive follow up. Trajectories of plasma cytokines, vaccine-specific antibodies, and antimalarial antibodies were examined. Results: HEU and HUU children had similar growth curves. HEU children had lower rates of malaria and respiratory illness. Trajectories of plasma cytokines and vaccine-specific antibodies were similar in HEU and HUU children. There were subtle differences in antimalarial antibody dynamics, in which HEU children had overall lower antibody levels against five of the 14 malaria antigens tested. Conclusions: HEU children born to optimally treated mothers living with HIV had similar growth characteristics and immune profiles compared to HUU children. HEU children had reduced risk for malaria and respiratory illness, which may be secondary to cotrimoxazole prophylaxis.

Evaluation of a training intervention to improve cancer care in Zimbabwe: Strategies to Improve Kaposi Sarcoma Outcomes (SIKO), a prospective community-based stepped-wedge cluster randomized trial.

INTRODUCTION: Most Zimbabweans access medical care through tiered health systems. In 2013, HIV care was decentralized to primary care clinics; while oncology care remained centralized. Most persons in Zimbabwe with Kaposi sarcoma (KS) are diagnosed late in their disease, and the prognosis is poor. Little is known about whether educational interventions could improve KS outcomes in these settings. METHODS: Interventions to improve KS detection and management were evaluated at eight Zimbabwe primary care sites (four rural/four urban) that provided HIV care. Interventions included a standardized KS clinical evaluation tool, palliative care integration, standardized treatment and improved consultative services. Interventions were implemented between February 2013 and January 2016 using a randomized stepped-wedge cluster design. Sites were monitored for KS diagnosis rates and KS outcomes, including early diagnosis (T0 vs. T1 tumour stage), participant retention and mortality. Analyses controlled for within-clinic correlations. RESULTS: A total of 1102 persons with suspected KS (96% HIV positive) were enrolled: 47% incident (new diagnosis), 20% prevalent (previous diagnosis) and 33% determined as not KS. Early (T0) diagnosis increased post-intervention, though not significant statistically (adjusted odds ratio [aOR] = 1.48 [95% confidence interval (95% CI): 0.66-3.79], p = 0.37). New KS diagnosis rates increased 103% (95% CI: 11-273%), p = 0.02) post-intervention; although paired with an increased odds of incorrectly diagnosing KS (aOR = 2.08 [95% CI: 0.33-3.24], p = 0.001). Post-intervention, non-significant decreases in 90-day return rates (adjusted hazard ratio [aHR] = 0.69 [95% CI: 0.38-1.45], p = 0.21) and survival (aHR = 1.36 [95% CI: 0.85-2.20], p = 0.20) were estimated. CONCLUSIONS: KS training interventions at urban and rural Zimbabwe decentralized primary care clinics significantly increased overall and incorrect KS diagnosis rates, but not early KS diagnosis rates, 90-day return rates or survival.

Environmental determinants of Kaposi's sarcoma-associated herpesvirus (KSHV) transmission in rural Uganda (ENDKU study): Contributions to research on KSHV infection and reactivation in African children; A longitudinal cohort study.

BACKGROUND: The Environmental Determinants of KSHV transmission in rural Uganda (ENDKU) study began enrollment in February 2020 with the purpose of defining the relationship between malaria, primarily caused by Plasmodium falciparum in sub-Saharan Africa, and KSHV susceptibility and reactivation. Uganda is an ideal study site, because both malaria and KSHV are endemic and widespread, even among young children. METHODS: ENDKU is a longitudinal cohort study of infants enrolled at six months of age and followed until three years of age. The main study, and one smaller sub-study, is nested within the General Population Cohort (GPC), a long-standing population cohort in rural Uganda. The ENDKU study was created to test the hypothesis that P. falciparum malaria increases an infant's susceptibility to KSHV infection. A sub-study to evaluate the effects of P. falciparum on KSHV reactivation involves an additional cohort of 5-10-year-old children with and without acute malaria who presented to the GPC study clinic. For each study, participants provided demographic and behavioral data through administered questionnaires and blood and saliva samples. RESULTS: Despite barriers presented by the COVID-19 pandemic, the study team was able to leverage the long-standing relationship of the UK Medical Research Council and the Uganda Virus Research Institute (MRC/UVRI) with the community, a strong commitment to research, and a multi-disciplinary team of experts to successfully implement the ENDKU study. CONCLUSION: The results of this multi-pronged approach will answer important questions about the etiology and transmission of KSHV in sub-Saharan Africa and the data and samples collected will be an important future resource for scientific research in the region.

Peri-Pregnancy Cannabis Use and Autism Spectrum Disorder in the Offspring: Findings from the Study to Explore Early Development.

The association of autism spectrum disorder (ASD) with self-reported maternal cannabis use from 3 months pre-conception to delivery ("peri-pregnancy") was assessed in children aged 30-68 months, born 2003 to 2011. Children with ASD (N = 1428) were compared to children with other developmental delays/disorders (DD, N = 1198) and population controls (POP, N = 1628). Peri-pregnancy cannabis use was reported for 5.2% of ASD, 3.2% of DD and 4.4% of POP children. Adjusted odds of peri-pregnancy cannabis use did not differ significantly between ASD cases and DD or POP controls. Results were similar for any use during pregnancy. However, given potential risks suggested by underlying neurobiology and animal models, further studies in more recent cohorts, in which cannabis use and perception may have changed, are needed.

Development and Validation of a Multiplex Microsphere Immunoassay Using Dried Blood Spots for SARS-CoV-2 Seroprevalence: Application in First Responders in Colorado, USA.

Serological testing of large representative populations for antibodies to SARS-CoV-2 is needed to estimate seroprevalence, transmission dynamics, and the duration of antibody responses from natural infection and vaccination. In this study, a high-throughput SARS-CoV-2 multiplex microsphere immunoassay (MMIA) was developed for the receptor binding domain (RBD) and nucleocapsid (N) that was more sensitive than enzyme-linked immunosorbent assay (ELISA) (98% versus 87%). The MMIA was then applied and validated in 264 first responders in Colorado using serum and dried blood spot (DBS) eluates, compared to ELISA, and evaluated for neutralizing antibodies. Four percent (11/264) of first responders were seropositive in July to August 2020. Serum and DBS were highly correlated for anti-RBD and anti-N antibodies (R = 0.83, P < 0.0001 and R = 0.87, P < 0.0001, respectively) by MMIA. The MMIA accurately predicted SARS-CoV-2 neutralizing antibodies using DBS (R = 0.76, P = 0.037). On repeat antibody testing 3 months later, anti-RBD IgG decreased less rapidly than anti-N IgG measured by MMIA, with a median change in geometric median fluorescence intensity of 62% versus 79% (P < 0.01) for anti-RBD and anti-N IgG, respectively. This novel MMIA using DBS could be scalable for rapid and affordable SARS-CoV-2 serosurveillance in the United States and globally.

Gastrointestinal Symptoms in 2- to 5-Year-Old Children in the Study to Explore Early Development.

Gastrointestinal symptoms (GIS) are commonly reported in children with autism spectrum disorder (ASD). This multi-site study evaluated the prevalence of GIS in preschool-aged children with ASD/(n = 672), with other developmental delays (DD)/(n = 938), and children in the general population (POP)/(n = 851). After adjusting for covariates, children in the ASD group were over 3 times more likely to have parent-reported GIS than the POP group, and almost 2 times more likely than the DD group. Children with GIS from all groups had more behavioral and sleep problems. Within the ASD group, children with developmental regression had more GIS than those without; however, there were no differences in autism severity scores between children with and without GIS. These findings have implications for clinical management.

Maternal HIV Infection as a Risk Factor for Primary Epstein-Barr Virus Infection in Kenyan Infants.

Human immunodeficiency virus (HIV) infection is known to be associated with EBV shedding in saliva suggesting an increased risk of EBV transmission to infants born to mothers with HIV at an earlier age. In this study we investigated (i) whether maternal HIV status was a risk factor for EBV in blood at delivery or for shedding in saliva and breast milk of 6- and 10-weeks post-partum mothers, (ii) if there was a difference in EBV strains shed between HIV+ and HIV- mothers, and (iii) if maternal HIV status was a determinant of EBV viral load in their infants. Samples were collected as part of a prospective cohort study that followed HIV-positive (HIV+) and HIV-negative (HIV-) pregnant women in Western Kenya through delivery and post-partum period. EBV viral load in blood was found to be significantly higher in mothers with HIV (p-value = 0.04). Additionally, a statistically significant difference was observed between EBV viral load in saliva samples and HIV status where HIV+ mothers had a higher EBV viral load in saliva at 6-weeks post-partum compared to HIV- mothers (p-value < 0.01). The difference in EBV shedding in breast milk was not found to be statistically significant. Furthermore, no difference in frequency of EBV strain was attributable to HIV- or HIV+ mothers. Interestingly, we found that infants born to HIV+ mothers had a higher EBV viral load at the time of their first EBV detection in blood than infants born to HIV- mothers and this was independent of age at detection. Overall, our study suggests that HIV infected mothers shed more virus in saliva than HIV-negative mothers and infants born to HIV+ mothers were at risk for loss of control of primary EBV infection as evidenced by higher EBV viral load following primary infection.

Malaria Is Associated With Kaposi Sarcoma-Associated Herpesvirus Seroconversion in a Cohort of Western Kenyan Children.

BACKGROUND: We aimed to determine whether Plasmodium falciparum infection affects age of Kaposi sarcoma-associated herpesvirus (KSHV) seroconversion in Kenyan children. METHODS: Kenyan children (n = 144) enrolled at age 1 month, from 2 sites with different levels of malaria transmission (stable/high vs unstable/low) were followed to age 24 months. Plasma was tested for KSHV antibodies using enzyme-linked immunosorbent assay (ELISA; K8.1 and LANA) and a multiplex bead-based assay (K8.1, K10.5, ORF38, ORF50, and LANA) and whole blood tested for P. falciparum DNA using quantitative PCR. Cox proportional hazards models were used to assess associations between P. falciparum DNA detection, malaria annualized rate (P. falciparum detections/person-years), and enrollment site (malaria-high vs malaria-low) with time to KSHV seroconversion. RESULTS: KSHV seroprevalence was 63% by age 2 years when assessed by multiplex assay. Children with P. falciparum were at increased hazards of earlier KSHV seroconversion and, among children with malaria, the hazard of becoming KSHV seropositive increased significantly with increasing malaria annualized rate. Children from the malaria-high transmission region had no significant difference in hazards of KSHV seroconversion at 12 months but were more likely to become KSHV seropositive by age 24 months. DISCUSSION: Malaria exposure increases the risk for KSHV seroconversion early in life.

Risk Factors of SARS-CoV-2 Antibodies in Arapahoe County First Responders-The COVID-19 Arapahoe SErosurveillance Study (CASES) Project.

OBJECTIVES: Define the seroprevalence and risk factors for SARS-CoV-2 antibodies in Arapahoe County, Colorado first responders (eg, law enforcement, human services, fire departments). METHODS: Two hundred sixty four first responders were enrolled June to July 2020. SARS-CoV-2 seropositivity was defined as detection of immunoglobulin G (IgG) antibodies to both spike receptor binding domain and nucleocapsid in venous blood by validated enzyme-linked immunosorbent assay. We compared risk factors for being seropositive versus seronegative. RESULTS: 4% (11/264) were SARS-CoV-2 seropositive. Seropositive participants were significantly more likely to have lung disease (% seropositive, % seronegative; P-value) (36%, 8%; P = 0.01), prior SARS-CoV-2/COVID-19 testing (36%, 8%; P ≤ 0.01), a prior positive result (18%, less than 1%), and to believe they previously had COVID-19 (64%, 15%; P < 0.01). Only 15% of those believing they had COVID-19 had anti-SARS-CoV-2 antibodies. CONCLUSIONS: Human services employees and individuals with lung disease are at SARS-CoV-2 exposure risk. Few individuals believed they had COVID-19 had prior exposure.

Using Online Surveys for Enteric Disease Case Investigations: A Pilot Project.

Typically conducted by telephone, routine enteric disease case interviews are critical for foodborne illness surveillance, outbreak detection, and disease control. However, an increasing case load, along with the increased use of mobile telephones, has made case interviews more challenging to complete. For this reason, the Colorado Integrated Food Safety Center of Excellence developed and evaluated a pilot program using online surveys to supplement routine telephone-based enteric disease case investigations. From April to September 2019, investigators offered laboratory-confirmed Giardia cases from three Colorado counties the option of either a telephone interview or an online survey. The paper-based Giardia case investigation form was mapped to an online survey in Research Electronic Data Capture. We evaluated the pilot project response rates, timeliness, data quality, demographics, and user feedback. Of the 32 Giardia cases contacted, 66% requested the online survey, and of these, 81% completed the survey. Online survey cases were slightly younger (median: 42 vs. 48 years) and the majority agreed that the survey was easy to use (93%), did not take too much time (87%), and was easy to understand (67%). Staff time decreased for online surveys compared with telephone interviews (median: 6 vs. 19 min); however, the time from case report to interview completion doubled (median: 4 vs. 2 d for telephone interview cases) and data quality decreased slightly. Given limited public health agency resources, supplementing telephone interviews with online surveys may increase the efficiency of routine enteric case investigations. The results of this pilot project indicate online surveys are popular with enteric disease cases and substantially reduce staff time. Methods to improve the timeliness and data quality of online surveys should be explored to reduce the impact on disease control and outbreak detection activities.

Malaria during pregnancy and transplacental transfer of Kaposi sarcoma-associated herpesvirus (KSHV) antibodies: a cohort study of Kenyan mother and child pairs.

BACKGROUND: Kaposi sarcoma-associated herpesvirus (KSHV) seroprevalence in sub-Saharan African children can range up to 50% by age 2 years but factors affecting early age of KSHV infection are not well understood. Malaria during pregnancy has been associated with hindered transplacental transfer of antibodies to several pathogens but whether it affects transplacental transfer of KSHV antibodies is unknown. We aimed to determine if in utero malaria exposure reduced the transfer of KSHV antibodies across the placenta. METHODS: A cohort study in Kisumu, Kenya enrolled pregnant women at their first antenatal clinic (ANC) visit and followed them through delivery. We included 70 KSHV-positive, HIV-negative mothers and their children. KSHV antibody levels were measured by ELISA (K8.1, ORF73) and multiplex assay (K8.1, ORF73, K10.5, ORF38, ORF50). Transplacental transfer of antibodies was measured by the cord to maternal blood ratio (CMR) of KSHV antibodies. Malaria during pregnancy was defined as detection of Plasmodium falciparum (Pf) DNA at any ANC visit or delivery. Among women with malaria during pregnancy, we examined time of last malaria infection prior to delivery (< 27 vs. 27+ weeks gestation) and malaria incidence rate (MIR) (episodes/100 person-weeks). RESULTS: KSHV seroprevalence (positive for K8.1 or ORF73 by ELISA) among pregnant women was 88%. Neither malaria during pregnancy, malaria infection timing, nor MIR were associated with maternal delivery KSHV antibody blood levels. Maternal delivery and cord blood KSHV antibody levels were highly correlated but these correlations did not differ by malaria during pregnancy. KSHV transplacental antibody transfer was not associated with malaria during pregnancy, malaria infection timing, nor MIR. CONCLUSIONS: Malaria during pregnancy does not appear to affect transfer of KSHV antibodies across the placenta.

Infection and Fever in Pregnancy and Autism Spectrum Disorders: Findings from the Study to Explore Early Development.

Maternal infection and fever during pregnancy have been implicated in the etiology of autism spectrum disorder (ASD); however, studies have not been able to separate the effects of fever itself from the impact of a specific infectious organism on the developing brain. We utilized data from the Study to Explore Early Development (SEED), a case-control study among 2- to 5-year-old children born between 2003 and 2006 in the United States, to explore a possible association between maternal infection and fever during pregnancy and risk of ASD and other developmental disorders (DDs). Three groups of children were included: children with ASD (N = 606) and children with DDs (N = 856), ascertained from clinical and educational sources, and children from the general population (N = 796), randomly sampled from state birth records. Information about infection and fever during pregnancy was obtained from a telephone interview with the mother shortly after study enrollment and maternal prenatal and labor/delivery medical records. ASD and DD status was determined by an in-person standardized developmental assessment of the child at 3-5 years of age. After adjustment for covariates, maternal infection anytime during pregnancy was not associated with ASD or DDs. However, second trimester infection accompanied by fever elevated risk for ASD approximately twofold (aOR = 2.19, 95% confidence interval 1.14-4.23). These findings of an association between maternal infection with fever in the second trimester and increased risk of ASD in the offspring suggest that the inflammatory response to the infectious agent may be etiologically relevant. Autism Res 2019, 12: 1551-1561. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Using data from a large multisite study in the United States-the Study to Explore Early Development-we found that women who had an infection during the second trimester of pregnancy accompanied by a fever are more likely to have children with ASD. These findings suggest the possibility that only more severe infections accompanied by a robust inflammatory response increase the risk of ASD.

Sleep Problems in 2- to 5-Year-Olds With Autism Spectrum Disorder and Other Developmental Delays.

: media-1vid110.1542/5984243260001PEDS-VA_2018-0492Video Abstract BACKGROUND: Sleep problems can impact daytime behavior, quality of life, and overall health. We compared sleep habits in young children with autism spectrum disorder (ASD) and other developmental delays and disorders and in children from the general population (POP). METHODS: We included 2- to 5-year-old children whose parent completed all items on the Children's Sleep Habits Questionnaire (CSHQ) in a multisite case-control study: 522 children with ASD; 228 children with other developmental delays and disorders with autism spectrum disorder characteristics (DD w/ASD); 534 children with other developmental delays and disorders without autism spectrum disorder characteristics (DD w/o ASD); and 703 POP. Multivariable analysis of variance compared CSHQ mean total score (TS) and subscale scores between groups. Logistic regression analysis examined group differences by using TS cutoffs of 41 and 48. Analyses were adjusted for covariates. RESULTS: Mean CSHQ TS for children in each group: ASD (48.5); DD w/ASD (50.4); DD w/o ASD (44.4); and POP (43.3). Differences between children with ASD and both children with DD w/o ASD and POP were statistically significant. Using a TS cutoff of 48, the proportion of children with sleep problems was significantly higher in children in the ASD group versus DD w/o ASD and POP groups (adjusted odds ratios [95% confidence intervals]: 2.12 [1.57 to 2.87] and 2.37 [1.75 to 3.22], respectively). CONCLUSIONS: Sleep problems are more than twice as common in young children with ASD and DD w/ASD. Screening for sleep problems is important in young children to facilitate provision of appropriate interventions.

Injury-related treatments and outcomes in preschool children with autism spectrum disorder: Study to Explore Early Development (SEED).

BACKGROUND: Evidence about injury management and outcomes in children with autism spectrum disorder (ASD) is limited. METHOD: Cross-sectional analyses included children aged 30-68 months with at least one medically attended injury. Standardized diagnostic instruments determined ASD cases. Parent-reported injury treatments and outcomes were examined in ASD cases (n = 224) versus developmental delays/disorders (DD) (n = 188) and population (POP) (n = 267) controls, adjusting for child and family characteristics using logistic regression. RESULTS: Injury characteristics were similar between groups. Most children (82.5%) had emergency care (EC) or hospitalization after injury. Nearly half (46.4%) ever received a medication or injection, mostly analgesics (53.4%) and local anesthetics (23.8%), while 9.4% ever received surgery, most often for open wound (47.0%) or fracture (16.7%). ASD group children were less likely than DD group children to receive medication/injection (41.1% vs. 53.2%, adjusted odds ratio [aOR] = 0.60 [0.40, 0.90]); receipt of EC/hospitalization and surgery were comparable. Children with ASD more often had surgery than POP children (14.3% vs. 4.9%, aOR = 2.62 [1.31, 5.25]); receipt of EC/hospitalization and medication/injection were similar. Loss of consciousness was uncommon (ASD = 6.3%, DD = 5.3%, POP = 3.4%), as was long-term or significant behavior change (ASD = 5.4%, DD = 3.2%, POP = 3.2%); differences were not significant. CONCLUSIONS: Injured children with ASD received fewer medications/injections than children with non-ASD developmental delays/disorders and more surgical treatments than general population children. Injury management was otherwise similar between groups. Understanding whether these results reflect child or injury characteristics or provider perceptions about behaviors and pain thresholds of children with ASD, and how these may influence care, requires further study.

Infections in children with autism spectrum disorder: Study to Explore Early Development (SEED).

Immune system abnormalities have been widely reported among children with autism spectrum disorder (ASD), which may increase the risk of childhood infections. The Study to Explore Early Development (SEED) is a multisite case-control study of children aged 30-69 months, born in 2003-2006. Cases are children previously diagnosed and newly identified with ASD enrolled from education and clinical settings. Children with a previously diagnosed non-ASD developmental condition were included in the developmental delay/disorder (DD) control group. The population (POP) control group included children randomly sampled from birth certificates. Clinical illness from infection during the first 28 days ("neonatal," from medical records) and first three years of life (caregiver report) in cases was compared to DD and POP controls; and between cases with and without regression. Children with ASD had greater odds of neonatal (OR = 1.8; 95%CI: 1.1, 2.9) and early childhood infection (OR = 1.7; 95%CI: 1.5, 1.9) compared to POP children, and greater odds of neonatal infection (OR = 1.5; 95%CI: 1.1, 2.0) compared to DD children. Cases with regression had 1.6 times the odds (95%CI: 1.1, 2.3) of caregiver-reported infection during the first year of life compared to cases without regression, but neonatal infection risk and overall early childhood infection risk did not differ. Our results support the hypothesis that children with ASD are more likely to have infection early in life compared to the general population and to children with other developmental conditions. Future studies should examine the contributions of different causes, timing, frequency, and severity of infection to ASD risk. Autism Research 2019, 12: 136-146. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We looked at infections during early childhood in relation to autism spectrum disorder (ASD). We found that children with ASD were more likely to have an infection in the first 28 days of life and before age three compared to children with typical development. Children with ASD were also more likely than children with other developmental delays or disorders to have an infection in the first 28 days of life.