Real-World Evidence to Supplement Randomized Clinical Trials: Tocilizumab for Severe COVID-19 Pneumonia vs. a Cohort Receiving Standard of Care.

Randomized controlled trials (RCTs) remain the gold standard for evaluating treatment efficacy, but real-world evidence can supplement RCT results. Tocilizumab was not found to reduce 28-day mortality in a phase III, double-blind, placebo-controlled trial (COVACTA) among hospitalized patients with severe coronavirus disease 2019 (COVID-19) pneumonia. We created a real-world external comparator arm mirroring the COVACTA trial to confirm findings and assess the feasibility of using an external comparator arm to supplement an RCT. Eligible COVACTA participants in both the tocilizumab treatment and placebo arms were matched 1:1 using propensity score matching to persons without tocilizumab exposure in an external comparator arm. Adjusted Cox proportional hazard models estimated differences in 28-day mortality comparing COVACTA participants to matched external comparator arm participants. Patients in the COVACTA tocilizumab treatment arm had a similar risk of death compared with patients in the external comparator arm (hazard ratio (HR): 1.09, 95% confidence interval (CI): 0.64-1.84) with similar estimated 28-day mortality in the COVACTA tocilizumab treatment arm compared with the external comparator arm (18%, 95% CI: 13-24 vs. 19%, 95% CI: 13-24, P > 0.9). COVACTA placebo treatment arm participants had a similar risk of mortality (adjusted HR: 0.69, 95% CI: 0.32-1.46) compared with the external comparator arm. Using an external comparator arm has the potential to supplement RCT data and support results of primary RCT analyses.

Retrospective cohort study to assess the association between treatment with tocilizumab and mortality among mechanically ventilated patients with COVID-19.

OBJECTIVES: Assess the association between tocilizumab administration and clinical outcomes among mechanically ventilated patients with COVID-19 pneumonia. DESIGN: Retrospective cohort study. SETTING: Large integrated health system with 9 million members in California, USA. PARTICIPANTS: 4185 Kaiser Permanente members hospitalised with COVID-19 pneumonia requiring invasive mechanical ventilation (IMV). INTERVENTIONS: Receipt of tocilizumab within 10 days of initiation of IMV. OUTCOME MEASURES: Using a retrospective cohort of consecutive patients hospitalised with COVID-19 pneumonia who required IMV in a large integrated health system in California, USA, we assessed the association between tocilizumab administration and 28-day mortality, time to extubation from IMV and time to hospital discharge. RESULTS: Among 4185 patients, 184 received tocilizumab and 4001 patients did not receive tocilizumab within 10 days of initiation of IMV. After inverse probability weighting, baseline characteristics were well balanced between groups. Patients treated with tocilizumab had a similar risk of death in the 28 days after intubation compared with patients not treated with tocilizumab (adjusted HR (aHR), 1.21, 95% CI 0.98 to 1.50), but did have a significantly longer time-to-extubation (aHR 0.71; 95% CI 0.57 to 0.88) and time-to-hospital-discharge (aHR 0.66; 95% CI 0.50 to 0.88). However, patients treated with tocilizumab ≤2 days after initiation of IMV had a similar risk of mortality (aHR 1.47; 95% CI 0.96 to 2.26), but significantly shorter time-to-extubation (aHR 0.37; 95% CI 0.23 to 0.58) and time-to-hospital-discharge (aHR 0.31; 95% CI CI 0.17 to 0.56) compared with patients treated with tocilizumab 3-10 days after initiation of IMV. CONCLUSIONS: Among mechanically ventilated patients with COVID-19, the risk of death in the 28-day follow-up period was similar, but time-to-extubation and time-to-hospital-discharge were longer in patients who received tocilizumab within 10 days of initiation of IMV compared with patients who did not receive tocilizumab.

Prenatal Maternal Serum Concentrations of Per- and Polyfluoroalkyl Substances in Association with Autism Spectrum Disorder and Intellectual Disability.

BACKGROUND: Emerging work has examined neurodevelopmental outcomes following prenatal exposure to per- and polyfluoroalkyl substances (PFAS), but few studies have assessed associations with autism spectrum disorder (ASD). OBJECTIVES: Our objective was to estimate associations of maternal prenatal PFAS concentrations with ASD and intellectual disability (ID) in children. METHODS: Participants were from a population-based nested case-control study of children born from 2000 to 2003 in southern California, including children diagnosed with ASD (n=553), ID without autism (n=189), and general population (GP) controls (n=433). Concentrations of eight PFAS from stored maternal sera collected at 15-19 wk gestational age were quantified and compared among study groups. We used logistic regression to obtain adjusted odds ratios for the association between prenatal PFAS concentrations (parameterized continuously and as quartiles) and ASD versus GP controls, and separately for ID versus GP controls. RESULTS: Geometric mean concentrations of most PFAS were lower in ASD and ID groups relative to GP controls. ASD was not significantly associated with prenatal concentrations of most PFAS, though significant inverse associations were found for perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) [adjusted ORs for the highest vs. lowest quartiles 0.62 (95% CI: 0.41, 0.93) and 0.64 (95% CI: 0.43, 0.97), respectively]. Results for ID were similar. CONCLUSIONS: Results from this large case-control study with prospectively collected prenatal measurements do not support the hypothesis that prenatal exposure to PFAS is positively associated with ASD or ID. https://doi.org/10.1289/EHP1830.

A Survey of Parents with Children on the Autism Spectrum: Experience with Services and Treatments.

INTRODUCTION: Autism spectrum disorders (ASD) are lifelong neurodevelopmental disorders, and little is known about how parents address the health and psychosocial consequences of ASD. Few studies have examined use of various treatments and services in a large, diverse sample of children with ASD and their families. OBJECTIVE: This paper presents methods to create an autism research resource across multiple large health delivery systems and describes services and treatments used by children with ASD and their families. METHODS: Four study sites conducted a Web survey of parents of children and adolescents with ASD who were members of Kaiser Permanente. We tabulated data distributions of survey responses and calculated χ2 statistics for differences between responders and nonresponders. RESULTS: The children of the 1155 respondents were racially and ethnically diverse (55% white, 6% black, 5% Asian, 9% multiracial, 24% Hispanic) and representative of the total population invited to participate with respect to child sex (83% male), child age (57% < 10 years), and ASD diagnosis (64% autistic disorder). The most frequently used services and treatments were Individualized Education Programs (85%), family physician visits (78%), and occupational and speech therapy (55% and 60%, respectively). Home-based programs frequently included implementation of social skills training (44%) and behavior management (42%). Prescription medication use was high (48%). Caregivers reported disruption of personal and family routines because of problem behaviors. CONCLUSION: These survey data help to elucidate parents' experiences with health services for their children with ASD and serve as a potential resource for future research.

Psychotropic Medication Use among Insured Children with Autism Spectrum Disorder.

This study examined psychotropic medication use among 7901 children aged 1-17 with autism spectrum disorder (ASD) in five health systems, comparing to matched cohorts with no ASD. Nearly half (48.5 %) of children with ASD received psychotropics in the year observed; the most common classes were stimulants, alpha-agonists, or atomoxetine (30.2 %), antipsychotics (20.5 %), and antidepressants (17.8 %). Psychotropic treatment was far more prevalent among children with ASD, as compared to children with no ASD (7.7 % overall), even within strata defined by the presence or absence of other psychiatric diagnoses. The widespread use of psychotropics we observed, particularly given weak evidence supporting the effectiveness of these medications for most children with ASD, highlights challenges in ASD treatment and the need for greater investment in its evaluation.

Health Services Utilization Among Children With and Without Autism Spectrum Disorders.

Using data from multiple health systems (2009-2010) and the largest sample to date, this study compares health services use among youth with and without an autism spectrum disorder (ASD)-including preventive services not previously studied. To examine these differences, we estimated logistic and count data models, controlling for demographic characteristics, comorbid physical health, and mental health conditions. Results indicated that youth with an ASD had greater health care use in many categories, but were less likely to receive important preventive services including flu shots and other vaccinations. An improved understanding of the overall patterns of health care use among this population could enable health systems to facilitate the receipt of appropriate and effective health care.

Prevalence and Predictors of Complementary and Alternative Medicine Use in a Large Insured Sample of Children with Autism Spectrum Disorders.

PURPOSE: The purpose of the present study was to examine the prevalence and predictors of complementary and alternative medicine (CAM) use as well as parental perceptions of CAM efficacy in a large, geographically diverse sample of children with Autism Spectrum Disorders (ASD). METHODOLOGY: Data were obtained from a web-based survey administered to parents of children with ASD at four sites participating in the Mental Health Research Network (MHRN). The web survey obtained information about services and treatments received by children with ASD as well as the caregivers' experiences with having a child with ASD. RESULTS: Approximately 88% of the sample had either used CAM in the past or had recently used some type of CAM. The following characteristics were associated with CAM use: greater parental education, younger child age, a mix of regular and special classroom settings and prescription drug use in the past three months. CONCLUSIONS: The use of CAM was very prevalent in this large, geographically diverse sample of children with ASD. It is critical that providers be prepared to discuss the advantages and potential side effects with families to help them make well-informed health care decisions and prevent possible CAM-drug interactions.

Prenatal and neonatal thyroid stimulating hormone levels and autism spectrum disorders.

Thyroid hormones are critical for normal brain development. This study examined autism spectrum disorders (ASD) and thyroid stimulating hormone (TSH) levels measured in mid-pregnancy maternal serum and infant blood after birth. Three groups of children born in Orange County, CA in 2000-2001 were identified: ASD (n = 78), developmental delay (n = 45), and general population controls (GP) (n = 149). Samples were retrieved from prenatal and newborn screening specimen archives. Adjusted logistic regression models showed inverse associations between ASD and log transformed TSH levels in maternal serum samples (ASD vs. GP: OR [95 % CI] 0.33 [0.12-0.91], Early Onset ASD vs. GP: 0.31 [0.10-0.98]). Results for thyroid levels in newborn blood samples were similar though not significant (ASD vs. GP: 0.61 [0.18-2.04]).

Prenatal and neonatal peripheral blood mercury levels and autism spectrum disorders.

BACKGROUND: Prenatal and early-life exposures to mercury have been hypothesized to be associated with increased risk of autism spectrum disorders (ASDs). OBJECTIVES: This study investigated the association between ASDs and levels of total mercury measured in maternal serum from mid-pregnancy and infant blood shortly after birth. METHODS: The study sample was drawn from the Early Markers for Autism (EMA) Study. Three groups of children who were born in Orange County, CA in 2000-2001 were identified: children with ASD (n=84), children with intellectual disability or developmental delay (DD) (n=49), and general population controls (GP) (n=159). Maternal serum specimens and newborn bloodspots were retrieved from the California Department of Public Health prenatal and newborn screening specimen archives. Blood mercury levels were measured in maternal serum samples using mass spectrometer and in infant bloodspots with a 213 nm laser. RESULTS: Maternal serum and infant blood mercury levels were significantly correlated among all study groups (all correlations >0.38, p<0.01). Adjusted logistic regression models showed no significant associations between ASD and log transformed mercury levels in maternal serum samples (ASD vs. GP: OR [95% CI]=0.96 [0.49-1.90]; ASD vs. DD: OR [95% CI]=2.56 [0.89-7.39]). Results for mercury levels in newborn blood samples were similar (ASD vs. GP: OR [95% CI]=1.18 [0.71-1.95]; ASD vs. DD: OR [95% CI]=1.96 [0.75-5.14]). CONCLUSIONS: Results indicate that levels of total mercury in serum collected from mothers during mid-pregnancy and from newborn bloodspots were not significantly associated with risk of ASD, though additional studies with greater sample size and covariate measurement are needed.

Effect of submarine groundwater discharge on bacterial indicators and swimmer health at Avalon Beach, CA, USA.

Use of fecal indicator bacteria (FIB) for monitoring beach water quality is based on their co-occurrence with human pathogens, a relationship that can be dramatically altered by fate and transport processes after leaving the human intestine. We conducted a prospective cohort study at Avalon Beach, California (USA), where the indicator relationship is potentially affected by the discharge of sewage-contaminated groundwater and by solar radiation levels at this shallow, relatively quiescent beach. The goals of this study were to determine: 1) if swimmers exposed to marine water were at higher risk of illness than non-swimmers; 2) if FIB measured in marine water were associated with swimmer illness, and; 3) if the associations between FIB and swimmer health were modified by either submarine groundwater discharge or solar radiation levels. There were 7317 individuals recruited during the summers of 2007-08, 6165 (84%) of whom completed follow-up within two weeks of the beach visit. A total of 703 water quality samples were collected across multiple sites and time periods during recruitment days and analyzed for FIB using both culture-based and molecular methods. Adjusted odds ratios (AOR) indicated that swimmers who swallowed water were more likely to experience Gastrointestinal Illness (GI Illness) within three days of their beach visit than non-swimmers, and that this risk was significantly elevated when either submarine groundwater discharge was high (AOR [95% CI]:2.18 [1.22-3.89]) or solar radiation was low (2.45 [1.25-4.79]). The risk of GI Illness was not significantly elevated for swimmers who swallowed water when groundwater discharge was low or solar radiation was high. Associations between GI Illness incidence and FIB levels (Enterococcus EPA Method 1600) among swimmers who swallowed water were not significant when we did not account for groundwater discharge, but were strongly associated when groundwater discharge was high (1.85 [1.06, 3.23]) compared to when it was low (0.77 [0.42, 1.42]; test of interaction: P = 0.03). These results demonstrate the need to account for local environmental conditions when monitoring for, and making decisions about, public health at recreational beaches. The views expressed in this article are those of the authors and do not necessarily reflect the views or policies of the U.S. Environmental Protection Agency.

Safety and tolerability of combination antimalarial therapies for uncomplicated falciparum malaria in Ugandan children.

BACKGROUND: Combination antimalarial therapy is recommended for the treatment of uncomplicated falciparum malaria in Africa; however, some concerns about the safety and tolerability of new regimens remain. This study compared the safety and tolerability of three combination antimalarial regimens in a cohort of Ugandan children. METHODS: A longitudinal, single-blind, randomized clinical trial of children was conducted between November 2004 and May 2007 in Kampala, Uganda. Upon diagnosis of the first episode of uncomplicated malaria, participants were randomized to treatment with amodiaquine + sulphadoxine-pyrimethamine (AQ+SP), artesunate + amodiaquine (AS+AQ), or artemether-lumefantrine (AL). Once randomized, participants received the same regimen for all subsequent episodes of uncomplicated malaria. Participants were actively monitored for adverse events for the first 14 days after each treatment, and then passively followed until their next study medication treatment, or withdrawal from study. Outcome measures included the risk of adverse events at 14 and 42 days after treatment. RESULTS: Of 601 enrolled children, 382 were diagnosed with at least one episode of uncomplicated malaria and were treated with study medications. The median age at treatment was 6.3 years (range 1.1 - 12.3 years). At 14 days of follow-up, AQ+SP treatment was associated with a higher risk of anorexia, weakness, and subjective fever than treatment with AL, and a higher risk of weakness, and subjective fever than treatment with AS+AQ. Treatment with AL was associated with a higher risk of elevated temperature. Repeated episodes of neutropaenia associated with AS+AQ were detected in one participant. Considering only children less than five years, those who received AQ+SP were at higher risk of developing moderate or severe anorexia and weakness than those treated with AL (anorexia: RR 3.82, 95% CI 1.59 - 9.17; weakness: RR 5.40, 95% CI 1.86 - 15.7), or AS+AQ (anorexia: RR 2.10, 95% CI 1.04 - 4.23; weakness: RR 2.26, 95% CI 1.01 - 5.05). Extending the analysis to 42 days of follow-up had little impact on the findings. CONCLUSION: This study confirms the safety and tolerability of AS+AQ and AL in Ugandan children, and suggests that AQ+SP is safe, but less well-tolerated, particularly in younger children. As newer antimalarial regimens are deployed, collecting data on their safety and tolerability will be essential. TRIAL REGISTRATION: Current Controlled Trials Identifier ISRCTN37517549.