Attention-Deficit/Hyperactivity Disorder Is Associated With Increased Rates of Childhood Infectious Diseases: A Population-Based Case-Control Study.

OBJECTIVE: Infectious diseases (IDs) pose a heavy burden on children. An association between pediatric attention-deficit/hyperactivity disorder (ADHD) and specific IDs has been documented. Our objective was to test the possibility that ADHD is associated with increased likelihood for pediatric IDs at large. METHOD: A population-based case-control study was conducted using Electronic Medical Records (EMRs) of a national Health Maintenance Organization, Leumit Health Services (LHS). ICD-9/10 criteria were used for all diagnoses. The study population consisted of all children and adolescents (aged 5-18 years), members of LHS between January 1, 2006-June 30, 2021. Case patients met International Classification of Diseases (ICD-9/10) criteria for ADHD. Controls included randomly selected persons without ADHD (2:1 ratio), matched individually by demographic indices. The EMRs retrieved 3 exposure categories: pediatric ID, anti-infective medications use, and number of physician visits. The study was approved by the review board of Shamir Medical Center and the Research Committee of LHS. RESULTS: Cases patients comprised 18,756 participants, with a mean age of 8.3 ± 2.6 years and a male/female ratio of 63%:37%. Matched controls comprised 37,512 participants, with a mean age of 8.3 ± 2.6 years and a male/female ratio of 63%:37%. Demographic variables were similar between the groups. The rates of all IDs were significantly higher in participants with ADHD than in controls and were not restricted to a single body system, including acute respiratory infection (OR = 1.4, 95% CI = 1.3-1.4, p < .001), acute gastroenteritis (OR = 1.3,95% CI 1.3-1.4, p < .001), salmonellosis (OR = 2.8, 95% CI = 2.3-3.5, p < .001), and urinary tract infection (OR = 1.3, 95% CI = 1.2-1.4, p < .001). All anti-infective agents were prescribed significantly more often to children with ADHD. There were significantly higher rates of physician visits for participants with ADHD. CONCLUSION: Study findings suggest an association between ID and pediatric ADHD Health care providers should be aware of this potential association. CLINICAL TRIAL REGISTRATION INFORMATION: The Health and Economic Impact of Treated and Untreated ADHD; https://www.shamir.org/; 005-18-LEU.

The Association between ADHD and the Severity of COVID-19 Infection.

OBJECTIVE: Patients with ADHD are at increased risk of acquiring COVID-19. The present study assessed the possibility that ADHD also increases the risk of severe COVID-19 infection. METHOD: We assessed 1,870 COVID-19 positive patients, aged 5 to 60 years, registered in the database of Leumit Health Services (LHS, Israel), February to -June 2020, of whom 231 with ADHD. Logistic regression analysis models evaluated the association between ADHD and the dependent variables of being symptomatic/referral to hospitalization, controlling for demographic and medical variables. RESULTS: Age, male sex, and BMI were confirmed to be significant risk factors for increased COVID-19 severity. ADHD was found to be associated with increased severity of COVID-19 symptoms (OR = 1.81, 95% CI [1.29, 2.52], p < .05) and referral to hospitalization (OR =1.93, 95% CI [1.06, 3.51], p = .03). CONCLUSION: ADHD is associated with poorer outcomes in COVID-19 infection.

The Placebo Response in Adult ADHD as Objectively Assessed by the TOVA Continuous Performance Test.

Objective: We compared the placebo response (PR) as measured by the Test of Variables of Attention (TOVA) and the Conners' Adult ADHD Rating Scale (CAARS) scores. Method: A retrospective data analysis from a double-blind placebo-controlled study of metadoxine-ER in adults with ADHD. An additional database was used for comparison to TOVA response after methylphenidate challenge (TOVA-MPH-R). Results: PR was highest when calculated from the TOVA-Attention Composite Score (ACS). The PR showed significantly fewer variables improving concomitantly compared with MPH-R. The most prominent correlation between the CAARS-PR and the TOVA-PR was in the Omissions score (p = .032), which was age-dependent (b = .0007, p <.001). Discussion: TOVA-PR has an index-specific profile compared with CAARS-PR and TOVA-MPH-R. The partial correlation of TOVA-PR with CAARS-PR suggests that a composite score of TOVA specific indices and CAARS could have a synergic impact to improve the reliability of the response assessment in adult ADHD.

ADHD as a Risk Factor for Infection With Covid-19.

Background: ADHD limits the ability to comply with Covid-19 prevention recommendations. We hypothesized that ADHD constitutes a risk factor for Covid-19 infection and that pharmacotherapy may lower that risk. Methods: Study population included all subjects (N = 14,022) registered with Leumit Health Services between February 1st and April 30, 2020, who underwent at least one Covid-19 test. Data were collected from the electronic health records. Purchasing consecutively at least three ADHD-medication-prescriptions during past year was considered drug-treatment. Results: A total of 1,416 (10.1%) subjects (aged 2 months-103 years) were Covid-19-positive.They were significantly younger, and had higher rates of ADHD (adjOR 1.58 (95% CI 1.27-1.96, p < .001) than Covid-19-negative subjects. The risk for Covid-19-Positive was higher in untreated-ADHD subjects compared to non-ADHD subjects [crudeOR 1.61 (95% CI 1.36-1.89, p < .001)], while no higher risk was detected in treated ones [crudeOR 1.07 (95% CI 0.78-1.48, p = .65)]. Conclusion: Untreated ADHD seems to constitute a risk factor for Covid-19 infection while drug-treatment ameliorates this effect.

Characterizing the Placebo Response in Adults With ADHD.

Objective: Several ADHD pharmacological trials reported high placebo response (PR) rates. This study aims to characterize the PR in adult ADHD. Method: A retrospective cohort analysis of the placebo arm (140 adults with ADHD, 18-55 yrs, M:F 46.4%-53.6%) of a 6-week randomized, multicenter, double-blind metadoxine study, using Conners' Adult ADHD Rating Scale (CAARS) and the Adult ADHD Self-Report Scale (ASRS), was conducted. Results: Pre-post changes in placebo-treated adults were significant for both the CAARS and ASRS, F(2.9, 404.5) = 61.2, p < .00001, F(2.8, 383.0) = 43.1, p < .00001, respectively. Less than half of the participants had a PR which began early in treatment and persisted; almost 50% had a variable, inconsistent PR. Conclusion: In the current sample, PR in adult ADHD was prominent on both symptom scales and the investigator-rater instrument. Therefore, using investigator ratings as a primary endpoint does not necessarily attenuate PR. Of note, about half of the PR is variable, suggesting unreliable determination of efficacy.

Apparent lack of practice effects in the Test of Variables of Attention (TOVA) in adult ADHD.

The test of variables of attention (TOVA) is a continuous performance test commonly used as an aid for diagnosis of ADHD and assessment of treatment response. It has been studied and standardized in both children and adults. As a repetitive measurement of treatment efficacy, used both in research and in the clinic, it's important to disprove a practice effect. A retrospective cohort analysis was done, using only the placebo-arm participants from two different randomized, multicenter, double-blind clinical trials on the efficacy of a non-stimulant (metadoxine-XR). In order to reveal the practice effects, only the participants that showed no placebo effect (< 25% improvement), in the Conners' Adult ADHD Rating Scale-investigator rated (CAARS-Inv), the gold standard, were included. Demographic data, CAARS-Inv baseline and TOVA results during each visit were recorded and analyzed. Ninety-one participants from two studies were pooled (2014 n = 24, 2016 n = 67). They did not differ significantly in any demographic parameter, most side effect frequencies, and CAARS-Inv baseline scores. The baseline TOVA performances demonstrated similarity in the degree of inattention, variability, impulsivity, and response time. The TOVA scores were not altered significantly between visits, as assessed by repeated-measures analysis of variance. No significant differences were detected between the TOVA baseline-to-endpoint scores as assessed by paired t test. No practice effects were detected, in both clinical trials, suggesting that the results of the TOVA are likely to represent genuine changes in attentional performance. Further studies are needed to replicate these findings.

Demographic and Clinical Predictors of Hospitalization in Preschoolers With ADHD.

Objective: This chart review study characterized demographic and clinical indicators of the need for hospitalization in preschoolers with ADHD. Method: Medical records of preschoolers with Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV-TR) ADHD during 2009-2012 were systematically reviewed. The cohort included 111 children (aged 5.13 ± 0.55 years, 77.47% boys). The demographic and clinical variables of hospitalized at a day-care unit (n = 30) and nonhospitalized (n = 81) preschoolers were compared. Results: Hospitalized preschoolers were younger (p < .0001), had higher rates of unmarried mothers (p < .001), and a higher number of comorbidities. The number of inattentive/hyperactivity-impulsivity symptoms was similar in both groups. Neurodevelopmental comorbidity (p < .0001), but not externalized (p = .82) or internalized (p = .20) psychopathology, was significantly higher in the hospitalized group. Conclusion: ADHD severity in preschoolers tends to be associated with younger age, specific parenthood constellations, and a high rate of neurodevelopmental, but not other, comorbidities. These findings emphasize the importance of the neurodevelopmental context in planning ADHD interventions at preschool age.