International Care programs for Pediatric Post-COVID Condition (Long COVID) and the way forward.

BACKGROUND: Pediatric Post-COVID-Condition (PPCC) clinics treat children despite limited scientific substantiation. By exploring real-life management of children diagnosed with PPCC, the International Post-COVID-Condition in Children Collaboration (IP4C) aimed to provide guidance for future PPCC care. METHODS: We performed a cross-sectional international, multicenter study on used PPCC definitions; the organization of PPCC care programs and patients characteristics. We compared aggregated data from PPCC cohorts and identified priorities to improve PPCC care. RESULTS: Ten PPCC care programs and six COVID-19 follow-up research cohorts participated. Aggregated data from 584 PPCC patients was analyzed. The most common symptoms included fatigue (71%), headache (55%), concentration difficulties (53%), and brain fog (48%). Severe limitations in daily life were reported in 31% of patients. Most PPCC care programs organized in-person visits with multidisciplinary teams. Diagnostic testing for respiratory and cardiac morbidity was most frequently performed and seldom abnormal. Treatment was often limited to physical therapy and psychological support. CONCLUSIONS: We found substantial heterogeneity in both the diagnostics and management of PPCC, possibly explained by scarce scientific evidence and lack of standardized care. We present a list of components which future guidelines should address, and outline priorities concerning PPCC care pathways, research and international collaboration. IMPACT: Pediatric Post-COVID Condition (PPCC) Care programs have been initiated in many countries. Children with PPCC in different countries are affected by similar symptoms, limiting many to participate in daily life. There is substantial heterogeneity in diagnostic testing. Access to specific diagnostic tests is required to identify some long-term COVID-19 sequelae. Treatments provided were limited to physical therapy and psychological support. This study emphasizes the need for evidence-based diagnostics and treatment of PPCC. The International Post-COVID Collaboration for Children (IP4C) provides guidance for guideline development and introduces a framework of priorities for PPCC care and research, to improve PPCC outcomes.

Neuropsychological functioning of pediatric patients with long COVID.

Objective: To determine the neurocognitive profile for youth with long COVID presenting with cognitive concerns. Method: This study is a case series of 54 pediatric patients (65% female, Mage = 13.48, SDage = 3.10, 5-19) with long COVID who were referred for neuropsychological testing from a post-COVID-19 multidisciplinary clinic. The outcomes of interest were neuropsychological test scores and parent ratings of mood, attention, and executive functioning. The percentage of patients with neuropsychological test scores below the 9th percentile (below average range) and those with at-risk or clinically significant scores (T-scores > 59) on parent-informant inventories were computed. Results: A portion of children with long COVID showed weaknesses in sustained attention (29%) and divided attention (35%). This portion of patients did not significantly differ when comparing patients with and without pre-existing attention and mood concerns. A high percentage of parents reported at-risk to clinically significant concerns for cognitive regulation (53%), depression (95%), anxiety (85%), and inattention (66%) on standardized questionnaires. Conclusions: The present case series showed that approximately a third of children with long COVID demonstrate objective weaknesses on sustained and divided attention tasks but were largely intact in other domains of neuropsychological functioning. Importantly, children with long COVID had similar difficulties in attention, regardless of pre-existing attention or mood concerns. Parents reported high rates of mood, anxiety, and executive functioning difficulties which likely impact daily functioning. Attention and emotional regulation should be closely monitored and treated as necessary in pediatric patients with long COVID to aid functional recovery.

Exploring the Influence of Pre-Existing Conditions and Infection Factors on Pediatric Long COVID Symptoms and Quality of Life.

OBJECTIVE: Pediatric post-acute sequelae of SARS-CoV-2 (PASC) or "long COVID" is a multisystemic disease with a wide range of symptoms more than 4 weeks after initial infection. This study explores the quality of life in children with long COVID and how pre-existing conditions affect symptoms and quality of life. DESIGN: A retrospective single-center study of 97 patients was completed to analyze PedsQLTM quality of life in pediatric patients with long COVID and associations between pre-existing conditions, long COVID symptoms, and PedsQLTM scores. RESULTS: Children with long COVID had significantly lower quality of life compared to previously published normative samples (PedsQLTM Core: p < 0.001; Fatigue: p < 0.001; Family Impact: p < 0.001). Number of long COVID symptoms, age, and pre-existing history of depression, allergies, and developmental delay affected the overall fatigue PedsQLTM scores. Pre-existing mood disorders were associated with a higher prevalence of worsening mental health symptoms (anxiety, p = 0.01; depression, p = 0.04), dizziness/lightheadedness/vertigo (p = 0.02) and change in appetite (p = 0.04). CONCLUSIONS: Long COVID has a significant impact on the quality of life of children and their families. Children with long COVID can benefit from multidisciplinary care addressing fatigue, mental health, and family coping.

Cognitive disengagement syndrome in pediatric patients with long COVID: associations with mood, anxiety, and functional impairment.

Children with long COVID often report symptoms that overlap with cognitive disengagement syndrome (CDS, previously sluggish cognitive tempo (SCT)), a set of behaviors distinct from attention-deficit/hyperactivity disorder (ADHD) including excessive daydreaming, mental fogginess, and slowed behavior and thinking. Those with long COVID also frequently report low mood and anxiety, which are linked to CDS. The relationships between cognitive difficulties, mood, and functional impairment have yet to be explored in pediatric long COVID. Specifically, it is unclear how much cognitive difficulties (CDS, inattention) contribute to functional impairment, when accounting for mood/anxiety symptoms in this population. Retrospective parent-reported data was collected from 34 patients with long COVID (22 females, Mage = 14.06 years, SD = 2.85, range 7-19) referred for neuropsychological consultation through a multidisciplinary Post-COVID-19 clinic. Compared to community and clinically referred samples, on average, long COVID patients showed elevated CDS symptoms, including Sluggish/sleepy (e.g., fatigue) and Low Initiation subscales (e.g., difficulty performing goal directed behaviors). Low Initiation, mood, anxiety, and inattention were associated with functional impairment. In multiple hierarchical regression models, after controlling for mood and anxiety, Low Initiation and inattention were no longer predictive of functional impairment. Instead, anxiety remained the sole predictor of functional impairment. Our results demonstrate that children with long COVID have high levels of CDS symptoms. The association between cognitive difficulties and functional impairment dissipated with the inclusion of mood and anxiety, suggesting behavioral health interventions targeting anxiety may help improve daily functioning and quality of life in pediatric long COVID patients.

Considerations in Children and Adolescents Related to Coronavirus Disease 2019 (COVID-19).

Pediatric post-acute sequelae of SARS-CoV-2 (PASC) or "long COVID" are a complex multisystemic disease that affects children's physical, social, and mental health. PASC has a variable presentation, time course, and severity and can affect children even with mild or asymptomatic acute COVID-19 symptoms. Screening for PASC in children with a history of SARS-CoV-2 infection is important for early detection and intervention. A multifaceted treatment approach and utilization of multidisciplinary care, if available, are beneficial in managing the complexities of PASC. Lifestyle interventions, physical rehabilitation, and mental health management are important treatment approaches to improve pediatric PASC patients' quality of life.

Comparing Cystatin C- and Creatinine-Estimated Glomerular Filtration Rates in Patients With Thoracic Versus Sacral Motor Levels of Spina Bifida.

OBJECTIVE: Patients with myelomeningocele-type spina bifida are at increased risk of developing kidney disease from neurogenic bladder. Differences between creatinine- and cystatin C-estimated glomerular filtration rates were examined in patients with thoracic versus sacral level myelomeningocele given presumed differences in muscle mass. DESIGN: A retrospective chart review (2005-2018) was performed on 57 adults with myelomeningocele [thoracic n = 44 (77%); sacral n = 13 (23%)]. Concurrently obtained creatinine and cystatin C levels were extracted and calculated creatinine- and cystatin C-estimated glomerular filtration rates were compared. RESULTS: Mean creatinine-estimated glomerular filtration rate was significantly higher for thoracic [140.8 ml/min (SD = 23.9)] versus sacral myelomeningocele [112.0 ml/min (SD = 22.6), P = 0.0003]. There was no difference in cystatin C-estimated glomerular filtration rate between sacral [116.6 ml/min (SD = 23.7)] and thoracic myelomeningocele [124.8 ml/min (SD = 17.9)]. The mean difference between creatinine- and cystatin C-estimated glomerular filtration rates in thoracic myelomeningocele [24.2 ml/min (SD = 16.3)] was significantly greater than in sacral myelomeningocele [-12.8 (SD = 15.7), P < 0.0001]. CONCLUSIONS: There was a significantly higher discrepancy between creatinine- and cystatin C-estimated glomerular filtration rates in thoracic versus sacral motor levels of myelomeningocele. These data suggest that creatinine-estimated glomerular filtration rate may overestimate kidney function in patients with thoracic myelomeningocele. Providers who manage patients with thoracic myelomeningocele should consider monitoring cystatin C to evaluate for underlying renal disease.

Neurocognitive and Psychosocial Characteristics of Pediatric Patients With Post-Acute/Long-COVID: A Retrospective Clinical Case Series.

OBJECTIVE: Studies suggest a large number of patients have persistent symptoms following COVID-19 infection-a condition termed "long COVID." Although children and parents often report cognitive difficulties after COVID, very few if any studies have been published including neuropsychological testing. METHODS: A retrospective chart review was completed for the first 18 patients referred for a neuropsychological evaluation from a multidisciplinary pediatric post-COVID clinic. The neuropsychological screening battery assessed verbal fluency and category switching, attention, working memory, processing speed, and verbal learning and memory. Patients' caregivers also completed standardized questionnaires regarding day-to-day mood and behavior. RESULTS: At intake, the most common neurologic symptoms reported by caregivers were attention problems (83.3%), fatigue/lethargy (77.7%), sleep disturbance (77.7%), dizziness/vertigo (72.2%), and headaches (72.2%). On rating scales, most caregivers endorsed concerns for depressed mood and anxiety (14/15 and 12/15). A large proportion of patients had difficulties with attention (9/18) and depressed mood/anxiety (13/18) before COVID. On cognitive testing, the majority of the patients performed within or above broad average range (≥16th percentile) across most domains. However, a little over half of the patients performed below average on auditory attention measures. CONCLUSIONS: Within our clinically referred sample, children who reported lingering cognitive symptoms after COVID-19 often had a preexisting history of attention and/or mood and anxiety concerns. Many of these patients performed below average in attention testing, but it remains to be seen whether this was due to direct effects of COVID, physical symptoms, and/or preexisting difficulties with attention or mood/anxiety.

Long-Term COVID 19 Sequelae in Adolescents: the Overlap with Orthostatic Intolerance and ME/CFS.

Purpose of Review: To discuss emerging understandings of adolescent long COVID or post-COVID-19 conditions, including proposed clinical definitions, common symptoms, epidemiology, overlaps with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and orthostatic intolerance, and preliminary guidance on management. Recent Findings: The recent World Health Organization clinical case definition of post-COVID-19 condition requires a history of probable or confirmed SARS-CoV-2 infection, with symptoms starting within 3 months of the onset of COVID-19. Symptoms must last for at least 2 months and cannot be explained by an alternative diagnosis. Common symptoms of the post-COVID-19 condition include, but are not limited to, fatigue, shortness of breath, and cognitive dysfunction. These symptoms generally have an impact on everyday functioning. The incidence of prolonged symptoms following SARS-CoV-2 infection has proven challenging to define, but it is now clear that those with relatively mild initial infections, without severe initial respiratory disease or end-organ injury, can still develop chronic impairments, with symptoms that overlap with conditions like ME/CFS (profound fatigue, unrefreshing sleep, post-exertional malaise, cognitive dysfunction, and orthostatic intolerance). Summary: We do not yet have a clear understanding of the mechanisms by which individuals develop post-COVID-19 conditions. There may be several distinct types of long COVID that require different treatments. At this point, there is no single pharmacologic agent to effectively treat all symptoms. Because some presentations of post-COVID-19 conditions mimic disorders such as ME/CFS, treatment guidelines for this and related conditions can be helpful for managing post-COVID-19 symptoms. Supplementary Information: The online version contains supplementary material available at 10.1007/s40124-022-00261-4.

Postacute/Long COVID in Pediatrics: Development of a Multidisciplinary Rehabilitation Clinic and Preliminary Case Series.

ABSTRACT: The long-term sequelae after SARS-CoV-2 infections in children is unknown. Guidance is needed on helpful models of care for an emerging subset of pediatric patients with postacute/long COVID who continue to experience persistent symptoms after initial COVID-19 diagnosis. Here, we describe a pediatric multidisciplinary post-COVID-19 rehabilitation clinic model as well as a case series of the initial cohort of patients who presented to this clinic. A consecutive sample of nine patients (pediatric patients <21 yrs of age) who presented to our clinic are included. The most common presenting symptoms were fatigue (8 of 9 patients), headaches (6 of 9), difficulty with schoolwork (6 of 8), "brain fog" (4 of 9), and dizziness/lightheadedness (4 of 9). Most patients had decreased scores on self-reported quality-of-life measures compared with healthy controls. In the patients who participated in neuropsychological testing, a subset demonstrated difficulties with sustained auditory attention and divided attention; however, most of these patients had preexisting attention and/or mood concerns. There were also some who self-reported elevated depression and anxiety symptoms. Pediatric patients with postacute/long COVID may present with a variety of physical, cognitive, and mood symptoms. We present a model of care to address these symptoms through a multidisciplinary rehabilitation approach.

Demographic and Behavioral Risk Factors for Oral Cancer among Florida Residents.

OBJECTIVES: Almost 29,000 new cases and approximately 7,500 deaths are directly attributable to oral cancer in the United States. Understanding the impact of specific behavioral and demographic characteristics on oral cancer is crucial to being able to promote early diagnoses through oral cancer screening. This study hypothesized that selected factors would be predictive of the incidence of oral cancer in Florida's population. MATERIALS AND METHODS: Approximately 74,000 cases from the Florida Cancer Data System (FCDS) were included in the study. Demographic and risk factors evaluated included sex, age, marital status, ethnicity, race, primary insurance payer, birthplace, cigarette use, smokeless tobacco use, cancer behavior, and other tobacco use. Logistic regression analysis was used to assess the association of 11 risk factors and oral cancer in Florida. RESULTS: Males, Blacks, Hispanics, married individuals, and current smokers were significantly more likely to be diagnosed with oral cancer compared to their counterparts. CONCLUSION: Florida's health providers need to be aware of the risk factors for oral cancer, look for early signs of oral cancer and recommend routine screenings in patients with history of known risk factors. Including additional reported elements such as human papillomavirus (HPV) history, sunlight exposure, vaping and use of e-cigarettes, and alcohol consumption (by amount) in the cancer registry would be greatly beneficial.

The role of polysomnography in decannulation of children with brain and spinal cord injuries.

OBJECTIVE: The objective of this retrospective review was to determine the utility of polysomnography (PSG) in influencing the decision to decannulate pediatric patients with brain and spinal cord injuries in an inpatient rehabilitation hospital setting. METHODS: Between 2010 and 2016, data were collected on pediatric patients with brain and/or spinal cord injuries who had PSG performed with the goal of decannulation. Patients underwent a decannulation protocol involving toleration of continuous tracheostomy capping and bedside tracheoscopy by otolaryngology. Decision to decannulate was determined with input from multiple disciplines. Associations were examined between decannulation success and findings on PSG as well as demographic factors, injury characteristics, otolaryngology findings, and timeline from initial injury to selected events. RESULTS: A total of 46 patients underwent PSG, after which 38 (83%) were deemed appropriate and eight (17%) were deemed inappropriate for decannulation. Individuals who were deemed ready for decannulation had significantly lower obstructive apnea hypopnea indexes (AHI) (1.7 vs 5.4 events/h, P = 0.03), respiratory disturbance indexes (RDI) (2.4 vs 7.6 events/h, P = 0.006), and peak end tidal carbon dioxide (CO2 ) levels (50.0 vs 58.7 torr, P = 0.009) on PSG compared to those who were not decannulated. There were no complications following decannulation prior to discharge. CONCLUSION: PSG provided important additional information as part of a multidisciplinary team assessment of clinical readiness for decannulation in pediatric patients with brain and spinal cord injuries who underwent a decannulation protocol. Obstructive AHI, RDI, and peak end tidal CO2 level were associated with successful decannulation prior to discharge from inpatient rehabilitation.

Versican knock-down compromises chondrogenesis in the embryonic chick limb.

Mesenchymal cell aggregation is critical for cartilage formation in the vertebrate limb. The extracellular matrix (ECM) plays a critical role in governing cell behavior and cell phenotype in this tissue, and the hyalectin versican is highly expressed in the ECM of precartilage mesenchymal cells and developing synovial joints. Although several in vitro studies have been conducted in an attempt to address versican's role during limb mesenchymal condensation, factors such as differences in cell density in culture, variations between chondrogenic cell lines, and the inability to prolong the viability of limb explants have led to conflicting data, mandating an in vivo analysis. By using a morpholino directed strategy in ovo, we performed knock-down of versican expression in the presumptive ulnar region of the developing chick wing at time points critical to skeletogenesis. These data indicate that in ovo misexpression of versican compromised mesenchymal condensation with resulting ulnar cartilages reduced in length distally by an average of 53% relative to contralateral control limbs. In select versican morphants the olecranon process was also reduced in size proximally and failed to cup the humerus, likely impairing joint morphogenesis. This study represents the first report assessing the role of versican in the developing chick limb in ovo, further demonstrating the importance of versican proteoglycan expression during chondrogenesis and extending previous findings to suggest a role for versican during synovial joint development.