Core outcome measurement set for research and clinical practice in post-COVID-19 condition (long COVID) in children and young people: an international Delphi consensus study "PC-COS Children".

The coronavirus disease 2019 (COVID-19) pandemic substantially impacted different age groups, with children and young people not exempted. Many have experienced enduring health consequences. Presently, there is no consensus on the health outcomes to assess in children and young people with post-COVID-19 condition. Furthermore, it is unclear which measurement instruments are appropriate for use in research and clinical management of children and young people with post-COVID-19. To address these unmet needs, we conducted a consensus study, aiming to develop a core outcome set (COS) and an associated core outcome measurement set (COMS) for evaluating post-COVID-19 condition in children and young people. Our methodology comprised of two phases. In phase 1 (to create a COS), we performed an extensive literature review and categorisation of outcomes, and prioritised those outcomes in a two-round online modified Delphi process followed by a consensus meeting. In phase 2 (to create the COMS), we performed another modified Delphi consensus process to evaluate measurement instruments for previously defined core outcomes from phase 1, followed by an online consensus workshop to finalise recommendations regarding the most appropriate instruments for each core outcome. In phase 1, 214 participants from 37 countries participated, with 154 (72%) contributing to both Delphi rounds. The subsequent online consensus meeting resulted in a final COS which encompassed seven critical outcomes: fatigue; post-exertion symptoms; work/occupational and study changes; as well as functional changes, symptoms, and conditions relating to cardiovascular, neuro-cognitive, gastrointestinal and physical outcomes. In phase 2, 11 international experts were involved in a modified Delphi process, selecting measurement instruments for a subsequent online consensus workshop where 30 voting participants discussed and independently scored the selected instruments. As a result of this consensus process, four instruments met a priori consensus criteria for inclusion: PedsQL multidimensional fatigue scale for "fatigue"; PedsQL gastrointestinal symptom scales for "gastrointestinal"; PedsQL cognitive functioning scale for "neurocognitive" and EQ-5D for "physical functioning". Despite proposing outcome measurement instruments for the remaining three core outcomes ("cardiovascular", "post-exertional malaise", "work/occupational and study changes"), a consensus was not achieved. Our international, consensus-based initiative presents a robust framework for evaluating post-COVID-19 condition in children and young people in research and clinical practice via a rigorously defined COS and associated COMS. It will aid in the uniform measurement and reporting of relevant health outcomes worldwide.

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.

Characterization of Neuropsychological Outcomes in a Cohort of Pediatric Patients with Moyamoya Arteriopathy.

INTRODUCTION: Moyamoya arteriopathy is a severe, progressive cerebral arteriopathy that places affected children at high risk for stroke. Moyamoya has been associated with a range of neuropsychological deficits in adults, but data on many cognitive domains remain limited in the pediatric population and little is known about the neuropsychological profile of children with syndromic moyamoya. METHODS: This is a single-center, retrospective cohort study of children with moyamoya arteriopathy followed at our center who underwent neuropsychological testing between 2003 and 2021. Test scores were extracted from neuropsychological reports. Medical records were reviewed with attention to individual neuropsychological test results, medical comorbidities, presence of infarct(s) on neuroimaging, and history of clinical ischemic stroke. RESULTS: Of the 83 children with moyamoya followed at our center between 2003 and 2021, 13 had completed neuropsychological testing across multiple cognitive domains. Compared to age-based normative data, children in this sample had lower scores in overall intelligence (p = 0.003), global executive functioning (p = 0.005), and overall adaptive functioning (p = 0.015). There was no significant difference in overall intelligence between children with (n = 6) versus without (n = 7) a history of clinical stroke (p = 0.368), though children with any radiographic infarct scored lower in this domain (p = 0.032). CONCLUSION: In our cohort, children with moyamoya demonstrated impaired intelligence and executive functioning, even in the absence of clinical stroke. Neuropsychological evaluation should be considered standard of care for all children with moyamoya, even those without a history of clinical stroke.

Tale of two nephropathies; co-occurring Alport syndrome and IgA nephropathy, a case report.

BACKGROUND: Alport Syndrome and IgA Nephropathy (IgAN) are both disorders that can cause hematuria. Alport syndrome is most commonly an X-linked disease, caused by COL4A5 mutation. Mutations of COL4A3 and COL4A4 on chromosome two are also common causes of Alport syndrome. IgAN is the most common glomerulonephritis worldwide. Though IgAN is usually sporadic, an estimated 15% of cases have an inheritable component. These cases of Familal IgA Nephropathy (FIgAN) can have mutations on genes which are known to cause Alport Syndrome. CASE PRESENTATION: We report a case of a 27-year-old man with strong family history of renal disease, who presented with hematuria and new non-nephrotic range proteinuria. Physical exam showed no abnormalities. His creatinine remained persistently elevated, and renal ultrasound exhibited bilaterally increased echogenicity consistent with Chronic Kidney Disease. Twenty-four-hour urinary collection revealed non-nephrotic range proteinuria of 1.4 g, with otherwise negative workup. On biopsy, he had IgA positive immunofluorescent staining as well as moderate interstitial fibrosis and tubular atrophy. Electron microscopy showed a basket-weave pattern of thickening and splitting of the lamina densa-consistent with Alport Syndrome, as well as mesangial expansion with electron-dense deposits -consistent with IgAN. CONCLUSIONS: Mutations of COL4A5 on the X chromosome, as well as mutations of COL4A3 and COL4A4 on chromosome 2, can cause both Alport Syndrome and FIgAN. Genome wide association studies identified certain Angiotensin Converting Enzyme gene polymorphisms as independent risk factors for progression of IgAN. Our Presentation with this co-occurring pathology suggests a new paradigm where Alport Syndrome and FIgAN may represent manifestations of a single disease spectrum rather than two disparate pathologies. Appreciating hematuria through this framework has implications for treatments and genetic counseling. Further genome wide association studies will likely increase our understanding of Alport Syndrome, FIgAN, and other causes of hematuria.

Acute eosinophilic pneumonia triggered by secondhand cigarette smoke exposure in an elderly man.

The spectrum of eosinophilic lung diseases comprises a diverse group of pulmonary disorders associated with tissue or peripheral eosinophilia. [Acute eosinophilic pneumonia (AEP)] is an uncommon eosinophilic lung disease that can be idiopathic, but identifiable causes include medications, inhalational exposures and infections. Most cases in the literature are associated with first-time cigarette smoking or resuming smoking. Herein, we present a case of AEP in an elderly man triggered by exposure to secondhand tobacco smoke, in whom a transbronchial biopsy was diagnostic. The patient recovered fully with glucocorticoid therapy without recurrence after avoiding further secondhand smoke.

Age-related forgetting in locomotor adaptation.

The healthy aging process affects the ability to learn and remember new facts and tasks. Prior work has shown that motor learning can be adversely affected by non-motor deficits, such as time. Here we investigated how age, and a dual task influence the learning and forgetting of a new walking pattern. We studied healthy younger (<30 yo) and older adults (>50 yo) as they alternated between 5-min bouts of split-belt treadmill walking and resting. Older subjects learned a new walking pattern at the same rate as younger subjects, but forgot some of the new pattern during the rest breaks. We tested if forgetting was due to reliance on a cognitive strategy that was not fully engaged after rest breaks. When older subjects performed a dual cognitive task to reduce strategic control of split-belt walking, their adaptation rate slowed, but they still forgot much of the new pattern during the rest breaks. Our results demonstrate that the healthy aging process is one component that weakens motor memories during rest breaks and that this phenomenon cannot be explained solely by reliance on a conscious strategy in older adults.

Anti-Tumor Necrosis Factor Treatment for Glomerulopathy: Case Report and Review of Literature.

Background: Glomerulopathy involves damage to the glomerular filtration barrier for several reasons, resulting in idiopathic nephrotic syndrome (NS). Treatment options are limited and often include steroids with varying levels of response. Case Presentation: A 7-year-old male with a history of NS at age 2 years that developed following a respiratory tract infection was found to have a heterozygous variant of uncertain significance in COL4A4 and TRPC6 genes. Biopsy findings included podocytopathy and changes in the basement membrane. Upon initial response to steroids, the patient was treated with a brief course of anakinra followed by adalimumab for > 2 years as steroid-sparing biological response modifiers. After a gradual taper, the patient remains in remission and has not received treatment in the last 12 months. Conclusions: This case shows the complex nature of biologically predetermined cascading events in the emergence of glomerular disease with environmental triggers and genetic factors. Downregulation of somatic tissue-driven proinflammatory milieu originating from the constituents of the glomerular microenvironment can help in recovery from emerging podocytopathy. Blocking tumor necrosis factor-α early in the disease course, even temporarily, may allow time for the de novo regenerative process to prevail. Additional research is warranted to test this hypothesis and minimize steroid use.

Two Head and Neck Carcinomas With Squamous and Mucinous Components and Human Papillomavirus Associations: Maxillary Mucoepidermoid Carcinoma ex Sinonasal Schneiderian Papilloma and Tonsillar Invasive Stratified Mucin Producing Carcinoma (ISMC).

Carcinomas of the head-and-neck region with squamous and glandular/mucinous features constitute a heterogeneous group, with a significant minority of tumors showing an human papillomavirus (HPV) association. The differential diagnosis is usually between mucoepidermoid carcinoma (MEC) and adenosquamous carcinoma. We present here two tumors that exemplify both the challenges of diagnostic classification, as well as the complex relationship to HPV: (a) a low risk HPV positive/p16 negative carcinoma that is most consistent with a relatively typical intermediate grade mucoepidermoid type carcinoma with complete MEC phenotype (three cell types), originating from intranasal sinonasal papillomas with exophytic and inverted patterns, and invading surrounding maxillary compartments, and (b) a p16 and keratin 7 (KRT7) positive carcinoma of the right tonsil, characterized by stratified squamous and mucinous cell (mucocyte) features. Whereas the first tumor represents a typical MEC ex-Schneiderian papilloma, the second is morphologically most consistent with the, novel for this anatomic location, diagnosis of "invasive stratified mucin producing carcinoma" (ISMC), pointing to an analogy to similar, high-risk HPV-driven malignancies recently described in the gynecologic (GYN) and genitourinary (GU) areas. Both tumors, despite their mucoepidermoid-like features had no connection to salivary glands and lacked the MAML2 translocation typical of salivary gland MEC, pointing to a mucosal/non-salivary gland origin. Using these two carcinomas as examples, we attempt to address questions related to: (a) the histological distinction between MEC, adenosquamous carcinoma, and ISMC, (b) similarities and differences between these histological entities in mucosal sites versus morphologically similar salivary gland tumors, and (c) the role of HPV in these tumors.

Persistent postural perceptual dizziness (PPPD) in pediatric patients after COVID-19 infection.

BACKGROUND: Patients with long-COVID suffer from symptoms that continue or develop after a COVID-19 or SARS-CoV-2 infection and are present for four or more weeks after the initial infection. This case series describes a group of previously healthy adolescent patients with long-COVID who were seen in a pediatric vestibular clinic for evaluation of severe dizziness and were diagnosed with persistent postural-perceptual dizziness (PPPD). By presenting their symptoms, management and treatment effects, this study aims to provide a diagnostic and therapeutic framework for providers who encounter these patients. METHODS: Patient records were reviewed for past medical history, symptoms, physical exam findings, results of audiometric and vestibular testing, dizziness handicap inventory for patient caregiver (DHI-pc) scores, and treatment recommendations. Parents of patients were contacted for a follow up survey to assess treatment adherence and outcomes including changes in symptoms and return to activity. RESULTS: A series of 9 adolescent patients were referred from a multidisciplinary long-COVID clinic and diagnosed with PPPD. Recommended treatment included vestibular physical therapy, selective serotonin reuptake inhibitor medication, and cognitive behavioral therapy. The majority of patients experienced an improvement in their symptoms, and all patients had improved activity levels and DHI-pc scores after treatment. CONCLUSION: To the best of our knowledge, no previous reports exist discussing PPPD in long-COVID patients. This case series provides insight into symptom evolution and treatment efficacy in this patient population.

Age-dependent predictors of effective reinforcement motor learning across childhood.

Across development, children must learn motor skills such as eating with a spoon and drawing with a crayon. Reinforcement learning, driven by success and failure, is fundamental to such sensorimotor learning. It typically requires a child to explore movement options along a continuum (grip location on a crayon) and learn from probabilistic rewards (whether the crayon draws or breaks). Here, we studied the development of reinforcement motor learning using online motor tasks to engage children aged 3 to 17 and adults (cross-sectional sample, N=385). Participants moved a cartoon penguin across a scene and were rewarded (animated cartoon clip) based on their final movement position. Learning followed a clear developmental trajectory when participants could choose to move anywhere along a continuum and the reward probability depended on final movement position. Learning was incomplete or absent in 3 to 8-year-olds and gradually improved to adult-like levels by adolescence. A reinforcement learning model fit to each participant identified three age-dependent factors underlying improvement: amount of exploration after a failed movement, learning rate, and level of motor noise. We predicted, and confirmed, that switching to discrete targets and deterministic reward would improve 3 to 8-year-olds' learning to adult-like levels by increasing exploration after failed movements. Overall, we show a robust developmental trajectory of reinforcement motor learning abilities under ecologically relevant conditions i.e., continuous movement options mapped to probabilistic reward. This learning appears to be limited by immature spatial processing and probabilistic reasoning abilities in young children and can be rescued by reducing the demands in these domains.

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.

Orthostatic Intolerance in Children With Long COVID Utilizing a 10-Minute Passive Standing Test.

Despite there being a wide variety of symptoms reported in pediatric long COVID, one condition that has become increasingly recognized is orthostatic intolerance (OI), which can cause significant morbidity, limiting activities of daily living. This study examines rates of OI in 92 children with long COVID who underwent a bedside passive standing test in a pediatric post-COVID-19 rehabilitation clinic. Seventy-one percent met criteria for an orthostatic condition, including postural orthostatic tachycardia syndrome (POTS), orthostatic tachycardia (OT), classic orthostatic hypotension (OH), delayed OH, and orthostatic hypertension. Our findings suggest that OI is common in pediatric long COVID, necessitating appropriate clinical screening and treatment.

An Initial Psychometric Evaluation of a Novel Upper Extremity Pediatric Stroke Hemiplegic Motor Impairment Scale.

BACKGROUND: Our team designed an innovative, observation-based motor impairment measure-the Pediatric Stroke Hemiplegic Motor Impairment Scale (Pedi HEMIs). Here we present the results of a survey describing common practices in the pediatric stroke community and the initial psychometric properties of the upper extremity subscale of the Pedi HEMIs (Pedi HEMIs-UE). METHODS: This is a cross-sectional study whereby participants completed a battery of assessments including the novel Pedi HEMIs-UE. Internal consistency was measured via Cronbach alpha (α). Intraclass correlation (ICC) was used to assess inter-rater reliability (IRR). Concurrent validity was investigated using Pearson or polychoric correlations and simple linear regressions. RESULTS: The study sample consisted of 18 children aged 1.08 to 15 years. Two participants completed two sets of evaluations, totaling 20 data sets. Cronbach α, a measure of internal consistency, was on average 0.91 (range: 0.89 to 0.92). IRR was excellent with the six raters in almost perfect agreement (ICC = 0.91; 95% confidence interval [CI]: 0.83 to 0.96). Pearson correlation coefficient between the Pedi HEMIs-UE and logit Assisting Hand Assessment (AHA)/mini-AHA was -0.938 (95% CI: -0.979 to -0.827, P < 0.001), indicating excellent concurrent validity. CONCLUSIONS: We found excellent feasibility, reliability, and validity of the Pedi HEMIs-UE in a convenience sample of youth with hemiparesis after stroke.

Stroke in the Developing Brain: Neurophysiologic Implications of Stroke Timing, Location, and Comorbid Factors.

BACKGROUND: Pediatric stroke, which is unique in that it represents a static insult to a developing brain, often leads to long-term neurological disability. Neuroplasticity in infants and children influences neurophysiologic recovery patterns after stroke; therefore outcomes depend on several factors including the timing and location of stroke and the presence of comorbid conditions. METHODS: In this review, we discuss the unique implications of stroke occurring in the fetal, perinatal, and childhood/adolescent time periods. First, we highlight the impact of the developmental stage of the brain at the time of insult on the motor, sensory, cognitive, speech, and behavioral domains. Next, we consider the influence of location of stroke on the presence and severity of motor and nonmotor outcomes. Finally, we discuss the impact of associated conditions on long-term outcomes and risk for stroke recurrence. RESULTS: Hemiparesis is common after stroke at any age, although the severity of impairment differs by age group. Risk of epilepsy is elevated in all age groups compared with those without stroke. Outcomes in other domains vary by age, although several studies suggest worse cognitive outcomes when stroke occurs in early childhood compared with fetal and later childhood epochs. Conditions such as congenital heart disease, sickle cell disease, and moyamoya increase the risk of stroke and leave patients differentially vulnerable to neurodevelopmental delay, stroke recurrence, silent infarcts, and cognitive impairment. CONCLUSIONS: A comprehensive understanding of the interplay of various factors is essential in guiding the clinical care of patients with pediatric stroke.

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.

A novel video game for remote studies of motor adaptation in children.

Here we designed a motor adaptation video game that could be played remotely (at home) through a web browser. This required the child to adapt to a visuomotor rotation between their hand movement and a ball displayed in the game. The task had several novel features, specifically designed to allow the study of the developmental trajectory of adaptation across a wide range of ages. We test the concurrent validity by comparing children's performance on our remote task to the same task performed in the laboratory. All participants remained engaged and completed the task. We quantified feedforward and feedback control during this task. Feedforward control, a key measure of adaptation, was similar at home and in the laboratory. All children could successfully use feedback control to guide the ball to a target. Traditionally, motor learning studies are performed in a laboratory to obtain high quality kinematic data. However, here we demonstrate concurrent validity of kinematic behavior when conducted at home. Our online platform provides the flexibility and ease of collecting data that will enable future studies with large sample sizes, longitudinal experiments, and the study of children with rare diseases.

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.