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Immunohistochemical staining for ENF using the PGP9.5-antibody, counter-stained by Eosin from the skin of the left calf and thigh. a Photomicrograph of left calf ENFs with a density of 8.9 ENFs. b Photomicrograph of left thigh ENFs with a density of 8.9 ENFs/mm skin. Original magnifications × 200. Courtesy of Kurenai Tanji MD, Department of Pathology and Cell Biology, Columbia University, New York. Abbreviations: ENF, epidermal nerve fiber; PGP9.5, protein gene product 9.5
Context in source publication
Context 1
... There was weakness versus gravity in the legs, resistance in the arms, with stocking sensory loss to vibration, cold temperature, and pin prick, and areflexia. EDX showed mixed chronic distal demyelinating and axonal changes. Thigh ENF density was 16.3 ENF/mm skin (normal 31.6 ± 13.2) and calf ENF density was 8.9 ENF/mm (normal 20.3 ± 7.4) (Fig. 1). HUT showed resting tachycardia of 118 bpm, with severe symptomatic orthostatic intolerance associated with a sustained fall in SBP to 63.25 mmHg (delta of 25.75 mmHg) so noted at 0.24 min following HUT, and further HR acceleration to 145 bpm (delta of change of 25 bpm) with HUT. PET/MRI showed hypometabolism of bilateral anterior and ...
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Citations
... The hypometabolic patterns in children and adults were similar but not completely identical, showing slight differences. Although not included in this analysis, we identified case reports that demonstrated hypometabolic patterns similar to those observed in our study (Younger, 2021). The presentation of neurological symptoms in COVID-19 disease patients is reported to exhibit differences between pediatric and adult populations (Casabianca et al., 2023;Cho et al., 2023). ...
COVID-19 disease, caused by the SARS-CoV-2 virus, has significantly altered modern society and lifestyles. We investigated its impact on brain glucose metabolism by meta-analyzing existing studies that utilized 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) scans of the brain. We conducted a systematic search of MEDLINE and EMBASE databases from inception to August 2024 for English-language publications using the keywords “positron emission tomography”, and “COVID-19”. We included original research articles that reported changes in brain glucose metabolism following COVID-19 disease. ALE values from these studies were aggregated and tested against a null hypothesis that anticipated a random distribution of ALE values, which proved to be significantly higher than chance. We identified nine papers that met our inclusion criteria. Significant increases in brain glucose metabolism were noted in the left anterior cingulate gyrus, right thalamus, and brainstem. In children with COVID-19 disease, decreased glucose metabolism was observed in the right and left cerebellum, left amygdala/hippocampus, left anterior cingulate gyrus, and right amygdala. In adults with COVID-19 disease, decreased metabolism was seen in the right temporal lobe, brainstem (acute phase), left occipital lobe, left and right temporal lobe (chronic phase). In conclusion, COVID-19 disease impacts brain glucose metabolism, typically manifesting as areas of decreased metabolism in ¹⁸F-FDG PET scans, though increases are also observed. These changes in metabolism vary with the patient’s age and the time elapsed between the diagnosis of COVID-19 disease and the PET scan.
... Particularly, severe organ damage is less in children in the acute stage, and children without MIS-C can also manifest multisystem symptoms (1,30). In addition, autonomic dysfunction has been suggested as a potential mechanism for the development of cardiovascular symptoms and symptoms resembling myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS) in individuals experiencing long COVID (31)(32)(33). ...
... Another study speculated that the changes might be related to the destruction of the myocardial mitochondria (48). Moreover, autonomic dysfunction may serve as a potential mechanism for circulatory system-related symptoms, including postural hypertension, fatigue discomfort, and syncope (32,49). The function of the autonomic nervous system is closely associated with the circulatory system (50), and several studies have indicated a potential association between primary COVID-19 infection and the development of autonomic nervous system disorders (51,52). ...
Background and Objective
In the context of the global pandemic of coronavirus disease 2019 (COVID-19), more than 700 million infections and millions of deaths have occurred in countries around the world. Currently, two main sequelae of this disease are considered to occur in children, namely, multi-system inflammatory syndrome in children and long COVID. Among these two, the incidence of long COVID is higher and its impact on the population is more extensive, which is the focus of us. However, due to the lack of relevant studies and the limitations of most studies, the studies on sequelae of COVID-19 infection lag behind those of adults, but they have begun to attract the attention of some clinicians and researchers. We aim to summarize the current knowledge of long COVID in children, helping pediatricians and researchers to better understand this disease and providing guidance on research and clinical treatment of it.
Methods
We reviewed all the studies on “long COVID”, pediatric, children, adolescent, post-COVID syndrome in PubMed published after 2019.
Key Content and Findings
This review summarizes the latest researches on epidemiology, pathogenesis, clinical manifestations, prevention and treatment of long COVID in children. Based on the existing research data, we summarized and analyzed the characteristics of long COVID in children, discovering the means to decipher the diagnosis of COVID-19 in children and some potential therapeutic treatments.
Conclusions
We aim to summarize existing research on long COVID in children and help pediatricians and government agencies quickly understand the disease so that it can be used for clinical diagnosis, treatment and prevention in the population. In addition, providing a research basis for further researches on the cellular and even molecular level to explain the occurrence and development of diseases, and has a guiding role for future research direction.
... Acutely, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been associated with multi-system manifestations of neurological, cardiac, respiratory and immune symptomology. [1][2][3] While most recover from acute COVID-19 infection, up to 10% of individuals seem to suffer a constellation of symptoms that persist beyond 12 weeks, including fatigue, dyspnea, chest pain, palpitations, headaches, nausea, abdominal pain, diarrhea, brain fog, and orthostatic intolerance. 4 Several nomenclatures exist to describe this phenomenon including long-haul COVID-19, long-COVID and post-acute sequelae of COVID-19 (PASC). ...
Background:
Autonomic dysfunction including postural orthostatic tachycardia syndrome (POTS) has been reported in individuals with post-acute sequelae of Covid-19 (PASC). However, the degree of dysautonomia in PASC has not been compared to those with POTS and healthy controls.
Methods:
All participants were prospectively enrolled between 5th August 2021 and 31st October 2022. Autonomic testing included beat-to-beat hemodynamic monitoring to assess respiratory sinus arrhythmia, Valsalva ratio and orthostatic changes during a 10-minute active standing test as well as Sudomotor assessment. The Composite Autonomic Symptom Score (COMPASS-31) was used to assess symptoms and the Euroquol 5-Dimension survey (EQ-5D-5L) was used to assess health-related quality of life (HrQoL) measures.
Results:
A total of 99 participants (n=33 PASC, n=33 POTS and n=33 healthy controls; median age 32 [18], 85.9% females) were included. Compared to healthy controls, the PASC and POTS cohorts demonstrated significantly reduced respiratory sinus arrhythmia (p<0.001), greater heart rate increase during 10-minute active standing test (p<0.001), greater burden of autonomic dysfunction evidenced by higher COMPASS-31 scores across all subdomains (all p<0.001) and poor HrQoL across all EQ-5D-5L domains (all p<0.001), lower median EQ-VAS (p<0.001) and lower utility scores (p<0.001). The majority (79%) of those with PASC met the internationally established criteria for POTS.
Conclusion:
The prevalence of autonomic symptomology or POTS was high in those with PASC, leading to poor HrQoL and high health disutility. Autonomic testing should be routinely undertaken in those with PASC to aid diagnosis and direct appropriate management to improve health outcomes.
Trial registration:
ANZCTR 12621000476831.
... The National Institutions of Health (NIH) launched the new RECOVER initiative in 2021 (1) to leverage electronic health record (EHR) data to better identify and characterize patients with post-acute sequelae of SARS-CoV-2 infection (PASC), defined by the NIH as failure to recover from COVID-19, or those persistently symptomatic for >30 days. (2) In the adult literature, advances have been made to predict PASC among COVID-19 affected patients (3) and to describe etiology, risk factors, and outcomes (4)(5)(6)(7). In contrast, there is currently a paucity of rigorous studies that accurately describe PASC in children (8). ...
Objectives
Post-acute sequalae of SARS-CoV-2 infection (PASC) is not well defined in pediatrics given its heterogeneity of presentation and severity in this population. The aim of this study is to use novel methods that rely on data mining approaches rather than clinical experience to detect conditions and symptoms associated with pediatric PASC.
Materials and Methods
We used a propensity-matched cohort design comparing children identified using the new PASC ICD10CM diagnosis code (U09.9) (N = 1309) to children with (N = 6545) and without (N = 6545) SARS-CoV-2 infection. We used a tree-based scan statistic to identify potential condition clusters co-occurring more frequently in cases than controls.
Results
We found significant enrichment among children with PASC in cardiac, respiratory, neurologic, psychological, endocrine, gastrointestinal, and musculoskeletal systems, the most significant related to circulatory and respiratory such as dyspnea, difficulty breathing, and fatigue and malaise.
Discussion
Our study addresses methodological limitations of prior studies that rely on prespecified clusters of potential PASC-associated diagnoses driven by clinician experience. Future studies are needed to identify patterns of diagnoses and their associations to derive clinical phenotypes.
Conclusion
We identified multiple conditions and body systems associated with pediatric PASC. Because we rely on a data-driven approach, several new or under-reported conditions and symptoms were detected that warrant further investigation.
... Although there are several case reports documenting the onset of POTS following COVID-19 infection in adults, 73,74 there is very limited literature available on pediatric patients. 75,76 Common presenting symptoms of PASC, including fatigue, brain fog, and nausea, overlap with symptoms of autonomic dysfunction and POTS. 77 In addition, it is important to screen for mental health concerns as symptoms of POTS may present similarly to somatic symptoms of anxiety and depression for which referral to mental health services may be warranted. ...
... The described phenomena may result from several pathomechanims. Perhaps the disturbance in interhemispheric connectivity is caused by desynchronization of the peripheral autonomic system [34][35][36]. Other studies also confirm that among patients with COVID-19, the hemispheric connectivity is lower, in particular regarding asymmetric distribution for EEG bands in temporal lobes [3]. ...
Previous research and clinical reports have shown that some individuals after COVID-19 infection may demonstrate symptoms of so-called brain fog, manifested by cognitive impairment and disorganization in behavior. Meanwhile, in several other conditions, related to intellectual function, a specific pattern of changes in electric brain activity, as recorded by quantitative electroencephalography (QEEG) has been documented. We hypothesized, that in post-COVID brain fog, the subjective complaints may be accompanied by objective changes in the QEEG profile. In order to test this hypothesis, we have performed an exploratory study on the academic staff of our University with previous records of QEEG originating in the pre-COVID-19 era. Among them, 20 subjects who revealed neurological problems in the cognitive sphere (confirmed as covid fog/brain fog by a clinical specialist) after COVID-19 infection were identified. In those individuals, QEEG was performed. We observed, that opposite to baseline QEEG records, increased Theta and Alpha activity, as well as more intensive sensimotor rhythm (SMR) in C4 (right hemisphere) in relation to C3 (left hemisphere). Moreover, a visible increase in Beta 2 in relation to SMR in both hemispheres could be documented. Summarizing, we could demonstrate a clear change in QEEG activity patterns in individuals previously not affected by COVID-19 and now suffering from post-COVID-19 brain fog. These preliminary results warrant further interest in delineating their background. Here, both neuroinflammation and psychological stress, related to Sars-CoV2-infection may be considered. Based on our observation, the relevance of QEEG examination as a supportive tool for post-COVID clinical workup and for monitoring the treatment effects is also to be explored.
... Information on pediatric post-COVID OI is more limited. One case report describes a previously healthy 12-year-old girl who contracted COVID-19 in March 2020; orthostatic symptoms progressed until she became bedbound by July 2020 [44]. Testing revealed severely symptomatic OI associated with a drop in blood pressure and resting tachycardia. ...
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.
... A very recent publication in press at the time of this writing [40] demonstrates PASC in a child with striking similarity to the adult conditionclinically and in its responsiveness to HD-IVIg suggesting a continuum of potentially prolonged post-COVID-19 neurological autoimmunity in the absence of effective treatment. ...
A subset of children and adolescents experience recurrent or persistent symptoms following SARS-CoV-2 infection, known as postacute sequelae of COVID-19 (PASC), however, the clinical epidemiology within the United States (US) is not yet well understood. This scoping review aims to synthesize the clinical epidemiology of pediatric PASC in the US. A comprehensive literature search was conducted and databases were queried from inception until January 29, 2024. Studies including US children and adolescents <21 years old were considered. From 1028 studies identified, 29 met the inclusion criteria. Prevalence of PASC ranged from less than 1%-27%. Risk factors included older age, female sex, asthma, obesity, and severe initial infection. Common symptoms were dyspnea, fatigue, headaches, and chest pain. A multidisciplinary approach for diagnosis and management was common across studies. Most studies had a high risk of bias and were limited by a lack of standardized definitions and short follow-up duration. This review establishes a foundation for understanding pediatric PASC and highlights the critical need for continued research to optimize prevention and treatment strategies.
