Tag: pediatric long covid

Long-term neurological implications of severe acute respiratory syndrome coronavirus 2 infections in neonates: Innate immune memory and chronic neuroinflammation

Abstract:

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can cause long-term neurological complications in adults. However, the mechanisms by which early-life SARS-CoV-2 infection increases the risk of abnormal neurodevelopment remain unknown.

Recent studies have shown an association with chronic proinflammatory cytokine/chemokine production in the central nervous system (CNS). Therefore, it was hypothesised that innate immune activation and induction of innate immune memory may play a potential role in the neonatal brain. Haematopoietic stem cells in the bone marrow are exposed to SARS-CoV-2, SARS-CoV-2 envelope protein (E protein), lipopolysaccharide (LPS)-bound spike proteins (S1 and S2 proteins), and damage-associated molecular patterns (DAMPs). Myeloid progenitors enter the stroma of the choroid plexus and are further directed to incessantly supply the brain parenchyma with resident innate immune cells. The S proteins-LPS complex can cross the blood–brain barrier and plays an important role in microglial and astrocytic inflammatory responses and innate immune memory.

Persistently activated microglia with memory release pro-inflammatory cytokines/chemokines which contribute to abnormal synaptic development in the frontal lobe and cerebellum, potentially leading to long-term neurological complications, similar to those observed in autism spectrum disorder (ASD). In addition, this hypothesis suggests that bacterial and fungal products may act as adjuvants to S proteins and may also explain why S proteins alone are insufficient to induce neuroinflammation in neonates.

Source: Tatsuro Nobutoki. Long-term neurological implications of severe acute respiratory syndrome coronavirus 2 infections in neonates: Innate immune memory and chronic neuroinflammation. Medical Hypotheses, Volume 181, December 2023, 111204 https://www.sciencedirect.com/science/article/pii/S0306987723002001 (Full text)

Incidence and persistence of post-COVID condition in children – a matched cohort study in Germany

Abstract:

Introduction: Long-term health effects of COVID-19 have been investigated by several large cohort studies. As most of these studies have been conducted in adults, data on the incidence and persistence of post-COVID-19 condition (PCC) among children and adolescents are still limited.
Methods: Using routine healthcare data from statutory health insurance in Germany, children and adolescents with laboratory-confirmed COVID-19 in 2020 were matched to controls (neither documented nor clinically suspected COVID-19) and followed for incident health conditions until 2021-09-30. To study PCC in children we considered selected health outcomes including malaise/fatigue (R53), dyspnea (R06.0), and cognitive dysfunction (F06.7, U51, R41), developmental delay (F80-89), adjustment disorder (F43), chronic fatigue syndrome (CFS; G93.3), and altered smell/anosmia (R43). The incidence of PCC was determined based on the lack of related diagnoses in the 12 months preceding the index quarter. For each outcome incidence rate ratios (IRR) were estimated using Poisson regression.
Results: At 3-month-follow-up, about 40% more individuals with COVID-19 suffered from at least one of the specified health conditions compared to controls. IRR were highest for smell/anosmia and CFS. IRR were generally higher among adolescents (≥12 years) than among younger children. Only a minority of PCC diagnoses persisted for 12 months within the COVID cohort. Diagnoses were more frequently persistent in the younger age group after one year.
Conclusions: Despite that long-term consequences of COVID-19 are less common and usually less severe in children, a considerable share of those diagnosed with PCC still suffered from specific symptoms 12 months after acute infection. Considering the high number of infected persons our findings suggest a relevant PCC related burden for health care even among children and adolescents.
Key messages:

• In routine healthcare data adolescents showed stronger associations between COVID-19 and post COVID-19 related ICD-10 diagnoses than children < 12 years of age.

• Serious ICD-10 diagnoses persisted for a longer time in younger children than adolescents.

Source: F Ehm, D Wende, F Loser, A Vivirito, S Menzer, M Batram, T Buschmann, G Sarganas, C Scheidt-Nave, J Schmitt, Incidence and persistence of post-COVID condition in children – a matched cohort study in Germany, European Journal of Public Health, Volume 33, Issue Supplement_2, October 2023, ckad160.095, https://doi.org/10.1093/eurpub/ckad160.095 https://academic.oup.com/eurpub/article/33/Supplement_2/ckad160.095/7327923 (Full text available as PDF file)

A qualitative study to explore children’s experience of having long-Covid

There is currently uncertainty and limited research surrounding long-COVID in the paediatric population. Reports are conflicting regarding the prevalence, duration, and impact of long COVID on children. Despite the limited evidence, it is becoming increasingly apparent that numerous children are experiencing long-term physical and psychological effects of COVID19 many months after the initial infection. This thesis aimed to investigate the lived experience of children with long-COVID.
Part one of this portfolio presents a systematic review of the experiences of parents who provide care for a child with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The findings of the review indicate a paucity of research on parents’ experiences. However, it is apparent that caring for a child with ME/CFS is an all-encompassing, relentless undertaking, which can detrimentally impact parents’ well-being, everyday life, and relationships.
Given both ME/CFS and long-COVID are both post-viral illnesses, sharing similar symptoms, with low-level immune system activation. It may be conjectured that the existing knowledge on children with ME/CFS could benefit both children suffering from long-COVID and help inform parents on how best to care for their children.
Part two of this portfolio presents an empirical paper exploring the lived-experience of young people with long-COVID. Reflexive thematic analysis found three key themes, specifically, the perceived barriers to coping with long-COVID, ongoing associated emotional distress, and a desire for an integrated approach to long-COVID care.
Source: Carolyn Noorderhaven. A qualitative study to explore children’s experience of having long-Covid. Doctoral thesis: University of Surrey, School of Psychology. https://openresearch.surrey.ac.uk/esploro/outputs/doctoral/A-qualitative-study-to-explore-childrens/99813065702346?institution=44SUR_INST (Full text available as PDF file)

Atopy and Elevation of IgE, IgG3, and IgG4 May Be Risk Factors for Post COVID-19 Condition in Children and Adolescents

Abstract:

SARS-CoV-2 infection causes transient cardiorespiratory and neurological disorders, and severe acute illness is rare among children. Post COVID-19 condition (PCC) may cause profound, persistent phenotypes with increasing prevalence. Its manifestation and risk factors remain elusive. In this monocentric study, we hypothesized that atopy, the tendency to produce an exaggerated immunoglobulin E (IgE) immune response, is a risk factor for the manifestation of pediatric PCC.
We present a patient cohort (n = 28) from an early pandemic period (2021–2022) with comprehensive evaluations of phenotypes, pulmonary function, and molecular investigations. PCC predominantly affected adolescents and presented with fatigue, dyspnea, and post-exertional malaise. Sensitizations to aeroallergens were found in 93% of cases.
We observed elevated IgE levels (mean 174.2 kU/L, reference < 100 kU/L) regardless of disease severity. Concurrent Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) was found in 29% of patients that also faced challenges in school attendance. ME/CFS manifestation was significantly associated with elevated immunoglobulin G subclasses IgG3 (p < 0.05) and IgG4 (p < 0.05). A total of 57% of patients showed self-limiting disease courses with mean recovery at 12.7 months (range 5–25 months), 29% at 19.2 months (range 12–30 months), and the rest demonstrated overall improvement. These findings offer additional insights into immune dysregulation as a risk factor for pediatric PCC.
Source: Körner RW, Bansemir OY, Franke R, Sturm J, Dafsari HS. Atopy and Elevation of IgE, IgG3, and IgG4 May Be Risk Factors for Post COVID-19 Condition in Children and Adolescents. Children. 2023; 10(10):1598. https://doi.org/10.3390/children10101598 https://www.mdpi.com/2227-9067/10/10/1598 (Full text)

Social Stigma in Children with Long COVID

Abstract:

There is growing evidence that adults with Long COVID suffer from different sets of stigmata related to their condition. In children with Long COVID, this aspect has never been investigated. This study aims to investigate if children with Long COVID also experience stigma.
Methods: Children with a previous SARS-CoV-2 infection evaluated at 3 month follow-ups in a pediatric post COVID unit were asked to fill in an online Long COVID Stigma Scale survey before they were assessed by a pediatrician. Doctors were unaware of children’s responses when they performed a diagnosis of Long COVID or full recovery from previous infection, according to the World Health Organization definition of pediatric Long COVID. Responses to the Stigma scale were then compared in the two cohorts of children.
Results: 224 patients responded to the questionnaire; 40 patients were diagnosed with Long COVID. Children with Long COVID significantly more frequently felt embarrassed about having Long COVID (p 0.035), felt embarrassed about having physical limitations (p < 0.001), felt they were valued less due to Long COVID (p 0.003), felt they were different from other peers due to Long COVID (p 0.033), felt significantly more frequently that people behaved differently towards them because they might be lying since the diagnosis of Long COVID (p 0.006), that they were less respected by others due to Long COVID (p 0.017), that other people thought that Long COVID is not a real disease (p 0.007), that other people thought that developing Long COVID is a sign of weakness (p 0.008), and that other people might judge them negatively due to their diagnosis of Long COVID (p < 0.001).
Conclusions: Children with Long COVID, similar to adults, are suffering from stigmata due to their condition. These data may have implication and should be used by the public, policy makers, and healthcare professionals regarding pediatric Long COVID.
Source: Buonsenso D, Camporesi A, Morello R, De Rose C, Fracasso M, Chieffo DPR, Valentini P. Social Stigma in Children with Long COVID. Children. 2023; 10(9):1518. https://doi.org/10.3390/children10091518 https://www.mdpi.com/2227-9067/10/9/1518 (Full text)

Pediatric and Adult Patients with ME/CFS following COVID-19: A Structured Approach to Diagnosis Using the Munich Berlin Symptom Questionnaire (MBSQ)

Abstract:

Purpose A subset of patients with post-COVID-19 condition (PCC) fulfill the clinical criteria of myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS). To establish the diagnosis of ME/CFS for clinical and research purposes, comprehensive scores have to be evaluated.

Methods We developed the Munich Berlin Symptom Questionnaires (MBSQs) and supplementary scoring sheets (SSSs) to allow for a rapid evaluation of common ME/CFS case definitions. The MBSQs were applied to young patients with chronic fatigue and post-exertional malaise (PEM) who presented to the MRI Chronic Fatigue Center for Young People (MCFC). Trials were retrospectively registered (NCT05778006, NCT05638724).

Results Using the MBSQs and SSSs, we report on ten patients aged 11 to 25 years diagnosed with ME/CFS after asymptomatic SARS-CoV-2 infection or mild to moderate COVID-19. Results from their MBSQs and from well-established patient-reported outcome measures indicated severe impairments of daily activities and health-related quality of life.

Conclusions ME/CFS can follow SARS-CoV-2 infection in patients younger than 18 years, rendering structured diagnostic approaches most relevant for pediatric PCC clinics. The MBSQs and SSSs represent novel diagnostic tools that can facilitate the diagnosis of ME/CFS in children, adolescents, and adults with PCC and other post-viral syndromes.

What is known ME/CFS is a frequent debilitating illness. For diagnosis, an extensive differential diagnostic workup is required and the evaluation of clinical ME/CFS criteria. ME/CFS following COVID-19 has been reported in adults but not in pediatric patients younger than 19 years of age.

What is new We present novel questionnairs (MBSQs), as tools to assess common ME/CFS case definitions in pediatric and adult patients with post-COVID-19 condition and beyond. We report on ten patients aged 11 to 25 years diagnosed with ME/CFS following asymptomatic SARS-CoV-2 infection or mild to moderate COVID-19.

Source: Laura C. Peo, Katharina Wiehler, Johannes Paulick, Katrin Gerrer, Ariane Leone, Anja Viereck, Matthias Haegele, Silvia Stojanov, Cordula Warlitz, Silvia Augustin, Martin Alberer, Daniel B. R. Hattesohl, Laura Froehlich, Carmen Scheibenbogen, Lorenz Mihatsch, Rafael Pricoco, Uta Behrends. Pediatric and Adult Patients with ME/CFS following COVID-19: A Structured Approach to Diagnosis Using the Munich Berlin Symptom Questionnaire (MBSQ). medRxiv 2023.08.23.23293081; doi: https://doi.org/10.1101/2023.08.23.23293081 https://www.medrxiv.org/content/10.1101/2023.08.23.23293081v1.full-text (Full text)

Modeling Long Covid Disease Network in Pediatric Population

Abstract:

The effects of COVID-19 have had a tremendous impact on the quality of life, work, and society. This has been exacerbated by the progression of COVID-19 into Long COVID. Long COVID is not a specific disease or symptom but a set of wide-ranging conditions that linger in COVID-19 patients for four weeks or beyond post-initial COVID-19 detection. This relatively new condition is challenging due to a lack of prior research and data specific to the pediatric population, comprising 25.24% of all Long COVID cases under study.

Besides, there is a lack of deeper understanding about who may develop Long COVID. Various comorbidities could provide insights into the path leading toward a patient’s Long COVID detection, as referenced in Berg et al. (2022). Thus, we address two research questions in our study. First, what chronic co-morbidities are prevalent in pediatric patients exhibiting Long COVID symptoms? Second, what nonchronic conditions are  associated with pediatric patients diagnosed with Long COVID?

To delve into the research questions, we use 80,000 Long COVID pediatric patients N3C (National COVID Cohort Collaboration) data across 72 healthcare units located in the US. The model we developed has 3 stages – First, we apply network analytics techniques to identify pre-existing chronic and non-chronic conditions among those diagnosed with Long COVID. Second, using CDC’s definition for Long COVID, we develop a bi-partite network representing a large pediatric population diagnosed with COVID-19 who subsequently developed Long-COVID. This bipartite network has patients on one side and diseases on the other with no connection among the patients and among the diseases. We take projection on the disease side to create disease-disease projection graph. Third, the projected disease-disease graph is processed such that we create bipartite network comprising pre-COVID diseases on one side and Long COVID diseases on the other side. We take the projection of both sides to carry out analysis regarding chronic and non-chronic pre-COVID conditions leading to Long COVID.

The above model was implemented using 0.5 million pediatric COVID patient dataset from the N3C (2020). Besides using Spark SQL and PySpark to analyze the data, we used graphical tools such as Gephi to integrate Community Detection algorithms and create visualizations. Since the size of the overall patient record is large, it necessitated implementation of various code optimization techniques for faster processing. This study provides critical building blocks for developing Long COVID prediction and recommendation systems models

Source: Kushagra, Kushagra; joghataee, mohammad; Gupta, Ashish; Kalgotra, Pankush; and Qin, Xiao, “Modeling Long Covid Disease Network in Pediatric Population” (2023). AMCIS 2023 TREOs. 107. https://aisel.aisnet.org/treos_amcis2023/107

Increased SARS-CoV-2 reactive low avidity T cells producing inflammatory cytokines in pediatric post-acute COVID-19 sequelae (PASC)

Abstract:

Background: A proportion of the convalescent SARS-CoV-2 pediatric population presents nonspecific symptoms, mental health problems and a reduction in quality of life similar to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID-19 symptomatic. However, data regarding its clinical manifestation and immune mechanisms are currently scarce.

Methods: In this study, we perform a comprehensive clinical and immunological profiling of 17 convalescent COVID-19 children with post-acute COVID-19 sequelae (PASC) manifestation and 13 convalescent children without PASC manifestation. A detailed medical history, blood and instrumental tests and physical examination were obtained from all patients. SARSCoV-2 reactive T cell response was analyzed via multiparametric flowcytometry and the humoral immunity was addressed via pseudovirus neutralization and ELISA assay.

Results: The most common PASC symptoms were shortness of breath/exercise intolerance, paresthesia, smell/taste disturbance, chest pain, dyspnea, headache and lack of concentration. Blood count and clinical chemistry showed no statistical differences among the study groups. We detected higher frequencies of spike (S) reactive CD4+ and CD8+ T cells among the PASC study group, characterized by TNFα and IFNγ production and low functional avidity. CRP levels are positively correlated with IFNγ producing reactive CD8+ T cells.

Conclusions: Our data might indicate a possible involvement of a persistent cellular inflammatory response triggered by SARS-CoV-2 in the development of the observed sequelae in pediatric PASC. These results may have implications on future therapeutic and prevention strategies.

Source: Krystallenia Paniskaki, et al. Increased SARS-CoV-2 reactive low avidity T cells producing inflammatory cytokines in pediatric post-acute COVID-19 sequelae (PASC) https://d197for5662m48.cloudfront.net/documents/publicationstatus/144335/preprint_pdf/a855de5e766f9457795050e56413075a.pdf (Full text)

Pediatric de novo movement disorders and ataxia in the context of SARS-CoV-2

Abstract:

Objective: In the fourth year of the COVID-19 pandemic, mortality rates decreased, but the risk of neuropsychiatric disorders remained the same, with a prevalence of 3.8% of pediatric cases, including movement disorders (MD) and ataxia.

Methods: In this study, we report on a 10-year-old girl with hemichorea after SARS-CoV-2 infection and immunostained murine brain with patient CSF to identify intrathecal antibodies. Additionally, we conducted a scoping review of children with MD and ataxia after SARS-CoV-2 infection.

Results: We detected antibodies in the patient’s CSF binding unknown antigens in murine basal ganglia. The child received immunosuppression and recovered completely. In a scoping review, we identified further 32 children with de novo MD or ataxia after COVID-19. While in a minority of cases, MD or ataxia were a symptom of known clinical entities (e.g. ADEM, Sydenham’s chorea), in most children, the etiology was suspected to be of autoimmune origin without further assigned diagnosis. (i) Children either presented with ataxia (79%), but different from the well-known postinfectious acute cerebellar ataxia (older age, less favorable outcome, or (ii) had hypo-/hyperkinetic MD (21%), which were choreatic in most cases. Besides 14% of spontaneous recovery, immunosuppression was necessary in 79%. Approximately one third of children only partially recovered.

Conclusions: Infection with SARS-CoV-2 can trigger de novo MD in children. Most patients showed COVID-19-associated-ataxia and fewer-chorea. Our data suggest that patients benefit from immunosuppression, especially steroids. Despite treatment, one third of patients recovered only partially, which makes up an increasing cohort with neurological sequelae.

Source: Wilpert NM, de Almeida Marcelino AL, Knierim E, Incoronato P, Sanchez-Sendin E, Staudacher O, Drenckhahn A, Bittigau P, Kreye J, Prüss H, Schuelke M, Kühn AA, Kaindl AM, Nikolaus M. Pediatric de novo movement disorders and ataxia in the context of SARS-CoV-2. J Neurol. 2023 Jul 29. doi: 10.1007/s00415-023-11853-5. Epub ahead of print. PMID: 37515734. https://link.springer.com/article/10.1007/s00415-023-11853-5 (Full text)

A Systematic Review of Persistent Clinical Features After SARS-CoV-2 in the Pediatric Population

Abstract:

Context: Long-term health effects after coronavirus disease 2019 (COVID-19) have been increasingly reported but their prevalence and significance in the pediatric population remains uncertain.

Objective: To present the prevalence and characteristics of the long-term clinical features of COVID-19 (long COVID) in the global pediatric population.

Data sources: PubMed, Embase, Web of Science, Cochrane Library, WHO COVID-19 database, google scholar, medRxiv, bioRxiv, and multiple national public health databases.

Study selection: Published articles and preprints from December, 2019 to December, 2022 investigating the epidemiology and characteristics of persistent clinical features at least 3 months after COVID-19 in children and adolescents (0-19 years old) were included.

Data extraction: Study characteristics and detailed description of long COVID were extracted into a predefined form.

Results: Twenty seven cohorts and 4 cross-sectional studies met the inclusion criteria and involved over 15 000 pediatric participants. A total of more than 20 persistent symptoms and clinical features were reported among children and adolescents. 16.2% (95% confidence interval 8.5% to 28.6%) of the pediatric participants experienced 1 or more persistent symptom(s) at least 3 months post COVID-19. Female gender might be associated with developing certain long COVID symptoms.

Limitations: Included studies presented with great heterogeneity because of significant variations in the definition of “long COVID,” follow up duration, and method. There could be nonresponse and other potential bias.

Conclusions: Persistent clinical features beyond 3 months among children and adolescents with proven COVID-19 are common and the symptom spectrum is wide. High-quality, prospective studies with proper controls are necessary in the future.

Source: Jiang L, Li X, Nie J, Tang K, Bhutta ZA. A Systematic Review of Persistent Clinical Features After SARS-CoV-2 in the Pediatric Population. Pediatrics. 2023 Aug 1;152(2):e2022060351. doi: 10.1542/peds.2022-060351. PMID: 37476923; PMCID: PMC10389775. https://pubmed.ncbi.nlm.nih.gov/37476923/