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COVID19

Microglia dysfunction, neurovascular inflammation and focal neuropathologies are linked to IL-1- and IL-6-related systemic inflammation in COVID-19

Fekete, R., Simats, A., Bíró, E., Pósfai, B., Cserép, C., Schwarcz, A., Szabadits, E., Környei, Z., Tóth, K., Fichó, E., Szalma, J., Vida, S., Kellermayer, A., Dávid, C., Acsády, L., Kontra, L., Silvestre-Roig, C., Moldvay, J., … Dénes, Á. (2025). Microglia dysfunction, neurovascular inflammation and focal neuropathologies are linked to IL-1- and IL-6-related systemic inflammation in COVID-19. Nature Neuroscience, 28(3), 558–576. DOI: 10.1038/s41593-025-01871-z

  • Neuropathological study examining brains of individuals with COVID-19.

  • Identifies microglial dysfunction, astrocyte involvement, and neurovascular inflammation linked to systemic IL-1 and IL-6 signaling.

  • Demonstrates blood–brain barrier disruption and gliovascular pathology even in the absence of direct viral invasion of brain tissue.

  • Provides strong evidence for self-sustaining inflammatory loops between peripheral immune signals and CNS cells.

Microglia dysfunction, neurovascular inflammation and focal neuropathologies are linked to IL-1- and IL-6-related systemic inflammation in COVID-19

Fekete R, Simats A, Bíró E, et al. Microglia dysfunction, neurovascular inflammation and focal neuropathologies are linked to IL-1- and IL-6-related systemic inflammation in COVID-19. Nat Neurosci. 2025;28(3):558-576. doi:10.1038/s41593-025-01871-z.

Impaired microglia function and vascular inflammation in COVID

  • Observational study evaluating Long COVID patients treated with H1/H2 antihistamines.

  • Reports improvement in fatigue, cognitive symptoms, tachycardia, and other systemic complaints.

  • Supports the hypothesis that mast cell activation contributes to Long COVID symptom persistence.

  • Suggests immune dysregulation—rather than viral persistence—may drive ongoing symptoms in a subset of patients.

The pattern of childhood infections during and after the COVID-19 pandemic
Nygaard U, Holm M, Rabie H, Rytter M. The pattern of childhood infections during and after the COVID-19 pandemic. Lancet Child Adolesc Health. 2024 Dec;8(12):910-920. doi: 10.1016/S2352-4642(24)00236-0. PMID: 39572124.
  • Initial Decline: Pediatric infections dropped during COVID-19 due to safety measures.
  • Post-Pandemic Surge: Infections rebounded as restrictions eased, with changes in severity, strains, and affected age groups.
  • Key Cause: Immunity debt from reduced exposure, not new variants or resistance.
  • Impact: Unusual symptoms emerged, offering new insights into disease spread and progression.
Long Neuro-COVID-19: Current Mechanistic Views and Therapeutic Options

Slama Schwok A, et al. Long Neuro-COVID-19: Current Mechanistic Views and Therapeutic Options. Biomolecules. 2024;14(9):1081. doi:10.3390/biom14091081.

  • Comprehensive review of proposed mechanisms underlying neurological Long COVID.

  • Describes neuroimmune activation, endothelial dysfunction, blood–brain barrier disruption, and microglial priming.

  • Emphasizes that neurological symptoms can persist without detectable viral RNA in the CNS.

  • Supports reframing Long COVID brain symptoms as a disorder of immune and vascular regulation.

Postacute Sequelae of SARS-CoV-2 in Children

Suchitra Rao, MBBS, MSCS; Rachel S. Gross, MD, MS; Sindhu Mohandas, MD; Cheryl R. Stein, PhD; Abigail Case, MD; Benard Dreyer, MD; Nathan M. Pajor, MD; H. Timothy Bunnell, PhD; David Warburton, MD; Elizabeth Berg, MD; Jonathan B. Overdevest, MD; Mark Gorelik, MD; Joshua Milner, MD; Sejal Saxena, BA; Ravi Jhaveri, MD; John C. Wood, MD, PhD; Kyung E. Rhee, MD, MSc, MA; Rebecca Letts, BA; Christine Maughan, BS; Nick Guthe, BA; Leah Castro-Baucom, MA; Melissa S. Stockwell, MD, MPH. Postacute Sequelae of SARS-CoV-2 in Children. AAP Publications, Feb 7, 2024, https://doi.org/10.1542/peds.2023-062570

  • The COVID-19 pandemic has had far-reaching impacts on health, society, and the economy, with some individuals experiencing lingering effects beyond the acute phase.
  • Emerging data on post-acute sequelae of SARS-CoV-2 infection (PASC) in children, or long COVID, is shedding light on persistent symptoms, new manifestations, and exacerbation of underlying conditions.
  • Children may develop new conditions such as postural orthostatic tachycardia syndrome (POTS), myalgic encephalomyelitis/chronic fatigue syndrome, autoimmune conditions, and multisystem inflammatory syndrome in children.
  • The review summarizes current knowledge on PASC in children, including its children, prevalence, epidemiology, risk factors, clinical characteristics, underlying mechanisms, and functional outcomes. It presents a framework based on NIH-funded research to understand PASC’s effect on children and young adults to guide treatments and prevention efforts. This research uses electronic health records and longitudinal studies to evaluate disease impact, progression, and clinical outcomes.

Section on Mental Health

  • The COVID-19 pandemic resulted in multiple mental health conditions among children, including anxiety, stress, depression, panic, irritability, impulsivity, sleep problems, emotional lability, posttraumatic stress disorder, eating disorders, and suicidal behavior.
    Research is needed to understand whether these conditions are directly related to the virus or influenced by pandemic-related factors like social distancing and school closures.
  • Large EHR cohort studies have shown a higher incidence of neurologic or psychiatric diagnoses in children in the 6 months after SARS-CoV-2 compared with those without confirmed infection.
  • A COVID-19 diagnosis is associated with experiencing a new mental health condition (within a median of 33 days after infection) compared with negative controls in children.
  • The common mental health issues seen in children post-COVID-19 infection are anxiety, attention-deficit/hyperactivity disorder, and trauma-related disorders. Additionally, there are reports of acute-onset neuropsychiatric syndrome in children following COVID-19 infection.
  • There have also been case reports of pediatric acute-onset neuropsychiatric syndrome in children after SARS-CoV-2 infection.72,73 
Antihistamines improve cardiovascular manifestations and other symptoms of long-COVID attributed to mast cell activation

Salvucci F, Codella R, Coppola A, et al. Antihistamines improve cardiovascular manifestations and other symptoms of long-COVID attributed to mast cell activation. Front Cardiovasc Med. 2023;10:1202696. doi:10.3389/fcvm.2023.1202696.

Mast cell activation in Long COVID (related work)

  • Observational study evaluating Long COVID patients treated with H1/H2 antihistamines.

  • Reports improvement in fatigue, cognitive symptoms, tachycardia, and other systemic complaints.

  • Supports the hypothesis that mast cell activation contributes to Long COVID symptom persistence.

  • Suggests immune dysregulation—rather than viral persistence—may drive ongoing symptoms in a subset of patients.

Long-term central nervous system (CNS) consequences of COVID-19 in children

Howe de la Torre, S., Parlatini, V., & Cortese, S. (2023). Long-term central nervous system (CNS) consequences of COVID-19 in children. Expert Review of Neurotherapeutics, 23(8), 703–720. https://doi.org/10.1080/14737175.2023.2239500

Read a deeper dive into Pediatric Long COVID: Neurological and Neuropsychiatric Symptoms

  • Neurological and neuropsychiatric symptoms are commonly reported in children and adolescents with long COVID, including headache, fatigue, cognitive difficulties, mood changes, and sleep problems
  • Reported prevalence varies widely due to study heterogeneity, small sample sizes, and limited long-term follow-up
  • Beyond mood and sleep issues, many neuropsychiatric conditions remain underexamined in pediatric long COVID
  • Persistent symptoms may significantly affect daily functioning and well-being
PANDAS/PANS in the COVID-19 Age: Autoimmunity and Epstein–Barr Virus Reactivation as Trigger Agents?
Pallanti S, Di Ponzio M. PANDAS/PANS in the COVID-19 Age: Autoimmunity and Epstein-Barr Virus Reactivation as Trigger Agents? Children (Basel). 2023 Mar 30;10(4):648. doi: 10.3390/children10040648. PMID: 37189896; PMCID: PMC10136983.
  • COVID-19 infection and pandemic-related stressors were associated with worsening neuropsychiatric symptoms in children and adolescents with PANS
  • Obsessions, tics, anxiety, mood symptoms, and overall wellbeing were most commonly affected
  • New symptoms and new-onset PANS cases were reported following SARS-CoV-2 infection
  • Case series of five adolescents showed symptom exacerbation after COVID-19 infection
  • Authors hypothesize roles for neuroinflammation, immune activation, viral reactivation (e.g., EBV), and social isolation–related inflammatory effects
  • PANS is presented as a model for understanding immune-mediated neuropsychiatric post-acute COVID syndromes (PACS)
SARS-CoV-2/COVID-19 associated pediatric acute-onset neuropsychiatric syndrome a case report of female twin adolescents
Efe A. SARS-CoV-2/COVID-19 associated pediatric acute-onset neuropsychiatric syndrome a case report of female twin adolescents. Psychiatry Res Case Rep. 2022 Dec;1(2):100074. doi: 10.1016/j.psycr.2022.100074. Epub 2022 Oct 14. PMID: 36267397; PMCID: PMC9562621.

The only relevant agent underlying those neuropsychiatric and somatic complaints was COVID-19, and it was validated with laboratory testing, such as positive IgG titers of SARS-CoV-2 and negative biomarkers for other possible bacterial or viral agents. Generalized epileptic anomaly and a vermian/folial atrophy in the cerebellum were detected in further evaluations. Treatment options consisted of psychotropic agents, antibiotics, antiepileptic, and intravenous immunoglobulin transfusion finely treated the neuropsychiatric symptoms. Clinicians should consider SARS-CoV-2 as a potential agent, when a child presents with abrupt onset, dramatic neuropsychiatric symptoms also consisting of PANS, even in asymptomatic patients or with mild respiratory symptoms.“

“As the first treatment option in suspicion of PANS, proper psychotropic treatments and antibiotic agents (amoxicillin-clavulanate, 2 gr/day, for 21 days) were administered to both sisters. The more affected sibling was treated with fluoxetine (40 mg/day), risperidone (1 mg/day), and sodium valproate (20 mg/kg/day) while the less affected sibling with milder symptoms was treated with sertraline (50 mg/day). After one month following these treatment options, IVIG transfusion was required, because of mildly decreased, however, severely continuing psychiatric and somatic complaints. Surprisingly, the somatic complaints, restrictive food intake, OCD symptoms, severe anxiety with hallucinations, depression, and even mild neurologic symptoms were significantly decreased 1 week after the IVIG transfusion; and the patients had weight gain.”

Long COVID Syndrome Presenting as Neuropsychiatric Exacerbations in Autism Spectrum Disorder: Insights for Treatment

Jyonouchi, H.; Geng, L.; Rossignol, D.A.; Frye, R.E. Long.COVID Syndrome Presenting as Neuropsychiatric Exacerbations in Autism Spectrum Disorder: Insights for Treatment. J. Pers. Med. 2022, 12,1815. https://doi.org/10.3390/jpm12111815

Neurological and neuropsychiatric symptoms are emerging as major long-term sequalae. In patients with pre-existing behavioral symptoms, such as individuals with autism spectrum disorders (ASD), the emergence of neuropsychiatric symptoms due to long COVID can be difficult to diagnose and manage. Herein, we present three ASD cases who presented with markedly worsening neuropsychiatric symptoms following COVID-19 exposure and subsequent difficulty in managing the post-COVID neuropsychiatric symptoms.

Long Covid brain fog: a neuroinflammation phenomenon?

Kavanagh E. Long Covid brain fog: a neuroinflammation phenomenon? J Neuroinflammation. 2022;19(1):265. doi:10.1186/s12974-022-02665-6.

Neuroinflammation and Long COVID “brain fog”

  • Reviews evidence that persistent cognitive symptoms after COVID are linked to neuroinflammation rather than ongoing viral infection.

  • Highlights roles for microglial activation, cytokine signaling, and disrupted neuroimmune regulation.

  • Proposes that immune-mediated effects on synaptic function and neuronal metabolism can explain attention, memory, and processing-speed deficits.

  • Frames brain fog as a biological inflammatory process, not a psychological or functional complaint.