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Inflammation

PANDAS and PANS: Pathophysiology, Diagnostics and Therapeutic Approaches in Pediatric Autoimmune Neuropsychiatric Disorders – a literature review. March 2025. Journal of Education Health and Sport 79:57830. DOI:10.12775/JEHS.2025.79.57830

• Identifies a subgroup of children with PANS characterized by the triad of PANS symptoms, joint complaints, and family history of autoimmunity (including psoriasis).

• Suggests this subgroup may be at increased risk for inflammatory bowel disease and other immune-mediated disorders. Recommends a low threshold for evaluation of gastrointestinal inflammation using biomarkers such as hemoglobin, CRP, fecal calprotectin, and endoscopy when indicated.

• Reports that PANS symptoms may improve with effective treatment of inflammatory bowel disease.

• Notes high prevalence of joint complaints and autoimmune family history, suggesting shared immune mechanisms with psoriasis and arthritis.

• Study Overview: Large population-based analysis of >56,000 Finnish adolescents in mental health services who received antibiotics.
• Key Finding: Doxycycline use linked to 30–35% lower risk of developing schizophrenia in adulthood vs. other antibiotics.
• Mechanism: May reduce brain inflammation and moderate excessive synaptic pruning, a process tied to schizophrenia.
• Implications: Suggests repurposing doxycycline as potential early preventive intervention for high-risk youth; needs clinical trials to confirm.

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.

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.

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.

Kinderlehrer DA. Inflammation as the Common Pathophysiology Linking Stress, Mental Illness, Autoimmunity and Chronic Disease: Implications for Public Health Policy. J Biomed Res Environ Sci. 2024 Mar 28; 5(3): 242-255. doi: 10.37871/jbres1889, Article ID: JBRES1889, Available at: https://www.jelsciences.com/articles/jbres1889.pdf

• The article discusses the interplay between genetics, epigenetics, stress, trauma, inflammation, mental illness, autoimmunity, and chronic disease.
• While modern medicine has made significant advances in disease care,
  it appears that lifestyle intervention, early childhood intervention, and socioeconomic
  investment and have the potential to make an even greater impact on the mental and
  physical well-being of the population.
• An individual’s genetic makeup influences susceptibility to conditions, but environmental factors like stress and trauma can modify this through epigenetics.
• Chronic stress and trauma can induce epigenetic changes and dysregulate immune responses, leading to inflammation, mental illness, autoimmunity, and chronic disease.
• Lifestyle changes like exercise, diet, and toxin management can reduce inflammation and risks of mental and physical illness. Stress is a key factor and reducing stress through mindfulness, meditation, and exercise can decrease inflammation. Loneliness is a significant stressor and healthy social connections are important.

Vaishnavi S. Transcranial magnetic stimulation for developmental neuropsychiatric disorders with inflammation. Developmental Neuroscience. 2023;45(6):342–348. doi:10.1159/000535103

• Reviews transcranial magnetic stimulation (TMS) as a noninvasive technique that induces electrical changes in the brain via magnetic fields.Describes how repetitive TMS can modulate synaptic and network-level plasticity.

• Notes that inflammation negatively affects synaptic plasticity and that TMS may help address inflammation-related dysfunction.

• Summarizes evidence suggesting TMS may directly downregulate inflammatory processes.

• Highlights potential utility of TMS for neuropsychiatric symptoms in inflammatory neurodevelopmental disorders, including autism, Tourette syndrome, and OCD.

• Emphasizes that TMS is best viewed as a technology platform for modulating dysfunctional brain networks and may expand as understanding of network dysfunction grows

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.

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.

Raposo-Lima, C., Pereira, I.M., Marques, F. et al. Elevated levels of neutrophil gelatinase-associated lipocalin among OCD patients: an exploratory study. BMC Psychiatry 21, 272 (2021). DOI: 10.1186/s12888-021-03289-w

“Although PANDAS might be of relevance for only a minor proportion of OCD cases, this immune/inflammation hypothesis may be significant given the prevalence of OCS among patients with autoimmune diseases [9]…. In conclusion, we herein report differences in NGAL levels among OCD patients compared to healthy controls. We offer additional evidence to the immune dysregulation hypothesis of OCD by reporting elevated levels of NGAL among OCD patients versus healthy controls, with higher differences being found among women”