Inflammation Sources Registry

1 S100 Proteins / Calprotectin (DAMPs)

1.1 Nunes et al. 2024 — S100-A9 Upregulation in ME/CFS Plasma Proteomics

Full Citation:: Nunes M, Vlok M, Proal A, Kell DB, Pretorius E. Data-independent LC-MS/MS analysis of ME/CFS plasma reveals a dysregulated coagulation system, endothelial dysfunction, downregulation of complement machinery. Cardiovascular Diabetology. 2024;23:260. DOI:: 10.1186/s12933-024-02315-x PMID:: 39014464 Key Findings::

- Significant upregulation of S100-A9 (calprotectin subunit) in ME/CFS plasma
- Dysregulated coagulation system with hyperactivated platelets
- Endothelial dysfunction markers
- Downregulation of complement machinery components at rest
- First data-independent acquisition (DIA) proteomics study in ME/CFS

Conclusion:: ME/CFS involves a pro-inflammatory and pro-thrombotic plasma proteome signature. S100-A9 may serve as biomarker and therapeutic target. Limitations:: Cross-sectional; moderate sample; single cohort; plasma only; no sex-stratified analysis. Certainty:: 0.75/1.0

2 cGAS-STING Pathway (mtDNA Sensing)

2.2 Yan et al. 2026 — cGAS-STING in Disease Pathogenesis

Full Citation:: Yan D, Hu J, Liu Z, Ouyang W. Spotlight on cGAS-STING: role in disease pathogenesis and therapeutic potential. Molecular Biomedicine. 2026;7(1):83. DOI:: 10.1186/s43556-026-00283-2 Key Findings::

- cGAS-STING is central sensor of cytosolic DNA driving type I interferon and NF-κB
- Key node in sterile inflammation; emerging therapeutic target

Conclusion:: cGAS-STING regulates autoimmune and inflammatory disease pathogenesis. Limitations:: Review; no ME/CFS data. Pathway role well-established generally but not in ME/CFS. Certainty:: 0.85/1.0 (general); 0.20/1.0 (ME/CFS-specific)

3 Specialized Pro-Resolving Mediators (SPMs)

3.1 Engert et al. 2026 — Sleep Disturbance Affects Inflammatory Resolution in Long COVID

Full Citation:: Engert LC, Dang R, Daniel S, Bertisch SM, Maley JH, Fong TG, Serhan CN, Mullington JM, Haack M. Sleep disturbance affects inflammatory resolution in Long COVID. Prostaglandins Leukotrienes and Essential Fatty Acids. 2026;204:102728. DOI:: 10.1016/j.plefa.2026.102728 PMID:: 41650882 Key Findings::

- Sleep disturbance promotes pro-inflammatory state in Long COVID
- Sleep disruption dysregulates SPMs (resolvins, protectins, maresins)
- Failed resolution of inflammation as Long COVID mechanism

Conclusion:: Sleep → SPM dysregulation → unresolved inflammation → Long COVID. SPM restoration may be therapeutic. Limitations:: Review/hypothesis; limited direct SPM level data in Long COVID. Certainty:: 0.60/1.0 — Serhan (SPM discoverer) co-author strengthens credibility.

3.2 Rauf et al. 2026 — PASC as Disorder of Impaired Innate Immune Resolution

Full Citation:: Rauf M, Naveed A, Asghar MU. Post-acute sequelae of COVID-19: A disorder of impaired innate immune resolution — A narrative review. Clinical Immunology. 2026;277:110701. DOI:: 10.1016/j.clim.2026.110701 PMID:: 41864480 Key Findings::

- PASC characterized by failed innate immune resolution, not persistent virus
- Chronic activation of TLR, RIG-I, NLR, cGAS-STING, and complement
- Alarmins and reactivated latent viruses sustain chronic inflammation

Conclusion:: Resolution failure model explains PASC; therapeutic focus should restore resolution. Limitations:: Narrative review; no primary data; PASC-specific. Certainty:: 0.65/1.0

3.3 Serhan et al. 2022 — E-Series Resolvin Metabolome and SPMs for Long COVID

Full Citation:: Serhan CN, Libreros S, Nshimiyimana R. E-series resolvin metabolome, biosynthesis and critical role of stereochemistry of specialized pro-resolving mediators (SPMs) in inflammation-resolution. Seminars in Immunology. 2022;59:101597. DOI:: 10.1016/j.smim.2022.101597 Key Findings::

- Detailed biosynthetic pathways of E/D-series resolvins, protectins, maresins
- Stereochemistry critical for SPM bioactivity
- Framework for applying SPM biology to Long COVID

Conclusion:: SPMs are ready for human clinical trials; stereochemistry determines therapeutic activity. Limitations:: Review; no clinical data; biochemistry-focused. Certainty:: 0.85/1.0 — Foundational review from SPM-discovering laboratory.

3.4 Gracia Aznar et al. 2024 — SPM Supplementation in Post-COVID Syndrome

Full Citation:: Gracia Aznar A, Moreno Egea F, Gracia Banzo R, Gutierrez R, Rizo JM, Rodriguez-Ledo P. Pro-Resolving Inflammatory Effects of a Marine Oil Enriched in Specialized Pro-Resolving Mediators (SPMs) Supplement in Patients with Post-COVID Syndrome. Biomedicines. 2024;12(10):2221. DOI:: 10.3390/biomedicines12102221 Key Findings::

- 12-week SPM-enriched marine oil supplementation in Post-COVID Syndrome
- Improvements in inflammatory resolution markers and symptoms

Conclusion:: SPM supplementation shows promise for restoring inflammation resolution in post-viral syndrome. Limitations:: Open-label; no placebo control; moderate sample; PCS-specific. Certainty:: 0.50/1.0

3.5 Klein et al. 2014 — D-Series Resolvins in Fibromyalgia-Like Model

Full Citation:: Klein CP, Sperotto ND, Maciel IS, Leite CE, Souza AH, Campos MM. Effects of D-series resolvins on behavioral and neurochemical changes in a fibromyalgia-like model in mice. Neuropharmacology. 2014;86:57-66. DOI:: 10.1016/j.neuropharm.2014.05.043 PMID:: 24929111 Key Findings::

- AT-RvD1 and RvD2 reversed mechanical allodynia and thermal sensitization in reserpine-induced fibromyalgia-like model
- Repeated AT-RvD1/RvD2 prevented depressive-like behavior
- RvD1 itself was inactive (stereochemistry-dependent)
- SPMs active at pM-nM concentrations

Conclusion:: SPMs reverse pain and comorbid depressive behavior in FM model. Predicts SPM efficacy for overlapping ME/CFS symptom domains. Limitations:: Mouse model; reserpine model may not capture ME/CFS pathophysiology; no fatigue measurement; acute treatment only. Certainty:: 0.65/1.0

4 Lithium and Specialized Pro-Resolving Mediators (SPMs)

4.1 Basselin et al. 2010 — Lithium Increases Brain 17-HDHA (Resolvin Precursor)

Full Citation:: Basselin M, Kim HW, Chen M, Ma K, Rapoport SI, Murphy RC, Farias SE. Lithium modifies brain arachidonic and docosahexaenoic metabolism in rat lipopolysaccharide model of neuroinflammation. Journal of Lipid Research. 2010;51(5):1049-1056. DOI:: 10.1194/jlr.M002469 PMID:: 20040630 Key Findings::

- Lithium increased 17-HDHA (17-hydroxy-DHA) 1.9-fold — the committed precursor for D-series resolvins and protectins
- Lithium increased 5-HETE (×1.8) and 5-oxo-ETE (×4.3) (5-LOX pathway products)
- Lithium increased 15-HETE at high-dose LPS (15-LOX product)
- Lithium prevented LPS-induced increases in PGE2, cPLA2-IV, sPLA2
- Unesterified DHA and DPA unaffected — effect on DHA oxygenation, not substrate release

Conclusion:: Lithium diverts brain ω-3 fatty acid metabolism toward the 17-HDHA → resolvin/protectin pathway while suppressing COX-2/AA cascade. This is the only direct evidence that Li enhances SPM biosynthetic intermediate formation. Limitations:: Rat brain only; therapeutic Li doses (~0.6-0.8 mM); acute LPS model; no ME/CFS data; measured 17-HDHA, not mature SPMs. Certainty:: 0.70/1.0 — single study, no replication for 17-HDHA finding, but consistent with Rapoport lab’s AA cascade program.

4.2 Abe et al. 2025 — Lithium-Releasing Glasses Promote Resolution via GSK3β/CD206

Full Citation:: Abe GL, Ahmed I, Hasan MS, Knowles JC, Coleman NJ. Fast Lithium-Releasing Phosphate Glasses Promote the Resolution of Inflammation. ACS Applied Bio Materials. 2025;8(6):4819-4828. DOI:: 10.1021/acsabm.5c00128 PMID:: 40448634 Key Findings::

- Lithium release from bioactive glasses accelerated resolution of inflammation in macrophages
- Mechanism: GSK3β inhibition + CD206 (M2 marker) upregulation
- Faster Li release → greater anti-inflammatory effect

Conclusion:: Lithium promotes pro-resolving macrophage phenotype via GSK3β inhibition. Supports resolution-enhancing potential. Limitations:: Biomaterials study; no SPM measurements; in vitro only; supra-therapeutic Li concentrations not directly comparable to nM-µM range. Certainty:: 0.50/1.0

4.3 Makola et al. 2020 — Lithium Anti-Inflammatory Gene Regulation in Macrophages

Full Citation:: Makola RT, Du Preez I, Laus MN, Steenkamp V. The Effect of Lithium on Inflammation-Associated Genes in Lipopolysaccharide-Activated Raw 264.7 Macrophages. International Journal of Inflammation. 2020;2020:8340195. DOI:: 10.1155/2020/8340195 PMID:: 32774832 Key Findings::

- Li suppressed LPS-induced NF-κB nuclear translocation
- Reduced iNOS and COX-2 mRNA expression
- Reduced nitric oxide production

Conclusion:: Lithium modulates inflammatory gene expression in macrophages via NF-κB suppression. Limitations:: Macrophage cell line; no resolution-specific endpoints (efferocytosis, SPMs, M2 markers); single Li concentration. Certainty:: 0.55/1.0

4.4 Beurel et al. 2014 — GSK3-Mediated Anti-Inflammatory Mechanism of Lithium

Full Citation:: Beurel E, Jope RS. Inflammation and lithium: clues to mechanisms contributing to suicide-linked traits. Translational Psychiatry. 2014;4:e488. DOI:: 10.1038/tp.2014.129 PMID:: 25514751 Key Findings::

- Li → GSK3 inhibition → ↓IL-6, ↓TNF-α
- Modulated STAT3 signaling
- Identifies GSK3 as central mediator of Li anti-inflammatory effects

Conclusion:: GSK3 is the mechanistic bridge between lithium and cytokine modulation. Establishes the GSK3β→NF-κB→cytokine axis relevant to SPM bridge hypothesis. Limitations:: No resolution endpoints; no lipid mediator measurements; mouse model. Certainty:: 0.65/1.0

4.5 Weerasinghe et al. 2004 — Lithium Does Not Involve LOX/P450 Pathways (Null Result)

Full Citation:: Weerasinghe GR, Rapoport SI, Bosetti F. The effect of chronic lithium on arachidonic acid release and metabolism in rat brain does not involve secretory phospholipase A2 or lipoxygenase/cytochrome P450 pathways. Brain Research Bulletin. 2004;63(6):485-489. DOI:: 10.1016/j.brainresbull.2004.04.003 (Weerasinghe, Rapoport, and Bosetti 2004) Key Findings::

- Li did NOT alter AA release/metabolism through LOX or P450 pathways
- Li effects attributed to cPLA2 inhibition and COX-2 downregulation

Conclusion:: Lithium’s primary mechanism in AA cascade is via cPLA2/COX-2, not direct LOX modulation. Limitations:: Measured bulk AA metabolism, not pathway-specific products; contradicted by Basselin 2010 (specific LOX product increases). Reconciliation: LOX pathway is a minor AA sink whose products rise via redirection, not direct activation. Certainty:: 0.50/1.0

5 HMGB1 (Prototypical DAMP)

5.1 Ibrahim et al. 2026 — HMGB1-Mediated Neuroinflammation

Full Citation:: Ibrahim KN, Wasim R, Rahman E. HMGB1-mediated neuroinflammation: molecular mechanisms and emerging therapeutic approaches. Inflammopharmacology. 2026;34:3085-3108. DOI:: 10.1007/s10787-026-02211-8 Key Findings::

- HMGB1 is central DAMP linking cellular stress to sustained neuroinflammation
- Signals via TLR4, TLR9, and RAGE
- Redox state determines bioactivity (disulfide = pro-inflammatory; reduced = chemotactic)
- Therapeutic approaches: anti-HMGB1 antibodies, Box A antagonist, TLR4 inhibitors

Conclusion:: HMGB1 is key therapeutic target for neuroinflammatory conditions. Limitations:: Review; no ME/CFS-specific data. Certainty:: 0.80/1.0

5.2 Chen et al. 2026 — HMGB1-pCTS-L Axis in Inflammatory Diseases

Full Citation:: Chen W, Li J, Qiang X, Lou L, Zhu CS, Deng M. Pharmacological intervention of the HMGB1-pCTS-L axis to ameliorate inflammatory diseases. Frontiers in Immunology. 2026;17:1843251. DOI:: 10.3389/fimmu.2026.1843251 Key Findings::

- HMGB1 forms complex with cathepsin L (pCTS-L) amplifying inflammation
- Therapeutic targeting of HMGB1-pCTS-L axis ameliorates disease in RA models

Conclusion:: HMGB1-pCTS-L represents a new chronic inflammatory disease target. Limitations:: Preclinical; RA-focused; no ME/CFS data. Certainty:: 0.65/1.0

6 Ferroptosis / Iron Dysregulation

6.1 Mantle et al. 2025 — Overlap of ME/CFS, FM, GWI, Long COVID via Ferroptosis

Full Citation:: Mantle D, Domingo JC, Golomb BA, Castro-Marrero J. Gulf War Illness, Fibromyalgia, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID Overlap: Implications for Future Therapeutic Strategies. Int J Mol Sci. 2025;26(19):9044. DOI:: 10.3390/ijms26199044 Key Findings::

- ME/CFS, FM, GWI, and Long COVID share overlapping pathophysiology
- Central role of mitochondrial dysfunction, oxidative stress, and ferroptosis
- CoQ10 deficiencies and altered redox status identified
- Ferroptosis (iron-dependent lipid peroxidation) implicated

Conclusion:: These are “low-energy associated disorders” with shared oxidative stress/ferroptosis mechanisms. Limitations:: Review; no primary data; overlaps associative not causal. Certainty:: 0.70/1.0

6.2 Hanson et al. 2024 — Iron Dysregulation and Inflammatory Stress Erythropoiesis Predicts Long-Term COVID-19 Outcome (Hanson et al. 2024)

Full Citation:: Hanson AL, Mulè MP, Ruffieux H, et al. Iron dysregulation and inflammatory stress erythropoiesis associates with long-term outcome of COVID-19. Nature Immunology. 2024;25(3):471–482. DOI:: 10.1038/s41590-024-01754-8 PMID:: 38429458 Study Design:: Prospective observational cohort, n=214, 12-month follow-up Key Findings::

- Multivariate signature (unresolving inflammation, anemia, low serum iron, altered iron-homeostasis gene expression, emerging stress erythropoiesis) detected beyond 2 weeks post-onset differentiated PASC vs non-PASC irrespective of acute severity
- Whole-blood heme-metabolism signature at months 1--3 coincided with iron-deficient reticulocytosis
- Single-cell analysis: monocyte iron loading + increased iron demand in proliferating lymphocytes = iron maldistribution
- Lymphopenia and low dendritic cell numbers persisted in PASC group

Conclusion:: Defects in iron homeostasis, dysregulated erythropoiesis and immune dysfunction contribute to inefficient oxygen transport, inflammatory disequilibrium and persisting symptomatology. May be therapeutically tractable. Limitations:: Single country; no pre-pandemic baseline; no direct ME/CFS comparator. ME/CFS Relevance:: Primary evidence that post-viral iron dysregulation is not just an acute-phase epiphenomenon but a persistent driver of chronic symptoms. The monocyte-vs-lymphocyte iron maldistribution model is novel and may apply to other post-infectious fatigue syndromes. Certainty:: 0.82/1.0 (Nature Immunology; prospective; n=214; single-cell + bulk transcriptomics; Drakesmith/Hal Smith labs)

6.3 Kavyani et al. 2023 — Hepcidin Decreased in ME/CFS: First Report (Kavyani et al. 2024)

Full Citation:: Kavyani B, Ahn SB, Missailidis D, et al. Dysregulation of the Kynurenine Pathway, Cytokine Expression Pattern, and Proteomics Profile Link to Symptomology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Molecular Neurobiology. 2024;61(7):3771–3787. DOI:: 10.1007/s12035-023-03784-z PMID:: 38015302 Key Findings::

- First assessment of hepcidin in ME/CFS: plasma hepcidin decreased nearly by half vs healthy controls
- Enhanced production of kynurenine correlated with symptom severity
- Lower levels of downstream KP metabolites 3-HK, 3-HAA, QUIN, PIC -- could negatively impact cellular energetics
- 5 of 7 most significantly modulated plasma proteins had roles in maintaining gut health

Conclusion:: Low hepcidin may reflect systemic low iron levels or ongoing hypoxia. Novel link: iron regulation (hepcidin) co-occurs with KP dysregulation and gut-derived protein changes in ME/CFS. Limitations:: Single-center; small sample; first report of hepcidin – needs replication; cross-sectional. ME/CFS Relevance:: The low hepcidin finding is paradoxical relative to classic inflammatory anemia (where IL-6 drives hepcidin up). Suggests ME/CFS iron dysregulation differs from simple ACD/AI. Could represent chronic hypoxia-driven hepcidin suppression or compensatory iron mobilization attempt. Certainty:: 0.65/1.0

6.4 Sonnweber et al. 2022 — Persistent Iron Dyshomeostasis After COVID-19 (CovILD) (Sonnweber et al. 2022)

Full Citation:: Sonnweber T, Grubwieser P, Sahanic S, et al. The Impact of Iron Dyshomeostasis and Anaemia on Long-Term Pulmonary Recovery and Persisting Symptom Burden after COVID-19. Metabolites. 2022;12(6):546. DOI:: 10.3390/metabo12060546 PMID:: 35736479 Study Design:: Prospective multicentre observational cohort, n=108, 60/100/180/360 day follow-up Key Findings::

- At 60 days post-COVID: hyperferritinaemia 35%, iron deficiency 24%, anaemia 9%
- Anaemia of inflammation (AI) predominant at early follow-up; shifted to IDA + mixed IDA/AI by 360 days
- Prevalence of anaemia decreased significantly over time but iron dyshomeostasis remained frequent
- Neither iron dyshomeostasis nor anaemia related to persisting structural lung impairment
- Both iron dyshomeostasis and anaemia associated with impaired stress resilience at long-term follow-up

Conclusion:: Iron dyshomeostasis and anaemia are frequent after COVID-19 and contribute to long-term symptomatic outcome independent of pulmonary damage. Limitations:: 75% had severe acute disease (may overrepresent); single country (Austria); stress resilience is subjective. ME/CFS Relevance:: Demonstrates iron dyshomeostasis persists up to 1 year post-COVID. The shift from AI to IDA suggests dynamic iron compartment changes over time. Weiss lab (Christian Doppler Lab for Iron Metabolism) – high iron biology expertise. Certainty:: 0.72/1.0

6.5 Kronstein-Wiedemann et al. 2024 — Long COVID Impaired RBC Function (Kronstein-Wiedemann et al. 2024)

Full Citation:: Kronstein-Wiedemann R, Tausche K, Kolditz M, et al. Long-COVID is Associated with Impaired Red Blood Cell Function. Hormone and Metabolic Research. 2024;56(4):318–323. DOI:: 10.1055/a-2186-8108 PMID:: 37890507 Key Findings::

- Long-COVID patients showed impaired oxygen binding to hemoglobin with concomitant increase in carbon monoxide binding
- Decreased plasma iron concentration and transferrin saturation
- Mean corpuscular hemoglobin (MCH) elevated, suggesting compensatory mechanism
- Base excess and bicarbonate values significantly lower (despite normal pH)
- Reduced lymphocyte levels

Conclusion:: Impaired erythrocyte functionality in Long-COVID leads to diminished oxygen supply – potential explanation for CFS, dyspnea and anemia. Limitations:: Small sample (>20 LC); cross-sectional; no pre-COVID baseline; mechanism unclear. ME/CFS Relevance:: Direct evidence for RBC-level oxygen transport defect in post-viral fatigue. Not described in ME/CFS literature – potentially LC-specific or underexamined in ME/CFS. Certainty:: 0.65/1.0

6.6 Kedor et al. 2022 — Post-COVID CFS vs Classic ME/CFS: Ferritin Distinguishes (Kedor et al. 2022)

Full Citation:: Kedor C, Freitag H, Meyer-Arndt L, et al. A prospective observational study of post-COVID-19 chronic fatigue syndrome following the first pandemic wave in Germany and biomarkers associated with symptom severity. Nature Communications. 2022;13(1):5104. DOI:: 10.1038/s41467-022-32507-6 PMID:: 36042189 Study Design:: Prospective observational, n=42 post-COVID fatigue + n=19 pre-pandemic ME/CFS comparator Key Findings::

- 19/42 post-COVID patients met CCC for ME/CFS
- Disease severity and symptom burden similar between post-COVID ME/CFS and classic ME/CFS
- Hand grip strength diminished in most patients
- Hand grip strength associated with ferritin in post-COVID ME/CFS subgroup (but not hemoglobin alone)
- Ferritin distinguished post-COVID ME/CFS vs post-COVID-without-ME/CFS

Conclusion:: Post-COVID ME/CFS is clinically similar to classic ME/CFS. Ferritin may serve as a biomarker distinguishing ME/CFS from non-ME/CFS fatigue post-COVID. Limitations:: Modest sample; single wave (ancestral strain); no pre-pandemic ferritin baselines. ME/CFS Relevance:: First direct comparative study from Scheibenbogen group. Ferritin as biomarker of post-infectious ME/CFS phenotype. Certainty:: 0.75/1.0

6.7 Gietl et al. 2024 — Hepcidin and Iron Recovery After COVID-19 (Gietl et al. 2024)

Full Citation:: Gietl M, Burkert F, Hofer S, et al. Laboratory parameters related to disease severity and physical performance after reconvalescence of acute COVID-19 infection. Scientific Reports. 2024;14(1):10388. DOI:: 10.1038/s41598-024-57448-6 PMID:: 38710760 Study Design:: Prospective observational, n=34, 12-month follow-up Key Findings::

- Fully recovered patients (ECOG 0) had higher iron parameters (ferritin, hepcidin, transferrin) at 12 months vs those with restricted work ability
- Kynurenine/tryptophan ratio and Phe/Tyr ratio still exceeding 95th percentile of healthy controls in ~2/3 of cohort at 12 months
- Lower tryptophan associated with B vitamin availability
- Women more frequently affected by long-term symptoms

Conclusion:: Persistent inflammation-mediated biochemical changes (KP activation, iron dysregulation) are related to long COVID symptoms. Adequate hepcidin recovery may be protective. Limitations:: Small n (34); single center; early 2020 cohort (ancestral strain). ME/CFS Relevance:: Higher hepcidin in recovered patients suggests hepcidin adequacy may be protective against chronic symptoms. Contrast with Kavyani2023 where ME/CFS patients had low hepcidin. Certainty:: 0.68/1.0

6.8 Yamamoto et al. 2023 — Serum Ferritin Predicts ME/CFS in Long COVID (Yamamoto et al. 2023)

Full Citation:: Yamamoto Y, Otsuka Y, Tokumasu K, et al. Utility of Serum Ferritin for Predicting Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in Patients with Long COVID. Journal of Clinical Medicine. 2023;12(14):4737. DOI:: 10.3390/jcm12144737 PMID:: 37510852 Study Design:: Retrospective observational, n=234 long COVID outpatients (Okayama, Japan) Key Findings::

- 21.4% met ME/CFS criteria; ME/CFS group had highest FAS, EuroQol, and SDS scores
- ME/CFS group: ferritin 193.0 µg/L (IQR 58.8--353.8) vs non-ME/CFS 98.2 µg/L (40.4--251.5), p $<$ 0.05
- Ferritin correlated with FAS (r=0.328) and SDS scores
- Ferritin elevation prominent in female patients
- ME/CFS group had higher TSH but lower growth hormone; IGF-I inversely correlated with ferritin (r=-0.328)

Conclusion:: Serum ferritin is a possible predictor of post-COVID ME/CFS, especially in female patients. May reflect ongoing inflammation rather than iron overload per se. Limitations:: Retrospective; single center; Japanese cohort; no pre-COVID baseline iron panels. ME/CFS Relevance:: First study proposing ferritin as clinical predictor for post-COVID ME/CFS development. Supports ferritin as cross-condition marker for post-infectious ME/CFS phenotype. Certainty:: 0.60/1.0

6.9 Morita et al. 2024 — ME/CFS Prevalence Varies by SARS-CoV-2 Variant (Morita2024ME?)-CFSphase

Full Citation:: Morita S, Tokumasu K, Otsuka Y, et al. Phase-dependent trends in the prevalence of myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) related to long COVID. PLoS One. 2024;19(12):e0315385. DOI:: 10.1371/journal.pone.0315385 PMID:: 39652555 Study Design:: Retrospective, n=739 long COVID patients, Feb 2021–Jul 2023 Key Findings::

- ME/CFS prevalence 8.4% overall (62/739); decreased from 23.9% (Preceding) → 13.7% (Delta) → 3.3% (Omicron)
- Serum ferritin significantly higher in female ME/CFS patients infected in Preceding period
- Brain fog increased across phases: 22.2% → 47.9% → 81.3%
- Factors related to ME/CFS: severe acute illness, smoking, alcohol, fewer vaccinations

Conclusion:: ME/CFS triggered by long COVID shows variant-dependent trends – decreasing prevalence but increasing brain fog proportion. Limitations:: Retrospective; single Japanese center; dominated by ancestral and Delta waves (before Omicron); ferritin only measured in subset. ME/CFS Relevance:: Ferritin elevation phase-dependent. Suggests ferritin may be a better marker for post-infectious ME/CFS from ancestral strains than later variants. Brain fog divergence from fatigue deserves attention. Certainty:: 0.55/1.0

6.10 Ruscitti et al. 2023 — Hyperferritinemic Syndrome Hypothesis for Post-COVID ME/CFS (Ruscitti, Ursini, and Shoenfeld 2023)

Full Citation:: Ruscitti P, Ursini F, Shoenfeld Y. Ferritin and myalgic encephalomyelitis/chronic fatigue syndrome in post COVID-19, an unexpected facet of the hyperferritinemic syndrome? Journal of Psychosomatic Research. 2023;169:111231. DOI:: 10.1016/j.jpsychores.2023.111231 PMID:: 36959046 Key Findings::

- Hypothesis: post-COVID ME/CFS may represent facet of hyperferritinemic syndrome
- Ferritin as both inflammatory marker and potential pathogenic mediator
- Macrophage iron sequestration as mechanism linking inflammation to chronic fatigue

Conclusion:: Letter/commentary format; hypothesis-generating. Ferritin elevation may not be innocent bystander but active contributor. Limitations:: No primary data; letter format; hypothesis untested. ME/CFS Relevance:: The concept that ferritin is not just a biomarker but part of the pathogenic mechanism (through macrophage iron sequestration and ferroptosis) is important for therapeutic decision-making. Certainty:: 0.35/1.0

6.11 Sousa et al. 2023 — Ferroptosis as Mechanism for Neuropsychiatric Post-COVID Syndrome (Sousa, Yehia, and Abulseoud 2023)

Full Citation:: Sousa RAL, Yehia A, Abulseoud OA. Attenuation of ferroptosis as a potential therapeutic target for neuropsychiatric manifestations of post-COVID syndrome. Frontiers in Neuroscience. 2023;17:1237153. DOI:: 10.3389/fnins.2023.1237153 PMID:: 37554293 Key Findings::

- COVID-19 cytokine storm enhances pro-inflammatory cytokines and immune-cell hyper-activation → iron dysregulation
- Severe COVID-19: iron overload as main feature of pathogenesis
- High ferritin = well-known inflammatory and iron overload biomarker
- Lipid peroxidation biomarkers elevated + GPX4 inactivation in COVID-19 patients
- Ferroptosis (iron-dependent lipid peroxidation + GPX4 inactivation) proposed as mechanism behind post-COVID neuropsychiatric deficits

Conclusion:: Ferroptosis is a testable mechanism for post-COVID cognitive and psychiatric symptoms. Limitations:: Review article; no primary data; mechanistic extrapolation from acute to post-acute. ME/CFS Relevance:: Ferroptosis as shared mechanism between LC and ME/CFS (Mantle2025FerroptosisOverlap). Iron dysregulation creates permissive environment for ferroptotic cell death in both conditions. Certainty:: 0.55/1.0

6.14 Hadidchi et al. 2025 — CFS/ME Risk After COVID-19 (Hadidchi et al. 2025)

Full Citation:: Hadidchi R, Patel B, Madan J, et al. Elevated risk of new-onset chronic fatigue syndrome/myalgic encephalomyelitis up to four years after SARS-CoV-2 infection. Journal of Translational Medicine. 2025;23(1):815. DOI:: 10.1186/s12967-025-06625-w PMID:: 40702518 PMCID:: PMC12288244 Study Design:: Retrospective cohort, n=147,377, Montefiore Health System, 4-year follow-up Research Stream:: hadidchi2025-cfs-me-4yrs-post-covid Key Findings::

- HR 1.46 (hospitalized) and 1.56 (non-hospitalized) for new-onset CFS/ME vs COVID-negative controls
- Females, liver disease, autoimmune disorders, anxiety disorders at higher risk
- Re-infection NOT associated with increased CFS/ME risk
- None of the acute blood biomarkers (ferritin, D-dimer, LDH, CRP, etc.) associated with future CFS/ME risk
- COVID-19 vaccination in initial rollout associated with increased CFS/ME risk

Conclusion:: SARS-CoV-2 infection increases CFS/ME risk independent of hospitalization severity, with risk persisting up to 4 years. Acute-phase biomarkers including ferritin do NOT predict who will develop CFS/ME — timing of measurement matters critically. First large-cohort study to show sustained 4-year risk horizon. Limitations:: Retrospective; EHR-based diagnosis (underascertainment); single US health system (Montefiore, Bronx); vaccination finding confounded by era. Certainty:: 0.75/1.0

6.15 RECOVER 2025 — Post-COVID ME/CFS Incidence (NIH RECOVER-Adult) (Jason et al. 2025)

Full Citation:: Jason LA, Dorri JA, Natelson BH, Bateman L, Vernon SD. Incidence and Prevalence of Post-COVID-19 Myalgic Encephalomyelitis: A RECOVER-Adult Study. Journal of General Internal Medicine. 2025. DOI:: 10.1007/s11606-024-09290-9 PMID:: 39804551 PMCID:: PMC11968624 Study Design:: Prospective observational cohort, n=11,785, NIH RECOVER consortium Research Stream:: hadidchi2025-cfs-me-4yrs-post-covid Key Findings::

- Post-COVID ME/CFS incidence 2.8-fold higher vs uninfected controls
- Largest US national post-COVID ME/CFS incidence estimate
- Used IOM-2015 criteria for ME/CFS classification

Conclusion:: SARS-CoV-2 infection substantially increases risk of developing ME/CFS, confirming Hadidchi 2025 in a national prospective cohort with formal ME/CFS criteria. Limitations:: Self-reported symptom criteria; selection bias toward healthcare-seeking population. Certainty:: 0.78/1.0

6.16 Unger et al. 2024 — ME/CFS After SARS-CoV-2 (INSPIRE) (Unger et al. 2024)

Full Citation:: Unger ER, Lin J-MS, Wisk LE, et al. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome After SARS-CoV-2 Infection. JAMA Network Open. 2024;7(7):e2423555. DOI:: 10.1001/jamanetworkopen.2024.23555 PMID:: 39046739 PMCID:: PMC11270135 Study Design:: Prospective cohort, n=4,376, 8 US sites, CDC INSPIRE study Research Stream:: hadidchi2025-cfs-me-4yrs-post-covid Key Findings::

- Post-COVID patients assessed for ME/CFS by IOM-2015 criteria at 6+ months
- Significant proportion met ME/CFS symptom criteria
- CDC-led, multicenter, prospective replication of post-COVID ME/CFS

Conclusion:: Prospective symptom assessment confirms elevated post-COVID ME/CFS risk in a large, geographically diverse US cohort. Complements EHR-based studies (Hadidchi, Vu) with direct symptom measurement. Limitations:: Self-reported symptoms; no pre-COVID baseline; follow-up started at 6 months. Certainty:: 0.78/1.0

6.17 Vu et al. 2024 — Post-COVID Fatiguing Illness Incidence (Vu et al. 2024)

Full Citation:: Vu QM, Fitzpatrick AL, Cope JR, et al. Estimates of Incidence and Predictors of Fatiguing Illness after SARS-CoV-2 Infection. Emerging Infectious Diseases. 2024;30(3):539–547. DOI:: 10.3201/eid3003.231194 PMID:: 38407166 PMCID:: PMC10902536 Study Design:: Retrospective matched cohort, n=4,589 COVID + 9,022 controls, median 11.4mo follow-up Research Stream:: hadidchi2025-cfs-me-4yrs-post-covid Key Findings::

- COVID-19 associated with significantly elevated incidence of post-COVID fatigue and chronic fatigue vs matched controls
- Incidence rates quantified with confidence intervals
- CDC-led EHR analysis using ICD codes

Conclusion:: Post-COVID fatigue is a measurable, elevated epidemiological signal in EHR data. Supports Hadidchi 2025 direction but with fatigue outcome (not ME/CFS-specific). Limitations:: Fatigue outcome via ICD codes (not ME/CFS); pre-Omicron era; single healthcare system. Certainty:: 0.68/1.0 (population-weighted: 0.85 × 0.68 = 0.58)

6.18 Cornelissen et al. 2024 — Post-COVID Fatigue Clusters (P4O2) (Cornelissen et al. 2024)

Full Citation:: Cornelissen MEB, Bloemsma LD, Vaes AW, et al. Fatigue and symptom-based clusters in post COVID-19 patients: a multicentre, prospective, observational cohort study. Journal of Translational Medicine. 2024;22(1):191. DOI:: 10.1186/s12967-024-04979-1 PMID:: 38383493 PMCID:: PMC10880228 Study Design:: Prospective multicentre cohort, Netherlands (P4O2 consortium) Research Stream:: hadidchi2025-cfs-me-4yrs-post-covid Key Findings::

- ME/CFS-like cluster identified among post-COVID patients, distinct from other fatigue clusters
- Substantial symptom overlap between post-COVID ME/CFS cluster and reference ME/CFS cohort
- Cluster analysis supports ME/CFS as a distinct post-COVID phenotype

Conclusion:: Not all post-COVID fatigue is identical — an ME/CFS cluster is distinguishable. Supports epidemiological separation of post-COVID ME/CFS from generic post-COVID fatigue. Limitations:: Questionnaire-based; cluster methodology limits direct incidence estimates. Certainty:: 0.65/1.0

6.19 Tack et al. 2026 — ME/CFS Incidence in Hospital Employees (Tack et al. 2026)

Full Citation:: Tack M, Gruber R, Betting L, et al. Assessment and Incidence Determination of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Following a SARS-CoV-2 Infection in a Prospective Cohort of Hospital Employees. Medicina (Kaunas). 2026;62(3):480. DOI:: 10.3390/medicina62030480 PMID:: 41901562 PMCID:: PMC13027803 Study Design:: Prospective cohort, n=221 hospital employees, clinical assessment with CCC Research Stream:: hadidchi2025-cfs-me-4yrs-post-covid Key Findings::

- 11.8% (CI95% 7.8--16.8) persistent fatigue; 3.2% (CI95% 1.3--6.4) diagnosed with ME/CFS by CCC
- GPCR autoantibodies in 66.6% (12/18), possible EBV reactivation in 86.7% (13/15)
- Coagulation parameters suggesting inflammation in 38.9%
- Demonstrates diagnostic pathway for post-COVID ME/CFS in occupational health setting

Conclusion:: Lower-bound incidence estimate of 3.2% post-COVID ME/CFS using CCC criteria with clinical assessment. GPCR autoantibodies and EBV reactivation are common in post-COVID ME/CFS. Limitations:: Small sample (7 ME/CFS cases); single hospital; selection bias (only those reporting fatigue were assessed). Certainty:: 0.55/1.0

6.20 Moldofsky and Patcai 2011 — Chronic Post-SARS Syndrome (Moldofsky and Patcai 2011)

Full Citation:: Moldofsky H, Patcai J. Chronic widespread musculoskeletal pain, fatigue, depression and disordered sleep in chronic post-SARS syndrome; a case-controlled study. BMC Neurology. 2011;11:37. DOI:: 10.1186/1471-2377-11-37 PMID:: 21435231 Study Design:: Case-control study, n=22 post-SARS (Toronto 2003), 7 fibromyalgia, 21 healthy controls, 1–3 years post-infection Research Stream:: hadidchi2025-cfs-me-4yrs-post-covid Key Findings::

- Chronic widespread pain, fatigue, depression, disordered sleep in post-SARS patients
- Alpha-wave intrusion during NREM sleep — identical EEG pattern to fibromyalgia
- Establishes historical precedent: coronavirus infection (SARS-CoV-1) causes chronic post-infectious fatigue/pain syndrome lasting years

Conclusion:: SARS-CoV-1 triggered a post-infectious syndrome resembling fibromyalgia/ME/CFS. Directly foreshadows post-COVID ME/CFS (SARS-CoV-2) and supports the post-coronavirus etiology model underlying Hadidchi 2025. Limitations:: Very small n (22); historical controls; no formal ME/CFS diagnosis (fibromyalgia framework). Certainty:: 0.50/1.0 (population-weighted: 0.85 × 0.50 = 0.43)

6.21 Poomkudy et al. 2024 — Joint Flexibility and ME/CFS After Mononucleosis (Poomkudy et al. 2024)

Full Citation:: Poomkudy JT, Torres C, Jason LA, Fishbein J, Katz BZ. Joint Flexibility and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome After Mononucleosis. Clinical Therapeutics. 2024;46(3):285–288. DOI:: 10.1016/j.clinthera.2023.12.011 PMID:: 38242746 PMCID:: PMC11009060 Study Design:: Prospective cohort of adolescents with infectious mononucleosis (EBV) Research Stream:: hadidchi2025-cfs-me-4yrs-post-covid Key Findings::

- Joint hypermobility identified as potential risk factor for ME/CFS after EBV infection
- Extends Katz 2009 EBV→ME/CFS prospective cohort findings
- Connective tissue phenotype may predispose to post-infectious ME/CFS

Conclusion:: EBV-triggered ME/CFS provides historical post-infectious precedent (pre-COVID baseline) against which post-COVID ME/CFS risk can be compared. Joint hypermobility identified as an additional risk modifier. Limitations:: Small sample; secondary analysis from a larger study. Certainty:: 0.45/1.0

6.22 Baklund et al. 2021 — Ferritin Elevated in ME/CFS vs Healthy Donors (Baklund et al. 2021)

Full Citation:: Baklund IH, Dammen T, Moum TÅ, et al. Evaluating Routine Blood Tests According to Clinical Symptoms and Diagnostic Criteria in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Journal of Clinical Medicine. 2021;10(14):3105. DOI:: 10.3390/jcm10143105 PMID:: 34300271 Study Design:: Cross-sectional, n=149 ME/CFS vs 264 healthy blood-donor controls Key Findings::

- ME/CFS patients: higher ferritin (mean diff +28.13 µg/L, 95% CI -1.41 to 57.67)
- Higher sedimentation rate, leukocytes, lymphocytes, neutrophils, monocytes
- Lower creatine kinase and creatinine
- Vitamin B12 higher in patients (mean diff +83.43)

Conclusion:: Routine labs show subtle but statistically significant differences between ME/CFS and healthy controls, including elevated ferritin and leukocyte counts. Low CK may suggest muscle damage/metabolic abnormalities. Limitations:: Blood-donor controls (healthier than general population – may inflate effect sizes); Canadian criteria; cross-sectional; Norway only. ME/CFS Relevance:: Population-level evidence for ferritin elevation as consistent feature of ME/CFS. Note: elevated ferritin + low CK is a distinctive pattern not seen in classic inflammatory states where CK is usually normal. Certainty:: 0.55/1.0

6.23 Li et al. 2021 — P2RX7 Regulates Acute Sickness Response

Full Citation:: Li H, Cvejic E, Gu B, Vollmer-Conna U, Hickie I, Wakefield D, Davenport T, Wiley J, Lloyd AR. Regulation of the Acute Sickness Response by the P2RX7 Receptor. J Infect Dis. 2021;224(5):874-884. DOI:: 10.1093/infdis/jiab027 Key Findings::

- P2RX7 is ATP-gated cationic pore regulating NLRP3 inflammasome
- Genetic variation in P2RX7 associated with altered sickness response intensity
- Bridges peripheral inflammation to central symptoms (fatigue, mood)
- Prospective infection cohort (DIOS study)

Conclusion:: P2RX7 is key regulator of the acute-to-chronic sickness response transition. Limitations:: Acute infection model; genetic association; moderate effect sizes. Certainty:: 0.70/1.0

7 Complement System (Exercise-Induced Activation)

7.1 Polli et al. 2019 — Complement and Elastase Activation After Exercise in ME/CFS

Full Citation:: Polli A, Van Oosterwijck J, Meeus M, Lambrecht L, Nijs J. Exercise-induced hyperalgesia, complement system and elastase activation in ME/CFS. Scand J Pain. 2019;19(4):693-704. DOI:: 10.1515/sjpain-2019-0058 Key Findings::

- Complement activation occurs after exercise in ME/CFS
- Neutrophil elastase activation accompanies complement activation
- Complement correlates with exercise-induced hyperalgesia
- Links immune activation to post-exertional pain worsening

Conclusion:: Complement and neutrophil activation contribute to post-exertional symptom worsening in ME/CFS. Limitations:: Secondary analysis; small sample; exercise challenge model. Certainty:: 0.60/1.0

8 ER Stress / Unfolded Protein Response (UPR)

8.1 Kawano et al. 2023 — ER Proteostasis Regulators Control Sleep Cell-Non-Autonomously

Full Citation:: Kawano T, Kashiwagi M, Kanuka M, Chen CK, Yasugaki S, Hatori S, Miyazaki S, Tanaka K, Fujita H, Nakajima T, Yanagisawa M, Nakagawa Y, Hayashi Y. ER proteostasis regulators cell-non-autonomously control sleep. Cell Reports. 2023;42(3):112267. DOI:: 10.1016/j.celrep.2023.112267 Key Findings::

- ERAD components (SEL-1, SEL-11) regulate sleep from peripheral non-neuronal tissues
- ER stress/UPR machinery generates systemic sleep-regulating signals
- First direct mechanistic link between ER proteostasis and sleep

Conclusion:: Cellular stress in peripheral tissues controls sleep via UPR signaling. Limitations:: C. elegans model; invertebrate; no ME/CFS or mammalian data. Certainty:: 0.55/1.0 — Elegant genetics; conserved mechanism; substantial species gap.

9 Neurogenic Inflammation (Substance P, CGRP, Mast Cells)

9.1 Theoharides et al. 2019 — Mast Cells, Neuroinflammation and Pain in FM

Full Citation:: Theoharides TC, Tsilioni I, Bawazeer M. Mast Cells, Neuroinflammation and Pain in Fibromyalgia Syndrome. Front Cell Neurosci. 2019;13:353. DOI:: 10.3389/fncel.2019.00353 Key Findings::

- Increased serum substance P (SP) and hemokinin-1 in FMS patients
- SP activates mast cells via MRGPRX2 (non-IgE pathway)
- Mast cell-derived mediators sustain neurogenic inflammation
- Thalamic mast cell involvement in central sensitization

Conclusion:: Mast cell-neural interactions via SP drive neuroinflammation in FM. Limitations:: FM-focused (not ME/CFS); review with some primary data. Certainty:: 0.65/1.0

9.2 Pintér et al. 2023 — Triple Function of Capsaicin-Sensitive Sensory Neurons

Full Citation:: Pintér E, Helyes Z, Szőke É, Bölcskei K, Kecskés A, Pethő G. The triple function of the capsaicin-sensitive sensory neurons. Temperature. 2023;10(1):13-34. DOI:: 10.1080/23328940.2022.2147388 Key Findings::

- TRPV1+ sensory neurons have sensory, efferent (neurogenic inflammation), and homeostatic functions
- CGRP and substance P release causes vasodilation, plasma extravasation, mast cell activation
- Neurogenic inflammation contributes to numerous chronic conditions

Conclusion:: Capsaicin-sensitive nerves coordinate inflammatory and homeostatic responses; dysfunction underlies chronic inflammation. Limitations:: Review; no ME/CFS-specific data. Certainty:: 0.80/1.0

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