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Long-COVID may wear out the immune system (Vitamin D might restore it) - May 2025

Long COVID and Biomarker Dysregulation—A Shift Toward Immune Exhaustion?

Medicina 2025, 61(6), 996; https://doi.org/10.3390/medicina61060996

Background: SARS-CoV-2 infection can lead to persistent or newly emerging symptoms lasting for months, a condition known as long COVID (LC). The pathophysiology of LC remains poorly understood, with cytokine dysregulation proposed as a key mechanism, although findings across the studies have been inconsistent.

Patients and methods: We conducted a longitudinal study using the Olink® Target 96 Inflammation Panel to assess cytokines in COVID-19 (COV) patients at three months and six months post-infection. These profiles were compared with those of individuals recovering from other upper respiratory tract infections (non-COV). Additionally, we analyzed differences between individuals with LC and those who recovered from COVID-19. Predictive models for LC at three months and sixth months post-infection were developed using inflammatory markers and relevant clinical cofactors, including gender, age, BMI, hemogram, Β2-microglobulin, D-dimers, LDH, AST, ALT, Ferritin, vitamin D, CRP, and the severity of acute COVID-19 infection as classified by WHO criteria.

Results: We observed a general decline in inflammatory biomarkers in post-COVID-19 patients over time, with only a few cytokines elevated (CCL4 at month 3 and CST5 at month 6) compared to non-COV controls. In LC patients, an early phase of low-grade inflammation transitioned into significant reduction in proinflammatory biomarkers compared to recovered individuals. Rather than indicating immune normalization, this pattern suggests a possible suppression or exhaustion of the immune response in the months following acute infection. Importantly, our predictive modeling demonstrated that this specific cytokine signature, in combination with acute disease severity and clinical cofactors, described well the presence of LC.

Conclusions: Our findings suggest that inflammation-related biomarker dysregulation following acute SARS-CoV-2 infection evolves dynamically over a six-month period. By the sixth month, compared to the third month, the presence of LC is more accurately predicted by a combination of persistent biomarker alteration and the severity of the initial infection, as defined by WHO criteria. This represents a novel insight, as previous studies have primarily associated LC with elevated proinflammatory markers, whereas our results suggest that immune suppression or exhaustion may play a more prominent role in the later stages.
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Immune Exhaustion in Long-COVID and the Therapeutic Potential of Vitamin D Perplexity AI - May 2025

Emerging research reveals that Long-COVID, particularly when symptoms persist beyond three months, is characterized by profound immune system dysregulation that resembles a state of immune exhaustion rather than recovery. This condition involves persistent inflammation, T cell dysfunction, and compromised immune responses that mirror patterns seen in chronic viral infections. Importantly, accumulating evidence suggests that vitamin D deficiency may contribute to this immune dysfunction, while supplementation could potentially restore immune homeostasis and alleviate Long-COVID symptoms.

Immune Exhaustion in Persistent Long-COVID

Characteristics of Immune Dysfunction
Long-COVID patients experiencing symptoms beyond three months demonstrate significant immune system abnormalities that suggest a state of immune exhaustion rather than normal recovery. Research indicates that these individuals exhibit "progressive loss of effector functions and increased expression of inhibitory receptors on immune cells" 19. This immune exhaustion is characterized by the upregulation of checkpoint molecules such as programmed cell death 1 (PD-1), cytotoxic T lymphocyte antigen 4 (CTLA-4), and T cell immunoglobulin and mucin domain protein 3 (TIM-3) on T lymphocytes 19.
Studies reveal that Long-COVID patients display exhausted SARS-CoV-2-specific CD8+ T cells, with this exhaustion being "typically seen in chronic viral infections such as HIV, and means the T cell branch of the immune system stops responding to a virus and no longer kills infected cells" 15. Furthermore, comprehensive immunological profiling shows that patients develop "increased CD8 T-cell senescence and a distinct transcriptional profile within CD4 and CD8 T-cells and monocytes" 2. This dysfunction extends beyond T cells to include persistent activation of monocytes with sustained inflammasome activation and oxidative stress 2.
Temporal Evolution of Immune Dysfunction
The immune dysfunction in Long-COVID appears to evolve dynamically over time, with research showing that "rather than indicating immune normalization, this pattern suggests a possible suppression or exhaustion of the immune response in the months following acute infection" 17. At six months post-infection, patients demonstrate a concerning shift from initial inflammation to what appears to be immune suppression. This temporal pattern reveals that "an early phase of low-grade inflammation transitioned into significant reduction in proinflammatory biomarkers compared to recovered individuals" 17.
The persistence of these immune abnormalities is particularly troubling, as studies document "profound metabolic and immune alterations at the proteomic, cellular, and epigenetic level" approximately four months after initial infection 2. These alterations include enrichment in immature monocytes, elevated arachidonic acid levels, decreased tryptophan, and significant variations in peripheral T-cell frequency and phenotype 2.

Mechanisms of Immune Dysregulation in Long-COVID

Complement System and Thromboinflammation
Recent research has identified the complement system as a key driver of immune dysfunction in Long-COVID. Studies demonstrate that "localized activation of the innate immune defense complement system as a likely culprit that induces thromboinflammation and prevents the restoration of fitness after acute COVID-19" 1. This complement activation creates a pathological feedback loop where "complement and coagulation systems are not only an integral part of the innate immune response but also are connected at several levels in feedforward amplification loops" 1.
The thromboinflammatory process involves complex interactions between complement activation, von Willebrand factor, and coagulation-mediated fibrin formation 1. This mechanism appears particularly relevant to Long-COVID pathogenesis, as it can perpetuate immune dysfunction and prevent normal recovery processes. The severity of Long-COVID symptoms correlates with cytomegalovirus reactivation, suggesting that persistent viral reactivation may drive continued complement activation 1.
Autoimmune and Inflammatory Components
Long-COVID is characterized by significant autoimmune manifestations that contribute to immune exhaustion. Research reveals that patients develop "various autoantibody alterations" with "decreased autoantibodies to the B cell–stimulating C-X-C motif chemokine 13 (CXCL13)" along with "increased interferon signaling" that may contribute to "persistent autoimmune pathologies" 1. These autoimmune features are accompanied by elevated levels of pro-inflammatory cytokines, with studies consistently reporting "elevated human leukocyte antigen (HLA), major histocompatibility complex class II (MHC-II) expression cells, increased exhausted CD4" T cells 19.
The inflammatory profile includes persistent elevation of key cytokines, with "a triad of IL-1β, IL-6, and TNF-α" being consistently associated with Long-COVID 19. Additionally, gene expression analysis reveals upregulation of TNFAIP3 and dysregulation of genes involved in antigen presentation, suggesting ongoing immune activation that fails to resolve normally 19.

Vitamin D and Immune System Modulation

Mechanisms of Immune Regulation
Vitamin D functions as a potent immune system modulator through its action on the vitamin D receptor (VDR), which is "expressed by most cells of the immune system, including regulatory T cells and antigen-presenting cells, such as dendritic cells and macrophages" 12. The active form of vitamin D, 1α,25-dihydroxyvitamin D, can be produced locally by immune cells under specific circumstances, allowing for targeted immune regulation 12.
Vitamin D's immunomodulatory effects are particularly relevant to Long-COVID pathogenesis. The hormone "inhibits cell proliferation and stimulates cell differentiation" while "providing innate immunity support for antimicrobial functions" and "reducing inflammatory activity and the capacity to initiate an adaptive immune response" 7. Specifically, vitamin D "boosts anti-inflammatory cytokine levels (IL-4, IL-5, IL-10, TGF-beta) via stimulating T Helper (Th) 2 cells" while "inhibiting Th 1 and Th 17 cells, proinflammatory cytokines (IL-2, IL-3, IFN-γ, TNF-alpha) production" 7.
Effects on T Cell Function and Exhaustion
Vitamin D demonstrates specific benefits for T cell function that could directly address immune exhaustion in Long-COVID. Research shows that vitamin D supplementation can significantly reduce "CD4 activation (CD4+CD38+HLA-DR+), CD8 activation (CD8+CD38+HLA-DR+), CD4 exhaustion (CD4+CD38+HLA-DR+PD1+), and inflammatory monocytes (CD14+CD16+)" 5. These effects are dose-dependent, with high-dose vitamin D (120,000 IU monthly) showing the greatest improvements in immune function markers 5.
The hormone also promotes the development of regulatory T (Treg) cells, which are crucial for immune homeostasis. Vitamin D "enhances IL-10 secretion by CD4+ T cells" and "increases the frequency of IL-10 producing Treg cells" while promoting "the development of Foxp3+CD4+ T cells" 4. This regulatory effect is particularly important in Long-COVID, where immune dysregulation and autoimmunity are prominent features.

Evidence for Vitamin D Deficiency in Long-COVID

Clinical Associations
Multiple studies have documented a strong association between vitamin D deficiency and Long-COVID development. A comprehensive case-controlled study found that "COVID-19 survivors with long COVID have lower 25(OH) vitamin D levels than matched patients without long COVID (20.1 vs 23.2 ng/mL)" 16 20. This association was particularly pronounced in patients with neurocognitive symptoms, who had significantly lower vitamin D levels (14.6 vs 20.6 ng/mL) compared to those without such symptoms 16.
In patients with persistent vitamin D deficiency (levels <20 ng/mL) both at hospital admission and at six-month follow-up, those affected by Long-COVID had significantly lower vitamin D levels compared to those who recovered (12.7 vs 15.2 ng/mL) 16. Multivariate analysis revealed that "lower 25(OH) vitamin D levels at follow-up were the only variable significantly associated with long COVID" with an odds ratio of 1.09 16 20.
Mechanistic Evidence
The relationship between vitamin D deficiency and Long-COVID appears to be mechanistically grounded rather than merely correlational. A comprehensive review of 58 clinical studies involving more than 14 million COVID-19 patients found that "86% demonstrated that having a higher vitamin D level was associated with less severe COVID-19 symptoms" 8. The researchers concluded that "vitamin D likely acts against COVID-19 by protecting the respiratory system and regulating the innate and adaptive immune system" 8.
Furthermore, research suggests that vitamin D deficiency may "increase risk for and possibly delay recovery from Long COVID" 8. This is supported by evidence that vitamin D supplementation can address key pathophysiological mechanisms underlying Long-COVID, including immune dysfunction, chronic inflammation, and autoimmune manifestations 8.

Therapeutic Potential and Clinical Applications

Evidence from Interventional Studies
While most evidence linking vitamin D to Long-COVID comes from observational studies, interventional research in similar conditions provides valuable insights. Studies in HIV-infected patients, who experience immune exhaustion similar to Long-COVID patients, demonstrate that high-dose vitamin D supplementation (120,000 IU monthly) significantly reduces markers of immune activation and exhaustion 5 13. These improvements include decreases in T-cell activation markers and inflammatory monocyte populations 5.
Additionally, research in otherwise healthy individuals with vitamin D deficiency shows that supplementation can significantly improve fatigue, a cardinal symptom of Long-COVID. A randomized controlled trial found that "vitamin D treatment significantly improved fatigue" with 72% of treated participants reporting improvement compared to 50% in the placebo group 6. The improvement in fatigue scores correlated directly with increases in vitamin D levels 6.
Dosing Considerations and Safety
Evidence suggests that higher doses of vitamin D may be necessary to achieve therapeutic benefits in immune dysfunction. Studies demonstrating significant improvements in immune markers used doses of 120,000 IU monthly, which safely raised serum concentrations to ≥30 ng/mL 5. This dose level appears to be necessary to achieve the immunomodulatory effects that could benefit Long-COVID patients.
Current research is investigating optimal dosing strategies for Long-COVID specifically. A pilot study is examining the effects of vitamin K2 and vitamin D3 supplementation on Long-COVID symptoms and underlying inflammatory processes, though results are pending 9. The study aims to determine whether targeted nutritional interventions can address the persistent inflammation and immune dysfunction characteristic of the condition.

Clinical Implications and Future Directions

Assessment and Monitoring
Given the strong association between vitamin D deficiency and Long-COVID, clinical guidelines should consider routine vitamin D assessment in patients with persistent symptoms. Research suggests that "vitamin D levels should be evaluated in COVID-19 patients after hospital discharge" 16 18 20. This is particularly important given that Long-COVID patients show significantly lower vitamin D levels even months after initial infection, suggesting either ongoing depletion or inadequate repletion.
The evidence also supports monitoring vitamin D levels in relation to specific symptom clusters, as neurocognitive symptoms appear particularly associated with lower vitamin D levels 16. This targeted approach could help identify patients most likely to benefit from supplementation and guide personalized treatment strategies.
Therapeutic Integration
The immunomodulatory effects of vitamin D suggest it could serve as an important adjuvant therapy in Long-COVID management. Research indicates that "high-dose vitamin D supplementation may attenuate immune activation and exhaustion and serve as adjuvant therapy" 5. This approach could be particularly valuable given the limited treatment options currently available for Long-COVID patients.
However, researchers emphasize that "the role of vitamin D supplementation as a preventive strategy of COVID-19 sequelae should be tested in randomized controlled trials" 16 18 20. Such trials are essential to establish definitive therapeutic protocols and determine optimal dosing regimens for Long-COVID prevention and treatment.

Conclusion

The evidence strongly suggests that Long-COVID lasting beyond three months involves significant immune system exhaustion characterized by

  • T cell dysfunction,
  • chronic inflammation,
  • compromised immune responses.

This immune exhaustion resembles patterns seen in chronic viral infections and represents a fundamental departure from normal recovery processes.
Vitamin D deficiency appears to be both a risk factor for Long-COVID development and a potential therapeutic target for addressing the underlying immune dysfunction.
The immunomodulatory properties of vitamin D, particularly its ability to reduce immune activation and exhaustion markers while promoting regulatory T cell function, make it a promising therapeutic intervention for Long-COVID. Current evidence supports routine vitamin D assessment in Long-COVID patients and suggests that high-dose supplementation may help restore immune homeostasis. However, definitive therapeutic recommendations await results from ongoing randomized controlled trials that will establish optimal dosing protocols and confirm clinical efficacy in Long-COVID populations.
Citations:

  1. https://www.science.org/doi/10.1126/science.adn1077
  2. https://www.medrxiv.org/content/10.1101/2025.04.16.25325949v1.full
  3. https://pmc.ncbi.nlm.nih.gov/articles/PMC10219649/
  4. https://pmc.ncbi.nlm.nih.gov/articles/PMC6032242/
  5. https://pmc.ncbi.nlm.nih.gov/articles/PMC6070412/
  6. https://journals.lww.com/md-journal/fulltext/2016/12300/effect_of_vitamin_d3_on_self_perceived_fatiguea.2.aspx
  7. https://www.amhsr.org/articles/vitamin-d-immune-system-and-its-relationship-with-diseases-11204.html
  8. https://www.yalemedicine.org/news/long-covid-treatment-does-your-vitamin-d-level-play-a-role
  9. https://ctv.veeva.com/study/pilot-study-of-vitamin-k2-mk-7-and-vitamin-d3-supplementation-and-the-effects-on-pasc-symptomatolo
  10. https://www.nature.com/articles/s41590-023-01724-6
  11. https://whn.global/covid-19-and-immune-dysregulation-a-summary-and-resource/
  12. https://lpi.oregonstate.edu/mic/vitamins/vitamin-D
  13. https://www.croiconference.org/wp-content/uploads/sites/2/posters/2016/826.pdf
  14. https://pmc.ncbi.nlm.nih.gov/articles/PMC10671780/
  15. https://gladstone.org/news/patients-long-covid-immune-cells-dont-follow-rules
  16. https://academic.oup.com/jcem/article/108/10/e1106/7116659
  17. https://www.mdpi.com/1648-9144/61/6/996
  18. https://www.medscape.com/viewarticle/992013
  19. https://insight.jci.org/articles/view/183810
  20. https://pubmed.ncbi.nlm.nih.gov/37051747/
  21. https://www.mayoclinic.org/diseases-conditions/coronavirus/in-depth/coronavirus-long-term-effects/art-20490351
  22. https://pubmed.ncbi.nlm.nih.gov/39489518/
  23. https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/
  24. https://en.wikipedia.org/wiki/Vitamin_D
  25. https://academic.oup.com/nutritionreviews/article/66/suppl_2/S116/1854987
  26. https://www.sciencedirect.com/science/article/pii/S0002916522037686
  27. https://www.sciencedirect.com/science/article/pii/S0946672X23001542
  28. https://www.mdpi.com/2072-6643/17/2/304
  29. https://pubmed.ncbi.nlm.nih.gov/40090177/
  30. https://pmc.ncbi.nlm.nih.gov/articles/PMC10490318/

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Long-COVID may wear out the immune system (Vitamin D might restore it) - May 2025        
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