From Co-Infections to Autoimmune Disease via Hyperactivated Innate Immunity: COVID-19 Autoimmune Coagulopathies, Autoimmune Myocarditis and Multisystem Inflammatory Syndrome in Children
Abstract
1. Introduction
1.1. Conceptual Framework for This Review
1.2. Overview of Innate Immune System Receptors
1.3. TLR and NLR Synergisms and Antagonisms
1.4. Hyperinflammation, Bacterial Co- and Super-Infections and Autoimmunity in COVID-19
2. TLR and NLR Activation in SARS-CoV-2, Severe COVID-19 and Its Autoimmune Complications
2.1. Overview
2.2. Innate Receptor Activation by SARS-CoV-2 and Its Vaccines
2.3. Innate Receptor Activation in Severe COVID-19
2.4. Innate Receptor Activation in MIS-C and KD
2.5. Innate Receptor Activation in Autoimmune Myocarditis
2.6. Innate Receptor Activation in Autoimmune Coagulopathies
2.7. Comparison of Innate Receptor Activation Patterns in COVID-19-Related Diseases
3. Receptor Synergisms May Hyper-Activate Innate Immunity
3.1. Neutrophil and Monocyte Activation in Severe COVID-19
3.2. Synergistic Innate Receptor Activation as a Cause of Cytokine Over-Production and Hyperinflammation in COVID-19
3.3. Innate Receptor Synergies in MIS-C and KD
3.4. Innate Receptor Synergisms in APS
3.5. SARS-CoV-2 Vaccines and Risks of Autoimmune Complications
3.6. Possible Roles of Underlying Diseases That Predispose Severe COVID-19
4. Future Directions for Further Research and Implications for Prevention and Treatment of COVID-19-Associated Autoimmune Diseases
5. Materials and Methods
Funding
Conflicts of Interest
Appendix A
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MIS-C [51] (n > 1116) * | MIS-C [48] (n = 543) | Mild–Moderate COVID-19 [48] (n = 4268) | Severe COVID-19 [49,63] (n = 1190) | |
---|---|---|---|---|
Neutrophilia | 68–90% | 0 = | 33.2–25% = | |
Lymphopenia | 80–95% | 42.5% | 1.5% | 24–45% = |
Diarrhea | 60–100% | 53.2% | 3% | 11.5% |
Nausea/Vomiting | 60–100% | 57.3% | 3% | 17.4% |
Persistent Fever | 100% | 97.6% | 45.8% | 64.3–82.7% = |
Septic Shock | 32–76% | 21.4% (84 ^–90% #) | 0.3% | 13.8% |
Rash | 45–76% | 19.5% | 0.2% | 0 |
D-dimer ↑ | 67–100% | 3% = | 12% = | |
Ferritin ↑ | 55–76% | |||
Fibrinogen ↑ | 80–100% | 0 = | 60% = | |
Troponin ↑ | 50–90% | 2% | ||
Procalcitonin ↑ | 80–95% | |||
C-Reactive Protein ↑ | 90–100% | 12% = | 23.5–58.7% = | |
Thrombocytopenia | 31–80% | 12% = | ||
Met KD Criteria | 22–64% | 0 | 0 | |
Syncope | 0.2% | 0 | ||
Ischemic Stroke | 0.2% | 0.05–1.5% ~ | 16% + |
Neutrophilia, NETs, CIC, Lymphopenia | Cytokine Over-Pro- duction | Virus Infection | Bacterial Infection | Virus– Bacterium Co-Infection | Auto- Antibodies | |
---|---|---|---|---|---|---|
SARS-CoV-2 Vaccination | Extremely Rare | Extremely Rare | Rare | Rare | Extremely Rare | Rare |
Mild COVID-19 | Rare | Rare | Always | Rare | Rare | Rare |
Severe COVID-19 | Frequent | Frequent | Always | Frequent | Frequent | Frequent |
MIS-C | Frequent | Frequent | Always | Frequent | Frequent | Always |
Kawasaki Disease | Frequent | Frequent | Possible | Possible | Unknown | Always |
Autoimmune Myocarditis | Frequent | Frequent | Frequent | Frequent | Often | Always |
COVID-19 Coagulopathies | Frequent | Frequent | Always | Frequent | Frequent | Always |
Anti-Phospholipid Syndrome (APS) | Frequent | Frequent | Frequent | Frequent | Probable | Always |
CL | β2GPI | PT | F VIII | F IX | vWF | PF4 | PDE | PL | Coll | Actin | Myosin | |
---|---|---|---|---|---|---|---|---|---|---|---|---|
Viruses | ||||||||||||
SARS SP | 230 | 235, NOT 230 | 230 | 234 | 230, 233, 234, | 233, 234 | 233, 234 | |||||
SARS-CoV-2 | 230 | 230 | 230, 235 | 230 | 234 | 230, 233, 234, | 233, 234 | 233, 234 | ||||
Adeno | 230 | 230 | 230 | 230 | 230 | |||||||
Infl A | ||||||||||||
Bacteria | ||||||||||||
GAS | 230 | 230 | 230 | 230 | 230 | 230 | 230 | 59, 60, 230 | 59, 60 | |||
E. coli | 230 | 230 | 230 | 230 | ||||||||
Staph | 230 | 230 | ||||||||||
Klebs | 230 | 230 | ||||||||||
Clost. | 230 |
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Root-Bernstein, R. From Co-Infections to Autoimmune Disease via Hyperactivated Innate Immunity: COVID-19 Autoimmune Coagulopathies, Autoimmune Myocarditis and Multisystem Inflammatory Syndrome in Children. Int. J. Mol. Sci. 2023, 24, 3001. https://doi.org/10.3390/ijms24033001
Root-Bernstein R. From Co-Infections to Autoimmune Disease via Hyperactivated Innate Immunity: COVID-19 Autoimmune Coagulopathies, Autoimmune Myocarditis and Multisystem Inflammatory Syndrome in Children. International Journal of Molecular Sciences. 2023; 24(3):3001. https://doi.org/10.3390/ijms24033001
Chicago/Turabian StyleRoot-Bernstein, Robert. 2023. "From Co-Infections to Autoimmune Disease via Hyperactivated Innate Immunity: COVID-19 Autoimmune Coagulopathies, Autoimmune Myocarditis and Multisystem Inflammatory Syndrome in Children" International Journal of Molecular Sciences 24, no. 3: 3001. https://doi.org/10.3390/ijms24033001
APA StyleRoot-Bernstein, R. (2023). From Co-Infections to Autoimmune Disease via Hyperactivated Innate Immunity: COVID-19 Autoimmune Coagulopathies, Autoimmune Myocarditis and Multisystem Inflammatory Syndrome in Children. International Journal of Molecular Sciences, 24(3), 3001. https://doi.org/10.3390/ijms24033001