COVID-19 can reactivate viruses that had previously remained inactive in the body for years. Reactivation is particularly common among viruses belonging to the Herpesviridae and Anelloviridae families. Moreover, the more severe the course of COVID-19, the more pronounced the reactivation of chronic viruses tends to be.
Chronic viral infections may contribute to COVID-19’s immunological consequences. For example, reactivation of Herpesviridae, including Epstein–Barr virus (EBV), cytomegalovirus (CMV), and human herpesviruses 6 and 8, has been associated with poorer clinical outcomes in patients with COVID-19.
American scientists analyzed data from more than 1,150 patients hospitalized with COVID-19 who were followed during the disease and for one year after recovery. The researchers examined nasal swabs, peripheral blood cells, and respiratory fluid samples. Unlike many previous studies, they assessed reactivation not only by antibody responses but also by detecting viral RNA produced during viral replication.
During acute COVID-19, chronic viral reactivation was associated with disease severity and outcomes, as well as immune response characteristics and patient demographics. This association also persisted in patients with Long COVID.
Viruses Reactivate at Different Stages of COVID-19
During acute COVID-19, researchers detected reactivation of at least one virus in nearly 48% of patients. Herpesviruses and viruses from the Anelloviridae family were detected most frequently. Different viruses reactivated at different stages:
- EBV – predominantly early in the disease;
- herpes simplex virus type 1 (HSV1) and CMV – at later stages;
- Anelloviridae activity remained relatively stable during the first 20 days after hospitalization.
Among most patients with reactivation – approximately 68% – only one virus was detected. Simultaneous reactivation of multiple viruses was uncommon.
Herpesviridae and Anelloviridae Reactivation Is Associated With Severe COVID-19
In patients with severe COVID-19, detection of CMV, EBV, and HSV1 was associated with increased mortality over the following year.
Viral reactivation was associated with various complications:
- CMV detected in nasal swabs was associated with pneumothorax, whereas CMV detected in peripheral blood was associated with bacteremia, pulmonary vascular injury, renal complications, acute circulatory failure, and stroke;
- EBV detected in nasal swabs was associated with transfer to the intensive care unit and acute circulatory failure, whereas EBV detected in peripheral blood was associated with liver failure and coinfections;
- HSV1 detected in nasal swabs was associated with venous thromboembolism and acute circulatory failure, although the virus was detected less frequently in patients with liver disease.
Anelloviridae were more frequently detected in older patients and in those receiving immunosuppressive drugs, but the association with severe COVID-19 remained independent of these factors.
Changes in the Immune Response accompany Viral Reactivation.
Patients with active EBV and CMV had elevated antibody levels against these viruses. At the same time, HSV1 detection in nasal swabs was more frequently accompanied by viral proteins in the blood.
Changes in immune cell composition accompanied herpesvirus reactivation:
- EBV was associated with an increased proportion of plasmablasts;
- CMV was associated with an increased proportion of CD4 and CD8 central memory T cells and a decreased proportion of CD4 effector memory T cells with low CD27 expression;
- EBV and CMV were associated with an increased proportion of activated CD4 and CD8 T cells.
The association between viral reactivation and severe COVID-19 persisted even after accounting for differences in immune cell composition.
Viral Reactivation Is Associated With Increased Inflammation
Cytokine levels changed with viral reactivation. Elevated CXCL10, CXCL11, and IL-18 levels were common to several viruses.
The most pronounced changes were observed with reactivation of the herpesviruses EBV, HSV1, and CMV. Levels of several pro-inflammatory cytokines associated with severe COVID-19 also increased:
- EBV in peripheral blood was associated with increased IL-6, CCL7, CCL2, IL-10, and CXCL10 – cytokines and chemokines that are also elevated in severe COVID-19.
- EBV in nasal swabs was associated with increased IL-18, CXCL11, CXCL10, IL-18R1, CD274, IL-15RA, IL22RA1, HGF, IFN-γ, CCL8, and MMP10, as well as decreased KITLG. This profile differed from the changes observed with EBV detected in the blood and may reflect more pronounced viral reactivation.
- HSV1 in nasal swabs and CMV in peripheral blood had a similar inflammatory profile. Both viruses were associated with increased IL-18, CXCL11, CXCL10, IL-18R1, CD274, IL-15RA, CD40, CXCL9, CX3CL1, TNF, and CDCP1.
- HSV1 was associated with increased CCL25, SLAMF1, CD5, FGF23, TNFRSF9, and IL-10RB.
- CMV was associated with increased HGF, IFN-γ, CCL8, CCL7, LIFR, CD8A, ADA, and CXCL8, as well as decreased MMP1 and IL-4.
- Anelloviridae were associated with increased CXCL11 and IL-18 and decreased TNFSF11.
Changes in Blood Metabolite Composition accompany Viral Reactivation
The changes primarily involved metabolites participating in amino acid and lipid metabolism:
- CMV was associated with the largest number of metabolomic changes, including increased levels of urea and TMAP;
- CMV and Anelloviridae were associated with increased levels of certain long-chain fatty acids and dimethylarginines – compounds involved in regulating nitric oxide synthesis.
Viral Reactivation Is Accompanied by Changes in Gene Activity in Blood Cells and the Upper Respiratory Tract
Different viruses produced distinct molecular profiles:
- Anelloviridae and CMV in the blood, as well as HSV1 in nasal swabs – decreased activity of processes involved in RNA processing and protein synthesis, together with increased neutrophil activation;
- EBV, CMV, and HSV1 – increased activity of processes associated with cell division;
- EBV in blood cells – increased platelet activation;
- EBV, CMV, and HSV1 in the upper respiratory tract – increased interleukin signaling, including IL-10 signaling, immunoregulatory interactions between lymphocytes, and neutrophil activation;
- CMV and EBV in the upper respiratory tract – increased activity of antiparasitic and phagocytic pathways;
- EBV – increased activity of genes associated with T-cell activation.
Viral Reactivation in Long COVID
Viral reactivation during acute COVID-19 was not associated with subsequent Long COVID symptoms.
During recovery, Anelloviridae were significantly more frequently detected in patients with persistent physical disability and fatigue. This association remained after accounting for age, sex, use of immunosuppressive drugs, and severity of acute COVID-19. Therefore, detection of Anelloviridae may serve as a potential marker of persistent physical disability in Long COVID.
Anelloviridae have previously been associated with chronic fatigue syndrome and multiple sclerosis, conditions whose symptoms partially overlap with Long COVID – including fatigue, cognitive impairment, and post-exertional worsening. These viruses are also linked to immune system aging, so increased activity in Long COVID may indicate impaired immune function.
Conclusion
Viral reactivation is associated with severe acute COVID-19 and manifestations of Long COVID. Managing viral reactivation in these conditions may improve patient outcomes.
Reference
Virus reactivation in acute and long COVID-19
