The correct answer is:

Cytomegalovirus (CMV) IgM and IgG levels

Educational Objective:

Describe the effects of reactivated CMV infection as one of the hypothesized drivers of severe COVID-19 disease.

Key Point:

Clinicians should consider reactivated CMV as a possible, treatable trigger of severe COVID-19 infection.

Explanation:

Latent human cytomegalovirus (CMV) is carried by 70–90% of the adult population. The primary infection produces mild or no clinical symptoms in most people. However, the primary event leads to a life-long latent infection from which reactivation may be triggered by a disease process that leads to immune activation and inflammation. The lungs are a major reservoir for the latent CMV virus.

In the past, it was thought that latent CMV did not have any effect on healthy people; however, more recent studies show that in some people, CMV (even without overt activation) creates a low grade chronic inflammatory state that leads to inflammation-triggered hypertension, cardiovascular disease, metabolic syndrome, and type II diabetes. 

In addition, it is now recognized that about 30% of patients admitted to intensive care units (ICU) for any reason reactivate their dormant CMV, which – if not recognized and treated – doubles their mortality rate. 

SARS-CoV-2 provides almost perfect conditions for CMV reactivation: the classic elevation of tumor necrosis factor alpha (TNF-α), macrophages, and cytokine IL-6 associated with SARS-CoV-2 are all known triggers of CMV reactivation.

Studies show that it takes CMV about 4–7 days to reactivate (about the time frame within which COVID-19 patients often suddenly worsen). 

Once reactivated, CMV can potentiate (or cause?) the three signature life-threatening features of severe COVID-19, cytokine storm, a weakened interferon response, and coagulopathy:

• CMV directly suppresses T cells and natural killer cell functions, thereby helping both viruses avoid immune-mediated elimination. 
• CMV induces other immunosuppressive factors such as TGF-β, which is found in the lungs of COVID-19 patients and is linked to fibrosis development.
• CMV-infected endothelial cells trigger microthrombi formation linked to deep vein thrombosis, stroke, and myocardial infarction. 

A recent study used a machine learning based method to predict the risk of COVID-19 severity in 4,510 adults and found that CMV specific antibodies were the strongest predictors of severe COVID-19 risk. Patients hospitalized for COVID-19 also showed greater antibody responses to individual CMV and HSV-1 peptides, than those who were not hospitalized. By contrast, antibody responses to peptides from common cold viruses such as rhinoviruses, influenza viruses, and enteroviruses were higher in patients with COVID-19 who did not require hospitalization.

The author concludes that CMV reactivation and induced immune dysfunction may be underestimated as a driver of immunopathogenesis in patients with severe COVID-19.  

Author’s Bottom Line:

1. In general (not specific to COVID-19), the diagnosis of co-existing CMV infection is frequently missed in severely ill patients in the ICU, as few doctors are aware of the high risk of CMV reactivation in patients with inflammatory dysregulation. 
2. Given that (1) CMV is known to be reactivated in 30% of ICU patients, (2) SARS-CoV-2 provides almost perfect conditions for CMV reactivation, and (3) untreated CMV in severely ill patients doubles mortality, testing for CMV should be strongly considered in patients presenting to the hospital with severe COVID-19, especially when tell-tale signs of chronic inflammation, such as hypertension, cardiovascular disease, and metabolic syndrome or diabetes II are present (all signs of possible, chronically active CMV).
3. Methods for CMV testing include ordering CMV IgM and IgG (can be ordered in the emergency department), and (after admission) examination of a lung or bowel tissue sample by immunostaining for CMV, or performing a PCR test for CMV.

References:

Söderberg-Nauclér C. Does reactivation of cytomegalovirus contribute to severe COVID-19 disease? Immun Ageing. 2021;18(1):12. Published 2021 Mar 12. doi:10.1186/s12979-021-00218-z

Rahbar A, Soderberg-Naucler C. Human cytomegalovirus infection of endothelial cells triggers platelet adhesion and aggregation. J Virol. 2005;79: 2211–20.

Silva, T.F., Concato, V.M., Tomiotto-Pellissier, F. et al. Reactivation of Cytomegalovirus Increases Nitric Oxide and IL-10 Levels in Sepsis and is Associated with Changes in Renal Parameters and Worse Clinical Outcome. Sci Rep 9, 9016 (2019).

Staras SA, Dollard SC, Radford KW, Flanders WD, Pass RF, Cannon MJ. Seroprevalence of cytomegalovirus infection in the United States, 1988– 1994. Clin Infect Dis. 2006;43:1143–51.