COVID-19 pneumonia, immunosuppression, and cytomegalovirus activation: A perspective.

In the current issue of this journal, Shah et al.[1] have published a case report of an elderly patient who developed cytomegalovirus (CMV) activation with persistent leucopenia while recovering from COVID-19 pneumonia. Astute observation, good clinical work up, and subsequent CMV-directed antiviral therapy rescued the patient. CMV activation occurs under many different clinical situations associated with immunosuppression, CD4 cytopenia, steroid use, etc.

CMV and herpes simplex virus (HSV) activation has been detected in up to 50% percent patients affected with severe COVID-19 disease.[2] COVID-19 infection in its severe form is associated with significant T-cell lymphopenia along with lower NK cell number coupled with neutrophilic leucocytosis.[34] This combination does produce a situation ripe for CMV activation.

This elderly patient also received two doses of COVID-19 immune plasma as well as remdesivir which has anti-viral activity and causes some amount of additional immunosuppression. CMV serostatus of the infused immune plasma was not known. This information is also important as the blood product transfusion can cause CMV infection.[5] We don't know whether this elderly patient was CMV positive before he received blood products, as his CMV status was not evaluated before he received the immune plasma from 3rd party donor. However knowing that an Indian patient by the age of 70 years will be universally CMV positive, we may presume that he was positive for the virus serology and had secondary activation of the virus due to disease/steroid/immune plasma infusion. Also, CMV and HSV activation may not be unusual with COVID-19 pneumonia,[2] and at least in subsets of cases with CMV activation, additional reason for development of CMV interstitial pneumonia is added and unless identified and treated early may complicate the management of COVID-19 pneumonia.[6]

In the present case, the linkage between CMV activation and COVID-19 pneumonia is not very clear, although histological suggestion of CMV status was available from esophageal ulcer. The cause of peripheral cytopenia was not investigated or explored in greater details in this patient. The clinical picture of this patient was consistent with CMV-induced myelosuppression. This was also proved following recovery of peripheral blood picture following ganciclovir therapy.

So what can we learn from this case report? If in a patient with COVID-19 pneumonia, peripheral neutrophilic leucocytosis is replaced by cytopenia, with persistent low T cell and NK cell numbers, coupled with deterioration of pneumonia, then additional causes for this complication needs to be investigated and managed. Though in the present case CMV did not complicate lung pathology per se, it may do so in certain other cases. Active search for CMV lesions in terms of esophageal ulcers, colitis, deterioration of liver or renal function, and altered pattern of pneumonia on imaging may help to nail the additional pathology.

In COVID-19 pneumonia, high-resolution chest tomography imaging does not show central or diffuse lesions, mediastinal lymphadenopathy, or pleural effusion. Hence, if during the evolution of the disease this is seen,[7] then causes like CMV activation and other additional causes of lung injury must be considered and treated.

Nowadays, CMV activation can easily be diagnosed by using flow cytometry (expression of pp65 antigen on neutrophils) or with PCR-based strategies. Where these are not available, IgM antibody against CMV and suspicious histopathological lesion need to be evaluated to make the diagnosis. Managing CMV activation will save some lives. How often CMV activation happens in this condition and how often CMV pneumonia complicates COVID-19 pneumonia remains an important area of exploration and future research.

Finally, it should be noted that except anticoagulation, judicious respiratory support, and corticosteroids to down regulate cytokine storm, no other medicine has yet been shown to be effective in reducing the mortality and morbidity in COVID-19 pneumonia.