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Clinical Infection & Immunity

Case Report

Volume 6, Number 3, September 2021, pages 86-91

Cytomegalovirus Reactivation During Steroid Therapy for COVID-19

Coronavirus disease 2019 (COVID-19) has been consistently treated with antibiotics and steroids [1, 2], often at high doses. Although the evidence supporting use of dexamethasone or other potent corticosteroids is quite strong, the optimal dose as well as the adequate duration of treatment remains unknown [3]. As a matter of fact, patients are often treated with immunosuppressive steroid doses for prolonged periods of time, sometimes several weeks, and may therefore develop opportunistic infections. Recently, reactivation of cytomegalovirus (CMV) in hospitalized patients with severe COVID-19 has been reported. In this article, we present one case from our own clinical practice and review existing evidence on this topic.

An 83-year-old man was admitted to our hospital for COVID-19 pneumonia in September 2020. His prior clinical history was significant for systemic arterial hypertension and stage III chronic kidney disease. He was nondiabetic and had no prior cancer or liver or pulmonary disease. Computed tomography (CT) scan showed bilateral, widespread, extensive and confluent parenchymal ground-glass opacities, with initial consolidation in the posterior basal area, and thin, sub-pleural consolidations in the left lower lobe, without pleural effusion. CT findings appeared consistent with bilateral interstitial pneumonia due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with a CT-severity score according to Chung et al [4] equal to15/20. After receiving standard treatment with methylprednisolone and enoxaparin, along with oxygen therapy, the patient experienced slight clinical improvement. Five weeks after hospital admission, he appeared to have cleared the infection, after two nasopharyngeal swabs turned negative and oxygen needs reduced.

He was then moved to a SARS-CoV-2 free, step-down unit, on lower-dose oral prednisone and enoxaparin. Here, the patient presented again shortness of breath and his repeat CT scan was again suggestive for diffuse, bilateral interstitial pneumonia. SARS-CoV-2 nasopharyngeal swab remained negative and procalcitonin did not show any significant increase. In contrast, whole blood CMV-deoxyribonucleic acid (DNA) resulted positive, with a viral load as high as 373,378 IU/mL. The patient was immediately started on ganciclovir 500 mg intravenous (IV) mg every 12 h for 2 days, followed by weight-adjusted 300 mg bid IV. Leukocyte count on the day of CMV infection diagnosis was normal (6,630 cells/µL), lymphocytes were 930 cells/µL, hemoglobin was 9.2 g/dL, platelets 177,000 cells/µL and D-dimer 826 ng/mL. There was a slight increase in alfa-1 and beta-2 globulin, and lactate dehydrogenase was slightly increased. Hemato-chemical parameters are shown in Table 1.

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Table 1. Hemato-Chemical Parameters at the Time of Cytomegalovirus (CMV) Infection Diagnosis and 3 Weeks Later

After treatment initiation, CMV viral load progressively decreased to 7,451 IU/mL after 2 weeks and 449 IU/mL after 3 weeks. Culture of the central venous catheter tip was positive for coagulase-negative Staphylococcus, which was treated with daptomycin for 1 week. Urine cultures were positive for Enterococcus faecium, but no treatment was given for this beyond the substitution of the urinary catheter. Three weeks after ganciclovir treatment initiation, a progressive clinical improvement was observed, leading us to switch the patient to oral valganciclovir, 450 mg twice daily, until a negative CMV-DNA was obtained.

During antiviral treatment with ganciclovir, lymphocyte count returned to normal, whereas hemoglobin levels remained low due to a gluteal hematoma which required enoxaparin treatment withdrawal. D-dimers and C-reactive protein remained elevated probably as a consequence of COVID-19.

The patient was discharged alive from the hospital on oral valganciclovir. Twenty days after discharge, follow-up nasopharyngeal swab for SARS-CoV-2 was negative. CT scan performed at further 30-day follow-up showed persistent, diffuse parenchymal ground-glass opacities with basal consolidation.

A PubMed search was conducted on September 17, 2021, using the following search terms: “Cytomegalovirus” (MeSH terms) or “Cytomegalovirus infections” (MeSH terms) or “Cytomegalovirus” or “CMV” and “COVID-19”. The survey retrieved 191 results; after careful scrutiny, 13 studies were selected and included in the review.

A number of studies reported on CMV reactivation following severe COVID-19 (Table 2) [5-17]. Most described patients were elderly with respiratory and/or other organ system failure, and CMV reactivation manifested either as gastrointestinal (GI) [5, 8-13] or respiratory deterioration [6, 7, 14, 15]. Identified risk factors for CMV disease or its recurrence in COVID-19 included corticosteroid use, prolonged mechanical ventilation and lymphopenia [15].

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Table 2. Studies Reporting on CMV After COVID-19 Diagnosis

GI symptoms mostly included abdominal pain, diarrhea (bloody and non-bloody), melena, ileus and dysphagia [5, 8-13]. Diagnosis was mostly done using imaging, or biopsy of the affected GI tract with direct visualization of CMV inclusion bodies. CMV-related symptoms appeared 9 - 38 days after hospitalization, and lead in certain patients to anemia requiring transfusions [10, 13], intestinal artery embolization [8] and/or hemi-colectomy [13]. On CT scan, most patients showed intestinal thickening with/without an obstructive pattern [5-8, 12, 13], and in some cases ulceration [11].

Respiratory symptoms, on the other hand, mostly presented as increased oxygen requirements and respiratory failure, in COVID-19 patients who were initially improving or weaned off respiratory support [6, 7, 14, 16]. Diagnosis of CMV, in these patients, was generally done after excluding other viral and bacterial causes of deterioration, with either polymerase chain reaction (PCR) on blood samples, or CMV immunoglobulin G (IgG) and IgM testing. Imaging studies were largely difficult to interpret, as patients had already been diagnosed with COVID-19, making differentiation of COVID-19 from CMV-induced changes more challenging. CMV-related respiratory deterioration seemed to result in higher mortality than GI complications; in the current reports, 7/18 (39%) patients with CMV pneumonia following COVID-19 died, compared to none in the group of patients with GI complications.

A detailed description of the individual studies reviewed is presented in Table 2.

CMV reactivation may occur during COVID-19 and can have a substantial prognostic significance. As all current literature entails anecdotal observations and case reports, the real incidence of CMV reactivation during COVID-19 remains unknown. However, we believe it might not be an uncommon phenomenon, and large prospective and targeted surveillance studies are clearly warranted.

The pathophysiology of CMV reactivation during or after COVID-19 also remains to be determined. Similar to other clinical settings, high-dose (immunosuppressive dose) corticosteroids administered for a prolonged time appear to be a major driver of CMV reactivation, possibly together with SARS-CoV-2-related factors, such as lymphopenia. Other opportunistic pathogens have also been described to emerge in the wake of COVID-19, including Aspergillus spp, Candida spp, Cryptococcus neoformans, Pneumocystis jiroveci, mucormycosis, Strongyloides stercoralis, Mycobacterium tuberculosis and Toxoplasma gondii [18-20]. Physicians caring for COVID-19 patients should be aware of the possibility that patients, during either the acute phase or the recovery, may develop opportunistic infections, which require a focused diagnostic workup and a targeted treatment.

Acknowledgments

None to declare.

Financial Disclosure

No specific funding was received for this study.

Conflict of Interest

Authors have no conflict of interest to disclose relevant to the contents of this article. EDM received funding, personal fees or advisory board membership honoraria from Roche, Genentech, Pfizer, MSD, Angelini, Advanz pharma, Nordic pharma, BioMerieux, Medtronic, Trx, outside of this work.

Informed Consent

Informed consent from the patient was obtained.

Author Contributions

MG performed laboratory tests. AK and EDM obtained clinical data. MSR performed literature review. EDM oversaw the study and drafted the article. All authors read, commented and approved the final version of the article.

Data Availability

The data supporting the findings of this study are available from the corresponding author upon reasonable request.

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