Coinfection with SARS-CoV-2 and Cytomegalovirus in a Patient with Mild COVID-19

Persistent fever due to coronavirus disease 2019 (COVID-19) is a considerable issue for patients and physicians that requires a broad differential diagnosis and evaluation of complications. Coinfections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and various respiratory viruses have also been reported. In severe cases of COVID-19, cytomegalovirus (CMV) reactivation or CMV coinfection with SARS-CoV-2 has been reported in association with critical illnesses and immunosuppressive therapy; however, in mild COVID-19 cases, CMV coinfection with SARS-CoV-2 has been reported only in severely immunocompromised patients, and its incidence and clinical importance remain unclear. Herein, we report a rare case of coinfection with SARS-CoV-2 and CMV in a patient with mild COVID-19 and untreated diabetes mellitus, which led to persistent fever for approximately 4 weeks. CMV coinfection should be considered in patients with COVID-19 who exhibit persistent fever.


Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID- 19), which continues to threaten global health [1]. Safe and efective vaccines and treatment options are now available [2]; however, COVID-19 still causes hospitalization or death, especially in the elderly and in people with pre-existing conditions. Persistent fever in patients with COVID-19 is of great concern to physicians and patients and requires a thorough evaluation for complications, such as pneumonia, thrombosis, or myocardial injury [3]. Tis may result in unnecessary antibiotic prescriptions.
Cytomegalovirus (CMV), a member of the Herpesviridae family, is ubiquitous in humans. CMV infection causes severe disease in immunocompromised patients; however, it can cause long-term fever in healthy adults due to infectious mononucleosis (IM) syndrome [4]. In many countries, the CMV seroprevalence rates are decreasing among young adults and children, particularly in developed countries, and these populations are at a higher risk of primary CMV infection [5]. Recently, CMV infection has been associated with severity or mortality of COVID-19 [6,7]. In severe COVID-19 cases, CMV reactivation or CMV and SARS-CoV-2 coinfection is a major complication associated with immunosuppressive therapy [8][9][10]. However, in mild COVID-19 cases, such as those without pneumonia or respiratory failure, there have been only a few reports of coinfection with SARS-CoV-2 and CMV in immunocompromised patients.
Herein, we describe a rare case of coinfection with SARS-CoV-2 and CMV that caused persistent fever in a patient diagnosed with mild COVID-19. Accurate diagnosis of CMV and SARS-CoV-2 coinfection as the cause of persistent fever in COVID-19 would beneft patients and clinicians by preventing unnecessary examinations and antimicrobial prescriptions.

Case Report
A 36-year-old man presented at our hospital complaining of a fever persisting for approximately 2 weeks. Tree weeks before admission, he became febrile and was diagnosed with COVID-19 by polymerase chain reaction (PCR) testing of a nasopharyngeal swab. Te following week, he developed a persistent low-grade fever while reposing at home, and then he developed a high-grade fever of higher than 39.0°C, along with mild headache, nausea, and anorexia. Two days prior to admission, he visited the emergency department of our hospital; however, chest computed tomography (CT) scans were negative for pneumonia, and the patient was prescribed acetaminophen. On the day of admission, he presented to our department for further evaluation.
Approximately 4-5 years earlier, he was diagnosed with diabetes mellitus (DM), for which he had not sought any medical attention, and he occasionally consumed alcohol but did not smoke. Prior to the presentation, his wife and daughter were diagnosed with COVID-19. He had not traveled nor been exposed to any animals recently. He was not prescribed any medication and had no known allergies. He had received two doses of a messenger RNA SARS-CoV-2 vaccine.
Upon examination, the patient was alert and did not experience acute distress. Te patient's blood pressure was 118/83 mmHg, heart rate was 84 beats per minute, axillary temperature was 36.7°C, and SpO 2 reading was 97% while breathing ambient air. No jolt accentuation or cervical lymphadenopathy was observed. Chest auscultation revealed no murmurs or rales. Tere was mild epigastric tenderness in the left upper quadrant, but no hepatosplenomegaly and no eruptions are observed.
Upon admission, a SARS-CoV-2 antigen test of the nasopharyngeal swab was negative at 0.83 pg/mL. Te patient's white blood cell (WBC) count was 8000/μL, with 29% neutrophils and 57% lymphocytes; however, no atypical lymphocytes were observed. Liver function test results revealed aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (T-Bil) levels of 40 U/L, 68 U/L, and 0.9 mg/dL, respectively. Te patient's blood urea nitrogen (BUN) and creatinine levels were 10.9 mg/dL and 0.59 mg/dL, respectively. Serum C-reactive protein (CRP) and procalcitonin levels were 7.81 mg/dL and 0.19 ng/mL, respectively. Hemoglobin A1c and blood glucose levels were 10.9% and 322 mg/dL, respectively. Te other laboratory test results are presented in Table 1. Abdominal CT without contrast revealed mild splenomegaly, mild fatty liver, and intra-abdominal lymphadenopathy suggestive of infammatory swelling ( Figure 1).
Te patient was admitted, and acetaminophen was administered orally and intravenously, which partially relieved his fever, fatigue, and headache. Blood and urine cultures were negative and no antimicrobials were prescribed; thus, we suspected a viral infection and performed serological screening for CMV, Epstein-Barr virus (EBV), herpes simplex virus, and human immunodefciency virus (HIV). Te patient's CMV immunoglobulin M (IgM) level was elevated, and other tests showed negative results or signs of a past infection. Given the possibility of primary CMV

Discussion
Here, we present a rare case of persistent fever due to CMV and SARS-CoV-2 coinfection in a patient with mild COVID-19. Te incubation period for a CMV infection is about 4 to 6 weeks; this indicates that the patient was infected with CMV when he was diagnosed with COVID-19. CMV and SARS-CoV-2 coinfection should be considered as a diferential diagnosis for patients with COVID-19 who present unexplained persistent fever. Persistent fever in COVID-19 has led to the identifcation of complications such as pneumonia; however, after the Omicron surge, when the incidence of pneumonia and respiratory failure were low, it became important to evaluate the cause of fevers associated with COVID-19 and those unrelated to COVID-19. Te Omicron variant was the dominant SARS-CoV-2 strain in Japan when the present patient was infected with SARS-CoV-2 in August 2022. Tus, we presumed this patient was infected with the Omicron variant, although the genotype of the virus was not assessed.
CMV infection has been associated with severity or mortality of COVID-19 [6,7]. Most reports on CMV coinfection with SARS-CoV-2 are limited to severe cases, such as patients treated with systemic glucocorticoids and invasive mechanical ventilation in the intensive care unit setting [8][9][10]. Tese reports were obtained during the early phase of the SARS-CoV-2 pandemic (to mid-2022) when the mortality rate was higher than that of the current pandemic (after late 2022, the Omicron phase). Although these reports [8][9][10] did not include SARS-CoV-2 patient vaccination data, a rare case of SARS-CoV-2 coinfection with CMV reactivation in an immunocompromised patient who received the SARS-CoV-2 vaccination was also reported [11].
CMV infection is usually asymptomatic, but it may cause IM syndrome in healthy adults and severe disease in neonates and immunocompromised patients. Here, the patient had only nonspecifc symptoms, such as abdominal discomfort, nausea, and a slight headache, which are mainly associated with fever. Compared with IM due to EBV, CMV-IM is reportedly less likely to induce typical symptoms, such as pharyngitis with exudates, cervical lymphadenopathy, or hepatosplenomegaly [21]. Terefore, it may be difcult to suspect a CMV infection based on clinical symptoms, and this infection cannot be diagnosed without performing specifc testing for viral markers.
Furthermore, CMV antigenemia, an assay for detecting the PP65 antigen (C7-HRP), is not routinely used to evaluate for CMV infections in immunocompetent patients. However, CMV-IgM reportedly exhibits cross-reactivity with other viral pathogens [22], a prolonged elevation 1 year after the onset of infection, and an elevation in reactivated CMV infection; thus, we performed an antigenemia and PCR to confrm CMV infection in this case.
Recently, the seroprevalence rates of CMV have decreased in young adults and children, particularly in the developed countries [5]. Tus, the range of populations susceptible to CMV is increasing worldwide. As long as the COVID-19 pandemic continues, similar cases of COVID-19 presenting persistent fever without COVID-19-associated sequelae, such as pneumonia, may increase. Te accurate diagnosis of CMV infection in these cases would be benefcial for patients and clinicians.  Several reports have described an association between CMV and SARS-CoV-2 infection. Both viruses infuence the immune system [6] and may have a detrimental efect on the course of these infections. High CMV-seropositivity is associated with severe COVID-19 [7], possibly due to CMV association with the acceleration of immune senescence and cardiovascular and metabolic diseases [9]. Furthermore, in patients with severe COVID-19, the reactivation of CMV has been associated with high mortality rate; however, little is known about the interactions between primary CMV and SARS-CoV-2 infections, as in the present case. It is unknown whether simultaneous primary CMV and SARS-CoV-2 infections are risk factors for severe COVID-19, and vice versa. In addition, there is a reported case of CMV reactivation after COVID-19 vaccination [23]; however, further reports on these cases and accumulation of knowledge are needed.
Here, the patient had DM, which causes immune dysfunction and is a recognized risk factor for severe COVID-19; however, DM has not been reported as a risk factor for CMV infection. Te patient in our case had a persistent fever for approximately 4 weeks, which was longer than that previously reported by a mean of 18 days [24], and a markedly high level of antigenemia. It is possible that the untreated DM infuenced the patient's clinical course.
In conclusion, we present a case of CMV coinfection in a patient with mild COVID-19. CMV infection screening in patients with COVID-19 who have unexplained persistent fever is important as it prevents unnecessary evaluations or antibiotic prescription and is benefcial to patients and physicians.

Data Availability
Te data supporting the fndings of this study are available within the article.

Consent
Written informed consent was obtained from the patient.

Conflicts of Interest
Te authors declare that they have no conficts of interest.