Concomitant Cytomegalovirus Viraemia in Multisystem Inflammatory Syndrome in Adults (MIS-A) following COVID-19

Multisystem inflammatory syndrome in adults (MIS-A) is recognised as an infrequent complication of coronavirus disease 2019 (COVID-19). This syndrome occurs following COVID-19 infection in some individuals and is characterised by inflammation of multiple organ systems, such as the heart, liver, bowel, and lymph nodes. Cytomegalovirus (CMV) viraemia is associated primarily with immunosuppression. In COVID-19 patients, it has been reported in severe and critical cases. We present a case of an adult patient diagnosed with MIS-A and concomitant CMV viraemia.


Background
Multisystem infammatory syndrome in adults (MIS-A) is a rare hyperinfammatory syndrome that was initially described in children (MIS-C) previously infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1].MIS-C is a post-infectious infammatory condition associated with an abnormal immune response, cardiac dysfunction, and multiorgan involvement.Tis condition is more commonly observed in children aged 5-13 years.Te diagnosis is clinically based on the following criteria: age <21 years, clinical severity necessitating hospitalization, absence of an alternative diagnosis, fever, C-reactive protein >3 mg/dL, prior documented SARS-CoV-2 infection by detection of RNA, antigen, or antibodies, and multisystem involvement in at least 2 categories, including cardiac involvement, mucocutaneous involvement, shock, gastrointestinal involvement, and haematologic involvement (thrombocytopenia or lymphopenia) [2].
Similar to children, MIS-A induces multiorgan infammation in adults and manifests with fever, abdominal pain, vomiting, diarrhoea, rash, and nonpurulent conjunctivitis [3].MIS-A could manifest as severe symptoms including myocardial dysfunction, thrombosis, hypotension, and organ failure.Te pathophysiology of the disease is not fully elucidated, though multiple immunologic mechanisms are proposed to be involved, such as molecular mimicry, epitope spreading, and bystander activation [4].Cytomegalovirus (CMV) viraemia has been described in patients with critical conditions or who are immunosuppressed.Terefore, it is recognised as a proxy of immunosuppression.Also, CMV viraemia has been described in severe coronavirus disease 2019 (COVID-19) cases [5].Specifc organ afection has been described, especially in the lung, as CMV pneumonitis [6].In multisystem infammatory syndrome, CMV has been described only in children [7].Here, we present a case of a man in his 40s with MIS-A and concomitant CMV viraemia.

Case Presentation
A Hispanic man in his 40s presented to the emergency department with a 10-day history of fever and malaise.One month prior, the patient had a mild COVID-19 infection that was successfully treated symptomatically.He had a relevant history of recently being diagnosed with hypertension and recent travels to Sweden and a ranch in Valle de Bravo, Mexico.
Five days prior to the frst consult in the emergency department, the patient was evaluated by another physician.At that time, the patient complained of fever, headache, photophobia, chills, and diarrhoea.Te physician prescribed ceftriaxone 1 g intramuscular every 24 horas and ordered blood tests, which revealed mild thrombocytopenia (146,000 per mm 3 ), elevated liver enzymes (AST: 97 U/L, ALT: 91 U/ L, GGT: 107 U/L, DHL: 319 U/L), and high C-reactive protein (CRP) levels (2.9 mg/dL).Te viral hepatitis panel was negative for active infection, and the Venereal Diseases Research Laboratory (VDRL) test and HIV test were negative.CMV was positive for only immunoglobulin G (IgG), indicating prior infection.A liver ultrasound was performed, and its results showed fatty infltration.
Despite the previous treatment, the patient continued experiencing intermittent fever, myalgias, arthralgias, headache, and abdominal pain, necessitating his admission to our emergency department.At the time, the patient had a fever of 39 °C, heart rate of 120 bpm, and tissue oxygenation saturation (StO 2 ) of 89%.A nonpurulent conjunctivitis and a maculopapular rash were observed on the abdomen and the anterior thorax.Te abdomen was tender but showed no signs of peritoneal irritation.Tere were no palpable cervical or inguinal lymphadenopathies, and the rest of the physical examination was unremarkable.
In the emergency department, an extensive work-up for the cause of the fever was conducted by our infectious disease team, which then requested laboratory and imaging studies.Given the clinical picture and the unknown origin of the fever, a mononucleosis-like syndrome was frst diagnosed, and the patient was admitted for further management and diagnostic work-up.Upon admission, antibiotic treatment was continued with ceftriaxone 1 g intravenous every 12 hours, and doxycycline 100 mg every 12 hours by mouth was added to the antibiotic's regimen, given the patient's history of recent travels to a ranch.Initial evaluation included serology for the Epstein-Barr virus (EBV), toxoplasma, rubeola, CMV, herpes simplex virus 1 and 2 (HSV), human immunodefciency virus (HIV), Coxiella, hepatitis A, B, C, and E virus, Leptospira, Bartonella, Ehrlichia, Anaplasma, dengue, chikungunya, Zika, and Brucella, which were negative for recent or current infection.Multiplex polymerase chain reaction (PCR) tests for respiratory and gastrointestinal pathogens were negative, including the PCR test for SARS-CoV-2.Blood and urine cultures were also negative.
Blood tests revealed a normal complete blood count, although toxic neutrophil granulation and activated atypical lymphocytes were observed on the thin flm.Remarkably, the results of the liver function tests were progressively worse (Table 1, Biochemical biomarkers).Elevated levels of D-dimer (2974 ng/ml), ferritin (944 ng/ml), beta-2-microglobulin (5.769 mg/L), and IL-6 (11.2 pg/mL) were observed.Te test results for antinuclear antibodies, anti-DNAds, anti-SSA, anti-SSB, antismooth muscle antibodies, anticitrullinated protein antibody, p-ANCA, and c-ANCA were all negative.Rheumatoid factor was slightly positive at 17.8 U/ml (reference values: 0-14 U/ml).C3 and C4 protein levels were normal.Test results for SARS-CoV2 IgG antinucleocapsid antibody were positive, indicating prior infection.An initial chest and abdominal computed tomography (CT) scan showed splenomegaly and retroperitoneal lymphadenopathies.Te echocardiogram was normal, with preserved ejection fraction.
Te patient's condition persisted during the hospital stay, with daily fever, intense body pain, and malaise despite paracetamol; however, the diarrhoea stopped.Because of these outcomes and the patient's clinical picture, haematologic neoplasia was suspected at this point.Te haematology unit ordered free serum kappa and lambda chains, immunofxation, and protein electrophoresis.Te protein electrophoresis detected polyclonal hypergammaglobulinemia.Peripheral blood immunophenotyping did not detect any cellular clones but revealed an elevated T lymphocyte subpopulation (CD3/CD8+).
A 18F-fuorodeoxyglucose (18-F) positron emission tomography scan (PET-CT) was requested, which revealed hypermetabolic retroperitoneal and intercavoaortic lymph nodes, measuring 12 × 10 mm, with a maximum standardized uptake value (SUV) of 9.8, inversion of liver/spleen metabolism, and hepatosplenomegaly (Figure 1).Furthermore, HIV, human herpesvirus-8 (HHV-8), CMV, and EBV load tests were requested, and the results of the latter two were positive.Te EBV viral load test result was positive but below the threshold for quantitative detection (<124 UI/ml).Te CMV viral load was 3,933 UI/ml, and CMV IgG was positive, indicating CMV reactivation in the context of an immunocompetent patient.
Given the lack of a defnite diagnosis and the suspicion of neoplasia, a retroduodenal lymph node biopsy and a liver biopsy were performed on the ffth day after admission.
While awaiting the biopsy results, the patient continued with fever.A follow-up CMV viral load test was requested two days after surgery, and it revealed an elevation in the CMV viral load (6,389 UI/ml; prior: 3,933 UI/ml).Terefore, antiviral treatment with ganciclovir (5 mg/kg intravenously) was initiated, although no organ damage was detected.
After one week from the surgery, the patient continued with daily fever; thus, methylprednisolone (80 mg per day) was prescribed.Despite corticoid treatment, the fever persisted, and on the twelfth day of admission, we decided to switch to high-dose dexamethasone (40 mg per day), and a new CT scan and bloodwork were ordered to re-evaluate the cause of the fever.Te bloodwork results continued to report elevated liver enzymes.
Te retroduodenal lymph node biopsy revealed sinusoidal and paracortical hyperplasia with small and medium lymphocytes, apoptotic cells, histocytes, plasmacytoid dendritic cells (CD123+), and hemophagocytes, with a few macrophages positive for SARS-CoV-2 in the cytoplasm (Figure 2).Liver biopsy showed a chronic infammatory infltrate negative for neoplasia.Immunohistochemistry was positive for CD20 and CD30 in reactive B lymphocytes; CD3 in reactive T lymphocytes; ki67 in 40% of the cells; Bcl-2 in plasmacytoid dendritic cells, kappa and lambda; and CD138 in plasmatic cells.Immunohistochemistry was negative for CMV.

2
Case Reports in Infectious Diseases Considering the patient's clinical evolution, adult multisystem infammatory syndrome secondary to SARS-CoV2 and CMV reactivation were diagnosed.Te patient meets the Centers for Disease Control and Prevention (CDC) case defnition of MSI-A: age of 21 years or older; documented fever of above 38 °C; exanthema and nonpurulent conjunctivitis; abdominal pain; vomiting or diarrhoea; thrombocytopenia; elevated CRP, ferritin and IL-6; and recent SARS-Cov2 infection [1].
After the initiation of treatment with high-dose dexamethasone on the twelfth day of hospitalization, the patient experienced resolution of the fever and improvement in liver function, as indicated by the test results.At hospital discharge, a dose-reduction regimen of dexamethasone was prescribed and valganciclovir 900 mg twice a day (oral ganciclovir prodrug) was continued to complete its 21-day scheme that was initiated with ganciclovir.During subsequent outpatient visits, weekly clinical exams and blood tests revealed further improvement in liver enzymes and fever resolution.A month after discharge, we stopped corticoid treatment after successful tapering.Furthermore, laboratory test results showed normal levels of D-dimer, LDH, CRP and liver enzymes.

Discussion
We present the case of a young man with controlled hypertension who presented with gastrointestinal symptoms, persistent fever, elevated infammatory markers, altered liver function, and altered liver enzymes a month after a mild SARS-CoV-2 infection.His symptoms were consistent with MIS-A after an extensive diagnostic work-up eliminated other aetiologies.MIS-A is a post-infectious hyperinfammatory syndrome that occurs after a SARS-CoV2 infection or COVID-19 vaccination [2].It was frst described in children (tagged MIS-C) in April 2020 [3].Te pathophysiology is not fully understood; however, it is known that after recovery from the infection, there is a dysregulated host immune response that produces a hyperinfammatory state 3-12 weeks (average of 4 weeks) after the initial viral [4].Although the MIS-A incidence rate is unknown, it is less frequent than MIS-C [5].Most of the information on MIS-A has been generated from clinical cases and series of cases [6,7].MIS-A predominantly afects males between 30 and 50 years of age.Te most common presenting symptoms are fever and gastrointestinal symptoms, as in our patient [8].Cardiac involvement is frequent but is not universally present, as evidenced by a recent systematic review and as observed in our case, in which there was no cardiac involvement [4].Several treatments have been proposed, including glucocorticoids [9].Interestingly, our patient did not respond positively to an 80 mg/day methylprednisolone dose (equivalent to 15 mg of dexamethasone), but he responded positively after a higher dexamethasone dose (40 mg/day) was administered.High-dose corticoids have been prescribed as a treatment option in children [10].
Reactivation of CMV has been observed in patients with COVID-19, likely due to the immune activation caused by the virus as well as the immunosuppressive treatments administered to patients [1,[11][12][13].To the best of our knowledge, there are no reports of MIS-A with CMV viraemia or reactivation.In contrast, CMV reactivation in a child with multisystem infammatory syndrome (MIS-C) related to COVID-19 has been reported [6].In our patient, it is possible that the CMV viraemia was an epiphenomenon since he did not develop a CMV-related organ disease.
Te PET scan showed abdominal lymphadenopathies, as has been previously reported in other MIS-A cases [9,14].Te lymph node biopsy fndings were of particular interest, as we were able to demonstrate the persistence of SARS-CoV-2 in macrophages.Although we were not able to assess viral load in the tissue or determine its viability, the positive immunohistochemistry results suggest that there may be a persistent infammatory stimulus that triggers the immune system, thereby contributing to the pathophysiology of MIS-A [11,15].Our fnding is consistent with that of previous reported cases on MIS-C, which showed SARS-CoV-2 persistence [16].
Te primary limitation of our case is the absence of molecular immunology studies to elucidate the underlying mechanisms related to the development of MIS-A following SARS-CoV-2 infection.Additionally, as a single case report, we lack information on whether other therapeutic modalities, such as immunomodulatory agents or targeted antiviral therapies, might be more efective in specifc cases.Finally, the presence of concomitant CMV viraemia in our patient adds complexity to the clinical presentation and treatment response.However, the precise role of CMV reactivation in the pathogenesis of MIS-A remains unclear.

Conclusion
In conclusion, we report a case of MIS-A in a man with concomitant CMV viraemia, following a mild SARS-CoV-2 infection.Our case underscores the importance of considering MIS-A in adults presenting with fever, gastrointestinal symptoms, and elevated infammatory markers, even in the absence of cardiac involvement.High-dose corticosteroids, such as dexamethasone, may be efective in managing MIS-A, as evidenced by the resolution of symptoms in our patient.