Cytomegalovirus infection in critically ill patients with COVID-19
Authors: Takayuki Niitsu, Takayuki Shiroyama, Haruhiko Hirata, Yoshimi Noda, Yuichi Adachi, Takatoshi Enomoto, Reina Hara, Saori Amiya, Akinori Uchiyama, Yoshito Takeda, Atsushi Kumanogoh
Journal: Journal of Infection (2021)

Previous studies have shown that patients hospitalised with coronavirus disease 2019 (COVID-19) have a high risk of secondary infections; intensive care unit (ICU) admission, prolonged mechanical ventilation, and severe lymphopenia are likely causes.1Ripa M. Galli L. Poli A. et al.Secondary infections in patients hospitalized with COVID-19: incidence and predictive factors.Clin Microbiol Infect. 2021; 27: 451-457Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar Cytomegalovirus (CMV) has infected the majority of people globally. The reactivation of CMV occurs in 30% of immunocompetent patients with acute respiratory distress syndrome (ARDS) and is associated with increased mortality.2Ong D.S.Y. Spitoni C. Klein Klouwenberg P.M.C. et al.Cytomegalovirus reactivation and mortality in patients with acute respiratory distress syndrome.Intensive Care Med. 2016; 42: 333-341Crossref PubMed Scopus (54) Google Scholar CMV reactivation is especially concerning in patients with COVID-19 because ARDS is a common complication of severe COVID-19. However, data on CMV infection in critically ill patients with COVID-19 is scarce. Therefore, we evaluated the frequency and clinical characteristics of CMV cases in COVID-19 patients who required mechanical ventilation. We retrospectively reviewed consecutive patients with COVID-19 requiring invasive mechanical ventilation for more than one week in our centre between April 2020 and February 2021. We collected data on clinical characteristics and laboratory findings from medical charts. All patients were confirmed as having severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positivity by reverse-transcription polymerase chain reaction (PCR) on nasopharyngeal and throat swabs. We screened for CMV infection using the CMV antigenaemia assay for detecting pp65 antigen in peripheral blood leukocytes. We analysed patients with serial assays for CMV screening during their ICU stay. CMV infection was defined as ≥ 1 antigen-positive cell per 50,000 leukocytes and two consecutive positive assays. CMV disease was classified as proven, probable, or possible according to a previous study.3Ljungman P. Boeckh M. Hirsch H.H. et al.Definitions of cytomegalovirus infection and disease in transplant patients for use in clinical trials.Clin Infect Dis. 2017; 64: 87-91Crossref PubMed Scopus (663) Google Scholar The institutional review board approved this study and waived the requirement for informed consent. Data is presented as median and interquartile range. Continuous variables were analysed using the Mann-Whitney U test, while categorical variables were analysed using Fisher's exact test. The duration of mechanical ventilation was analysed using the Kaplan–Meier method, and the differences between groups were compared using the log-rank test. The duration of mechanical ventilation in the CMV group was defined as the time from initiation of mechanical ventilation to CMV diagnosis. All p-values were two-sided, and a p-value < 0.05 was considered statistically significant. All statistical analyses were conducted using R, version 3.6.3. A total of twenty-six patients were enroled in our study. All patients had negative CMV antigenaemia screening tests on ICU admission. Of twenty-six patients, 6 patients (23.1%) developed CMV infection during mechanical ventilation (CMV group), while the remaining patients did not develop CMV during mechanical ventilation (non-CMV group). There was no significant difference in the testing interval for CMV antigenaemia assay between the groups (median, 8 days vs. 7 days, P = 0.76). Table 1 summarises patient characteristics at ICU admission and clinical course. The median ages were 76.5 (66.25–80) years and 72 (62.5–76) years in the CMV and non-CMV groups, respectively (P = 0.38). Lymphocyte count on ICU admission was lower in the CMV group than in the non-CMV group (393 /μL vs. 525 /μL; P = 0.062). C-reactive protein, serum albumin, and D-dimer levels were not significantly different between the groups. The CMV group had a significantly longer duration of mechanical ventilation than the non-CMV group (40.5 days vs. 18.0 days, respectively, P = 0.010). The CMV group also had a significantly higher incidence of complications from bacterial or fungal infections and mortality rate. Two out of six patients in the CMV group died, whereas none of the patients in the non-CMV group died (P = 0.046).Table 1Characteristics at ICU admission and clinical course according to CMV infection.CMV infection (n = 6)Non-CMV infection (n = 20)p-valueCharacteristics at ICU admissionAge, yrSex, female, n (%)PaO2 / FiO2 ratioLymphocyte count, /μLNeutrophil-to-lymphocyte ratioC-reactive protein, mg/dLSerum albumin, g/dLD-dimer, μg/mL76.5 (66.25–80)3 (50%)173.5 (161.3–180.8)393 (234–476)20.2 (13.0–32.2)8.42 (5.45–16.02)2.75 (2.63–3.10)1.49 (1.08–1.95)72 (62.5–76)8 (40%)188.2 (155.6–246.2)525 (412–723)12.0 (7.5–21.7)5.29 (4.26–10.24)2.70 (2.40–3.23)2.13 (1.21–6.79)0.38>0.990.390.0620.0830.320.780.24Clinical courseCorticosteroid use, n (%)Duration of mechanical ventilation, daysBacterial infection, n (%)Fungal infection, n (%)Death, n (%)6 (100%)40.5 (31.0-NA)5 (83.3%)4 (66.7%)2 (33.3%)20 (100%)18.0 (13.0–31.0)5 (25%)2 (10%)0 (0%)>0.990.0100.0180.0130.046Duration of mechanical ventilation in the CMV group indicates the time from initiation of MV to CMV diagnosis. CMV: cytomegalovirus; NA: not available. Open table in a new tab Duration of mechanical ventilation in the CMV group indicates the time from initiation of MV to CMV diagnosis. CMV: cytomegalovirus; NA: not available. Table 2 summarises the six patients who developed CMV infection. Although all patients received ganciclovir therapy for CMV infection, two patients eventually died from refractory respiratory failure. The patient in Case 1 died four days after a positive CMV antigenaemia test result; the patient was diagnosed with CMV pneumonia from post-mortem lung findings. In this patient, the antigenaemia assay was performed four times, with a median test interval of 9 days, except for a two-week gap between the negative third and the positive fourth results (high positive cell count). The patient in Case 6, the only patient who developed neither bacterial nor fungal secondary infection, was considered to have died from ARDS due to refractory COVID-19 pneumonia.Table 2Clinical summary of six patients with CMV infection.CaseAge/SexMV duration (days)Median test interval (days)Days since the last negative testpp65 cell count (/105 WBC)CMV diseaseOutcome180/F339141348ProvenDeath280/M318616PossibleRecovery382/M38762−Recovery458/F43788PossibleRecovery564/F589342PossibleRecovery673/M38852−DeathMV duration indicates the time from initiation of MV to CMV diagnosis. CMV: cytomegalovirus; MV: mechanical ventilation; WBC: white blood cell. Open table in a new tab MV duration indicates the time from initiation of MV to CMV diagnosis. CMV: cytomegalovirus; MV: mechanical ventilation; WBC: white blood cell. We investigated the frequency and characteristics of CMV infection in critically ill patients with COVID-19 requiring mechanical ventilation for more than one week. In our study, approximately one in four patients developed CMV infection during mechanical ventilation and one patient died from CMV pneumonia. CMV infection was associated with lymphopenia on ICU admission, prolonged mechanical ventilation, and increased mortality. Our results suggest that CMV disease may be underestimated in COVID-19 patients in the ICU setting. Risk factors for CMV disease or its recurrence include corticosteroid use, prolonged mechanical ventilation, and lymphopenia.4Al-Omari A. Aljamaan F. Alhazzani W. et al.Cytomegalovirus infection in immunocompetent critically ill adults: literature review.Ann Intensive Care. 2016; 6: 110Crossref PubMed Scopus (69) Google Scholar,5Gardiner B.J. Nierenberg N.E. Chow J.K. et al.Absolute lymphocyte count: a predictor of recurrent cytomegalovirus disease in solid organ transplant recipients.Clin Infect Dis. 2018; 67: 1395-1402Crossref PubMed Scopus (54) Google Scholar COVID-19 contains these aspects due to its disease characteristics. Moreover, these are risk factors for disease recurrence or secondary infections in patients with COVID-19.1Ripa M. Galli L. Poli A. et al.Secondary infections in patients hospitalized with COVID-19: incidence and predictive factors.Clin Microbiol Infect. 2021; 27: 451-457Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar,6Adachi Y. Shiroyama T. Yamaguchi Y. et al.Predicting recurrence of respiratory failure in critically ill patients with COVID-19: a preliminary study.J Infect. 2021; 82: e33-e35Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar,7van Paassen J. Vos J.S. Hoekstra E.M. et al.Corticosteroid use in COVID-19 patients: a systematic review and meta-analysis on clinical outcomes.Crit Care. 2020; 24: 696Crossref PubMed Scopus (232) Google Scholar Further, infection with SARS-CoV-2 induces M1 polarisation of macrophages that promote the reactivation of latent CMV; inflammatory cytokines such as tumour necrosis factor-α may be directly associated with CMV reactivation. Importantly, CMV infection may be associated with accelerated immunosenescence, leading to the attrition of naive T cells.8Moss P. The ancient and the new": is there an interaction between cytomegalovirus and SARS-CoV-2 infection?.Immun Ageing. 2020; 17: 14Crossref PubMed Scopus (51) Google Scholar The decreased naive T-cell response may contribute to subsequent uncontrolled cytokine production and worse clinical outcomes. Therefore, physicians should be extremely aware of CMV infection in patients with COVID-19 ARDS compared to that in those with non-COVID-19 ARDS. CMV reactivation and virus-induced immune dysfunction may be overlooked as a cause of immunomodulation in patients with severe COVID-19.9Söderberg-Nauclér C. Does reactivation of cytomegalovirus contribute to severe COVID-19 disease?.Immun Ageing. 2021; 18: 12Crossref PubMed Scopus (38) Google Scholar Considering that the lung is a major reservoir for CMV and patients with COVID-19 are at risk for CMV disease,10Poole E. Juss J.K. Krishna B. et al.Alveolar macrophages isolated directly from human cytomegalovirus (HCMV)-seropositive individuals are sites of HCMV reactivation in vivo.J Infect Dis. 2015; 211: 1936-1942Crossref PubMed Scopus (37) Google Scholar CMV pneumonia may be underestimated in critically ill patients with COVID-19 pneumonia.11Le Balc'h P. Pinceaux K. Pronier C. et al.Herpes simplex virus and cytomegalovirus reactivations among severe COVID-19 patients.Crit Care. 2020; 24: 530Crossref PubMed Scopus (118) Google Scholar Untreated infection can lead to rapid deterioration and fatal outcomes. Therefore, routine monitoring for CMV infection may help improve outcomes in COVID-19 patients in the ICU setting. This study had some limitations. First, this is a preliminary retrospective study with a small sample, precluding definite conclusions. Second, we screened for CMV infection using the CMV antigenaemia assay. This might be inferior to PCR in case of leukopenia. Finally, in patients with COVID-19, the optimal threshold value for CMV infection and the significance of pre-emptive anti-CMV therapy remains unclear. Further research is needed to define the management of secondary CMV infection in critically ill patients with COVID-19 who are at high risk for CMV reactivation. This study was supported in part by the centre of Innovation program (COISTREAM) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT) (to A.K.); the Japan Society for the Promotion of Science (JSPS) KAKENHI (JP18H05282 to A.K.); the Japan Agency for Medical Research and Development (AMED)(J200705023, J200705710, J200705049, JP18cm016335 and JP18cm059042 to A.K.); a grant from the Kansai Economic Federation (KANKEIREN); and Grants from Mitsubish Zaidan1(to A.K.). The research was designed, conducted, analysed, and interpreted by the authors entirely independently of the funding sources.