key: cord-0833066-czye6lr5 authors: Yamamoto, Yuji; Shiroyama, Takayuki; Hirata, Haruhiko; Kuge, Tomoki; Matsumoto, Kinnosuke; Yoneda, Midori; Yamamoto, Makoto; Uchiyama, Akinori; Takeda, Yoshito; Kumanogoh, Atsushi title: Prolonged corticosteroid therapy and cytomegalovirus infection in patients with severe COVID‐19 date: 2021-11-03 journal: J Med Virol DOI: 10.1002/jmv.27421 sha: e030c9374015c7b5b4465a54ee55888477813d0f doc_id: 833066 cord_uid: czye6lr5 Systemic corticosteroid therapy is frequently used to treat coronavirus disease 2019 (COVID‐19). However, its maximum duration without secondary infections remains unclear. We aimed to evaluate the utility of monitoring cytomegalovirus (CMV) infection in patients with COVID‐19 and estimate the maximum duration of systemic corticosteroid therapy without secondary infections. We included 59 patients with severe COVID‐19 without CMV infection on admission to the intensive care unit (ICU). All patients received systemic corticosteroid therapy under invasive mechanical ventilation, with examination for plasma CMV‐deoxyribonucleic acid (DNA) levels during the ICU stay. We analyzed the correlations among patient characteristics, CMV infection, diseases, and patient mortality. CMV infections were newly identified in 15 (25.4%) patients; moreover, anti‐CMV treatment was administered to six (10.2%) patients during the ICU stay. Four (6.8%) patients had secondary infection‐related mortality. The cumulative incidences of CMV infection and anti‐CMV treatment during the ICU stay were 26.8% (95% confidence interval [CI], 15.8%–39.0%) and 12.3% (95% CI, 4.8%–23.4%), respectively. Furthermore, the median duration of systemic corticosteroid therapy without CMV infection was 15 days (95% CI, 13–16 days). The presence of CMV infection was associated with mortality during the ICU stay (p = 0.003). Monitoring plasma CMV‐DNA levels could facilitate the detection of secondary CMV infection due to prolonged systemic corticosteroid therapy. The duration of systemic corticosteroid therapy for COVID‐19 should be limited. macrophages and granulocytes. This process leads to acute respiratory distress syndrome (ARDS). 3 Numerous studies have investigated treatments for improving the outcomes of patients with COVID-19. Systemic corticosteroid therapy is an effective treatment for severe COVID-19 with ARDS. 4, 5 It ameliorates COVID-19-induced cytokine storm and improves patient outcomes; however, it can trigger immunosuppression, which causes secondary infections. 6 Additionally, COVID-19 is associated with cytomegalovirus (CMV) reactivation in patients with severe COVID-19. 7, 8 Therefore, systemic corticosteroid therapy acts as a double-edged sword in patients with severe COVID-19. Occasionally, the duration of systemic corticosteroid therapy requires extension due to recurrent respiratory failure. 9 This retrospective observational study was conducted at Osaka University Hospital (a 1086-bed National University Hospital in Osaka, Japan). Patients with severe COVID-19 were directly admitted via ambulance transport or gathered from other hospitals and treated in the intensive care unit (ICU). Noninvasive ventilation or high-flow nasal cannula oxygen therapy was not administered to avoid aerosolizing virus particles; accordingly, all patients received invasive mechanical ventilation. All screened patients were adults with COVID-19 (age ≥20 years) who were admitted to Osaka University Hospital between April 1, 2021, and May 31, 2021. We excluded patients with a history of immunodeficiency or CMV infection on admission to the ICU, as well as those with baseline corticosteroid or other immunosuppressant usages before symptom onset. Moreover, we excluded patients with an ICU stay of <7 days to determine the association between prolonged systemic corticosteroid therapy and CMV infection. All patients were followed until discharge from the ICU, end of the study period (May 31, 2021), or death. To identify factors influencing the incidence of CMV infection, we analyzed the correlations between CMV infection with patient characteristics and laboratory data. Additionally, we evaluated the association of the requirement for anti-CMV treatment with patient prognosis. The experimental protocol followed the Ethical Guidelines of the Japan Ministries of Health and Labor for Medical and Health Research Involving Human Subjects. This study was performed in accordance with the principles of the Declaration of Helsinki. The study protocol was approved by the Institutional Review Board of Osaka University Hospital (approval number: 21146). An opt-out system was applied to obtain patients' informed consent for a retrospective review, which allowed patients the opportunity to decline participation in the study. Information regarding patient characteristics was collected through individual case reviews. Baseline characteristics were obtained for hospital admission. Clinical characteristics included age, sex, body mass index (BMI), comorbidities, and immunosuppressive therapy before ICU admission. Laboratory data included the levels of plasma CMV-deoxyribonucleic acid (DNA), leukocytes, D-dimer, C-reactive protein, lactate dehydrogenase, ferritin, immunoglobulin G (IgG), IgA, and IgM. Furthermore, we monitored CMV infection and diseases that occurred during ICU stay. All-cause mortality during ICU stay was recorded for all patients. Upon ICU admission, SARS-CoV-2 infection was confirmed through reverse-transcription polymerase chain reaction (RT-PCR) using nasopharyngeal and throat swabs. RT-PCR was conducted using Xpert Xpress SARS-CoV-2 and GeneXpert (Beckman Coulter Inc.). Immunosuppressants and corticosteroid pulse therapy initiated before ICU admission were discontinued. During the ICU stay, 6 mg dexamethasone was administered once daily for 10 days (or until ICU discharge if it occurred sooner). 4 When patients could not be extubated after 10 days of dexamethasone administration due to respiratory failure, ≤6 mg dexamethasone was administered once daily until extubation or death to prevent recurrence of respiratory failure. The dose was tapered to 1-3 mg once daily, if possible. CMV infection was diagnosed using real-time PCR to detect viral nucleic acids in plasma. 10 Plasma CMV-DNA levels were quantified by real-time PCR using the Cobas CMV and Cobas 6800 system (Roche Diagnostics Co.), with follow-up measurements at least once per week. CMV-DNAemia was defined as two or more positive results for CMV-DNA in plasma samples. 10 Proven, probable, and possible CMV diseases were defined as described by Ljungman et al. 10 Possible CMV diseases were defined by the presence of CMV in the blood (i.e., CMV-DNAemia), as well as symptoms and/ or signs. 10 Although the absolute cut-off value of plasma CMV-DNA levels for antiviral treatment initiation remains to be established, 11 the cutoff value for CMV-DNAemia is useful for guiding pre-emptive therapy for CMV infection. 12 Accordingly, patients with CMV-DNAemia >200 IU/ml and CMV diseases (including proven, probable, and possible cases) received 5 mg/kg of intravenous ganciclovir twice daily to prevent disease progression. All statistical analyses were performed using EZR version 1.54 (based on R version 4.0.3, R commander version 2.7-1; Jichi Medical University Saitama Medical Center). 13 Mann-Whitney U test, Fisher's exact test, and log-rank test were used to compare patient characteristics and laboratory data between patients with and without CMV infection during the ICU stay. The cumulative incidence of CMV infection and diseases was calculated using Gray's method, with discharge from the ICU and death without CMV infection being considered as competing events. Univariate regression analyses were performed to identify factors related to CMV infection. For all analyses, a p < 0.05 was considered statistically significant. This study included 59 Japanese patients with severe COVID-19 ( Figure 1 ). The median age (interquartile range) was 60 (56-69) years. (Table 1) . Compared with patients without CMV infection, those with CMV infection showed lower BMI, as well as higher age, duration of systemic corticosteroid therapy and ICU stay, and mortality. On admission, there were higher D-dimer levels in patients with CMV infection than in those without. There were no significant between-group differences in the other laboratory findings (Table 2 ). In total, six (40.0%) patients required antiviral treatment for CMV-DNAemia >200 IU/ml (two patients), possible CMV gastrointestinal diseases (two patients), and possible CMV pneumonia (two patients) (Table S1 ). Four and zero patients with and without CMV infection, respectively, died during the ICU stay (p = 0.003). The causes of death included bacterial septic shock (two patients), bacterial pneumonia (one patient), and possible CMV pneumonia (one patient). Logistic regression coefficients were calculated to identify factors related to CMV infection (Table 3) In patients with COVID-19, interleukin-2 (IL-2) inhibition decreases the number of CD8 + T-lymphocytes; however, blood IL-6 and IL-10 levels increase. 14 As IL-6 is crucially involved in cytokine storms, 15 abnormal IL-6 levels affect the dysregulated inflammatory response and reflect the COVID-19 severity. 16 Our findings indicated that monitoring plasma CMV-DNA levels might contribute to the differentiation of immunosuppressed patients. In immunocompetent patients with critical illness, reactivation from latency, rather than primary infection, is considered to be the cause of CMV infection. 26 Corticosteroids exert immunosuppressive effects mainly by inhibiting the activity of crucial transcriptional regulators of proinflammatory genes and reducing lymphocyte levels. 27 Therefore, exposure to systemic corticosteroids can be a risk factor for bacterial and CMV infection in patients with severe COVID-19. 28, 29 This study showed that the presence of CMV infection and the requirement for anti-CMV treatment were associated with all-cause ICU mortality. Since the mortality causes were critical infectious diseases, the presence of CMV disease and infection with The authors declare that there are no conflict of interests. Kumanogoh. All the authors reviewed and approved the submission of the final manuscript. 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