Does treatment with antiviral medication affect mortality among immunocompetent individuals with cytomegalovirus reactivation? A systematic review and meta-analysis

Cytomegalovirus (CMV) infection is widespread and usually asymptomatic in immunocompetent individuals. However, during immune suppression, especially after hematopoietic stem cell transplantation (HSCT), viral reactivation may result in symptomatic infection and end-organ disease. Because there is high incidence of CMV seropositivity in Bulgaria, CMV infection/reactivation is an expected common complication in HSCT recipients which requires frequent monitoring. CMV reactivation monitoring via qRT PCR has a significant role in terms of the moment of initiating pre-emptive therapy in these high-risk patients in order to avoid the development of CMV disease and better clinical management. The aim of this study was to determine and analyze the incidence of CMV reactivation in HSCT recipients in a new transplant center in Bulgaria. The incidence of early CMV reactivation after HSCT in our center is very high (76.7%) most likely related to the high-risk donor/recipient (D/R) profile of our recipients. The mean period from HSCT to the first positive PCR result was quite short, 21.5 days on average. The highest-risk group donor-/recipient+ (D-/R+) experienced the longest and the highest levels of viremia, as well as the highest number of reactivations. The nature of the D/R status most significantly affected the degree of viral load. Our data demonstrate the essential role of monitoring of CMV with reliable and sensitive laboratory methods, such as qRT-PCR to avoid development of CMV disease in high-risk patients.

e19065 Background: The impact of early absolute lymphocyte repopulation after allogeneic hematopoietic stem cell transplant has historically been shown to predict the risk of post-transplant infection, and subsequently, non-relapse mortality (NRM). Previous studies have shown that ALC recovery after allogeneic stem cell transplant is associated with risk of viral reactivation and survival. In this study we aim to investigate the role of ALC recovery in the contemporary era with myeloablative haploidentical hematopoietic stem cell transplant (HI-HSCT). Methods: We retrospectively analyzed adult patients at University of Southern California (USC) Norris Cancer Hospital who received myeloablative conditioning haplo-HSCT (Fludarabine with 12 Gy of radiation) from 2014 to 2020. The primary endpoint was correlation between ALC recovery day 21 and risk of viral reactivation including cytomegalovirus (CMV), Epstein-Barr Virus (EBV) and BK virus. ALC recovery cut off was chosen to be 175/uL on day +21 and 500/uL on day +60 based on prior reports. Results: 58 patients were identified as recipients of MAC haploidentical-HSCT. 17 had ALC recovery at day +21. Mean age was 49 years, 31 (53.4%) were males and 27 (46.6%) were females. 41 (70%) patients were Hispanic, 12 (20%) were non-Hispanic White, and the majority had AML (51%). 76% received > 5*106/kg CD34+ cell dose and 78% received CD3 + cell dose < 3*108/kg. Serum CMV, EBV and urine BK virus were detected in 38 (65.5%), 8 (15.7%) and 11 (32.4%) respectively. Clinically significant CMV reactivation (required treatment with antiviral therapy) was detected in 26 (44.8%) patients. Lack of ALC recovery on day +21 did not show correlation with CMV, EBV and BK virus reactivation. Also, the risk of CMV reactivation was not related to day +60 ALC recovery (p-value = 0.469). On univariate analysis, ALC recovery day +21, day +60, and CMV reactivation did not show correlation with overall survival. In multivariate analysis when adjusted for age and pre-transplant CMV status, higher CD 3+ cell dose of > 3*108/kg was associated with reduced risk of CMV reactivation HR = 0.35 (0.15-0.85) p-value = 0.02. Conclusions: Previous studies have established ALC recovery as a predictor of better outcome. This has not been established in patients undertaking myeloablative HI-HSCT. Our study shows that lack of ALC recovery on day +21 does not affect CMV, EBV and BK virus reactivation and risk of CMV reactivation does not correlate with day +60 ALC recovery. Also, ALC recovery and CMV reactivation does not impact overall survival. The use of Letermovir, effective CMV therapies and close viral surveillance in contemporary practice is likely responsible for mitigating poor outcomes with CMV reactivation. Graft composition needs to be studied prospectively, as higher CD3+ cell dose may present an opportunity to reduce CMV reactivation in HI-HSCT.

Cytomegalovirus (CMV) reactivation is widely documented in non-immunosuppressed critically ill patients and was reported in a previous issue of Critical Care to be associated with poor outcomes [1]. Although the question of the causative role of CMV remains under debate, a clinical trial aiming to evaluate the efficacy and safety of prophylactic treatment for prevention of CMV reactivation in immunocompetent patients in critical care has started [2]. To date, few data on patients with burns have been published. However, we know that patients with burns are predisposed to herpes virus infection and that they are good ‘candidates’ for CMV reactivation. As expected, data show a high CMV reactivation rate in patients with burns, from 55 % to 71 % [3,4]. Moreover, CMV reactivation seems to be intense, as 67 % of patients reactivated CMV with a plasma viral load of greater than 1,000 copies/mL and 33 % did so with av iral load of greater than 10,000 copies/mL in the study by Bordes and colleagues [4]. However, available data in the literature are extracted from a subgroup of 20 patients with burns among a cohort of 120 critically ill patients for the study by Limaye and colleagues [3] and from a cohort of 29 patients with severe burns for the study by Bordes and colleagues [4]. These preliminary results emphasize the fact that it is absolutely necessary to better investigate the natural history of CMV reactivation in burns, as antiviral prophylaxis is being evaluated in critically ill patients. Indeed, if antiviral therapy is proved to be efficient on the CMV reactivation, should we treat more than 50 % of our burn patients with antiviral treatment? That is why we think that CMV reactivation still has to be studied in patients with burns, with the aim of answering the following questions: Is CMV reactivation as frequent as previously reported in patients with severe burns? What are the risk factors for CMV reactivation in patients with burns? Is CMV reactivation associated with a poor outcome? And is there a quantitative association between CMV reactivation and poor outcome? The community of burn caregivers should promote large and prospective cohorts of patients in order to investigate CMV reactivation in severe burns as a first step to support the potential indication of antiviral therapy in the coming years.

Cytomegalovirus reactivation in teclistamab-treated multiple myeloma patients: Clinical outcomes and risk factors

Introduction: Some treatments are associated with cytomegalovirus (CMV) reactivation (CMVRA) in patients with multiple myeloma (MM). However, no reports exist on the association between elotuzumab and CMVRA. Therefore, we assessed the incidence of CMVRA in patients with MM who received elotuzumab therapy. Methods: The medical records of 85 patients who underwent elotuzumab therapy were included in the retrospective analysis for CMV positivity. Results: Thirty patients were tested for CMV antigenemia during elotuzumab therapy, and 16 were positive for CMV antigenemia; the cumulative incidence rate of CMVRA 6 months after elotuzumab initiation was 18.4%. The history of allogeneic stem cell transplantation (allo-HSCT) was significantly more common in the CMVRA group (31.2%) than that of the group without CMVRA (8.7%). However, even among patients who did not undergo allo-HSCT, the cumulative incidence rate of CMVRA at 6 months was 15.1%. During CMVRA, the symptoms included fever in 8 cases, while retinitis was observed in 1 case. Five patients required antiviral therapy and CMV antigenemia resolved in all but 1 case. Conclusion: Although the patient population was heterogeneous, CMVRA cannot be underestimated during elotuzumab therapy, and evaluation of CMVRA, especially in symptomatic cases, is clinically important.

Critically-ill patients are at increased risk for cytomegalovirus (CMV) reactivation, associated with adverse clinical outcomes. Given the surge in intensive care unit (ICU) admissions during the COVID-19 pandemic and the continued burden of critical illness associated with the ongoing circulation of SARS-CoV-2, we sought to resolve risk factors for CMV reactivation and disease within the broader ICU patient population including those with and without COVID-19, to identify common and potentially distinct contributors to CMV reactivation and disease in this vulnerable setting. This prospective study included 208 adult ICU (85 COVID-19, and 123 concomitant non-COVID-19) patients, monitored weekly for CMV DNAemia. CMV reactivation was categorized as any detectable DNAemia or as clinically-significant reactivation characterized by high-level DNAemia (≥ 1000 IU/mL) and/or CMV disease. Overall, 29.8% of ICU patients experienced CMV reactivation, with 10.6% exhibiting clinically-significant reactivation. COVID-19 ICU patients had significantly higher rates of any CMV reactivation (40% vs. 23%, p = 0.009), high-level DNAemia (18% vs. 2%, p = 0.001), and CMV disease (12% vs. 1%, p = 0.001) compared to concomitant non-COVID-19 patients. Risk factors associated with clinically-significant CMV reactivation in ICU patients included septic shock, lower absolute lymphocyte count, high-dose steroid use, multiple blood transfusions, and COVID-19. CMV reactivation correlated with prolonged ventilation, hospitalization, and ICU stay, and increased in-hospital mortality. The high rates of clinically-significant CMV reactivation in both COVID-19 and non-COVID-19 ICU patients and the identified risk factors, along with the worse clinical outcomes linked to CMV reactivation, highlight the need for vigilant monitoring of CMV reactivation and for consideration of early antiviral treatment in ICU patients at risk, and support future interventional trials.

To analyze the relationship between cytomegalovirus (CMV) reactivation and leukemia relapse after haploidentical hematopoietic stem cell transplantation (haplo-HSCT). A total of 61 patients diagnosed as hematological malignancies undergoing haplo-HSCT were analyzed retrospectively in our center. In the cohort, 36 patients had CMV reactivation after haplo-HSCT. The 100-day cumulative incidence of CMV reactivation was 59%. Compared with that in patients without CMV reactivation after transplantation, the incidence of leukemia relapse was lower in patients with CMV reactivation (16.9% vs 40.0%, P=0.034). The correlation of CMV reactivation and decreased relapse rate was only found in patients with acute myeloid leukemia (P=0.019). In multivariate analysis, relapsed disease status before transplant was a significant negative predictor of overall survival (OS) and relapse after transplant (RR was 2.866 and 3.331 respectively). CMV reactivation after transplant had a protective effect on disease relapse (RR=0.300, P=0.047). The rate of CMV reactivation after haplo-HSCT is high. CMV reactivation may reduce risk of relapse in patients diagnosed as acute myeloid leukemia undergoing haplo-HSCT. However, CMV reactivation is one of the important predictors of non-relapse death after transplant, active anti-viral treatment is still needed.

CMV Infection after Transplant from Cord Blood Compared to Other Alternative Donors: The Importance of Donor-Negative CMV Serostatus

Epidemiology, risk factors, and outcomes of cytomegalovirus (CMV) reactivation in allogeneic hematopoietic stem cell transplantation: A retrospective observational single-centre study from western India

Incidence and Outcomes of Cytomegalovirus Reactivation after Chimeric Antigen Receptor T Cell Therapy

IntroductionSepsis has been identified as a risk factor for human cytomegalovirus (CMV) reactivation in critically ill patients. However, the contribution of CMV reactivation on morbidity and mortality is still controversial. Therefore, we analyzed the incidence and impact of CMV reactivation on outcome in patients with severe sepsis.MethodsIn a prospective longitudinal double-blinded observational study, 97 adult nonimmunosuppressed CMV-seropositive patients with new onset of severe sepsis were included. Leukocytes, plasma and tracheal secretions were examined weekly for CMV-DNA by PCR. Tracheal secretions were additionally tested for HSV (Herpes Simplex Virus)-DNA. The influence of CMV-reactivation on the endpoints was analysed by Cox proportional-hazard regression analysis. Time-dependency was evaluated by landmark analysis.ResultsSix out 97 died and five were discharged from the hospital within 72 hours and were excluded of the analysis. CMV reactivation occurred in 35 of the 86 (40.69%) analysed patients. HSV infection occurred in 23 of the 35 (65.7%) CMV reactivators. In 10 patients CMV-plasma-DNAemia appeared with a DNA-content below 600 copies/ml in four cases and a peak amount of 2,830 copies/ml on average. In patients with and without CMV reactivation mortality rates were similar (37.1% vs. 35.3%, P = 0.861), respectively. However, in the multivariate COX regression analyses CMV reactivation was independently associated with increased length of stay in the ICU (30.0, interquartile range 14 to 48 vs. 12.0, interquartile range 7 to 19 days; HR (hazard ratio) 3.365; 95% CI (confidence interval) 1.233 to 9.183, P = 0.018) and in the hospital (33.0, interquartile range 24 to 62 vs. 16.0, interquartile range 10 to 24 days, HR 3.3, 95% CI 1.78 to 6.25, P < 0.001) as well as prolonged mechanical ventilation (22.0, interquartile range 6 to 36 vs. 7.5, interquartile range 5 to 15.5 days; HR 2.6,CI 95% 1.39 to 4.94; P < 0.001) and impaired pulmonary gas exchange (six days, interquartile range 1 to 17, vs. three, interquartile range 1 to 7, days in reactivators vs. non-reactivators, P = 0.038). HSV reactivation proved not to be a risk factor for these adverse effects.ConclusionsThese data indicate an independent correlation between CMV reactivation and increased morbidity in the well-defined group of nonimmunosuppressed patients with severe sepsis, but CMV reactivation had no impact on mortality in this group with low CMV-DNA plasma levels. Thus, the potential harms and benefits of antiviral treatment have to be weighed cautiously in patients with severe sepsis or septic shock.

目的分析接受嵌合抗原受体T（CAR-T）细胞治疗的B淋巴细胞肿瘤患者巨细胞病毒（CMV）再激活情况及其影响因素。方法回顾性分析2021年1月至2023年12月于苏州大学附属第一医院接受CAR-T细胞治疗后100 d内进行2次及以上CMV DNA检测和（或）病原体宏基因组测序的B淋巴细胞肿瘤患者的临床资料，比较CMV再激活组和未激活组的临床特征，通过卡方检验和非参数秩和检验分析影响CMV再激活的因素，通过Logistic回归进行危险因素分析。结果共纳入86例患者，其中18例（20.9％）发生了CMV再激活，再激活的中位时间为治疗后20（1～95）d，均为CMV血症，未观察到CMV病的发生。7例患者CMV自然转阴，11例患者抗病毒治疗升级为更昔洛韦、膦甲酸钠等一线药物后CMV转为潜伏状态。CAR-T细胞治疗前抗肿瘤治疗疗程数≥6、CAR-T细胞治疗前2年内行allo-HSCT、治疗前肿瘤未缓解、使用大剂量糖皮质激素和（或）托珠单抗与CMV再激活相关，其中治疗前2年内行allo-HSCT和使用大剂量糖皮质激素和（或）托珠单抗治疗是CMV再激活的独立危险因素。结论接受CAR-T细胞治疗的B淋巴细胞肿瘤患者存在CMV再激活风险，特别是治疗前2年内行allo-HSCT和接受大剂量糖皮质激素和（或）托珠单抗治疗的患者。

We retrospectively compared the impact of the areas over and under the lymphocyte curve (L_AOC vs L_AUC) on cytomegalovirus (CMV) reactivation after allogeneic hematopoietic stem cell transplantation (HSCT). Among 394 consecutive patients who underwent their first allogeneic HSCT at our center between 2007 and 2018, 301 patients met the inclusion criteria. L_AOC was calculated as the area over the lymphocyte curve during lymphopenia (absolute lymphocyte count [ALC] <700/μL). We calculated L_AOC and L_AUC from day 0 to day 15 (L_AOC15, L_AUC15) and from day 0 to day 30 (L_AOC30, L_AUC30). CMV antigenemia was defined as more than 3cells/2 slides by the C10/11 method and detected in 204 cases (CMV reactivation) at a median of 39days after HSCT. Although there were significant differences in L_AOC15, L_AOC30, L_AUC15, and L_AUC30 between patients with and without CMV reactivation, there was no difference in accuracy for predicting CMV reactivation between L_AOC and L_AUC. In a multivariate analysis, L_AOC15 and L_AUC15 were each identified as independent predictive factors for CMV reactivation, along with advanced age and CMV serostatus. However, ALC at day 14 or day 21 was as accurate as area-based indexes such as L_AOC15 and L_AUC15. L_AOC15 and L_AUC15 were significantly associated with longer duration of anti-CMV antiviral therapy while ALC was not. L_AOC15 and L_AUC15 had similar impacts on CMV reactivation. Although these area-based indexes were not superior to ALC for predicting CMV reactivation, they might predict patients who need longer duration of antiviral therapy more accurately.

There is a matter of debate about the clinical impact of cytomegalovirus (CMV) reactivation on the development of late-onset invasive aspergillosis (IA), which occurs 40days or later after allogeneic hematopoietic stem cell transplantation (HSCT). Using a Japanese transplant registry database, we analyzed the risk factors for the development of late-onset IA in 21,015 patients who underwent their first allogeneic HSCT between 2006 and 2017. CMV reactivation was defined as the initiation of preemptive anti-CMV antiviral therapy. Overall, there were 582 cases of late-onset IA, which occurred at a median of 95days after HSCT. The 2-year cumulative incidence was 3.4% (95% confidence interval (CI), 3.0-3.9) in patients with CMV reactivation within 40days after HSCT and 2.5% (95% CI, 2.3-2.8) in those without it (P < 0.001). In a multivariate analysis, CMV reactivation as a time-dependent covariate was significantly associated with the development of late-onset IA (hazard ratio (HR) 1.40, P < 0.001), as well as grade II-IV acute GVHD, age > 50 and HCT-CI ≥ 3 in the entire cohort. If we focus on the subgroup without grade II-IV acute GVHD, which is generally an indication for systemic corticosteroid therapy (n = 12,622), CMV reactivation was still a significant factor for the development of late-onset IA (HR 1.37, P = 0.045) as well as age > 50years, HCT-CI ≥ 3, and cord blood transplantation. In conclusion, CMV reactivation was associated with an increased risk of late-onset IA after allogeneic HSCT independently of acute GVHD. Close monitoring for late-onset IA is necessary for patients who develop CMV reactivation even without grade II-IV acute GVHD.

The introduction of novel antimyeloma agents has improved the outcome of multiple myeloma (MM) dramatically. However, it has also led to an increasing incidence of Herpesviridae family virus infections, including a high incidence of post-transplant cytomegalovirus (CMV) reactivation after treatment with novel agents. We herein retrospectively assessed the CMV reactivation in all 120 newly diagnosed patients with MM consecutively seen and treated at our hospital. CMV antigenemia tests were ordered in 58 patients depending on the clinical context, and the incidence of CMV reactivation and proven/suspected CMV disease requiring antiviral therapy was 20% (24 of 120) and 11% (13 of 120) respectively, including those without stem cell transplantation (SCT). The clinical and laboratory characteristics of these patients were compared with those in 34 CMV antigenemia-negative (CMV-negative) patients. Patients with extramedullary disease or a low absolute lymphocyte count (ALC) had a higher risk of developing CMV reactivation. In addition, the median duration from the time of MM diagnosis to CMV reactivation was 5.0 months. These results suggest that, regardless of whether or not undergoing SCT, elderly patients with MM receiving novel agents should be monitored for CMV reactivation to allow for the timely diagnosis and treatment, especially for those with extramedullary disease.