Risk Factors For Cytomegalovirus Reactivation Research Articles

Risk Factors for Cytomegalovirus Reactivation during the Treatment of ANCA-Associated Vasculitis: A retrospective cohort study of the J-CANVAS study.

Cytomegalovirus (CMV) reactivation during immunosuppressive therapy poses a risk of severe infections. This study aimed to investigate the risk factors of CMV reactivation in patients with microscopic polyangiitis and granulomatosis with polyangiitis using a nationwide cohort in Japan. This retrospective cohort study used data from the Japan Collaborative Registry of anti-neutrophil cytoplasmic antibody-associated vasculitis. The outcome was as CMV reactivation up to 48 weeks after treatment initiation. We explored the risk factors for CMV reactivation by comparing the two groups. Of the 454 patients, CMV reactivation occurred in 89 (19.6%). The univariate analysis showed that patients with CMV reactivation were older (p<0.001), had higher Birmingham Vasculitis Activity Scores (BVAS) (p=0.004) and BVAS renal scores (p<0.001), and had received glucocorticoid pulse (p=0.004). The logistic regression analysis showed that hypoalbuminemia (odds ratio [OR]: 0.55, 95% confidence interval [CI]: 0.31-0.98), and low serum IgG (OR: 0.94, 95% CI: 0.89-1.00) were risk factors for CMV reactivation. Hypoalbuminemia and low serum IgG levels were risk factors for CMV reactivation. It is necessary to accurately identify high-risk patients and closely monitor their condition.

Expansion of effector memory Vδ2neg γδ T cells associates with cytomegalovirus reactivation in allogeneic stem cell transplant recipients.

Cytomegalovirus (CMV) reactivation is a significant concern following allogeneic stem cell transplantation. While previous research has highlighted the anti-CMV reactivation effect of γδ T cells in immunocompromised transplant patients, their characterization in recipients at high risk of CMV reactivation remains limited. This study focused on D+/R+ recipients (where both donor and recipient are CMV seropositive) at high risk of CMV reactivation. We analyzed 28 patients who experienced CMV recurrence within 100 days post-allogeneic hematopoietic stem cell transplantation, along with 36 matched recipients who did not experience CMV recurrence. Clinical data from both groups were compared, and risk factors for CMV reactivation were identified. Additionally, CMV viral load was measured, and flow cytometric analysis was conducted to assess changes in peripheral blood γδ T cell proportions, subpopulation distribution, and differentiation status. We also analyzed the CDR3 repertoire of the TCR δ chain in different γδ T cell subsets. Functional analysis was performed by measuring the lysis of CMV-infected cells upon stimulation. CMV reactivation post-transplantation was associated with acute graft-versus-host disease (aGvHD) and reactivation of non-CMV herpesviruses. Notably, CMV reactivation led to sustained expansion of γδ T cells, primarily within the Vδ2neg γδ T cell subpopulation, with a trend toward differentiation from Naive to effector memory cells. Analysis of the δ chain CDR3 repertoire revealed a delay in the reconstitution of clonal diversity in Vδ2neg γδ T cells following CMV reactivation, while Vδ2pos T cells remained unaffected. Upon stimulation with CMV-infected MRC5 cells, the Vδ2neg γδ T cell subpopulation emerged as the primary effector cell group producing IFN-γ and capable of lysing CMV-infected cells. Moreover, our findings suggest that NKG2D is not necessary involved in Vδ2neg γδ T cell-mediated anti-CMV cytotoxicity. This study provides novel insights into the role of γδ T cells in the immune response to CMV reactivation in transplantation recipients at high risk of CMV infection. Specifically, the Vδ2neg γδ T cell subpopulation appears to be closely associated with CMV reactivation, underscoring their potential role in controlling infection and reflecting CMV reactivation in HSCT patients.

Prevalence and risk factors of cytomegalovirus reactivation in critically Ill patients with COVID-19 pneumonia.

In critically ill patients with COVID-19, secondary infections are potentially life-threatening complications. This study aimed to determine the prevalence, clinical characteristics, and risk factors of CMV reactivation among critically ill immunocompetent patients with COVID-19 pneumonia. A retrospective cohort study was conducted among adult patients who were admitted to ICU and screened for quantitative real-time PCR for CMV viral load in a tertiary-care hospital during the third wave of the COVID-19 outbreak in Thailand. Cox regression models were used to identify significant risk factors for developing CMV reactivation. A total of 185 patients were studied; 133 patients (71.9%) in the non-CMV group and 52 patients (28.1%) in the CMV group. Of all, the mean age was 64.7±13.3 years and 101 patients (54.6%) were males. The CMV group had received a significantly higher median cumulative dose of corticosteroids than the non-CMV group (301 vs 177 mg of dexamethasone, p<0.001). Other modalities of treatments for COVID-19 including anti-viral drugs, anti-cytokine drugs and hemoperfusion were not different between the two groups (p>0.05). The 90-day mortality rate for all patients was 29.1%, with a significant difference between the CMV group and the non-CMV group (42.3% vs. 24.1%, p = 0.014). Median length of stay was longer in the CMV group than non-CMV group (43 vs 24 days, p<0.001). The CMV group has detectable CMV DNA load with a median [IQR] of 4,977 [1,365-14,742] IU/mL and 24,570 [3,703-106,642] in plasma and bronchoalveolar fluid, respectively. In multivariate analysis, only a cumulative corticosteroids dose of dexamethasone ≥250 mg (HR = 2.042; 95%CI, 1.130-3.688; p = 0.018) was associated with developing CMV reactivation. In critically ill COVID-19 patients, CMV reactivation is frequent and a high cumulative corticosteroids dose is a significant risk factor for CMV reactivation, which is associated with poor outcomes. Further prospective studies are warranted to determine optimal management.

Letermovir prophylaxis reduced cytomegalovirus reactivation and resistance post umbilical cord blood transplantation.

To explore the impact of letermovir (LET) prophylaxis on cytomegalovirus (CMV) reactivation and resistance in both adult and paediatric umbilical cord blood transplantation (UCBT) patients, we retrospectively compared 43 UCBT patients who received LET as CMV prophylaxis with a historical cohort of 207 UCBT patients without LET usage. LET was administered from Day +1 to Day +100. The 180-day cumulative incidence of CMV reactivation (47.3% vs. 74.4%, p < 0.001) and the proportion of refractory CMV reactivation (15.0% vs. 42.9%, p = 0.016) were significantly lower than those in the control group. However, more frequent late CMV infection (31.0% vs. 4.3%, p = 0.002) and the 180-day cumulative incidence of Epstein-Barr virus (EBV) reactivation (9.3% vs. 3.4%, p = 0.087) were observed in UCBT patients with LET prophylaxis. Meanwhile, older age (>15 years old) and the occurrence of pre-engraftment syndrome were identified as the significant risk factors for CMV reactivation, and in patients at high risk, the incidence of CMV reactivation in the LET group was lower than that in the control group (46.7% vs. 86.5%, p < 0.001), while this decline was less pronounced among patients at low risk (47.8% vs. 62.1%, p = 0.120).

Cytomegalovirus Reactivations in Allogeneic Hematopoietic Stem Cell Transplantation from HLA-Matched and Haploidentical Donors with Post-Transplantation Cyclophosphamide

Cytomegalovirus (CMV) reactivations cause significant morbidity in allogeneic hematopoietic stem cell transplantation (HSCT) recipients. Graft-versus-host disease (GVHD) prophylaxis with post-transplantation cyclophosphamide (PTCy) is associated with an increased risk of CMV infections. Data are limited comparing HSCT with PTCy performed from matched sibling donors (MSDs), matched unrelated donors (MUDs), and haploidentical (Haplo) donors. In the present study, we aimed to characterize CMV reactivation and recurrence in patients with hematologic malignancies undergoing HSCT from MSD, MUD, and Haplo donors using PTCy as GVHD prophylaxis in the pre-letermovir era. We also analyzed risk factors of CMV reactivation, including GVHD as a time-dependent variable, on the incidence and mortality associated with CMV infections. We analyzed CMV reactivation in patients undergoing HSCT from 160 MSDs, 124 MUDs, and 82 Haplo donors from a single institution. Uniform GVHD prophylaxis with PTCy, sirolimus, and mycophenolate mofetil was given irrespective of donor type. Overall, 46% of patients had at least 1 CMV reactivation. The 1-year cumulative incidence of CMV infection was 39% for MSD, 44% for MUD, and 62% for Haplo donors (P < .001), with 96% of reactivations occurring before day +100. Multivariate analysis identified factors associated with the first CMV reactivation, including Haplo donor, positive recipient CMV serology, older patient age, and grade II-IV acute GVHD. The 1-year cumulative incidence of second reactivation from HSCT was 13%. Recipient CMV seropositivity, older patient age, and grade II-IV acute GVHD, but not type of donor, were identified as adverse factors for second CMV reactivation in multivariate analysis. The 1-year cumulative incidence of a third reactivation post HSCT was 4.4%. Ten cases of CMV disease were recorded, with no attributable deaths. Nevertheless, the risk for nonrelapse mortality was greater for patients who experienced CMV reactivation in multivariate time-dependent Cox model analysis. CMV reactivation is frequent in HSCT with PTCy in patients not receiving letermovir prophylaxis. Identified risk factors include the use of a Haplo donor, recipient CMV seropositivity, and grade II-IV acute GVHD. The prevalence of recurrent CMV reactivations is a noteworthy issue, especially after acute GVHD, warranting trials of secondary prophylaxis strategies.

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

Introduction: Cytomegalovirus (CMV) reactivation is a major complication among seropositive allogeneic hematopoietic cell transplantation (HCT) recipients; however, the incidence and outcomes of CMV reactivation in patients undergoing chimeric antigen receptor T (CAR T) cell therapy remain poorly understood. Methods: Single-center retrospective study of 109 adult CMV seropositive patients who received CAR T cell therapy between February 2018 and February 2023. CMV viral load was monitored at the discretion of the treating physician. CMV outcomes were CMV reactivation (any viremia) and clinically significant CMV (viremia or tissue invasive disease requiring antiviral treatment). The study was approved by our institutional review board and conducted consistent with the principles in the Declaration of Helsinki. A p-value of &amp;lt;0.05 was considered statistically significant. Statistical analyses were performed using GraphPad Prism Software, version 10.0.0. Results: During the study period, there were a total of 148 patients who received CAR T cell therapy. Patients who were CMV seronegative, had history of previous allogeneic HCT, or those who received letermovir prophylaxis were excluded. In total, 109 patients who were CMV seropositive met the inclusion criteria. The patient characteristics are presented in Table 1. Of the 109 patients, 69% received Axicabtagene Ciloleucel (Yescarta), 15% received Brexucabtagene Autoleucel (Tecartus), 8% received Tisagenlecleucel (Kymriah), 5% received Idecabtagene Vicleucel (ABECMA), and 3% received Lisocabtagene Maraleucel (Breyanzi). Eighty-four patients (77%) developed any grade of CRS with the median day of CRS onset being 4 days (IQR, 2 to 6). Forty-six patients (42%) developed any grade of ICANS. Among patients who developed CRS, 74 (88%) received tocilizumab, 58 (69%) received dexamethasone, and 9 (11%) received anakinra. For dexamethasone group, the median dosage was 103 mg (IQR, 45 to 160). In those receiving tocilizumab, the median number of doses was 2.5 (IQR, 1 to 4) and the dosage was standard 8 mg/kg. 31 patients (28%) had evidence of CMV reactivation (any viremia) and 10 patients (9%) had clinically significant CMV reactivation requiring treatment. The median time from CAR T cell infusion to CMV reactivation was 19 days (IQR, 9 to 31). Among those with clinically significant CMV reactivation, the median peak viremia was 2388 IU/mL; six of these patients (60%) developed CMV syndrome with none having tissue invasive disease; and 9 (90%) had documented clearance of the virus in response to antiviral therapy. In this group, there were 2 deaths but were not attributed to CMV reactivation. One was due to fungemia while the other patient's death was attributed to CAR T therapy related toxicities causing multiorgan failure. Among those who didn't reactivate CMV, 37 patients (47%) received dexamethasone, at a median dose of 90 mg (IQR, 25 to 145), whereas in the 10 patients with clinically significant CMV reactivation, 100% received dexamethasone (P=0.001) with a median dose of 130 mg (IQR, 74 to 263). Additionally, those who received tocilizumab and anakinra were also at a significantly higher risk for clinically significant CMV reactivation (p=0.027 and p=0.03, respectively). Conclusions: CMV reactivation is a common complication of CAR T cell therapy in CMV seropositive individuals. Although confirmatory studies are needed, our data shows that administration of immunosuppression, in particular steroids, for management of CAR T cell toxicities is a major risk factor for CMV reactivation, and close monitoring for preemptive therapy or antiviral prophylaxis might be indicated in this setting.

Time-dependent analysis of the impact on early cytomegalovirus reactivation of HLA mismatch and acute graft-versus-host disease after allogeneic hematopoietic cell transplantation from related donors in acquired aplastic anemia.

Cytomegalovirus (CMV) reactivation is an important issue in allogeneic hematopoietic cell transplantation (HCT). The incidence of early CMV reactivation is notably high in HLA-mismatched HCT. However, the interactions between HLA mismatch and acute graft-versus-host disease (aGvHD), a time-dependent event, make it methodologically challenging to evaluate the independent impact on CMV reactivation of the two variables. We retrospectively analyzed 355 patients with acquired aplastic anemia who received related donor transplants using a unified antithymocyte globulin-based platform. Patients were divided into group 1 (6/6 HLA match), group 2 (1-2/6 HLA allelic mismatch), and group 3 (3/6 HLA allelic mismatch). The impact of covariates was analyzed through two models: (1) time-dependent Cox and (2) dynamic landmarking analysis. The time-dependent Cox model showed that the HLA mismatch of 3/6 alleles (hazard ratio (HR) =1.852, P = .004) and aGvHD (HR = 1.009, P = .019) were independent risk factors for CMV reactivation. With the dynamic landmarking analysis, a higher HLA disparity correlated to increased early CMV reactivation (HR = 1.606, P = .001) at all time points. Developing aGvHD following HCT was generally associated with a higher incidence of CMV reactivation (HR = 1.623, P = .013), though its impact decreased with successive later landmark time points. In conclusion, our data suggest that the higher HLA disparity and aGvHD increases susceptibility to early CMV reactivation. In particular, the dynamic landmarking analysis demonstrated the time-varying effect of aGvHD on CMV reactivation, and HLA mismatch showed a profound impact over time following HCT.

Cytomegalovirus Infection Post-Allogeneic Stem Cell Transplantation: Experience from a Country with High Seropositivity

Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Limited data are available from developing countries regarding the frequency of CMV infection and treatment outcomes. We enrolled 230 consecutive patients undergoing allogeneic HSCT for various hematologic disorders at the Armed Forces Bone Marrow Transplant Center/National Institute of Blood And Marrow Transplant between February 2017 and December 202. CMV reactivation post-HSCT was monitored weekly starting at day +30 and continuing until day +100, and preemptive antiviral therapy was administered to prevent CMV disease in all HSCT recipients with ≥2000 CMV copies/mL. The median age of the study cohort was 9.5 years (range, .6 to 53 years), and the male:female ratio was 2.4:1. The most frequent indication for HSCT was beta thalassemia major (36.1%), followed by aplastic anemia (23.9%). Malignant disorders constituted 20% of all the patients. Pretransplantation CMV seropositivity was 99.1% for the recipients and 99.5% for the donors. CMV infection was seen in 66.1% of the patients, and the median time to CMV DNAemia was 36 days (range, 12 to 95 days). Preemptive antiviral therapy was administered to 140 patients with a CMV viral load ≥2000 copies/mL (61%). In multivariate analysis, patient age >12 years, steroid administration, and use of mycophenolate mofetil with or without post-transplantation cyclophosphamide was associated with the greatest probability of CMV reactivation. Overall survival was 97.4% in patients without CMV reactivation, compared to 80.3% in those with CMV reactivation (P=.001). Event-free survival was 78.7% in the total study cohort, including 89.7% for patients without CMV reactivation and 73% for patients with CMV reactivation (P=.003). Our study is the first from this region to explore the frequency of CMV seropositivity and CMV infection, risk factors for CMV reactivation, and outcomes of antiviral therapy in HSCT recipients.

CMV infection is a risk factor for hemorrhagic cystitis after hematopoietic stem cell transplantation.

Hemorrhagic cystitis (HC) is a common complication after transplantation. The purpose of this study was to examine the incidence and risk factors for HC after hematopoietic stem cell transplantation (HSCT). The records of patients who underwent allogenic HSCT from January 2012 to December 2018 at our institution were retrospectively reviewed. Cox proportional regression and Kaplan-Meier analyses were performed to determine independent risk factors for HC. The statistical analysis was performed in May 2020. A total of 173 patients underwent HSCT, and 53 (30.6%) developed grade 2 or 3 HC cystitis at a median of 37days (range - 5 to 98days) after transplantation. Thirty-two patients developed moderate (grade 2) cystitis and 21 severe (grade 3) cystitis. Of the 173 patients, 61 developed acute graft-versus-host disease (GVHD) (median onset day 24) and 79 experienced cytomegalovirus (CMV) reactivation (median onset day 35). The relative risk (RR) of developing a CMV infection for patients with acute GVHD was 2.77 times that of patients without acute GVHD (P < 0.001). CMV infection was the only independent variable significantly associated with HC in both univariate and multivariate analyses. The estimated hazard ratio (HR) of CMV infection for the development of HC was 5.57 (95% confidence interval [CI]: 2.52 to 12.33, P < 0.001). CMV infection is an independent risk factor for the development of HC after HSCT, and acute GVHD is a risk factor for CMV reactivation. Decreasing the frequency of GVHD after HSCT may result in a lower frequency of HC.

Risk factors associated with cytomegalovirus reactivation in patients receiving immunosuppressive therapy for rheumatic diseases: a retrospective study

Immunosuppressive treatment is a common cause of cytomegalovirus (CMV) reactivation. However, there is no consensus regarding the risk factors for CMV reactivation in rheumatic diseases. Therefore, this study aimed to elucidate the risk factors associated with CMV reactivation. We retrospectively collected the data of 472 patients with rheumatic diseases whose CMV pp65 antigen (C7-HRP) titer was measured. We divided the patients into those with and those without C7-HRP. We retrospectively collected data on age, sex, primary condition and organ involvement, and blood test results. We also investigated the use of immunosuppressants and the maximum and cumulative doses of prednisolone (PSL). We performed univariate and multivariate analyses to identify risk factors for CMV reactivation. Multivariate analysis showed that higher age (71.2 vs. 64.4 years, p = 0.0022), hypoalbuminemia (2.9 vs. 3.4 g/dL, p = 0.0104), higher creatinine level (1.2 vs. 0.9 mg/dL, p = 0.0026), cyclosporine use (8.2 vs. 3.6%, p = 0.0101), and higher maximum (552.4 vs. 243.3 mg, p < 0.0001) and cumulative (2785.9 vs. 1330.5 mg, p < 0.0001) doses of PSL were associated with CMV reactivation. Older age, hypoalbuminemia, higher creatinine level, cyclosporine use, and higher maximum and cumulative doses of PSL were significant risk factors for CMV reactivation in rheumatic diseases.

S2489 Differentiating CMV Colitis From GVHD in Post-Transplant Patients: A Case Study

Introduction: Cytomegalovirus (CMV) infection can complicate the clinical course of immunocompromised patients including allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients, where the infection can be serious. CMV can involve different organs including lungs, brain, eyes, and the GI tract. Signs and symptoms of CMV infection may overlap with other conditions including graft-versus-host disease (GVHD), a multisystem disorder commonly seen in allo-HSCT recipients. Case Description/Methods: A 57-year-old female presented with abdominal pain and diarrhea. Past medical history included relapsed acute myeloid leukemia, treated with azacitidine and venetoclax followed by allo-HSCT. She was recently hospitalized for suspected GVHD with skin, liver, and gastrointestinal involvement. She was also found to have a CMV viral load of 920 IU/mL. Endoscopy showed diffuse inflammation across the GI tract, with biopsies revealing apoptotic bodies consistent with acute GVHD. She was treated with ruxolitinib and prednisone for GVHD, and valganciclovir prophylactically for CMV viremia. At this presentation, labs were notable for lymphocytes of 39 x103/uL and platelets of 22 x 103/uL, and CMV viral load of 1,822,242 IU/mL. CT imaging revealed thickened distal small bowel loops, cecum, and right colon, and edematous gastric walls with submucosal enhancement. Infectious work-up, including stool culture, ova/parasite, and clostridium, was negative. She underwent endoscopic evaluation; EGD showed white discoloration that washed off in the esophagus and diffuse erythematous mucosa in the stomach (Figure). Biopsies from gastric mucosa and right colon mucosa revealed focal nuclear changes. Immunohistochemical stains were positive for CMV. She was diagnosed with refractory CMV colitis and treated with maribavir with improvement of symptoms and reduction of viral load, and prior course of steroids was tapered. Discussion: Immunosuppression for GVHD has been identified as an important risk factor for CMV reactivation. Differentiating CMV colitis and GI-GVHD poses a diagnostic challenge, and endoscopic evaluation is needed to address this. Endoscopy can identify cecal ulcers, a reliable finding for CMV colitis in patients with GVHD after allo-HSCT.1 It is important to timely identify CMV colitis to prevent post-transplant morbidity and mortality. This case also demonstrates effectiveness of maribavir, a novel antiviral, for refractory post-transplant CMV colitis.Figure 1.: EGD images showing white discoloration in the entire esophagus and diffuse erythematous mucosa in the entire examined stomach.

Risk factor analysis for cytomegalovirus reactivation under prophylaxis with letermovir after allogeneic hematopoietic stem cell transplantation.

Letermovir has been approved as a novel cytomegalovirus (CMV) prophylactic agent after allogeneic hematopoietic stem cell transplantation (HSCT). However, there are still insufficient data to properly evaluate the real-world role of letermovir, and the risk factors for CMV reactivation under letermovir prophylaxis have not been clarified. We performed a single-institution retrospective analysis of patients under prophylaxis with or without letermovir who underwent allogeneic HSCT between March 2012 and December 2019. In August 2018, letermovir was added to the clinical practice at our institution for the prophylaxis of CMV reactivation in allogeneic HSCT recipients. Patients who underwent HSCT without prophylactic letermovir from March 2012 until September 2018 served as a historical control. The cumulative incidence of clinically significant CMV infection (CS-CMVi) was significantly lower in the letermovir group than in the historical control group not receiving letermovir (30.2%vs. 71.6%, p < .05, at 100 days). In addition, the cumulative incidence of non-relapse mortality (NRM) at day 500 was significantly lower in the letermovir group (4.7%vs. 19.8%, p < .05). We then performed a risk factor analysis for developing CS-CMVi in the letermovir group. The only significant factor identified by this multivariable analysis was transplantation from a CMV seronegative donor to a seropositive recipient (Hazard ratio = 2.76, 95% confidence interval 1.14-6.68, p < .05). Our study showed that letermovir prophylaxis significantly reduced the incidence of CS-CMVi and NRM in a real-world setting and that the CMV serostatus of the donor remained as a risk factor for CS-CMVi even under letermovir prophylaxis.

Anti-Cytomegalovirus Therapy: Whether and When to Initiate, Those Are the Questions.

Cytomegalovirus (CMV) reactivation in patients with autoimmune bullous disease (AIBD) or severe drug eruption treated with immunosuppressive therapy was traditionally thought to be merely an epiphenomenon of the underlying immunosuppression. However, a detailed review of the clinical course of these patients revealed that CMV reactivation occurs upon rapid immune recovery, which is termed immune reconstitution inflammatory syndrome (IRIS), and that the timely initiation of anti-CMV therapy, when combined with maintenance doses of immunosuppressive agents, contributes to a rapid resolution of severe infectious complications thought to be refractory to conventional immunosuppressive therapies and unrelated to CMV reactivation. Thus, CMV reactivation resulting in fatal outcomes (CMV-IRIS) can be prevented by the timely detection of CMV DNA or antigens in the blood and by rapidly starting anti-CMV therapy while maintaining immunosuppressive therapy. Anti-CMV therapy is highly recommended for patients with CMV-IRIS or severe drug eruption who have risk factors for CMV reactivation resulting in fatal outcomes.

Graft-Vs-Host Disease (GvHD) Prophylaxis with Post-Transplant Cyclophosphamide (PTCy) and Thymoglobulin (ATG) Are More Important Determinants of Cytomegalovirus (CMV) Reactivation after Allogeneic Hematopoietic Cell Transplantation (HCT) Than Ex-Vivo T-Cell Depletion in the Era of Pre-Emptive Therapy

Background:Cytomegalovirus (CMV) is a common cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT) despite major advances in diagnostic techniques and antiviral prophylactic strategies. The relative impacts of donor/recipient CMV serologic status, disease-specific and transplant-related prognostic factors on the risk of CMV reactivation and survival are undefined.Methods:We studied the outcome of 199 patients (median age, 46 years; range 17-71 years) receiving allogeneic HCT at National University Cancer Institute of Singapore (NCIS) between January 2016 and December 2020. Their hematologic diseases included AML (n=92), ALL (n=46), MDS (n=19), lymphomas (n=19), MPN (n=7) and others (n=16) such as refractory myelomas and aplastic anemias. The conditioning regimens used were either myeloablative (n=80) or reduced intensity conditioning (n=119) prior to an allograft from different donor sources. T-cell depletion (TCD) was used for GVHD prophylaxis in 124 patients; and this included post-transplant cyclophosphamide (PTCy, n=31), ex-vivo T-cell receptor alpha-beta / CD45RA depletion (TCRab/CD45RA) (ex-vivo TCD, n=31) for haploidentical HCT, or thymoglobulin (ATG, n=62) for matched unrelated donor (MUD) HCT.Results:With a median follow-up duration of 15.6 months (range, 0.2-63.6 months), 136 (68.3%) patients had CMV reactivation (median onset, 27.5 days) while 6 (3.0 %) patients developed clinically significant CMV disease, such as colitis, retinitis and encephalitis. The cumulative incidences of CMV reactivation within the first 100 days among the recipients of matched unrelated donor (MUD) (n=60), mismatched related donor or unrelated donor (MMRD/MMUD) (n=60), umbilical cord blood (UCB) (n=18) and matched related donor (MRD) (n=61) HCT were 71.6 %, 61.7 %, 50.0 % and 32.7 %, respectively (p<0.001).There were no statistically significant differences in overall survival (OS, p=0.830) and disease-free survival (DFS, p=0.983) at 5 years between CMV-seropositive (D+/R+ or D-/R+, n=181) and CMV-seronegative recipients (D-/R- or D+/R-, n=18). There were also no significant differences in the cumulative incidences of CMV reactivation within 100 days (p=0.879), CMV end-organ disease (p=0.522) and non-relapse mortality (NRM, p=0.202), respectively. HCT-CI score of ≥1 (p=0.005) and the use of reduced intensity conditioning regimen (p<0.001) were associated with a higher NRM at 2 years. There was also a trend towards higher NRM among patients with peak CMV DNA titers of above 1000 IU/ml, but this did not reach statistical significance (p=0.188).The secondary objective of this study was to determine the risk factors associated with CMV reactivation within the first 100 days post-transplant. There was no statistically significant impact of the donor or recipient CMV serostatus (p=0.790) on the risk of CMV reactivation. In multivariable analysis, the use of any T-cell depletion (p<0.001) was a significant predictor of CMV reactivation. In a subset analysis comparing the 3 different methods of TCD, the use of ATG (p=0.004) and PTCy (p=0.005) was found to be associated with an increased risk of CMV reactivation, but not in patients receiving ex-vivo TCD (p=0.184) (Figure 1). Notably, patients receiving ex-vivo TCD haploidentical HCT was not associated with a higher risk of CMV reactivation as compared to the recipients of MRD HCT without any TCD.Conclusions:Our study concluded that CMV serologic status did not affect the incidence of CMV reactivation, NRM, OS and DFS in patients undergoing allogeneic HCT. The use of PTCy and ATG for GVHD prophylaxis, remains the most important risk factor for CMV reactivation in the era of pre-emptive therapy and hence, the need for aggressive prevention strategies in this vulnerable group of patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Risk Factors of Cytomegalovirus Reactivation in Ulcerative Colitis Patients: A Meta-Analysis.

Cytomegalovirus (CMV) infection is associated with exacerbation of disease activity in patients with ulcerative colitis (UC). However, the risk factors for CMV reactivation in this population remain debatable. This meta-analysis was performed to identify the risk factors for CMV reactivation in UC patients. PubMed, Cochrane Library, EMBASE, Web of Science, and China National Knowledge Infrastructure were searched from the inception of these databases to 31 August 2021, with the aim of identifying studies that investigated the risk factors of CMV reactivation in UC patients. A quality assessment of the included studies was performed with the Newcastle-Ottawa Scale. The publication bias was assessed respectively via a funnel plot and Egger’s regression asymmetry test. The robustness and reliability of each outcome were evaluated by sensitivity analysis. Twenty studies were included in the final meta-analysis, comprising a total of 2099 patients with UC. A significantly higher risk of CMV reactivation was observed in patients with severe UC (OR = 1.465, 95% CI: 1.107 to 1.939, p = 0.008), pancolitis (OR = 2.108, 95% CI: 1.586 to 2.800, p = 0.0001), older age of UC onset (MD = 6.212, 95% CI: 2.552 to 9.971, p = 0.001), as well as use of glucocorticoids (OR = 4.175, 95% CI: 3.076 to 5.666, p = 0.001), immunosuppressants (OR = 1.795, 95% CI: 1.289 to 2.501, p = 0.001), and azathioprine (OR = 1.444, 95% CI: 1.012 to 2.061, p = 0.043). However, infliximab treatment was observed not to increase the occurrence of CMV reactivation in patients who suffered from UC. In contrast, 5-aminosalicylic acid (OR = 0.674, 95% CI: 0.492 to 0.924, p = 0.014) was associated with a lower risk of CMV reactivation. Patients with UC should be closely monitored for risk factors of CMV reactivation in order to provide timely diagnosis and antiviral treatment.

Early cytomegalovirus reactivation after heart transplantation: A case report and literature review

Reactivation of cytomegalovirus is one of the most significant morbidities in solid organ transplant recipients. Reports describing the risk factors for cytomegalovirus reactivation in heart transplantation are scarce. We present a case in which viral reactivation 9 days after heart transplantation resulted in cytomegalovirus enterocolitis. Before transplantation, the patient received extracorporeal membrane oxygenation. Cytomegalovirus reactivation occurred under prophylactic medication with valganciclovir and progressed to cytomegalovirus enterocolitis, complicated by ischemia and a small bowel perforation. The patient died of repeated septic shock, severe gastrointestinal tract complications, and cytomegalovirus hepatitis. A review of 70 heart transplant recipients at our hospital from 2005 to 2020 revealed that cytomegalovirus reactivation occurred more frequently in those who received pretransplantation extracorporeal membrane oxygenation than in those who did not (36.4% vs. 6.8%, P = 0.018). This finding suggests that early diagnosis and prompt management of cytomegalovirus reactivation in patients receiving extracorporeal membrane oxygenation as a bridge to heart transplantation is crucial.

Risk factors for cytomegalovirus reactivation in patients with kidney disease under immunosuppressive therapy.

Cytomegalovirus (CMV) is a herpes virus that causes latent infections, and its reactivation due to immunosuppression can cause fatal complications. CMV reactivation is a complication frequently occurring in patients with kidney disease who require immunosuppressive therapy, and, therefore, this study retrospectively examined its risk factors. Patients who received immunosuppressive therapy and underwent the CMV antigenemia test (CMV antigenemia: C7-HRP) for the treatment of primary nephritis (minimal change disease, membranous nephropathy, membranoproliferative glomerulonephritis, focal glomerulosclerosis, and IgA nephropathy) and anti-neutrophil cytoplasmic autoantibody (ANCA)-associated nephritis diagnosed at Saiseikai Kurihashi Hospital from January 2014 to December 2019 were recruited as study participants. Risk factors of CMV reactivation were examined using univariable and multivariable analyses. Among the 64 patients (36 men and 28 women; median age, 72years) included, 34 had primary nephritis (20 minimal disease changes, 10 membranous nephropathy, 1 membranoproliferative glomerulonephritis, 1 focal glomerulosclerosis, and 2 IgA nephropathy) and 30 had ANCA-associated nephritis. Regarding glucocorticoid (GC), 43 patients received oral GC therapy, whereas 21 received GC pulse therapy. CMV reactivation participants showed significant differences in age, ANCA-associated nephritis, hemoglobin level, lymphocyte count, maximum GC dosage, and hemodialysis in univariable analysis. Multivariate analysis showed significantly lower lymphocyte counts in CMV-reactivated patients, but no significant difference in other factors. In patients with kidney disease, who require immunosuppressive therapy, CMV reactivation risk is high in patients with low lymphocyte count, and monitoring CMV during the treatment course could lead to early diagnosis and treatment of CMV disease.

Genetic variants associated with cytomegalovirus infection after allogeneic hematopoietic cell transplantation

AbstractHuman cytomegalovirus (CMV) reactivation is a frequent complication of allogeneic hematopoietic cell transplantation (HCT). Despite routine screening for CMV reactivation and early antiviral treatment, the rates of CMV-related complications after HCT remain high. Genetic variants in both the donor and recipient have been associated with the risk of CMV reactivation and disease after HCT, but these associations have not been validated, and their clinical importance remains unclear. In this study, we assessed 117 candidate variants previously associated with CMV-related phenotypes for association with CMV reactivation and disease in a cohort of 2169 CMV-seropositive HCT recipients. We also carried out a genome-wide association study (GWAS) for CMV reactivation and disease in the same cohort. Both analyses used a prespecified discovery and replication approach to control the risk of false-positive results. Among the 117 candidate variants, our analysis implicates only the donor ABCB1 rs1045642 genotype as a risk factor for CMV reactivation. This synonymous variant in P-glycoprotein may influence the risk of CMV reactivation by altering the efflux of cyclosporine and tacrolimus from donor lymphocytes. In the GWAS analysis, the donor CDC42EP3 rs11686168 genotype approached the significance threshold for association with CMV reactivation, although we could not identify a mechanism to explain this association. The results of this study suggest that most genomic variants previously associated with CMV phenotypes do not significantly alter the risk for CMV reactivation or disease after HCT.

High Incidence of CMV Reactivation after Haploidentical Donor Hematopoietic Cell Transplantation Using High-Dose Post-Transplant Cyclophosphamide, and Its Impact on Transplant Outcomes

Haploidentical donor hematopoietic cell transplantation (HaploHCT) using high-dose post-transplant cyclophosphamide (PTCy) has been increasingly used in patients with hematologic disorders with promising results. However, limited data is available on the incidence, pattern, and risk factors for cytomegalovirus (CMV) reactivation after HaploHCT with PTCy. Furthermore, the impact of CMV reactivation on HaploHCT outcomes has not been well understood in these patients. In this retrospective study we evaluated 119 consecutive patients undergoing HaploHCT for hematological diseases using PTCy between January 2008 and December 2016 at City of Hope under the IRB approved protocol. CMV reactivation was monitored by our institutional PCR assay (quantitative detection limit: 500gc/ml, qualitative limit: 250gc/ml) at least once a week for 100 days post-HCT, with preemptive anti-CMV therapy for positive PCR according to the institutional guidelines.The median age of the cohort was 43 years (range: 2 to 71 years); 47 patients were female and 72 were male. CMV serostatus of donor/recipient was D-R- in 7, D+R- in 6, D-R+ in 23, and D+R+ in 82 patients. Patients received fully ablative (n=46) or reduced-intensity/non-myeloablative conditioning (n=73) followed by peripheral blood stem cell (n=81) or bone marrow (n=38) graft from sibling (n=42) or non-sibling Haplo donor (n=77). Graft versus host disease (GVHD) prophylaxis was PTCy plus tacrolimus/mycophenolate mofetil. Diagnoses of these patients were acute leukemia (n=80), bone marrow failure (n=15), lymphoma (n=11), chronic leukemia (n=6), hemoglobinopathies (n=5), and multiple myeloma (n=2). The HCT-comorbidity index was more than 2 in 42% (n=50) of the patients.Cumulative incidence (CI) of CMV reactivation for the entire cohort was 69.2% (95%CI: 59.8-76.8%) at 100-days, with the median time to reactivation at 35 days (Figure 1a). While for seropositive recipients (n=105), cumulative incidence of CMV reactivation was 76.5% (95%CI: 66.9-83.6%) with the median onset at 33 days. The median CMV PCR values at onset was 624 gc/ml (range: <500 - 9,930) while the median peak PCR value during the 100-day period was 2965 gc/ml (range: <500 - 221,125). The median duration of CMV reactivation was 21 days and 28% (n=33) of patients had recurrent CMV reactivation during the first 100 days post-HCT. In our cohort there was no patient who developed CMV disease.In univariate analyses the only significant risk factor for CMV reactivation was recipient serostatus (HR=0.06, 95%CI: 0.01 to 0.40 for R- compared to R+, p<0.001) (Figure 1b). Acute GVHD (aGVHD) was not associated with CMV reactivation when analyzed as a time-dependent variable partly due to lower incidence and later onset of aGVHD (100 days incidence: 36.7%; median onset day was not reached, range= 18 to 88) than CMV reactivations (median: 33 days, range= 7 to 54).We then evaluated the impact of CMV reactivation in a landmark analysis of 101 patients who were relapse free for 100 days. The median follow up duration in this subgroup was 12.3 months (range: 3.4 to 99.1). In univariate analysis, CMV reactivation was not associated with overall survival (OS), relapse-free survival (RFS), relapse incidence, or non-relapse mortality (NRM). Similarly, the high-peak CMV reactivation or prolonged CMV reactivation (total duration or total episodes) was not predictive of poor outcomes in this cohort. Interestingly, the risk of chronic GVHD was greater in patients who had no CMV reactivation than those who developed prolonged/recurrent CMV reactivations (56.0% vs. 20.5%, p= 0.048, Figure 2).In conclusion, HaploHCT with PTCy was associated with a high rate of CMV reactivations in seropositive recipients. However, due to pre-emptive therapy approach, CMV reactivation did not translate into higher rate of CMV disease. Despite many patients requiring a long course of preemptive anti-CMV therapy, there was no obvious association between CMV reactivation and survival outcomes. The observed association between CMV reactivation and reduced risk of chronic GVHD warrant further clinical and correlative immunologic studies. [Display omitted] DisclosuresNademanee:seattle Genetics: Speakers Bureau.

Latent Cytomegalovirus Reactivation in Patients With Liver Failure: A 10-Year Retrospective Case-Control Study, 2011-2020.

BackgroundThe aim of this study was to explore potential risk factors for cytomegalovirus (CMV) reactivation and their impact on liver failure patient outcomes.MethodsA 10-year retrospective case–control study was conducted in adult participants, who were diagnosed with liver failure and had undergone CMV DNA tests. CMV reactivation cases were matched with controls at a 2:1 ratio based on age, sex, and year of admission. Univariate and multivariate analyses were used to explore risk factors for CMV reactivation.ResultsBetween January 2011 and April 2020, 198 adult patients with liver failure and available CMV DNA test results were enrolled into the study. Among them, 33 patients had detectable CMV DNA in their plasma (16.7%). Clinical manifestations and liver function were comparable between the CMV reactivation and non-reactivation groups. However, CMV reactivation may triple mortality in patients with liver failure. We found that nearly 50% of patients in the CMV-positive group received glucocorticoids, compared to 13.6% in the CMV-negative group (P=0.000). The median total glucocorticoid dose included 836.5 mg of methylprednisolone (IQR 308.7-1259.0 mg) in the CMV-positive group, which was significantly higher than that in the CMV-negative group. A multivariate analysis revealed that glucocorticoid use significantly increased the risk of CMV reactivation (adjusted OR, 4.84; 95% CI, 1.61–14.49; P=0.005). Patients with CMV reactivation tended to be associated with higher white cell counts (adjusted OR, 1.21; 95% CI, 1.08–1.36; P=0.002).ConclusionsHigh intravenous glucocorticoid doses may be the most important risk factor for CMV reactivation in liver failure.