Encephalopathy Associated with Severe Cytomegalovirus Infection in an Immunocompetent Young Woman

Primary cytomegalovirus (CMV) infection in healthy young adults is usually an asymptomatic or mononucleosis-like syndrome, whereas in immunocompromised patients, CMV can cause significant disease. In this study, we report an unusual case of primary CMV infection wherein the patient, an immunocompetent 21-year-old woman, presented severe encephalopathy, acute hepatitis, retinitis, and reactivation of latent Epstein–Barr virus. She developed confusion, high fever, headache, and tonic-clonic seizures. Brain magnetic resonance imaging showed high-intensity lesions in the medial temporal lobe and basal ganglia. Liver dysfunction was observed, and abdominal computed tomography revealed splenohepatomegaly. After fundus findings, the patient was diagnosed with CMV retinitis. Upon admission, she was treated with intravenous acyclovir and steroid pulse therapy. Considering both her serious clinical condition and elevated serum levels of interleukin-6, we speculated that her condition was similar to cytokine-storm-induced encephalopathy. On day 2 after admission, she showed prompt recovery from these clinical manifestations. Since blood CMV pp65 antigenemia was found to be positive, we administered ganciclovir for 2 weeks. On the basis of her clinical manifestations and the presence of blood CMV DNA and CMV pp65 antigenemia along with IgM kinetics, we finally diagnosed this patient with severe primary CMV infection. She left our hospital without sequelae 20 days after admission. The incidence of severe CMV disease in immunocompetent young adults might be higher than previously recognized. Noninvasive testing for CMV (such as CMV pp65 antigenemia and CMV DNAemia) is widely available and can help early diagnosis. Short-term glucocorticoid therapy might be beneficial in the treatment of encephalopathy in the early stages of primary CMV infection. Considering such a background, clinicians should keep severe primary CMV infection in mind as a differential diagnosis in the clinical setting.

Early Cytomegalovirus Reactivation and Donor Constellation Reduce Early and Late Relapse Incidence of Acute Myeloid Leukemia in a Long-Term Study

Introduction After allogeneic cell transplantation (HCT) for acute myeloid leukemia (AML) relapse remains the main cause of morbidity and mortality. Relapse rates directly translate into patients' overall survival. The connection between early human cytomegalovirus (CMV) replication and reduced leukemic recurrence has first been established by this group (Elmaagacli et. al. Blood 2011), using a pp65-antigenemia assay and confirmed by Green et al. (Blood 2013), Takenaka et al. (BBMT 2015) and others. In a more recent study by Teira et al. (Blood 2016) using PCR to detect reactivation, this effect has been questioned and the controversy remains probably due to methodological differences between studies. Methods Patients with AML received allogeneic HCT at the Department of Bone Marrow Transplantation of the University Hospital Essen between 10/1997 and 10/2017. All patient-, donor-, HCT- and virology data was prospectively documented and retrospectively analyzed. The immunosuppressive regimen consisted of cyclosporine A and methotrexate. The conditioning was according to physician's choice and included only non-anti-thymocyte globuline (ATG) conditioning regimens. Early supportive and follow-up care was identical for all patients. Patients were followed for up to 60 months. Surviving patients were censored at last follow-up date. Competing risk analysis was performed for calculating cause-specific relapse-incidences with non-relapse mortality as competing risk. CMV titers were measured at the Department of Virology using quantitative PCR (qPCR) and a pp65 antigenemia assay. CMV reactivation was defined as a replication of >500 CMV copies per ml EDTA blood or as >25 pp65 antigen expressing cells per 5×105 white blood cells. If several CMV reactivation episodes occurred, only the interval to the first episode after HCT was analyzed. Results A total of 420 consecutive adult patients (median age, 48 years; range, 16-73 years) with AML and HCT were included for analysis. Over 60 months of follow-up, cumulative incidence of CMV reactivation was detected in 28% of patients and AML relapsed in 34%. In this cohort, the sensitivity of qPCR or pp65 detection methods did not differ (p=0.35) with regard to the incidence of CMV reactivation. CMV reactivation associated with significantly reduced AML relapse risk. The relapse incidence (RI) for patients with CMV reactivation was 0.18 (95% Confidence interval (CI), 0.12-0.25) compared to 0.41 (95% CI, 0.35-0.46) for patients without CMV reactivation (p<0.0001). This significant difference was reproduced for prognostic AML subgroups in first complete remission (RI, 0.14 with CMV reactivation versus 0.35 without; p=0.02) and for higher risk AML (RI, 0.20 versus 0.45; p<0.0001). Notably, donor-recipient serostatus constellation significantly (p=0.005) associated with AML relapse reduction, independently of CMV reactivation. CMV positive donors had a RI of 0.40 (95% CI, 0.33-0.46) compared to 0.28 in CMV negative donors (95% CI, 0.22-0.34). Discussion This new PCR dataset confirms previous reports (Elmaagacli et al. 2011; Takenaka et al. 2015) of an independent reduction of AML relapse risk after CMV reactivation, using qPCR detection in a homogeneous population of AML patients. While the association between CMV reactivation and early relapse (< day+100) has also been confirmed by Green et al. (Blood 2013) and relapse (>day +100) by Takenaka et al. (BBMT 2015), our data shows that late relapse (>24 months) may occur in patients without CMV reactivation. While the aforementioned studies exclusively used pp65 antigenemia titers as a determinant of CMV reactivation, Teira et al. (Blood 2016) analyzed PCR samples. The sensitivity of CMV reactivation using PCR or pp65 antigen titers was identical in our dataset. With regard to the on-going controversy on the role of CMV reactivation and AML relapse, this data shows a reduction of relapse in the quantitative PCR age. Disclosures Turki: Neovii Biotech: Other: subsidies for the costs of travel. Beelen:Medac: Consultancy, Other: Travel Support.

Pp65 antigenemia and cytomegalovirus diagnosis in patients with lupus nephritis: report of a series.

ABSTRACT Introduction: In contrast to organ transplantation, few studies correlate the monitoring of pp65 antigenemia with a diagnosis of cytomegalovirus (CMV) in patients with systemic lupus erythematosus (SLE). Objective: To highlight the importance of CMV outside transplantation, we monitored pp65 antigenemia in a series of SLE patients. Methods: From March 2015 to March 2016, SLE patients presenting kidney involvement, fever, and an unclear infection at hospital admission were monitored through pp65 antigenemia. The pp65 antigenemia assay, revealed by immunofluorescence, was correlated with clinical and laboratory findings. Results: We included 19 patients with a suspected unclear infection. A positivity for pp65 antigenemia was found in seven patients (36.8%). The mean age was 33.5 ± 11.2 years, 16 (84%) were females, and 16 (84%) were black. Lymphopenia, anemia, and higher scores of SLEDAI were significantly more common in pp65-positive patients. Five patients received antiviral therapy with ganciclovir. Although receiving specific CMV treatment, one patient died because of suspected CMV disease. Conclusions: Pp65 antigenemia might be relevant in SLE patients, and studies with a greater number of patients are needed in order to establish sensitivity and specificity of pp65 antigenemia in different clinical contexts of SLE patients.

Cytomegalovirus (CMV) Serostatus: High Importance of Choosing Seropositive Donors for Seropositive Patients When Using Rabbit Antithymocyte Globulin (ATG)

Introduction: In published studies that included mostly hematopoietic cell transplants (HCTs) not using in vivo T cell depletion by ATG, there is a substantial survival difference between D-R- and D+R- patients, and a very small or no survival difference between D-R+ and D+R+ patients. We set out to determine the impact of donor CMV serostatus on survival after HCTs using ATG. Methods: A total of 919 patients underwent myeloablative HCT for hematologic malignancies in Alberta between 1999 and 2014, with a uniform graft versus host disease (GVHD) prophylaxis using ATG (4.5 mg/kg given between day -2 and 0) in addition to methotrexate and cyclosporine. Monitoring for CMV reactivation was performed until at least day 100 after transplant using pp65 antigenemia (before 2008) or CMV DNAemia by quantitative polymerase chain reaction (since 2008). Preemptive therapy typically with ganciclovir was started whenever pp65 antigenemia exceeded 10 to 20 positive cells/200,000 granulocytes or CMV DNAemia exceeded 25,000 IU/mL plasma. Significance of survival difference between patient groups was tested using Cox proportional hazards analysis. Significance of difference in nonrelapse mortality (NRM) or cumulative incidence of relapse (CIR) was tested using Fine-Gray analysis (nonrelapse death was a competing risk of relapse and vice versa, in addition to graft failure and second malignancy). In all analyses, covariates included patient age (>45 vs ≤45), disease stage (acute leukemia in first remission, chronic myeloid leukemia in first chronic phase and myelodysplasia with <5% marrow blasts were considered good risk, all others poor risk), graft type (marrow vs PBSCs) and donor type (human leucocyte antigen [HLA] matched sibling vs other [typically matched unrelated]). Results: D-R- and D+R- patients had similar survival (no significant difference) (blue vs orange curve, figure 1). D-R+ patients had a substantially lower survival than D+R+ patients with an estimated 5 year survival of 41% versus 60% respectively (Hazard Ratio [HR], 1.6; P = 0.001; 95% confidence interval[CI], 1.22-2.09) (red vs green curve, figure 1). This was due to higher NRM (sub hazard ratio [SHR], 1.76; P = 0.003; 95% CI, 1.212-2.58), not CIR. This appeared to be due to higher GVHD-associated mortality. We then compared D-R+ HLA matched sibling transplants with D+R+ HLA matched unrelated donor transplants to assess whether for a CMV seropositive patient with a CMV seronegative HLA matched sibling, search for a CMV seropositive HLA matched unrelated donor could be justified. D-R+ HLA matched sibling transplant recipients had a substantially lower survival than D+R+ 8/8 HLA allele matched unrelated donor transplant recipients with an estimated 5 year survival of 45% versus 66% respectively (HR, 1.7, P = 0.01, 95% CI, 1.10-2.89) (green vs orange curve, figure 2). This suggests that in the scenario of a seropositive patient with a seronegative matched sibling, unrelated donor search is justified. Conclusion: Contrary to recommendations for HCTs not using ATG, choosing a seronegative donor for a seronegative patient is unimportant, whereas choosing a seropositive donor for a seropositive patient is very important (~20% absolute 5 year survival gain). Even if a seronegative HLA matched sibling donor is available for a seropositive patient, it is better to select a seropositive HLA matched unrelated donor. Disclosures No relevant conflicts of interest to declare.

CMV Reactivation Is Associated With a Lower Incidence Of Relapse After Allo-SCT For ALL

Background CMV reactivation is an important cause of morbidity and mortality of allogeneic stem cell transplantation (allo-SCT). Recent studies demonstrated reduction of relapse risk after early replicative CMV infection in acute myelocytic leukemia (AML) and chronic myeloid leukemia (CML) patients. Here, we studied the relationship between CMV reactivation and leukemic relapse in acute lymphoblastic leukemia (ALL) patients. Patients and Methods 115 patients (median age, 28 years; range, 14-56) with de novo ALL underwent allo-SCT from HLA-matched sibling (n=59) donors or unrelated (n=56) donors. CMV pp65 antigenemia was used for monitoring posttransplant CMV reactivation. Results CMV reactivation before day 100 was observed in 47 patients (40.9%) (median day, 44 days, range, 10-100 days). The follow-up time varied from 10 to 90 months (median, 43 months), the estimated overall survival at 5 years was 52% in patients without opposed to 68% in patients with early pp65-antigenemia (P =.035). The 5-year disease free survival (DFS) was 39% vs 47% (P =.018). CMV pp65 antigenemia was associated with a decreased risk of relapse by day 100 among patients with ALL (HR 0.41, 95%CI 0.2-0.9) by multivariate analysis. Furthermore, CMV reactivation was associated with increased non-relapse mortality (HR 1.15, 95% CI 0.3-3.6). Conclusion Early replicative CMV infection is an independent and substantial factor associated with decreased leukemic relapse risk in ALL transplant recipients. Disclosures: No relevant conflicts of interest to declare.