Unexpected Cytomegalovirus (CMV) Replication Kinetics in CMV Donor-Seropositive, Recipient-Seronegative Liver Transplant Recipients Receiving Preemptive Antiviral Therapy.

BACKGROUND: Detailed cytomegalovirus (CMV) kinetics in donor CMV-seropositive, recipient CMV-seronegative (D+/R-) transplant recipients receiving preemptive therapy (PET) have not been fully defined. METHODS: The study population consisted of the PET arm of a randomized CMV prevention trial in D+/R- liver transplant recipients. CMV DNA polymerase chain reaction (PCR) assays were performed weekly for 100 days using a sensitive assay. Viral load and clinical parameters were compared for patients with or without high-level increase (defined as higher than the group median log10 increase in viral load from baseline after PET initiation). RESULTS: Among 79 patients, 93.6% (74/79) developed an increase from baseline viral loads of median 120 IU/mL to 3350 IU/mL; 25.7% (19/74) of the patients had peak levels >10 000 IU/mL. None of the patients with rise in viral load underwent testing for CMV resistance, and viremia resolved with PET with valganciclovir. Patients with high-level increase in viral load had a significantly lower rate of recurrent viremia than those without such increase (16/40 [40%] vs 28/39 [71.8%], respectively; P = .004). CONCLUSIONS: A majority of D+/R- recipients had a marked increase in viral load after initiation of PET before resolution of viremia. This phenomenon is associated with lower rates of subsequent recurrent viremia and does not necessarily imply antiviral resistance.

Risk Factors for Cytomegalovirus Viremia following Liver Transplantation With a Seropositive Donor and Seronegative Recipient Receiving Antiviral Therapy.

BACKGROUND: The risk factors for development of viremia in high-risk donor cytomegalovirus (CMV)-seropositive and recipient CMV-seronegative (D+R-) transplant recipients are incompletely defined. METHODS: The study population comprised patients in the preemptive therapy (PET) arm of a randomized, controlled trial of PET versus prophylaxis using valganciclovir in D+R- liver transplant recipients. Weekly surveillance monitoring for viremia for 100 days was performed using a sensitive CMV-DNA polymerase chain reaction assays. Risk factors for viremia and time to onset (≤4 vs >4 weeks) of viremia were examined using logistic regression models. RESULTS: Viremia developed in 84% (79/94) of recipients and older donor age was the only independent factor associated with viremia (odds ratio, 2.20 for each quartile increase in donor age; 95% confidence interval [CI], 1.07-4.52; P = .031). Recipients who developed early-onset viremia (within 4 weeks) also had significantly older donors than those with later-onset viremia (difference in age 10.1 years; 95% CI, 2-19; P = .03). CONCLUSIONS: Older donor age was an independent predictor of viremia and earlier-onset of viremia in D+R- liver transplant recipients. Future studies should assess the mechanistic links underlying this novel association. CLINICAL TRIAL REGISTRATION: NCT01552369.

Clinical consequences of primary CMV infection after renal transplantation: a case-control study.

The impact of primary cytomegalovirus infection (pCMV) on renal allograft function and histology is controversial. We evaluated the influence on incidence of acute rejection, allograft loss, allograft function and interstitial fibrosis/tubular atrophy (IF/TA). Retrospective case-control study, recipients transplanted between 2000 and 2014. Risk of acute rejection and allograft loss for those who experienced pCMV infection compared with those who did not, within an exposure period of two months after transplantation. Besides, its influence on allograft function and histology at one to three years after transplantation. Of 113 recipients experienced pCMV infection, 306 remained CMV seronegative. pCMV infection in the exposure period could not be proven as increasing the risk for acute rejection [HR = 2.18 (95% CI 0.80-5.97) P = 0.13] or allograft loss [HR = 1.11 (95%CI 0.33-3.72) P = 0.87]. Combination of pCMV infection and acute rejection posed higher hazard for allograft loss than acute rejection alone [HR = 3.69 (95% CI 1.21-11.29) P = 0.02]. eGFR(MDRD) values did not significantly differ at years one [46 vs. 50], two [46 vs. 51] and three [46 vs. 52]. No association between pCMV infection and IF/TA could be demonstrated [OR = 2.15 (95%CI 0.73-6.29) P = 0.16]. pCMV infection was not proven to increase the risk for acute rejection or allograft loss. However, it increased the risk for rejection-associated allograft loss. In remaining functioning allografts, it was not significantly associated with decline in function nor with presence of IF/TA.

CMV-Specific Cell-Mediated Immunity in Immunocompetent Adults with Primary CMV Infection: A Case Series and Review of the Literature.

Cytomegalovirus-specific cell-mediated immunity (CMV-CMI) in actively infected healthy immunocompetent hosts has been poorly investigated. Conversely, correlates of maternal protective immunity for the fetus after primary infection in pregnancy continue to be studied. The kinetics and magnitude of CMV-specific CMI in immunocompetent primary CMV-infected adults are described. A literature review on CMV-CMI in primarily infected pregnant women and its correlation to the risk of vertical virus transmission is included. Immunological measurements after infection were performed by enzyme-linked ImmunoSPOT assay enumerating IFN-γ secreting CMV-specific T cells, at a single cell level, upon in vitro stimulation with viral antigens. Simultaneously, serological and virological profiles of infected patients were investigated. Patients displayed mild-to-moderate clinical and laboratory profiles for infection, and all showed positive EliSpot results in the early stage of infection (<20 days after onset). The virus-CMI was strong in the majority of patients (58.8%) in which the lowest CMV-DNAemia levels (<300 copies/mL) were detected. Significantly higher viral loads were observed in patients with weak CMV-CMI at the same time-point post-infection (up to 15,104 copies/mL; p < 0.001). T cell response magnitudes to IE-1 and pp65-UL83 peptides were overlapping and stable over time. In these case series, the early presence of CMV-CMI was probably pivotal in controlling viral replication and led to spontaneous viral clearance.

Risk of Symptomatic Infection after Non-Primary Congenital Cytomegalovirus Infection.

Cytomegalovirus (CMV) is the leading cause of congenital infection. Its occurrence is phenotypically heterogeneous. The type of maternal infection, primary or non-primary, is an important factor related to the symptomatic disease, the primary infection was long considered the only cause of severe neonatal disease. We aimed to analyze the association of primary and non-primary infection with pathological outcomes in infants and with long-term sequelae at follow-up. This was a monocentric retrospective observational study on a population of 91 infants diagnosed with a CMV infection at the Neonatal Care Unit of Neonatology at the Sant'Anna Hospital of Turin during the period of June 2005 to December 2018. Infants underwent clinical, laboratory, and neuroradiological evaluations at birth. Subsequently, the patients were monitored in an auxological, neurodevelopment, and audiological follow-up. Regarding primary vs. non-primary infection, we found a higher percentage of incidence of symptomatic and neurological localized infection, as well as long-term sequelae in the latter. However, no significant difference between the two populations was found. We underline the possibility of re-infection in previously immunized mothers (non-primary infection) with unfavorable neonatal and long-term outcomes.

Fulminant anaplastic large cell lymphoma (ALCL) concomitant with primary cytomegalovirus (CMV) infection, and human herpes virus 8 (HHV-8) infection together with Epstein-Barr-virus (EBV) reactivation in a patient with asymptomatic HIV-infection.

BACKGROUND: Most malignant lymphomas in HIV-patients are caused by reactivation of EBV-infection. Some lymphomas have a very rapid fulminant course. HHV-8 has also been reported to be a cause of lymphoma. The role of CMV in the development of lymphoma is not clear, though both CMV and HHV-8 have been reported in tissues adjacent to the tumour in Burkitt lymphoma patients. Here we present a patient with asymptomatic HIV infection, that contracted a primary cytomegalovirus (CMV) infection and human herpes virus 8 (HHV-8) infection. Three weeks before onset of symptoms the patient had unprotected sex which could be possible source of his CMV and also HHV-8 infection He deteriorated rapidly and died with a generalized anaplastic large cell lymphoma (ALCL). METHODS: A Caucasian homosexual male with asymptomatic human immunodeficiency virus (HIV) infection contracted a primary cytomegalovirus (CMV) infection and human herpes virus 8 (HHV-8) infection. He deteriorated rapidly and died with a generalized anaplastic large cell lymphoma (ALCL). Clinical and laboratory records were compiled. Immunohistochemistry was performed on lymphoid tissues, a liver biopsy, a bone marrow aspirate and the spleen during the illness and at autopsy. Serology and PCR for HIV, CMV, EBV, HHV-1-3 and 6-8 was performed on blood drawn during the course of disease. RESULTS: The patient presented with an acute primary CMV infection. Biopsies taken 2 weeks before death showed a small focus of ALCL in one lymph node of the neck. Autopsy demonstrated a massive infiltration of ALCL in lymph nodes, liver, spleen and bone marrow. Blood samples confirmed primary CMV- infection, a HHV-8 infection together with reactivation of Epstein- Barr-virus (EBV). CONCLUSION: Primary CMV-infection and concomitant HHV-8 infection correlated with reactivation of EBV. We propose that these two viruses influenced the development and progression of the lymphoma. Quantitative PCR blood analysis for EBV, CMV and HHV-8 could be valuable in diagnosis and treatment of this type of very rapidly developing lymphoma. It is also a reminder of the importance of prevention and prophylaxis of several infections by having protected sex.

Symptomatic primary Cytomegalovirus infection in a HIV-positive pregnant woman.

We describe a case of symptomatic primary Cytomegalovirus infection in a HIV-positive pregnant woman on antiretroviral treatment with a CD4 count >200 × 10(6)/l requiring intravenous ganciclovir. No adverse consequences from ganciclovir or evidence of congenital Cytomegalovirus infection were found.