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.

Cost-effectiveness of Preemptive Therapy Versus Prophylaxis in a Randomized Clinical Trial for the Prevention of Cytomegalovirus Disease in Seronegative Liver Transplant Recipients With Seropositive Donors.

BACKGROUND: The relative costs of preemptive therapy (PET) or prophylaxis for the prevention of cytomegalovirus (CMV) disease in high-risk donor CMV-seropositive/recipient-seronegative (D+/R-) liver transplant recipients have not been assessed in the context of a randomized trial. METHODS: A decision tree model was constructed based on the probability of outcomes in a randomized controlled trial that compared valganciclovir as PET or prophylaxis for 100 days in 205 D+/R- liver transplant recipients. Itemized costs for each site were obtained from a federal cost transparency database. Total costs included costs of implementation of the strategy and CMV disease treatment-related costs. Net cost per patient was estimated from the decision tree for each strategy. RESULTS: PET was associated with a 10% lower absolute rate of CMV disease (9% vs 19%). The cost of treating a case of CMV disease in our patients was $88 190. Considering cost of implementation of strategy and treatment-related cost for CMV disease, the net cost-savings per patient associated with PET was $8707 compared to prophylaxis. PET remained cost-effective across a range of assumptions (varying costs of monitoring and treatment, and rates of disease). CONCLUSIONS: PET is the dominant CMV prevention strategy in that it was associated with lower rates of CMV disease and lower overall costs compared to prophylaxis in D+/R- liver transplant recipients. Costs were driven primarily by more hospitalizations and higher CMV disease-associated costs due to delayed onset postprophylaxis disease in the prophylaxis group.

Effect of Preemptive Therapy vs Antiviral Prophylaxis on Cytomegalovirus Disease in Seronegative Liver Transplant Recipients With Seropositive Donors: A Randomized Clinical Trial.

Importance: Despite the use of a cytomegalovirus (CMV) prevention strategy of antiviral prophylaxis for high-risk CMV-seronegative liver transplant recipients with seropositive donors, high rates of delayed-onset postprophylaxis CMV disease occur. An alternate approach, preemptive therapy (initiation of antiviral therapy for early asymptomatic CMV viremia detected by surveillance testing), has not previously been directly compared with antiviral prophylaxis in these patients. Objective: To compare preemptive therapy with antiviral prophylaxis in CMV-seronegative liver transplant recipients with seropositive donors for the prevention of CMV disease. Design, Setting, and Participants: Randomized clinical trial of preemptive therapy vs antiviral prophylaxis in 205 CMV-seronegative liver transplant recipients with seropositive donors aged older than 18 years. The trial was conducted at 6 academic transplant centers in the United States between October 2012 and June 2017, with last follow-up in June 2018. Interventions: Patients were randomized 1:1 to receive either preemptive therapy (valganciclovir, 900 mg, twice daily until 2 consecutive negative tests a week apart) for viremia detected by weekly plasma CMV polymerase chain reaction for 100 days (n = 100) or valganciclovir, 900 mg, daily for 100 days as antiviral prophylaxis (n = 105). Main Outcomes and Measures: The primary outcome was incidence of CMV disease by 12 months, defined as CMV syndrome (CMV viremia and clinical or laboratory findings) or end-organ disease. Secondary outcomes included acute allograft rejection, opportunistic infections, graft and patient survival, and neutropenia. Results: Among 205 patients who were randomized (mean age, 55 years; 62 women [30%]), all 205 (100%) completed the trial. The incidence of CMV disease was significantly lower with preemptive therapy than antiviral prophylaxis (9% [9/100] vs 19% [20/105]; difference, 10% [95% CI, 0.5% to 19.6%]; P = .04]). The incidence of allograft rejection (28% vs 25%; difference, 3% [95% CI, -9% to 15%]), opportunistic infections (25% vs 27%; difference, 2% [95% CI, -14% to 10%]), graft loss (2% vs 2%; difference, <1% [95% CI, -4% to 4%]), and neutropenia (13% vs 10%; difference, 3% [95% CI, -5% to 12%]) did not differ significantly for the preemptive therapy vs antiviral prophylaxis group, respectively. All-cause mortality at last follow-up was 15% in the preemptive therapy vs 19% in the antiviral prophylaxis group (difference, 4% [95% CI, -14% to 6%]; P = .46). Conclusions and Relevance: Among CMV-seronegative liver transplant recipients with seropositive donors, the use of preemptive therapy, compared with antiviral prophylaxis, resulted in a lower incidence of CMV disease over 12 months. Further research is needed to replicate these findings and assess long-term outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT01552369.

Transmission of Eastern Equine Encephalitis Virus From an Organ Donor to 3 Transplant Recipients.

BACKGROUND: In fall 2017, 3 solid organ transplant (SOT) recipients from a common donor developed encephalitis within 1 week of transplantation, prompting suspicion of transplant-transmitted infection. Eastern equine encephalitis virus (EEEV) infection was identified during testing of endomyocardial tissue from the heart recipient. METHODS: We reviewed medical records of the organ donor and transplant recipients and tested serum, whole blood, cerebrospinal fluid, and tissue from the donor and recipients for evidence of EEEV infection by multiple assays. We investigated blood transfusion as a possible source of organ donor infection by testing remaining components and serum specimens from blood donors. We reviewed data from the pretransplant organ donor evaluation and local EEEV surveillance. RESULTS: We found laboratory evidence of recent EEEV infection in all organ recipients and the common donor. Serum collected from the organ donor upon hospital admission tested negative, but subsequent samples obtained prior to organ recovery were positive for EEEV RNA. There was no evidence of EEEV infection among donors of the 8 blood products transfused into the organ donor or in products derived from these donations. Veterinary and mosquito surveillance showed recent EEEV activity in counties nearby the organ donor's county of residence. Neuroinvasive EEEV infection directly contributed to the death of 1 organ recipient and likely contributed to death in another. CONCLUSIONS: Our investigation demonstrated EEEV transmission through SOT. Mosquito-borne transmission of EEEV to the organ donor was the likely source of infection. Clinicians should be aware of EEEV as a cause of transplant-associated encephalitis.

Macrophage Activation Marker Soluble CD163 Associated with Fatal and Severe Ebola Virus Disease in Humans1.

Ebola virus disease (EVD) is associated with elevated cytokine levels, and hypercytokinemia is more pronounced in fatal cases. This type of hyperinflammatory state is reminiscent of 2 rheumatologic disorders known as macrophage activation syndrome and hemophagocytic lymphohistiocytosis, which are characterized by macrophage and T-cell activation. An evaluation of 2 cohorts of patients with EVD revealed that a marker of macrophage activation (sCD163) but not T-cell activation (sCD25) was associated with severe and fatal EVD. Furthermore, substantial immunoreactivity of host tissues to a CD163-specific antibody, predominantly in areas of extensive immunostaining for Ebola virus antigens, was observed in fatal cases. These data suggest that host macrophage activation contributes to EVD pathogenesis and that directed antiinflammatory therapies could be beneficial in the treatment of EVD.

Detecting Infections Rapidly and Easily for Candidemia Trial, Part 2 (DIRECT2): A Prospective, Multicenter Study of the T2Candida Panel.

Background: Blood cultures are approximately 50% sensitive for diagnosing invasive candidiasis. The T2Candida nanodiagnostic panel uses T2 magnetic resonance and a dedicated instrument to detect Candida directly within whole blood samples. Methods: Patients with Candida albicans, Candida glabrata, Candida parapsilosis, Candida tropicalis, or Candida krusei candidemia were identified at 14 centers using diagnostic blood cultures (dBCs). Follow-up blood samples were collected concurrently for testing by T2Candida and companion cultures (cBCs). T2Candida results are reported qualitatively for C. albicans/C. tropicalis, C. glabrata/C. krusei, and C. parapsilosis. T2Candida and cBCs were positive if they detected a species present in the dBC. Results: Median time between collection of dBC and T2Candida/cBC samples in 152 patients was 55.5 hours (range, 16.4-148.4). T2Candida and cBCs were positive in 45% (69/152) and 24% (36/152) of patients, respectively (P < .0001). T2Candida clinical sensitivity was 89%, as positive results were obtained in 32/36 patients with positive cBCs. Combined test results were both positive (T2+/cBC+), 21% (32/152); T2+/cBC-, 24% (37/152); T2-/cBC+, 3% (4/152); and T2-/cBC-, 52% (79/152). Prior antifungal therapy, neutropenia, and C. albicans candidemia were independently associated with T2Candida positivity and T2+/cBC- results (P values < .05). Conclusions: T2Candida was sensitive for diagnosing candidemia at the time of positive blood cultures. In patients receiving antifungal therapy, T2Candida identified bloodstream infections that were missed by cBCs. T2Candida may improve care by shortening times to Candida detection and species identification compared to blood cultures, retaining sensitivity during antifungal therapy and rendering active candidemia unlikely if results are negative. Clinical Trials Registration: NCT01525095.

New Lineage of Lassa Virus, Togo, 2016.

We describe a strain of Lassa virus representing a putative new lineage that was isolated from a cluster of human infections with an epidemiologic link to Togo. This finding extends the known range of Lassa virus to Togo.

Persistence of Ebola Virus in Ocular Fluid during Convalescence.

Among the survivors of Ebola virus disease (EVD), complications that include uveitis can develop during convalescence, although the incidence and pathogenesis of EVD-associated uveitis are unknown. We describe a patient who recovered from EVD and was subsequently found to have severe unilateral uveitis during convalescence. Viable Zaire ebolavirus (EBOV) was detected in aqueous humor 14 weeks after the onset of EVD and 9 weeks after the clearance of viremia.

Human Ebola virus infection results in substantial immune activation.

Four Ebola patients received care at Emory University Hospital, presenting a unique opportunity to examine the cellular immune responses during acute Ebola virus infection. We found striking activation of both B and T cells in all four patients. Plasmablast frequencies were 10-50% of B cells, compared with less than 1% in healthy individuals. Many of these proliferating plasmablasts were IgG-positive, and this finding coincided with the presence of Ebola virus-specific IgG in the serum. Activated CD4 T cells ranged from 5 to 30%, compared with 1-2% in healthy controls. The most pronounced responses were seen in CD8 T cells, with over 50% of the CD8 T cells expressing markers of activation and proliferation. Taken together, these results suggest that all four patients developed robust immune responses during the acute phase of Ebola virus infection, a finding that would not have been predicted based on our current assumptions about the highly immunosuppressive nature of Ebola virus. Also, quite surprisingly, we found sustained immune activation after the virus was cleared from the plasma, observed most strikingly in the persistence of activated CD8 T cells, even 1 mo after the patients' discharge from the hospital. These results suggest continued antigen stimulation after resolution of the disease. From these convalescent time points, we identified CD4 and CD8 T-cell responses to several Ebola virus proteins, most notably the viral nucleoprotein. Knowledge of the viral proteins targeted by T cells during natural infection should be useful in designing vaccines against Ebola virus.

Favipiravir and Ribavirin Treatment of Epidemiologically Linked Cases of Lassa Fever.

Two patients with Lassa fever are described who are the first human cases treated with a combination of ribavirin and favipiravir. Both patients survived but developed transaminitis and had prolonged detectable virus RNA in blood and semen, suggesting that the possibility of sexual transmission of Lassa virus should be considered.