Evaluation of the effects of Astragalus polysaccharides as immunostimulants on the immune response of crucian carp and against SVCV in vitro and in vivo.

This experiment was conducted to evaluate the immunomodulatory effect and antiviral activity of Astragalus polysaccharides (APS) in crucian carp and epithelioma papulosum cyprinid (EPC) cells. Two diets containing 0 and 2 g/kg, APS were fed crucian carp for 56 days. The results showed that supplementation with APS significantly upregulated the immune-related indices including the levels of IgM, the activities of LZM, AKP and ACP, and the contents of C3 and C4. At the same time, compared with the CK group, adding APS to the feed significantly upregulated the expression of IL-8, IL-10, IL-1ß, IFN-α, IFN-γ, MyD88, TGF-ß and TNF-α in the spleen, kidney, liver and intestine of crucian carp. In addition, when the crucian carp were injected with SVCV, the survival rates of fish in the APS group and the control group were 48.87% and 13.76%, respectively. These results indicated that dietary APS could improve the resistance of crucian carp against SVCV infection. APS also significantly decreased viral titer and inhibited apoptosis induced by SVCV in EPC cells. These results indicated that APS could stimulate the immune response of crucian carp and improve the abilities of crucian carp and EPC cells to resist SVCV infection.

IL-6 and IL-10 Levels, Rather Than Viral Load and Neutralizing Antibody Titers, Determine the Fate of Patients With Severe Fever With Thrombocytopenia Syndrome Virus Infection in South Korea.

Severe fever with thrombocytopenia syndrome (SFTS) is a new tick-borne viral disease, and most SFTS virus (SFTSV) infections occur via bites from the tick Haemaphysalis longicornis; however, SFTSV transmission can also occur through close contact with an infected patient. SFTS is characterized by acute high fever, thrombocytopenia, leukopenia, elevated serum hepatic enzyme levels, gastrointestinal symptoms, and multiorgan failure and has a 16.2 to 30% mortality rate. In this study, we found that age, dyspnea rates, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase, multiorgan dysfunction score (MODS), viral load, IL-6 levels, and IL-10 levels were higher in patients with fatal disease than in patients with nonfatal disease during the initial clinical course of SFTS. In addition, we found that IL-6 and IL-10 levels, rather than viral load and neutralizing antibody titers, in patients with an SFTSV infection strongly correlated with outcomes (for severe disease with an ultimate outcome of recovery or death).

SARS-CoV-2 RNAaemia in children: An Iranian referral hospital-based study.

Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA is generally detected in nasopharyngeal swabs, viral RNA can be found in other samples including blood. Recently, associations between SARS-CoV-2 RNAaemia and disease severity and mortality have been reported in adults, while no reports are available in pediatric patients with coronavirus disease 2019 (COVID-19). The aim of this study was to evaluate the mortality, severity, clinical, and laboratory findings of SARS-CoV-2 RNA detection in blood in 96 pediatric patients with confirmed COVID-19. Among all patients, 6 (6%) had SARS-CoV-2 RNAaemia. Out of the six patients with SARS-CoV-2 RNAaemia, four (67%) had a severe form of the disease, and two out of the 6 patients with SARS-CoV-2 RNAaemia passed away (33%). Our results show that the symptoms more commonly found in the cases of COVID-19 in the study (fever, cough, tachypnea, and vomiting), were found at a higher percentage in the patients with SARS-CoV-2 RNAaemia. Creatine phosphokinase and magnesium tests showed significant differences between the positive and negative SARS-CoV-2 RNAaemia groups. Among all laboratory tests, magnesium and creatine phosphokinase could better predict SARS-CoV-2 RNAemia with area under the curve  levels of 0.808 and 0.748, respectively. In conclusion, 67% of individuals with SARS-CoV-2 RNAaemia showed a severe COVID-19 and one-third of the patients with SARS-CoV-2 RNAaemia passed away. Our findings suggest that magnesium and creatine phosphokinase might be considered as markers to estimate the SARS-CoV-2 RNAaemia.

The impact of viremia on organ failure, biomarkers and mortality in a Swedish cohort of critically ill COVID-19 patients.

The spread of virus via the blood stream has been suggested to contribute to extra-pulmonary organ failure in Coronavirus disease 2019 (COVID-19). We assessed SARS-CoV-2 RNAemia (RNAemia) and the association between RNAemia and inflammation, organ failure and mortality in critically ill COVID-19 patients. We included all patients with PCR verified COVID-19 and consent admitted to ICU. SARS-CoV-2 RNA copies above 1000/ml measured by PCR in plasma was defined as RNAemia and used as surrogate for viremia. In this cohort of 92 patients 59 (64%) were invasively ventilated. RNAemia was found in 31 patients (34%). Hypertension and corticosteroid treatment was more common in patients with RNAemia. Extra-pulmonary organ failure biomarkers and the extent of organ failure were similar in patients with and without RNAemia, but the former group had more renal replacement therapy and higher mortality (26 vs 16%; 35 vs 16%, respectively, p = 0.04). RNAemia was not an independent predictor of death at 30 days after adjustment for age. SARS-CoV2 RNA copies in plasma is a common finding in ICU patients with COVID-19. Although viremia was not associated with extra pulmonary organ failure it was more common in patients who did not survive to 30 days after ICU admission.Trial registration: ClinicalTrials NCT04316884.

Dynamics of Blood Viral Load Is Strongly Associated with Clinical Outcomes in Coronavirus Disease 2019 (COVID-19) Patients: A Prospective Cohort Study.

The prevalence and clinical relevance of viremia in patients with coronavirus disease 2019 (COVID-19) have not been well studied. A prospective cohort study was designed to investigate blood viral load and clearance kinetics in 52 patients (median age, 62 years; 31 [59.6%] male) and explore their association with clinical features and outcomes based on a novel one-step RT droplet digital PCR (RT-ddPCR). By using one-step RT-ddPCR, 92.3% (48 of 52) of this cohort was quantitatively detected with viremia. The concordance between the blood and oropharyngeal swab tests was 60.92% (53 of 87). One-step RT-ddPCR was tested with a 3.03% false-positive rate and lower 50% confidence interval of detection at 54.026 copies/mL plasma. There was no reduction in the blood viral load in all critical patients, whereas the general and severe patients exhibited a similar ability to clear the viral load. The viral loads in critical patients were significantly higher than those in their general and severe counterparts. Among the 52 study patients, 30 (58%) were discharged from the hospital. Among half of the 30 discharged patients, blood viral load remained positive, of which 76.9% (10 of 13) completely cleared their blood viral load at follow-up. Meanwhile, none of their close contacts had evidence of infection. Quantitative determination of the blood viral test is of great clinical significance in the management of patients with coronavirus disease 2019.

Prognostic Factors on Graft Function in Pediatric Kidney Recipients.

BACKGROUND: Graft survival in pediatric kidney transplant recipients has increased in the last decades. Determining prognostic factors for graft function over time allows the identification of patients at risk for graft loss and could lead to improvement of current guidelines. METHODS: Data were collected among pediatric kidney transplant recipients in a single center during the first 5 years after transplantation. Mixed model analysis was used to indicate possible prognostic factors for the loss of graft function. RESULTS: A total of 100 pediatric kidney transplant recipients were analyzed. Negative prognostics of graft function are higher donor age and higher recipient age, presence of obstructive uropathology, re-transplant, and occurrence of BK viremia. The negative influence on graft function of both donor age and presence of obstructive uropathology increased over time. In this study, the factors that did not influence graft function over time were the number of HLA mismatches, pre-transplant dialysis, intra-abdominal graft placement, ischemia time, occurrence of acute rejection, presence of lower urinary tract dysfunction, occurrence of urinary tract infections, and infections with cytomegalovirus and Epstein-Barr virus. CONCLUSIONS: This study showed that a higher donor age and higher recipient age, presence of obstructive uropathology, a re-transplant, and the occurrence of BK viremia were negative prognostic factors of graft function over time, in the first 5 years after transplant. Graft function was comparable between steroid-sparing regimens (preferable in low-risk patients) and regimens including steroids (for special reasons).

Coronavirus Disease 2019 Viremia, Serologies, and Clinical Course in a Case Series of Transplant Recipients.

Here we report a single-center cohort of 6 patients (4 kidney only, and 2 simultaneous liver/kidney transplants) diagnosed with COVID-19 at a median of 1.9 years (range = 0.2-9.3 years) post transplant. Five (of 6) patients required inpatient admission, 2 patients (mortality = 33%) died. Among those with mortality, an increased concentration of inflammatory biomarkers (interleukin-6 and C-reactive protein) was noted with a lack of response to interleukin-6 blockade, remdesivir, and/or convalescent plasma. None of the kidney-only transplants (4/6; 67%) had elevation in plasma donor-derived cell-free DNA above the previously published cut-off of 1%, suggesting absence of significant allo-immune injury. Four (of 5) admitted patients had detectable SARS-CoV-2 (severe acute respiratory syndrome-coronavirus 2) in blood on samples obtained at/during hospitalization. Of the 4 discharged patients, 2 patients with undetectable virus on repeat nasopharyngeal swabs had seroconversion with positive SARS-CoV-2 IgG formation at 30 to 48 days post infection. One patient had prolonged shedding of virus on nasopharyngeal swab at 28 days post discharge despite lack of symptoms. In this preliminary report, we find that immunocompromised transplant patients had higher rates of RNAemia (67%) than reported in the general population (15%), seeming absence of allo-immune injury despite systemic inflammation, and formation of IgG overtime after recovery from infection.

Adenovirus Viral Kinetics and Mortality in Ex Vivo T Cell-Depleted Hematopoietic Cell Transplant Recipients With Adenovirus Infection From a Single Center.

BACKGROUND: We report on predictors of adenovirus (ADV) viremia and correlation of ADV viral kinetics with mortality in ex vivo T-cell depleted (TCD) hematopoietic cell transplant (HCT). METHODS: T cell-depleted HCT recipients from January 1, 2012 through September 30, 2018 were prospectively monitored for ADV in the plasma through Day (D) +100 posttransplant or for 16 weeks after the onset of ADV viremia. Adenovirus viremia was defined as ≥2 consecutive viral loads (VLs) ≥1000 copies/mL through D +100. Time-averaged area under the curve (AAUC) or peak ADV VL through 16 weeks after onset of ADV viremia were explored as predictors of mortality in Cox models. RESULTS: Of 586 patients (adult 81.7%), 51 (8.7%) developed ADV viremia by D +100. Age <18 years, recipient cytomegalovirus seropositivity, absolute lymphocyte count <300 cells/µL at D +30, and acute graft-versus-host disease were predictors of ADV viremia in multivariate models. Fifteen (29%) patients with ADV viremia died by D +180; 8 of 15 (53%) died from ADV. Peak ADV VL (hazard ratio [HR], 2.25; 95% confidence interval [CI], 1.52-3.33) and increasing AAUC (HR, 2.95; 95% CI, 1.83-4.75) correlated with mortality at D +180. CONCLUSIONS: In TCD HCT, peak ADV VL and ADV AAUC correlated with mortality at D +180. Our data support the potential utility of ADV viral kinetics as endpoints in clinical trials of ADV therapies.

96-week results of a dual therapy with darunavir/ritonavir plus rilpivirine once a day vs triple therapy in patients with suppressed viraemia: virological success and non-HIV related morbidity evaluation.

Antiretroviral therapies have been tested with the goal of maintaining virological suppression with a particular attention in limiting drug-related toxicity. With this aim we designed the DUAL study: a randomized, open-label, multicenter, 96 weeks-long pilot exploratory study in virologically suppressed HIV-1+ patients with the aim of evaluating the immunovirological success and the impact on non-HIV related morbidity of switching to a dual therapy with darunavir-ritonavir (DRV/r) and rilpivirine (RPV). We recruited patients who received a PI/r-containing HAART for ≥6 months, HIV-RNA < 50 cp/mL for ≥3 months, eGFR > 60 mL/min/1,73m2, without DRV or RPV RAMs. We randomized patients in arm A: RPV + DRV/r QD or arm B: ongoing triple therapy. The primary endpoint has been defined as the percentage of patients with HIV-RNA < 50 cp/mL at week 48 (ITT). VACS index, Framingham CVD risk (FRS) and urinary RBP (uRBP) were calculated. We used Chi-square or Fisher statistics for categorical variables and Mann-Whitney U for continuous ones. Forty-one patients were enrolled (22 in arm A, 14 in arm B, plus 5 screening failures): 30 patients reached 96 weeks: 100% had HIV-RNA < 50 cp/mL in arm A versus 91.7% in arm B. Similar changes were observed in median CD4/mL between baseline and week 96 (+59 versus - 31, p: n.s.). Thirty-one in arm A and 23 in arm B adverse events took place, whereas only 1 was serious (arm A: turbinate hypertrophy, unrelated to HAART). Among the 6 discontinuations (3 in A, 3 in B), only 1 was related to adverse event (arm A: G3 depression, insomnia, weakness). VACS index, median FRS and median uRBP values did not vary from baseline to week 96. At 96-weeks all patients switched to a QD 2-drug regimen based on DRV/r + RPV maintained HIV-RNA suppression, but a single patient who showed a virological failure at week 4. CD4 counts increased overtime without significant differences between the two arms. The novel dual regimen was well tolerated with the same amount of discontinuation as the control arm. VACS index, FRS and uRBP did not differ between arms at week 96.

Outcomes of kidney transplant recipients admitted to the intensive care unit: a retrospective study of 200 patients.

BACKGROUND: Risk of over-immunosuppression or immunization may mitigate the overall and long-term renal outcomes of kidney transplant recipients (KTR) admitted to the ICU in the modern era but remain poorly described. Thus, there is an unmet need to better characterize the survival of KTR admitted to the ICU, but also the renal and immunological outcomes of survivors. METHODS: Retrospective observational study that included 200 KTR admitted between 2010 and 2016 to the ICU of a teaching hospital (median age 61 years [IQR 50.7-68]; time from transplantation 41 months [IQR 5-119]). Survival curves were compared using the Log-rank test. RESULTS: Mortality rates following admission to the ICU was low (26.5% at month-6), mainly related to early mortality (20% in-hospital), and predicted by the severity of the acute condition (SAPS2 score) but also by Epstein Barr Virus proliferation in the weeks preceding the admission to the ICU. Acute kidney injury (AKI) was highly prevalent (85.1%). Progression toward chronic kidney disease (CKD) was observed in 45.1% of survivors. 15.1% of survivors developed new anti-HLA antibodies (donor-specific antibodies 9.2% of cases) that may impact the long-term renal transplantation function. CONCLUSIONS: Notwithstanding the potential biases related to the retrospective and monocentric nature of this study, our findings obtained in a large cohort of KTR suggest that survival of KTR admitted in ICU is good but in-ICU management of these patients may alter both survival and AKI to CKD transition, as well as HLA immunization. Further interventional studies, including systematic characterization of the Epstein Barr virus proliferation at the admission (i.e., a potential surrogate marker of an underlying immune paralysis and frailty) will need to address the optimal management of immunosuppressive regimen in ICU to improve survival but also renal and immunological outcomes.

DNA Viremia Is Associated with Hyperferritinemia in Pediatric Sepsis.

OBJECTIVE: To evaluate the relationship between detection of DNA viruses, ferritin, and outcomes in children with severe sepsis. STUDY DESIGN: We enrolled 75 pediatric patients with severe sepsis admitted to a tertiary care children's hospital. Plasma ferritin was measured within 48 hours of diagnosis and subsequently twice weekly. Herpes simplex type 1, human herpesvirus 6, Epstein-Barr virus, cytomegalovirus, and adenovirus DNAemia were assessed by polymerase chain reaction. RESULTS: The incidence of DNAemia was increased significantly in patients with ferritin ≥1000 ng/mL (78% vs 28%; P < .05). Patients with ferritin ≥1000 ng/mL were more likely to have multiple DNA viruses detected in plasma (39% vs 4%; P < .001). The number of viruses detected in plasma directly correlated with the degree of hyperferritinemia and development of combined hepatobiliary and hematologic dysfunction after we controlled for bacterial and fungal coinfections (P < .05) as well as increased mortality after we controlled for severity of illness and cancer diagnosis (OR 2.6, 95% CI 1.1-6.3, P < .05). CONCLUSIONS: Viral DNAemia was associated with hyperferritinemia and adverse outcome in pediatric severe sepsis. Prospective studies are needed to determine whether hyperferritinemia may be used to identify patients at risk of occult DNAemia.

The yield of monitoring adenovirus in pediatric hematopoietic stem cell transplant patients.

Human adenovirus (HAdV) is recognized as a serious pathogen after allogeneic hematopoietic stem cell transplantation (HSCT), causing morbidity and mortality. Currently, there is no universal agreement regarding routine HAdV surveillance after HSCT. We assessed the impact of HAdV weekly monitoring by polymerase chain reaction (PCR) on HAdV viremia rates and the risk factors that influence survival. Three-hundred and fifty-six pediatric allogeneic HSCT were done between 2007 and 2015. Until July 2011, HAdV testing was performed based on clinical suspicion (cohort 1, n = 175) and from August 2011, weekly blood-HAdV monitoring was done (cohort 2, n = 181) until day +100. Twenty-three patients (4 [2.3%] from cohort 1 and 19 [10.5%] from cohort 2, p = .001) were found with HAdV viremia and seven of them died. Both cohorts had a similar incidence of HAdV-associated mortality (3/175; 1.7% in cohort 1 and 4/181; 2.2% in cohort 2). Respiratory failure was the cause of death in all patients. Clinical symptoms appeared prior to or within 5 days of HAdV detection in cohort 2. In summary, weekly monitoring was associated with higher detection of HAdV. The study could not assess survival benefit due to small numbers of HAdV-positive cases. In many instances, symptoms occurred with the development of positive HAdV blood PCR results and hence, symptomatology could have triggered the test. Future studies are needed to provide data that help establishing a uniform approach for regular monitoring of HAdV post-transplant.

Clinical significance of human cytomegalovirus viruria and the effect of antiviral therapy in hematopoietic stem cell transplant recipients.

BACKGROUND: Cytomegalovirus (CMV) causes life-threatening infections in immunocompromised host. The clinical significance of asymptomatic CMV viruria in patients receiving hematopoietic stem cell transplantation (HSCT) remains unclear. This study aims to clarify whether antiviral therapy is associated with a favorable clinical outcome. METHODS: HSCT recipients whose urine was culture-positive for CMV were retrospectively reviewed and followed. Viruria episodes were divided according to whether or not antiviral therapy was used. Mortality and the estimated glomerular filtration rate (eGFR) in 2 years following CMV viruria were compared between patients with and without antiviral therapy. RESULTS: Sixty-two episodes of culture-proven asymptomatic CMV viruria were identified in 28 HSCT recipients. Antiviral therapy was used in 35 (56.5%) and spared in 27 (43.5%) viruric episodes. Compared with the baselines, there were no significant difference in the decrements of eGFR between the two groups at the end the 1st year (4.78 vs 5.02 mL/min/1.73 m2, p = 0.968) and the 2nd year (1.13 vs 7.66 mL/min/1.73 m2, p = 0.276). Antiviral therapy for asymptomatic CMV viruria was also not associated with a favorable survival (p = 0.288). On the other hand, presence of CMV viremia correlated with a poorer survival (2-year mortality rate 60% vs 13.33%, p < 0.001). CONCLUSION: Antiviral therapy for asymptomatic CMV viruria is not associated with a clear clinical benefit in HSCT recipients. Further studies may be needed to identify if specific patient populations may benefit from antiviral therapy in CMV viruria.

Viremia copy-years and mortality among combination antiretroviral therapy-initiating HIV-positive individuals: how much viral load history is enough?

OBJECTIVE: Ongoing HIV replication while receiving combination antiretroviral therapy (cART) may reduce survival. Viremia copy-years (VCY) has shown improved mortality risk prediction over single time-point viral load measures. However, the timing of a patient's viral load history most associated with later mortality has not been studied. Here we determined the optimal duration and temporality of viral load history for predicting mortality. DESIGN: Survival analysis among HIV-positive men who initiated cART in the Multicenter AIDS Cohort Study (1995-2015). METHODS: VCY measures were derived from area-under-the-viral load-curve. The overall VCY based upon the complete post-cART viral load history was compared with 20 VCYs derived from viral loads assessed during different shorter time periods (the most recent 1-10 years and initial 1-10 years following cART initiation) for associations with mortality. RESULTS: Each 10-fold increase in VCYs based on the most recent 3-8 years was significantly associated with 23-26% decrease in survival times, a magnitude of effect greater than that of the most recent viral load (16%). These associations were independent of CD4 cell count and single time-point viral loads. In addition, the degree of pre-cART immunodeficiency did not affect the mortality prognostic value of VCY based on viral loads in the most recent 3 years. Conversely, the overall VCY and VCYs based on viral loads immediately following cART initiation were not independent predictors of mortality. CONCLUSION: Among cART-treated men, VCY based upon viral loads in the recent 3 years (six viral loads) has a mortality prognostic value greater than that of the overall VCY and single time-point viral loads, making the former a more feasible measure for use.

Antiviral combination therapy for cytomegalovirus infection in high-risk infants.

BACKGROUND: Cytomegalovirus (CMV) infection is a major risk factor for mortality in infants with severe combined immunodeficiency (SCID) and other profound immune defects. Specific antiviral therapy must be initiated early and aggressively because of the potential for antiviral resistance, rapid dissemination and poor transplant outcomes. Combination antiviral therapy is routinely administered for some viral infections, but the value of this approach for the treatment of CMV is unclear. Here we explore a strategy of initial combination therapy for high-risk infants with CMV infection. METHODS: We reviewed medical records of infants ≤6 months of age hospitalized between 2007-2015 who received ganciclovir (GCV) or foscarnet (FOS) monotherapy or initial combination GCV + FOS for CMV disease. The combination therapy group consisted of severely immunocompromised infants being considered for haematopoietic cell transplantation (HCT). RESULTS: Four patients received initial combination antiviral therapy and 26 patients received initial monotherapy during the study period. Combination antiviral recipients demonstrated initial improvement in viraemia and two of three who continued with this therapy survived the infection. Clinically significant resistance mutations did not emerge. Toxicity was common; neutropenia, thrombocytopenia and electrolyte abnormalities were the most frequent adverse events in both groups. Creatinine elevation was uncommon in both groups. CONCLUSIONS: Combination GCV + FOS therapy may be a safe alternative to monotherapy in high-risk infants, especially those who are pre-transplant with primary immune deficiency syndromes and high viral loads.

Long-term outcome of Epstein-Barr virus DNAemia and PTLD with the use of preemptive rituximab following allogeneic HSCT.

We studied retrospectively the outcome of Epstein-Barr virus (EBV)-related disease with EBV monitoring and preemptive rituximab to prevent post-transplant lymphoproliferative disorder (PTLD) in 319 consecutive allogeneic stem cell transplantations 2004-2012. Patients who received anti-thymocyte globulin (ATG) or alemtuzumab were regarded as high-risk for PTLD (n = 214). EBV DNAemia ≥1000 copies/mL plasma was observed in 50 (23%) of the high-risk patients. Thirty-three of the high-risk (15%) and one of the low-risk (1%) patients received rituximab, in combination with reduction of immunosuppression (n = 24) or chemotherapy (n = 4). Although rituximab was initiated only 5 d after first EBV load ≥1000 copies/mL, 85% of the rituximab-treated patients developed symptoms (lymphadenopathy 50%, fever 76%, and encephalitis/meningitis 12%). Response-rate to EBV treatment was 88%. Overall survival at 1- and 5-year was 71 and 52% for rituximab-treated patients, which was not inferior to all other patients post-transplant. In conclusion, rituximab therapy for EBV DNAemia does not affect long-term survival negatively.

High human herpesvirus 6 viral load in pediatric allogeneic hematopoietic stem cell transplant patients is associated with detection in end organs and high mortality.

Human Herpes Virus 6 (HHV-6) reactivation occurs in approximately half of patients following allogeneic hematopoietic stem cell transplant (HSCT). While encephalitis and delayed engraftment are well-documented complications of HHV-6 following HSCT, the extent to which HHV-6 viremia causes disease in children is controversial. We performed a retrospective review of HHV-6 reactivation and possible manifestations in pediatric allogeneic HSCT patients at a single institution. Of 89 children and young adults who underwent allogeneic HSCT over a three-and-a-half-year period, 34 patients reactivated HHV-6 early post-transplant. Unrelated donor stem cell source and lack of antiviral prophylaxis were risk factors for the development of HHV-6 viremia. Viremia correlated with the presence of acute graft-versus-host disease, but not chronic graft-versus-host disease. We identified two subgroups within the viremic patients-a high-risk viremic and tissue-positive group that reactivated HHV-6 and had suspected end-organ disease and a low-risk viremic but asymptomatic group that reactivated HHV-6 but did not exhibit symptoms or signs of end-organ disease. Peak viral load was found to be strongly associated with mortality. Prospective studies in larger numbers of patients are needed to further investigate the role of HHV-6 in causing symptomatic end-organ disease as well as the association of viral load with mortality.

Kinetics of Double-Stranded DNA Viremia After Allogeneic Hematopoietic Cell Transplantation.

Background: Improved understanding of double-stranded DNA (dsDNA) virus kinetics after hematopoietic cell transplantation (HCT) would facilitate development of therapeutic strategies. Methods: We tested weekly plasma samples from 404 patients through day 100 after allogeneic HCT for cytomegalovirus (CMV), human herpesvirus (HHV) 6A and 6B, BK polyomavirus (BKV), adenovirus (AdV), and Epstein-Barr virus (EBV) using quantitative polymerase chain reaction. Episodes lasting ≤1 week were defined as blips and >1 week as persistent. We described virus-specific kinetics, analyzed the association of virus area under the curve (AUC) with overall mortality, and identified risk factors for persistent episodes. Results: We identified 428 episodes of CMV, 292 of BKV, 224 of HHV-6B, 46 of AdV, and 53 of EBV. CMV and BKV had the highest proportions of persistent episodes (68% and 80%, respectively). Detection and kinetics varied by virus. HHV-6B episodes reached maximum levels fastest and had the shortest intervals between detection and end-organ disease. End-organ disease occurred within 14 days of viremia in 68% of cases, generally during persistent episodes. For all viruses, higher viral load AUC increased risk for overall mortality through day 365, persistent episodes had higher viral load than blips, and higher first positive viral load significantly increased risk for persistent episodes. First viral load >2 log10 copies/mL (range, 2.04-3.06 per virus) had high specificity for persistent episodes. Conclusions: Persistent high viral load dsDNA viremia episodes after allogeneic HCT predict mortality. Virus-specific kinetics can guide timing and thresholds for early intervention in studies of novel agents.

Strategies to manage hepatitis C virus infection disease burden-Volume 4.

The hepatitis C virus (HCV) epidemic was forecasted through 2030 for 17 countries in Africa, Asia, Europe, Latin America and the Middle East, and interventions for achieving the Global Health Sector Strategy on viral hepatitis targets-"WHO Targets" (65% reduction in HCV-related deaths, 90% reduction in new infections and 90% of infections diagnosed by 2030) were considered. Scaling up treatment and diagnosis rates over time would be required to achieve these targets in all but one country, even with the introduction of high SVR therapies. The scenarios developed to achieve the WHO Targets in all countries studied assumed the implementation of national policies to prevent new infections and to diagnose current infections through screening.

The present and future disease burden of hepatitis C virus infections with today's treatment paradigm: Volume 4.

Factors influencing the morbidity and mortality associated with viremic hepatitis C virus (HCV) infection change over time and place, making it difficult to compare reported estimates. Models were developed for 17 countries (Bahrain, Bulgaria, Cameroon, Colombia, Croatia, Dominican Republic, Ethiopia, Ghana, Hong Kong, Jordan, Kazakhstan, Malaysia, Morocco, Nigeria, Qatar and Taiwan) to quantify and characterize the viremic population as well as forecast the changes in the infected population and the corresponding disease burden from 2015 to 2030. Model inputs were agreed upon through expert consensus, and a standardized methodology was followed to allow for comparison across countries. The viremic prevalence is expected to remain constant or decline in all but four countries (Ethiopia, Ghana, Jordan and Oman); however, HCV-related morbidity and mortality will increase in all countries except Qatar and Taiwan. In Qatar, the high-treatment rate will contribute to a reduction in total cases and HCV-related morbidity by 2030. In the remaining countries, however, the current treatment paradigm will be insufficient to achieve large reductions in HCV-related morbidity and mortality.