Publications by authors named "Aneesh K Mehta"

66 Publications

Racial and Ethnic Differences and Clinical Outcomes of COVID-19 Patients Presenting to the Emergency Department.

Clin Infect Dis 2021 Apr 2. Epub 2021 Apr 2.

Health Services Research Center, Emory University School of Medicine, Department of Medicine, Department of Surgery, Emory University School of Medicine, and Department of Epidemiology, Rollins School of Public Health, Atlanta, Georgia, United States of America.

Background: Since the introduction of remdesivir and dexamethasone for severe COVID-19 treatment, few large multi-hospital system US studies have described clinical characteristics and outcomes of minority COVID-19 patients who present to the emergency department (ED).

Methods: This cohort study from the Cerner Real World Database (87 US health systems) from December 1, 2019 to September 30, 2020 included PCR-confirmed COVID-19 patients who self-identified as non-Hispanic Black (Black), Hispanic White (Hispanic), or non-Hispanic White (White). The main outcome was hospitalization among ED patients. Secondary outcomes included mechanical ventilation, intensive care unit care, and in-hospital mortality. Descriptive statistics and Poisson regression compared sociodemographics, comorbidities, receipt of remdesivir, receipt of dexamethasone, and outcomes by racial/ethnic groups and geographic region.

Results: 94,683 COVID-19 patients presented to the ED. Blacks comprised 26.7% and Hispanics 33.6%. Nearly half (45.1%) of ED patients presented to hospitals in the South. 31.4% (n=29,687) were hospitalized. Lower proportions of Blacks were prescribed dexamethasone (29.4%; n=7,426) compared to Hispanics (40.9%; n=13,021) and Whites (37.5%; n=14,088). Hospitalization risks, compared to Whites, were similar in Blacks (Risk Ratio (RR)=0.94; 95% CI:0.82, 1.08; p=0.4)) and Hispanics RR=0.99 (95% CI:0.81, 1.21; p=0.91), but risk of in-hospital mortality was higher in Blacks, RR=1.18 (95% CI:1.06, 1.31; p=0.002) and Hispanics, RR=1.28 (95% CI: 1.13, 1.44; p < 0.001).

Conclusions: Minority patients were overrepresented among COVID-19 ED patients, and while they had similar risks of hospitalization as Whites, in-hospital mortality risk was higher. Interventions targeting upstream social determinants of health are needed to reduce racial/ethnic disparities in COVID-19.
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http://dx.doi.org/10.1093/cid/ciab290DOI Listing
April 2021

TIGIT regulates apoptosis of risky memory T cell subsets implicated in belatacept-resistant rejection.

Am J Transplant 2021 Mar 23. Epub 2021 Mar 23.

Emory Transplant Center, Department of Surgery, Emory University School of Medicine, Atlanta.

Belatacept confers increased patient and graft survival in renal transplant recipients relative to calcineurin inhibitors, but is associated with an increased rate of acute rejection. Recent immunophenotypic studies comparing pre-transplant T cell phenotypes of patients who reject vs. those that remain stable on belatacept identified three potential "risky" memory T cell subsets that potentially underlie belatacept-resistant rejection: CD4 CD28 T , CD8 CD28 and CD4 CD57 PD1 subsets. Here, we compared key phenotypic and functional aspects of these human memory T cell subsets, with the goal of identifying additional potential targets to modulate them. Results demonstrate that TIGIT, an increasingly well-appreciated immune checkpoint receptor, was expressed on all three risky memory T cell subsets in vitro and in vivo in the presence of belatacept. Co-culture of human memory CD4 and CD8 T cells with an agonistic anti-TIGIT mAb significantly increased apoptotic cell death of all three risky memory T cell subsets. Mechanistically, TIGIT-mediated apoptosis of risky memory T cells was dependent on FOXP3 Treg, suggesting that agonism of the TIGIT pathway increases FOXP3 Treg suppression of human memory T cell populations. Overall, these data suggest that TIGIT agonism could represent a new therapeutic target to inhibit belatacept-resistant rejection during transplantation.
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http://dx.doi.org/10.1111/ajt.16571DOI Listing
March 2021

Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19.

N Engl J Med 2021 03 11;384(9):795-807. Epub 2020 Dec 11.

From the University of Nebraska Medical Center, Omaha (A.C.K., L.L.); University of Texas Health San Antonio, University Health, and the South Texas Veterans Health Care System, San Antonio (T.F.P., P.O.P., B.S.T.), UT Southwestern Medical Center, Parkland Health and Hospital System (M.K.J.) and Baylor Scott and White Health (U.S.), Dallas, and Baylor College of Medicine, Houston (H.M.E.S.) - all in Texas; Emory University (A.K.M., N.G.R., Y.S., V.C.M., V.D.C.) and Grady Memorial Hospital (V.D.C.), Atlanta, and Atlanta Veterans Affairs Medical Center, Decatur (V.C.M.) - both in Georgia; the National Institute of Allergy and Infectious Diseases, National Institutes of Health (K.M.T., V.G., R.T.D., M.P., G.A.D., W.D., S.U.N., L.E.D., J.H.B.), and the Infectious Disease Clinical Research Program, Uniformed Services University of the Health Sciences (T.H.B.), Bethesda, and Emmes (J.F., M.G., M.M.) and Clinical Monitoring Research Program Directorate, Frederick National Laboratory (T.B.), Rockville - both in Maryland; Duke University, Durham, NC (C.R.W., E.R.K., J.J.E.); Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, (G.M.R.-P.) and Instituto Nacional de Enfermedades Respiratorias (J.R.P.), Mexico City; University of California Irvine, Irvine (L.H., A.N.A., M.W.), Cedars-Sinai Medical Center, Los Angeles (V.T.), University of California, San Diego, La Jolla (D.A.S.), University of California, San Francisco, San Francisco (A.F.L.), University of California, Davis, Davis (S.H.C.), and Stanford University, Stanford (N.A.) - all in California; University of Minnesota Medical School, Minneapolis (S.K., J.B.); University of Florida, Gainesville (N.M.I., M.-C.E.); University of Rochester, Rochester, NY (A.R.B.); National Center for Infectious Diseases, Tan Tock Seng Hospital, Lee Kong Chian School of Medicine, and Yong Loo Lin School of Medicine (D.C.L.), and Changi General Hospital (S.Y.T.), Singapore; University of Massachusetts Medical School, Worcester (R.W.F.); University of Virginia, Charlottesville (P.E.H.J.); Northwestern University, Chicago (B.T.); Penn State Health Milton S. Hershey Medical Center, Hershey, PA (C.I.P.); Providence Sacred Heart Medical Center, Spokane, WA (H.A.); University of Alabama at Birmingham, Birmingham (N.E.); Denver Health and Hospital Authority, Denver (M.F.); Seoul National University Hospital, Seoul (M.O.), and Seoul National University Bundang Hospital, Seongnam (E.-S.K.) - both in South Korea; Kaiser Permanente Northwest, Portland, OR (R.A.M.); Aalborg University Hospital, Aalborg, Denmark (H.N.); and Eli Lilly, Indianapolis (A.C., S.B.).

Background: Severe coronavirus disease 2019 (Covid-19) is associated with dysregulated inflammation. The effects of combination treatment with baricitinib, a Janus kinase inhibitor, plus remdesivir are not known.

Methods: We conducted a double-blind, randomized, placebo-controlled trial evaluating baricitinib plus remdesivir in hospitalized adults with Covid-19. All the patients received remdesivir (≤10 days) and either baricitinib (≤14 days) or placebo (control). The primary outcome was the time to recovery. The key secondary outcome was clinical status at day 15.

Results: A total of 1033 patients underwent randomization (with 515 assigned to combination treatment and 518 to control). Patients receiving baricitinib had a median time to recovery of 7 days (95% confidence interval [CI], 6 to 8), as compared with 8 days (95% CI, 7 to 9) with control (rate ratio for recovery, 1.16; 95% CI, 1.01 to 1.32; P = 0.03), and a 30% higher odds of improvement in clinical status at day 15 (odds ratio, 1.3; 95% CI, 1.0 to 1.6). Patients receiving high-flow oxygen or noninvasive ventilation at enrollment had a time to recovery of 10 days with combination treatment and 18 days with control (rate ratio for recovery, 1.51; 95% CI, 1.10 to 2.08). The 28-day mortality was 5.1% in the combination group and 7.8% in the control group (hazard ratio for death, 0.65; 95% CI, 0.39 to 1.09). Serious adverse events were less frequent in the combination group than in the control group (16.0% vs. 21.0%; difference, -5.0 percentage points; 95% CI, -9.8 to -0.3; P = 0.03), as were new infections (5.9% vs. 11.2%; difference, -5.3 percentage points; 95% CI, -8.7 to -1.9; P = 0.003).

Conclusions: Baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status among patients with Covid-19, notably among those receiving high-flow oxygen or noninvasive ventilation. The combination was associated with fewer serious adverse events. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT04401579.).
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http://dx.doi.org/10.1056/NEJMoa2031994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745180PMC
March 2021

Cryptococcus transmission through solid organ transplantation in the United States: A report from the Ad Hoc Disease Transmission Advisory Committee.

Am J Transplant 2020 Dec 8. Epub 2020 Dec 8.

Department of Pediatrics, Division of Pediatric Infectious Diseases University of Pittsburgh School of Medicine, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Cryptococcus species can cause serious life-threatening infection in solid organ transplant recipients by reactivation of prior infection, posttransplant de novo infection, or donor transmission from the transplanted organ. Although previously reported in the literature, the extent of donor-derived cryptococcosis in the United States has not been documented. We analyzed potential donor-derived Cryptococcus transmission events reported to the Organ Procurement and Transplantation Network (OPTN) for investigation by the Ad Hoc Disease Transmission Advisory Committee (DTAC). All reports between 2009 and 2019 in which transmission to recipients was designated proven or probable, or determined to be averted due to implementation of prophylaxis (intervention without disease transmission-"IWDT") were included. During 2009-2019, 58 reports of potential donor-derived cryptococcosis were submitted to DTAC. Among these reports, 12 donors were determined to have resulted in proven or probable transmission to 23/34 (67.6%) recipients. Most of these donors (10/12 [83%]) exhibited central nervous system-related symptoms prior to death and 5/23 (22%) infected recipients died. For 11 different donors, prophylaxis, most often with fluconazole, was administered to 23/35 (65.7%) recipients. Clinicians should maintain awareness of donor-derived cryptococcosis and consider prompt prophylaxis or treatment followed by reporting to OPTN for further investigation.
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http://dx.doi.org/10.1111/ajt.16433DOI Listing
December 2020

Racial Disproportionality in Covid Clinical Trials.

N Engl J Med 2020 12 6;383(25):2487-2488. Epub 2020 Nov 6.

Johns Hopkins University School of Medicine, Baltimore, MD.

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http://dx.doi.org/10.1056/NEJMc2029374DOI Listing
December 2020

Serosurvey on healthcare personnel caring for patients with Ebola virus disease and Lassa virus in the United States.

Infect Control Hosp Epidemiol 2020 04 20;41(4):385-390. Epub 2020 Jan 20.

Division of Infectious Diseases, Department of Medicine, School of Medicine, Emory University, Atlanta, Georgia.

Objective: Healthcare personnel (HCP) were recruited to provide serum samples, which were tested for antibodies against Ebola or Lassa virus to evaluate for asymptomatic seroconversion.

Setting: From 2014 to 2016, 4 patients with Ebola virus disease (EVD) and 1 patient with Lassa fever (LF) were treated in the Serious Communicable Diseases Unit (SCDU) at Emory University Hospital. Strict infection control and clinical biosafety practices were implemented to prevent nosocomial transmission of EVD or LF to HCP.

Participants: All personnel who entered the SCDU who were required to measure their temperatures and complete a symptom questionnaire twice daily were eligible.

Results: No employee developed symptomatic EVD or LF. EVD and LF antibody studies were performed on sera samples from 42 HCP. The 6 participants who had received investigational vaccination with a chimpanzee adenovirus type 3 vectored Ebola glycoprotein vaccine had high antibody titers to Ebola glycoprotein, but none had a response to Ebola nucleoprotein or VP40, or a response to LF antigens.

Conclusions: Patients infected with filoviruses and arenaviruses can be managed successfully without causing occupation-related symptomatic or asymptomatic infections. Meticulous attention to infection control and clinical biosafety practices by highly motivated, trained staff is critical to the safe care of patients with an infection from a special pathogen.
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http://dx.doi.org/10.1017/ice.2019.349DOI Listing
April 2020

Donor derived hepatitis B virus infection: Analysis of the Organ Procurement & Transplantation Network/United Network for Organ Sharing Ad Hoc Disease Transmission Advisory Committee.

Transpl Infect Dis 2021 Feb 22;23(1):e13458. Epub 2020 Sep 22.

Department of Pediatrics, Division of Pediatric Infectious Diseases, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.

Hepatitis B virus (HBV) can be transmitted from organ donor to recipient, but details of transmission events are not widely published. The Disease Transmission Advisory Committee (DTAC) evaluated 105 cases of potential donor derived transmission events of HBV between 2009-2017. Proven, probable or possible transmission of HBV occurred in 25 (23.8%) cases. Recipients of liver grafts were most commonly infected (20 of 21 exposed recipients) compared to 9 of 21 exposed non-hepatic recipients. Eleven of 25 donors were HBV core antibody (HBcAb) positive/HBV surface antigen (HBsAg) negative and infected 8/20 recipients. Of the 10 liver recipients and 1 liver-kidney recipient who received organs from these donors: six were not given antiviral prophylaxis, two developed infection after antiviral prophylaxis was discontinued, two developed HBV while on lamivudine prophylaxis, one was on antiviral prophylaxis and did not develop HBV viremia or antigenemia. One recipient of a HBcAb positive/HBsAg negative kidney developed active HBV infection. Unexpected donor-derived transmission of HBV was a rare event in reports to DTAC, but was often detected in the recipient late post-transplant. Six of 11 recipients (54.5%) of a liver from a HBcAb positive donor did not receive prophylaxis; all of these were potentially preventable with the use of anti-viral prophylaxis.
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http://dx.doi.org/10.1111/tid.13458DOI Listing
February 2021

Rapid Generation of Neutralizing Antibody Responses in COVID-19 Patients.

Cell Rep Med 2020 Jun 8;1(3):100040. Epub 2020 Jun 8.

Center for Childhood Infections and Vaccines; Children's Healthcare of Atlanta and Emory University Department of Pediatrics, Atlanta, GA 30322, USA.

SARS-CoV-2, the virus responsible for COVID-19, is causing a devastating worldwide pandemic, and there is a pressing need to understand the development, specificity, and neutralizing potency of humoral immune responses during acute infection. We report a cross-sectional study of antibody responses to the receptor-binding domain (RBD) of the spike protein and virus neutralization activity in a cohort of 44 hospitalized COVID-19 patients. RBD-specific IgG responses are detectable in all patients 6 days after PCR confirmation. Isotype switching to IgG occurs rapidly, primarily to IgG1 and IgG3. Using a clinical SARS-CoV-2 isolate, neutralizing antibody titers are detectable in all patients by 6 days after PCR confirmation and correlate with RBD-specific binding IgG titers. The RBD-specific binding data were further validated in a clinical setting with 231 PCR-confirmed COVID-19 patient samples. These findings have implications for understanding protective immunity against SARS-CoV-2, therapeutic use of immune plasma, and development of much-needed vaccines.
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http://dx.doi.org/10.1016/j.xcrm.2020.100040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276302PMC
June 2020

Influenza vaccine-induced human bone marrow plasma cells decline within a year after vaccination.

Science 2020 10 13;370(6513):237-241. Epub 2020 Aug 13.

Emory Vaccine Center and Department of Microbiology and Immunology, Emory University, Atlanta, GA, USA.

A universal vaccine against influenza would ideally generate protective immune responses that are not only broadly reactive against multiple influenza strains but also long-lasting. Because long-term serum antibody levels are maintained by bone marrow plasma cells (BMPCs), we investigated the production and maintenance of these cells after influenza vaccination. We found increased numbers of influenza-specific BMPCs 4 weeks after immunization with the seasonal inactivated influenza vaccine, but numbers returned to near their prevaccination levels after 1 year. This decline was driven by the loss of BMPCs induced by the vaccine, whereas preexisting BMPCs were maintained. Our results suggest that most BMPCs generated by influenza vaccination in adults are short-lived. Designing strategies to enhance their persistence will be a key challenge for the next generation of influenza vaccines.
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http://dx.doi.org/10.1126/science.aaz8432DOI Listing
October 2020

Bioaerosol sampling of a ventilated patient with COVID-19.

Am J Infect Control 2020 12 4;48(12):1540-1542. Epub 2020 Aug 4.

Division of Infectious Diseases, Department of Medicine, Emory University, Atlanta, GA; Emory Healthcare, Atlanta, GA; Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA. Electronic address:

Bioaerosol samples were collected in an airborne infection isolation room, bathroom, and anteroom of a ventilated patient with coronavirus disease 2019. Twenty-eight samples were negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleic acid, possibly due to the patient being on a closed-circuit ventilator or the efficiency of the air exchanges in the room.
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http://dx.doi.org/10.1016/j.ajic.2020.07.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402277PMC
December 2020

Adenovirus causing hepatic abscess formation and unexplained fever in adult liver transplant recipients.

Transpl Infect Dis 2021 Feb 16;23(1):e13435. Epub 2020 Aug 16.

Emory Transplant Center, Atlanta, GA, USA.

Adenovirus infection is commonly associated with self-limited respiratory and gastrointestinal illnesses. However, infection in immunocompromised individuals, such as transplant recipients, can cause severe life-threatening illness including pneumonitis, hemorrhagic cystitis, nephritis, hepatitis, and enterocolitis. In orthotopic liver transplant recipients, adenovirus viremia can cause hepatitis leading to marked transaminitis, allograft loss, and death. Although hepatic abscesses mediated by adenovirus have been described in other immunosuppressed patient populations, it has very rarely been described in liver transplant recipients. Here, we report two adult cases of hepatic abscesses following liver transplantation secondary to adenovirus infection and describe the successful treatment of these patients. Adenovirus should be considered as an uncommon etiology of hepatic abscess and unexplained fevers in adults following liver transplantation.
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http://dx.doi.org/10.1111/tid.13435DOI Listing
February 2021

Avoidance of CNI and steroids using belatacept-Results of the Clinical Trials in Organ Transplantation 16 trial.

Am J Transplant 2020 12 13;20(12):3599-3608. Epub 2020 Jul 13.

Emory Transplant Center, Emory University School of Medicine, Atlanta, Georgia, USA.

Immunosuppression devoid of corticosteroids has been investigated to avoid long-term comorbidities. Likewise, alternatives to calcineurin inhibitors have been investigated as a strategy to improve long-term kidney function following transplanion. Costimulatory blockade strategies that include corticosteroids have recently shown promise, despite their higher rates of early acute rejection. We designed a randomized clinical trial utilizing depletional induction therapy to mitigate early rejection risk while limiting calcineurin inhibitors and corticosteroids. This trial, Clinical Trials in Organ Transplantation 16 (CTOT-16), sought to evaluate novel belatacept-based strategies employing tacrolimus and corticosteroid avoidance. Sixty-nine kidney transplant recipients were randomized from 4 US transplant centers comparing a control group of with rabbit antithymocyte globulin (rATG) induction, rapid steroid taper, and maintenance mycophenolate and tacrolimus, to 2 arms using maintenance belatacept. There were no graft losses but there were 2 deaths in the control group. However, the trial was halted early because of rejection in the belatacept treatment groups. Serious adverse events were similar across groups. Although rejection was not uniform in the belatacept maintenance therapy groups, the frequency of rejection limits the practical implementation of this strategy to avoid both calcineurin inhibitors and corticosteroids at this time.
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http://dx.doi.org/10.1111/ajt.16152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710570PMC
December 2020

Kidney transplantation using alemtuzumab, belatacept, and sirolimus: Five-year follow-up.

Am J Transplant 2020 12 30;20(12):3609-3619. Epub 2020 Jun 30.

Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA.

Kidney transplant outcomes are limited by toxicities associated with calcineurin inhibitors and steroids. This trial was conducted to determine whether a costimulation blockade (CoB)-based regimen could achieve acceptable long-term outcomes and graft survival could be maintained solely with CoB. Forty patients underwent alemtuzumab induction followed by belatacept and sirolimus maintenance therapy. Patients were offered weaning to belatacept monotherapy after 1 year and followed for 5 years. Five-year patient and graft survival rates were 100% and 95%, respectively. Graft function remained stable with a mean estimated glomerular filtration rates of 67 ± 21 and 71 ± 19 at 36 and 60 months, respectively. There was no clinical rejection in the first year; subclinical rejection was detected by protocol biopsy in 4 patients. Twelve patients were successfully weaned to belatacept monotherapy. Cytomegalovirus and Epstein-Barr virus reactivations were well controlled, but 9 patients experienced transient BK viremia during the first year. Alemtuzumab produced profound lymphopenia followed by gradual T cell and more rapid B cell reconstitution to a repertoire deviated toward naïve cells with increased regulatory T cells. This regimen effectively prevents allograft rejection without using steroids or calcineurin inhibitors, enriches for naïve cells susceptible to control with CoB, and permits control of rejection with belatacept monotherapy in selected patients.
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http://dx.doi.org/10.1111/ajt.16121DOI Listing
December 2020

Remdesivir for the Treatment of Covid-19 - Final Report.

N Engl J Med 2020 11 8;383(19):1813-1826. Epub 2020 Oct 8.

From the National Institute of Allergy and Infectious Diseases, National Institutes of Health (J.H.B., K.M.T., L.E.D., S.N., H.C.L.), and the Infectious Disease Clinical Research Program, Uniformed Services University of the Health Sciences (T.H.B.), Bethesda, the Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research, Frederick (T. Bonnett), and Emmes, Rockville (M.G., M.M.) - all in Maryland; Emory University, Atlanta (A.K.M.); Montefiore Medical Center-Albert Einstein College of Medicine (B.S.Z.) and NYU Langone Health and NYC Health and Hospitals-Bellevue (K.D.), New York; University of Nebraska Medical Center, Omaha (A.C.K., M.G.K.); Massachusetts General Hospital, Boston (E.H.), and University of Massachusetts Medical School, Worcester (R.W.F.); University of Washington, Seattle (H.Y.C.), and Evergreen Health Medical Center, Kirkland (D.L.C.) - both in Washington; University of California, San Francisco, San Francisco (A.L.), Cedars-Sinai Medical Center, Los Angeles (V.T.), University of California, Irvine, Irvine (L.H.), University of California, San Diego, La Jolla (D.A.S.), and Gilead Sciences, Foster City (A.O.) - all in California; University of Minnesota (S.K.) and University of Minnesota School of Public Health and INSIGHT (J.D.N.), Minneapolis; University of Texas Health San Antonio, University Health System, and the South Texas Veterans Health Care System, San Antonio (T.F.P.), and Baylor College of Medicine, Houston (R.L.A.); Hospital Germans Trias i Pujol and irsiCaixa AIDS Research Institute, Badalona, Spain (R.P.); University of Pennsylvania, Philadelphia (W.R.S.); Medical School, National and Kapodistrian University of Athens, Athens (G.T.); National Center for Infectious Diseases-Tan Tock Seng Hospital-Lee Kong Chian School of Medicine-Yong Loo Lin School of Medicine, Singapore, Singapore (D.C.L.); the National Center for Global Health and Medicine Hospital, Tokyo (N.O.); Seoul National University Hospital, Seoul, South Korea (M.O.); Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City (G.M.R.-P.); the Department of Infectious Diseases, Amager Hvidovre Hospital-University of Copenhagen, Hvidovre (T. Benfield), and Rigshospitalet, Department of Infectious Diseases (CHIP) and INSIGHT, Copenhagen (J.L.) - both in Denmark; University Hospital of Cologne, Cologne, Germany (G.F.); Vanderbilt University Medical Center, Nashville (C.B.C.); and University College London, MRC Clinical Trials Unit at UCL and INSIGHT, London (A.G.B., S.P.).

Background: Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), no antiviral agents have yet been shown to be efficacious.

Methods: We conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only.

Results: A total of 1062 patients underwent randomization (with 541 assigned to remdesivir and 521 to placebo). Those who received remdesivir had a median recovery time of 10 days (95% confidence interval [CI], 9 to 11), as compared with 15 days (95% CI, 13 to 18) among those who received placebo (rate ratio for recovery, 1.29; 95% CI, 1.12 to 1.49; P<0.001, by a log-rank test). In an analysis that used a proportional-odds model with an eight-category ordinal scale, the patients who received remdesivir were found to be more likely than those who received placebo to have clinical improvement at day 15 (odds ratio, 1.5; 95% CI, 1.2 to 1.9, after adjustment for actual disease severity). The Kaplan-Meier estimates of mortality were 6.7% with remdesivir and 11.9% with placebo by day 15 and 11.4% with remdesivir and 15.2% with placebo by day 29 (hazard ratio, 0.73; 95% CI, 0.52 to 1.03). Serious adverse events were reported in 131 of the 532 patients who received remdesivir (24.6%) and in 163 of the 516 patients who received placebo (31.6%).

Conclusions: Our data show that remdesivir was superior to placebo in shortening the time to recovery in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; ACTT-1 ClinicalTrials.gov number, NCT04280705.).
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http://dx.doi.org/10.1056/NEJMoa2007764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262788PMC
November 2020

Immunologic timeline of Ebola virus disease and recovery in humans.

JCI Insight 2020 05 21;5(10). Epub 2020 May 21.

Viral Special Pathogens Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.

A complete understanding of human immune responses to Ebola virus infection is limited by the availability of specimens and the requirement for biosafety level 4 (BSL-4) containment. In an effort to bridge this gap, we evaluated cryopreserved PBMCs from 4 patients who survived Ebola virus disease (EVD) using an established mass cytometry antibody panel to characterize various cell populations during both the acute and convalescent phases. Acute loss of nonclassical monocytes and myeloid DCs, especially CD1c+ DCs, was noted. Classical monocyte proliferation and CD38 upregulation on plasmacytoid DCs coincided with declining viral load. Unsupervised analysis of cell abundance demonstrated acute declines in monocytic, NK, and T cell populations, but some populations, many of myeloid origin, increased in abundance during the acute phase, suggesting emergency hematopoiesis. Despite cell losses during the acute phase, upregulation of Ki-67 correlated with recovery of cell populations over time. These data provide insights into the human immune response during EVD.
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http://dx.doi.org/10.1172/jci.insight.137260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259516PMC
May 2020

Challenges of calcineurin inhibitor withdrawal following combined pancreas and kidney transplantation: Results of a prospective, randomized clinical trial.

Am J Transplant 2020 06 8;20(6):1668-1678. Epub 2020 Mar 8.

Emory University, Atlanta, Georgia, USA.

In a phase 2 multicenter open-label randomized trial sponsored by the National Institutes of Health, simultaneous pancreas-kidney (SPK) recipients were randomized to a calcineurin inhibitor (CNI)-based immunosuppressive regimen (tacrolimus) (n = 21), or an investigational arm using low-dose CNI plus costimulation blockade (belatacept) with intended CNI withdrawal (n = 22). Both arms included induction therapy with rabbit ATG, mycophenolate sodium, or mycophenolate mofetil and rapid withdrawal of steroids. Enrollment and CNI withdrawal were stopped after 43/60 planned subjects had been enrolled. At that time, the rate of biopsy-proven acute rejection (BPAR) of the pancreas was low in both groups until CNI was withdrawn, with four of the five pancreas rejections occurring during or after CNI withdrawal. The rate of BPAR of kidney allografts was low in both control (9.5%) and investigational (9.1%) arms. Pancreas graft survival at 52 weeks, defined by insulin independence, was 21 (100%) in the control group and 19 (86%) in the investigational arm. One subject in the investigational arm died with functioning pancreas and kidney grafts. Renal function at week 52 was similar in both arms. Costimulation blockade with belatacept did not provide sufficient immunosuppression to reliably prevent pancreas rejection in SPK transplants undergoing CNI withdrawal.
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http://dx.doi.org/10.1111/ajt.15817DOI Listing
June 2020

Left Ventricular Assist Device Infections and the Potential Role for Dalbavancin: A Case Report.

Open Forum Infect Dis 2019 Sep 4;6(9):ofz235. Epub 2019 Sep 4.

Division of Infectious Diseases, Atlanta, Georgia.

Left ventricular assist device infections (LVADIs) are common but challenging to treat, often requiring prolonged courses of intravenous antibiotics. Dalbavancin could have a role in treating patients with chronic LVADIs given its less frequent dosing requirements. Here, we illustrate a case in which dalbavancin was used as suppressive therapy for an LVADI for greater than 7 months.
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http://dx.doi.org/10.1093/ofid/ofz235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736362PMC
September 2019

B cell reconstitution following alemtuzumab induction under a belatacept-based maintenance regimen.

Am J Transplant 2020 03 13;20(3):653-662. Epub 2019 Nov 13.

Department of Surgery, Duke University School of Medicine, Durham, North Carolina.

Lymphocyte depletion has been shown to control costimulation blockade-resistant rejection but, in some settings, to exacerbate antibody-mediated rejection (AMR). We have used alemtuzumab, which depletes T and B cells, combined with belatacept and rapamycin and previously reported control of both costimulation blockade-resistant rejection and AMR. To evaluate this regimen's effect on B cell signatures, we investigated 40 patients undergoing this therapy. B cell counts and phenotypes were interrogated using flow cytometry, and serum was analyzed for total IgG, IgM, and donor-specific alloantibody (DSA). Alemtuzumab induction produced pan-lymphocyte depletion; B cells repopulated faster and more completely than T cells. Reconstituting B cells were predominantly naïve, and memory B cells were significantly reduced (P = .001) post repopulation. Two B cell populations with potential immunomodulatory effects-regulatory (CD38 CD24 IgM CD20 ) and transitional B cells (CD19 CD27 IgD CD38 )-were enriched posttransplant (P = .001). Total serum IgG decreased from baseline (P = .016) while IgM levels remained stable. Five patients developed DSAs within 36 months posttransplant, but none developed AMR. Baseline IgG levels in these patients were significantly higher than those in patients without DSAs. These findings suggest that belatacept and rapamycin together limit homeostatic B cell activation following B cell depletion and may lessen the risk of AMR. This regimen warrants prospective, comparative study. ClinicalTrials.gov NCT00565773.
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http://dx.doi.org/10.1111/ajt.15639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202689PMC
March 2020

Longitudinal Analysis of the Human B Cell Response to Ebola Virus Infection.

Cell 2019 05 16;177(6):1566-1582.e17. Epub 2019 May 16.

Emory Vaccine Center and Department of Microbiology and Immunology, Emory University, Atlanta, GA, USA. Electronic address:

Ebola virus (EBOV) remains a public health threat. We performed a longitudinal study of B cell responses to EBOV in four survivors of the 2014 West African outbreak. Infection induced lasting EBOV-specific immunoglobulin G (IgG) antibodies, but their subclass composition changed over time, with IgG1 persisting, IgG3 rapidly declining, and IgG4 appearing late. Striking changes occurred in the immunoglobulin repertoire, with massive recruitment of naive B cells that subsequently underwent hypermutation. We characterized a large panel of EBOV glycoprotein-specific monoclonal antibodies (mAbs). Only a small subset of mAbs that bound glycoprotein by ELISA recognized cell-surface glycoprotein. However, this subset contained all neutralizing mAbs. Several mAbs protected against EBOV disease in animals, including one mAb that targeted an epitope under evolutionary selection during the 2014 outbreak. Convergent antibody evolution was seen across multiple donors, particularly among VH3-13 neutralizing antibodies specific for the GP1 core. Our study provides a benchmark for assessing EBOV vaccine-induced immunity.
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http://dx.doi.org/10.1016/j.cell.2019.04.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6908968PMC
May 2019

New filovirus disease classification and nomenclature.

Nat Rev Microbiol 2019 05;17(5):261-263

World Health Organization Regional Office for Africa, Brazzaville, Democratic Republic of the Congo.

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http://dx.doi.org/10.1038/s41579-019-0187-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6637750PMC
May 2019

The Special Pathogens Research Network: Enabling Research Readiness.

Health Secur 2019 02 19;17(1):35-45. Epub 2019 Feb 19.

Christopher J. Kratochvil, MD, is Associate Vice Chancellor for Clinical Research, the University of Nebraska Medical Center, Omaha, NE.

The 2013-2016 epidemic of Ebola virus disease (EVD) that originated in West Africa underscored many of the challenges to conducting clinical research during an ongoing infectious disease epidemic, both in the most affected countries of Guinea, Liberia, and Sierra Leone, as well as in the United States and Europe, where a total of 27 patients with EVD received care in biocontainment units. The Special Pathogens Research Network (SPRN) was established in the United States in November 2016 to provide an organizational structure to leverage the expertise of the 10 Regional Ebola and Other Special Pathogen Treatment Centers (RESPTCs); it was intended to develop and support infrastructure to improve readiness to conduct clinical research in the United States. The network enables the rapid activation and coordination of clinical research in the event of an epidemic and facilitates opportunities for multicenter research when the RESPTCs are actively caring for patients requiring a biocontainment unit. Here we provide an overview of opportunities identified in the clinical research infrastructure during the West Africa EVD epidemic and the SPRN activities to meet the ongoing challenges in the context of Ebola virus and other special pathogens.
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http://dx.doi.org/10.1089/hs.2018.0106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669031PMC
February 2019

A prospective multicenter observational study of cell-mediated immunity as a predictor for cytomegalovirus infection in kidney transplant recipients.

Am J Transplant 2019 09 15;19(9):2505-2516. Epub 2019 Mar 15.

Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts.

T cell immunity is essential for the control of cytomegalovirus (CMV) infection after transplantation. We evaluated a CMV-specific peptide-based enzyme-linked immunosorbent spot (ELISPOT) assay to determine whether assay results could predict subsequent CMV events. Adult kidney transplant recipients at 43 centers underwent ELISPOT testing to enumerate interferon gamma (IFN-γ) binding spot-forming units (sfu) after stimulation of cells with an overlapping peptide pool of CMV phosphoprotein 65 (pp65) and immediate early-1 (IE-1) protein at the end of antiviral prophylaxis (EOP) and various time points thereafter. The primary outcome was a CMV event in the first posttransplant year. In 583 kidney transplant recipients (260 seropositive donor [D+]/seronegative recipient [R-] and 277 R+), CMV events occurred in 44 of 368 eligible patients (11.8%) at a median of 227 days (range 92-360) posttransplant. A cutoff value of >40 sfu/2.5 × 10  cells for either IE-1 or pp65 was derived as a threshold for positivity, with a negative predictive value of >97% for CMV events. CMV events were significantly lower in assay positive vs assay negative patients (3.0% vs 19.5%, P < .0001 for pp65). Time to CMV event post-EOP was significantly greater in those with sfu >40 at EOP (P < .0001). In this large, multicenter trial of kidney transplant recipients, we show that an assessment of CMV-specific immunity using a novel ELISPOT assay is able to predict protection from CMV infection.
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http://dx.doi.org/10.1111/ajt.15315DOI Listing
September 2019

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

Emerg Infect Dis 2019 02;25(2):290-298

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.
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http://dx.doi.org/10.3201/eid2502.181326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6346465PMC
February 2019

The Use of Microbiome Restoration Therapeutics to Eliminate Intestinal Colonization With Multidrug-Resistant Organisms.

Am J Med Sci 2018 11 29;356(5):433-440. Epub 2018 Aug 29.

Division of Infectious Diseases, Emory University, Atlanta, Georgia; Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia. Electronic address:

Antibiotic resistance (AR) has been described by the World Health Organization as an increasingly serious threat to global public health. Many mechanisms of AR have become widespread due to global selective pressures such as widespread antibiotic use. The intestinal tract is an important reservoir for many multidrug-resistant organisms (MDROs), and next-generation sequencing has expanded understanding of the resistome, defined as the comprehensive sum of genetic determinants of AR. Intestinal decolonization has been explored as a strategy to eradicate MDROs with selective digestive tract decontamination and probiotics being notable examples with mixed results. This review focuses on fecal microbiota transplantation and the early evidence supporting its efficacy in decolonizing MDROs and potential mechanisms of action to reduce AR genes. Current evidence suggests that fecal microbiota transplantation may have promise in restoring healthy microbial diversity and reducing AR, and clinical trials are underway to better characterize its safety and efficacy.
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http://dx.doi.org/10.1016/j.amjms.2018.08.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6330116PMC
November 2018

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

Clin Infect Dis 2019 07;69(3):450-458

Division of Vector-Borne Diseases, NCEZID, CDC, Fort Collins, Colorado.

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.
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http://dx.doi.org/10.1093/cid/ciy923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6488434PMC
July 2019

Breadth and Functionality of Varicella-Zoster Virus Glycoprotein-Specific Antibodies Identified after Zostavax Vaccination in Humans.

J Virol 2018 07 29;92(14). Epub 2018 Jun 29.

Merck Research Laboratories, Department of Infectious Diseases and Vaccines, Merck & Co., Inc., Kenilworth, New Jersey, USA

Herpes zoster (HZ) (shingles) is the clinical manifestation of varicella-zoster virus (VZV) reactivation. HZ typically develops as people age, due to decreased cell-mediated immunity. However, the importance of antibodies for immunity against HZ prevention remains to be understood. The goal of this study was to examine the breadth and functionality of VZV-specific antibodies after vaccination with a live attenuated HZ vaccine (Zostavax). Direct enumeration of VZV-specific antibody-secreting cells (ASCs) via enzyme-linked immunosorbent spot assay (ELISPOT assay) showed that Zostavax can induce both IgG and IgA ASCs 7 days after vaccination but not IgM ASCs. The VZV-specific ASCs range from 33 to 55% of the total IgG ASCs. Twenty-five human VZV-specific monoclonal antibodies (MAbs) were cloned and characterized from single-cell-sorted ASCs of five subjects (>60 years old) who received Zostavax. These MAbs had an average of ∼20 somatic hypermutations per VH gene, similar to those seen after seasonal influenza vaccination. Fifteen of the 25 MAbs were gE specific, whereas the remaining MAbs were gB, gH, or gI specific. The most potent neutralizing antibodies were gH specific and were also able to inhibit cell-to-cell spread of the virus Most gE-specific MAbs were able to neutralize VZV, but they required the presence of complement and were unable to block cell-to-cell spread. These data indicate that Zostavax induces a memory B cell recall response characterized by anti-gE > anti-gI > anti-gB > anti-gH antibodies. While antibodies to gH could be involved in limiting the spread of VZV upon reactivation, the contribution of anti-gE antibodies toward protective immunity after Zostavax needs further evaluation. Varicella-zoster virus (VZV) is the causative agent of chickenpox and shingles. Following infection with VZV, the virus becomes latent and resides in nerve cells. Age-related declines in immunity/immunosuppression can result in reactivation of this latent virus, causing shingles. It has been shown that waning T cell immunity correlates with an increased incidence of VZV reactivation. Interestingly, serum with high levels of VZV-specific antibodies (VariZIG; IV immunoglobulin) has been administered to high-risk populations, e.g., immunocompromised children, newborns, and pregnant women, after exposure to VZV and has shown some protection against chickenpox. However, the relative contribution of antibodies against individual surface glycoproteins toward protection from shingles in elderly/immunocompromised individuals has not been established. Here, we examined the breadth and functionality of VZV-specific antibodies after vaccination with the live attenuated VZV vaccine Zostavax in humans. This study will add to our understanding of the role of antibodies in protection against shingles.
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http://dx.doi.org/10.1128/JVI.00269-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6026762PMC
July 2018

Tacrolimus concentration to dose ratio in solid organ transplant patients treated with fecal microbiota transplantation for recurrent Clostridium difficile infection.

Transpl Infect Dis 2018 Apr 13;20(2):e12857. Epub 2018 Mar 13.

Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.

Fecal microbiota transplantation (FMT) is increasingly being performed for Clostridium difficile infection in solid organ transplant (SOT) patients; however, little is known about the potential pharmacokinetic or pharmacomicrobial effects this may have on tacrolimus levels. We reviewed the medical records of 10 SOT patients from September 2012-December 2016 who were taking tacrolimus at time of FMT for recurrent C. difficile infection. We compared the differences in tacrolimus concentration/dose ratio (C/D ratio) 3 months prior to FMT vs 3 months after FMT. The mean of the differences in C/D ratio calculated as (ng/mL)/(mg/kg/d) was -17.65 (95% CI -1.25 to 0.58) (ng/mL)/(mg/kg/d), P-value .43 by Wilcoxon signed-rank test. The mean of the differences in C/D ratio calculated as (ng/mL)/(mg/d) was -0.33 (95% CI -1.25 to 0.58) (ng/mL)/(mg/d), P-value .28 by Wilcoxon signed-rank test. Of these patients, 2/10 underwent allograft biopsy for allograft dysfunction in the year after FMT, with no evidence of allograft rejection on pathology. These preliminary data suggest that FMT may not predictably alter tacrolimus levels and support its safety for SOT patients however further study in randomized trials is needed.
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http://dx.doi.org/10.1111/tid.12857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891373PMC
April 2018

Varicella-Zoster Virus DNA in Blood After Administration of Herpes Zoster Vaccine.

J Infect Dis 2018 03;217(7):1055-1059

Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora.

We studied the relationship between varicella-zoster virus (VZV) DNAemia and development of VZV-specific immunity after administration of live-attenuated zoster vaccine. VZV-DNAemia, detected by polymerase chain reaction (PCR), and VZV-specific effector (Teff) and memory (Tmem) T cells, was measured in 67 vaccinees. PCR was positive in 56% (9 direct, 28 nested) on day 1 and in 16% (1 direct, 10 nested) on day 14. Teff progressively increased in direct-PCR-positive vaccinees up to day 30, but Tmem did not. Conversely, Tmem, but not Teff, increased in direct-PCR-negative vaccinees on day 7. The kinetics of these immune responses and VZV DNAemia suggested that direct-PCR sample positive represented viremia.
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http://dx.doi.org/10.1093/infdis/jix653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5939641PMC
March 2018

Invasive Fungal Sinusitis due to Mucor Species in a Patient on Ibrutinib.

Clin Infect Dis 2018 04;66(9):1482-1483

Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia.

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http://dx.doi.org/10.1093/cid/cix1058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6248539PMC
April 2018