Publications by authors named "Michael Boeckh"

305 Publications

Monoclonal antibodies for prophylaxis and treatment of respiratory viral infections.

Curr Opin Infect Dis 2022 08 5;35(4):280-287. Epub 2022 Jul 5.

Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center.

Purpose Of Review: Monoclonal antibody (mAb) administration represents an important strategy for preventing and treating respiratory viral infections in vulnerable populations, including immunocompromised individuals. The purpose of this review is to provide an overview of mAbs in clinical use against respiratory viruses, highlight factors that modulate mAb clinical efficacy, and provide a perspective on future innovations in the field. This review focuses on publications from the last year.

Recent Findings: Historically, clinical development of a single mAb has taken over a decade. The COVID-19 pandemic has demonstrated that this timeframe can be reduced to less than a year and has catalyzed rapid innovations in the field. Several novel mAbs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have received emergency use authorization by the Food and Drug Administration (FDA) for the early treatment of mild to moderate COVID-19. However, the majority of these mAbs have ultimately failed due to the emergence of variants, highlighting an important lesson about predicting and countering resistance. Novel mAbs are also in clinical use or in late-stage development for the prevention of infection by SARS-CoV-2 and respiratory syncytial virus (RSV) in vulnerable populations. Several factors can be modulated to improve the clinical efficacy of mAbs. For example, Fc modifications can extend mAb half-life and increase respiratory tract bioavailability, both of which are attractive properties for achieving protection against respiratory viruses.

Summary: The mAb landscape is rapidly evolving with numerous examples of success and failure. The armamentarium of clinically-available mAbs to protect vulnerable populations is expected to undergo continued growth.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/QCO.0000000000000846DOI Listing
August 2022

Clinical and Economic Burden of Multiple Double-Stranded DNA Viral Infections after Allogeneic Hematopoietic Cell Transplantation.

Transplant Cell Ther 2022 Jun 25. Epub 2022 Jun 25.

Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon.

Conditioning regimens for allogeneic hematopoietic cell transplantation (allo-HCT) are immunosuppressive and increase the risk for reactivation of and infection with double-stranded DNA (dsDNA) viruses, which contribute to morbidity and mortality after allo-HCT. This retrospective observational study evaluated the association of dsDNA viral infections with clinical outcomes, health resource utilization (HRU), and health care reimbursement after allo-HCT. Patients who underwent allo-HCT between 2012 and 2017 were identified from a US open-source claims database (Decision Resource Group Real-World Evidence Data Repository; n = 13,363) and categorized according to the presence or absence of dsDNA viral infection, defined as having ≥1 diagnosis code for cytomegalovirus (CMV), adenovirus (AdV), human herpesvirus 6 (HHV-6), or BK virus (BKV)/Epstein-Barr virus (EBV)/John Cunningham virus (JCV) (grouped together given a lack of specific diagnoses codes) within 1 year after allo-HCT. Only first allo-HCT data were used in patients who underwent multiple procedures. Study outcomes included clinical outcomes (eg, time to all-cause mortality, new diagnosis of renal impairment), HRU (hospital and intensive care unit length of stay [LOS], readmission rates), and health care reimbursement (total, inpatient, and outpatient costs as reported reimbursements from insurance claims). For all outcomes, patients were stratified by the presence/absence of any dsDNA viral infection and number (none, 1, 2, or ≥3) and type(s) of infection. The effect of graft-versus-host disease (GVHD) was assessed as well. Twenty-nine percent of patients were diagnosed with CMV, 13% with BKV/EBV/JCV, 5% with AdV, and 4% with HHV-6 in the year following their first allo-HCT. A single dsDNA viral infection was documented in 30% of individuals, 2 in 8%, and ≥3 in 2%. Patients with no viral infections had an overall hospital LOS (index hospitalization plus readmissions) of 41.3 days and a total health care reimbursement of $266,345. These numbers increased for every additional viral infection, regardless of the presence or absence of GVHD; the overall hospital LOS was 61.4 days and total healthcare reimbursement was $431,614 in patients with 1 viral infection, 77.0 days and $639,097 in patients with 2 viral infections, and 103.3 days and $964,378 in patients with ≥3 viral infections. An increase in the number of dsDNA viral infections was associated with a significantly higher adjusted hazard of all-cause mortality (1 versus 0 dsDNA viral infections: hazard ratio [HR], 1.5; [95% confidence interval (CI), 1.3 to 1.6]; 2 versus 0: HR, 2.0 [95% CI, 1.7 to 2.3]; ≥3 versus 0: HR, 2.4 [95% CI, 1.8 to 3.3]) and a significantly higher incidence of new diagnosis of renal impairment, regardless of the presence of GVHD (35% of patients with ≥3 infections, 31% of patients with 2 infections, 26% of patients with 1 infection, and 19% of patients with no infection). These results indicate that more directed prevention and treatment strategies for dsDNA viral infections could substantially improve clinical outcomes and reduce HRU.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtct.2022.06.016DOI Listing
June 2022

Structure, receptor recognition, and antigenicity of the human coronavirus CCoV-HuPn-2018 spike glycoprotein.

Cell 2022 06 27;185(13):2279-2291.e17. Epub 2022 May 27.

Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA. Electronic address:

The isolation of CCoV-HuPn-2018 from a child respiratory swab indicates that more coronaviruses are spilling over to humans than previously appreciated. We determined the structures of the CCoV-HuPn-2018 spike glycoprotein trimer in two distinct conformational states and showed that its domain 0 recognizes sialosides. We identified that the CCoV-HuPn-2018 spike binds canine, feline, and porcine aminopeptidase N (APN) orthologs, which serve as entry receptors, and determined the structure of the receptor-binding B domain in complex with canine APN. The introduction of an oligosaccharide at position N739 of human APN renders cells susceptible to CCoV-HuPn-2018 spike-mediated entry, suggesting that single-nucleotide polymorphisms might account for viral detection in some individuals. Human polyclonal plasma antibodies elicited by HCoV-229E infection and a porcine coronavirus monoclonal antibody inhibit CCoV-HuPn-2018 spike-mediated entry, underscoring the cross-neutralizing activity among ɑ-coronaviruses. These data pave the way for vaccine and therapeutic development targeting this zoonotic pathogen representing the eighth human-infecting coronavirus.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2022.05.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9135795PMC
June 2022

Correlation of initial upper respiratory tract viral burden with progression to lower tract disease in adult allogeneic hematopoietic cell transplant recipients.

J Clin Virol 2022 Jun 4;150-151:105152. Epub 2022 Apr 4.

Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA; Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Medicine, University of Washington, Seattle, WA, USA.

Background: Some respiratory viruses have been evaluated for the association between viral burden and respiratory disease progression in hematopoietic cell transplant (HCT) recipients, and no significant association has been reported.

Objectives: To assess whether initial viral burden of respiratory viruses predicts risk of progression to lower respiratory tract infection (LRTI) among adult allogeneic HCT recipients who presented with upper respiratory tract infection (URTI) with 12 viruses in the PCR era.

Study Design: We reviewed adult allogeneic HCT recipients (4/2008-9/2018) who presented with their first symptomatic respiratory viral infection following transplantation at the Fred Hutchinson Cancer Center. Cox proportional hazards models were used to investigate whether viral burden as measured by initial Ct values at the diagnosis of URTI is associated with progression to LRTI within 90 days for each virus, treating death as a competing risk.

Results: Among 2,148 adult HCT recipients during the study periods, 1,102 episodes of URTI met the study inclusion criteria. Higher viral burden (lower Ct value) were associated with an increased risk of progression to LRTI for influenza after adjusting for immunodeficiency scoring index and initiation of antiviral therapy, respectively. The association between viral burden and progression to LRTI was not found for other viruses.

Conclusions: Our findings suggest that routine reporting of viral burden in current molecular diagnostic platforms may be beneficial. Further studies are needed to investigate the impact of viral burden on LRTI in other populations including pediatric HCT recipients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcv.2022.105152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9206235PMC
June 2022

Respiratory viruses in hematopoietic cell transplant candidates: impact of preexisting lower tract disease on outcomes.

Blood Adv 2022 Apr 21. Epub 2022 Apr 21.

University of Washington, United States.

Pretransplant respiratory virus infections (RVIs) have been shown to negatively impact hematopoietic cell transplantation (HCT) outcomes. The impact of and need for delay of HCT for pretransplant infection with human rhinovirus (HRV) or endemic human coronavirus (HCoV) (229E, OC43, NL63, and HKU1) remains controversial. We analyzed the impact of symptomatic RVI within <90 days prior to HCT on overall mortality, posttransplant lower respiratory tract disease (LRD), and days alive and out of hospital (DAOH) by day 100 post HCT in multivariable models. Among 1,643 adult HCT recipients (58% allogeneic recipients), 704 (43%) were tested for RVI before HCT and 307 (44%) tested positive. HRV was most commonly detected (56%). Forty-five (15%) of 307 HCT recipients had LRD with the same virus early after HCT. Pretransplant upper respiratory infection (URI) with influenza, respiratory syncytial virus, adenovirus, human metapneumovirus, parainfluenza virus, HRV or endemic HCoV was not associated with increased overall mortality or fewer DAOH. However, in allogeneic recipients who received myeloablative conditioning, LRD due to any respiratory virus, including HRV alone, was associated with increased overall mortality (adjusted hazard ratio 10.8 [95% CI 3.29, 35.1] for HRV and 3.21 [95% CI 1.15, 9.01] for all other viruses). HRV LRD was also associated with fewer DAOH. Thus, the presence of LRD due to common respiratory viruses, including HRV, before myeloablative allogeneic HCT was associated with increased mortality and hospitalization. Pretransplant URI due to HRV and endemic HCoV was not associated with these outcomes. Improved management strategies for pretransplant LRD are warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2021004915DOI Listing
April 2022

Pathogen-Specific Humoral Immunity and Infections in B Cell Maturation Antigen-Directed Chimeric Antigen Receptor T Cell Therapy Recipients with Multiple Myeloma.

Transplant Cell Ther 2022 06 11;28(6):304.e1-304.e9. Epub 2022 Mar 11.

Department of Medicine, University of Washington, Seattle, Washington; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Chimeric antigen receptor (CAR) T cell therapy targeting B cell maturation antigen (BCMA-CARTx) is an emerging treatment for relapsed or refractory multiple myeloma (R/R MM). Here we characterize the epidemiology of infections, risk factors for infection, and pathogen-specific humoral immunity in patients receiving BCMA-CARTx for R/R MM. We performed a retrospective cohort study in 32 adults with R/R MM enrolled in 2 single-institution phase 1 clinical trials of BCMA-CARTx administered after lymphodepleting chemotherapy alone (n = 22) or with a gamma secretase inhibitor (GSI). We tested serum before and up to approximately 180 days after BCMA-CARTx for measles-specific IgG and for any viral-specific IgG using a systematic viral epitope scanning assay to describe the kinetics of total and pathogen-specific IgG levels pre- and post-BCMA-CARTx. We identified microbiologically documented infections to determine infection incidence and used Poisson regression to explore risk factors for infections within 180 days after BCMA-CARTx. Most individuals developed severe neutropenia, lymphopenia, and hypogammaglobulinemia after BCMA-CARTx. Grade ≥3 cytokine release syndrome (CRS; Lee criteria) occurred in 16% of the participants; 50% of the participants received corticosteroids and/or tocilizumab. Before BCMA-CARTx, 28 of 32 participants (88%) had an IgG <400 mg/dL, and only 5 of 27 (19%) had seropositive measles antibody titers. After BCMA-CARTx, all participants had an IgG <400 mg/dL and declining measles antibody titers; of the 5 individuals with baseline seropositive levels, 2 remained above the seroprotective threshold post-treatment. Participants with IgG MM (n = 13) had significantly fewer antibodies to a panel of viral antigens compared with participants with non-IgG MM (n = 6), both before and after BCMA-CARTx. In the first 180 days after BCMA-CARTx, 17 participants (53%) developed a total of 23 infections, of which 13 (57%) were mild-to-moderate viral infections. Serious infections were more frequent in the first 28 days post-treatment. Infections appeared to be more common in individuals with higher-grade CRS. Individuals with R/R MM have substantial deficits in humoral immunity. These data demonstrate the importance of plasma cells in maintaining long-lived pathogen-specific antibodies and suggest that BCMA-CARTx recipients need ongoing surveillance for late-onset infections. Most infections were mild-moderate severity viral infections. The incidence of early infection appears to be lower than has been reported after CD19-directed CARTx for B cell neoplasms, possibly due to differences in patient and disease characteristics and regimen-related toxicities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtct.2022.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9197988PMC
June 2022

Novel factors to predict respiratory viral disease progression in allogeneic hematopoietic cell transplant recipients.

Bone Marrow Transplant 2022 04 16;57(4):649-657. Epub 2022 Feb 16.

Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

We assessed novel factors and the immunodeficiency scoring index (ISI) to predict progression to lower respiratory tract infection (LRTI) among hematopoietic cell transplant (HCT) recipients presenting with upper respiratory tract infection (URTI) with 12 viruses in the PCR era. We retrospectively analyzed the first respiratory virus detected by multiplex PCR in allogeneic HCT recipients (4/2008-9/2018). We used Cox proportional hazards models to examine factors for progression to LRTI within 90 days among patients presenting with URTI. A total of 1027 patients (216 children and 811 adults) presented with URTI only. Among these, 189 (18%) progressed to LRTI (median: 12 days). Multivariable models demonstrated a history of  >1 transplant, age  ≥40 years, time post-HCT (≤30 days), systemic steroids, hypoalbuminemia, hyperglycemia, cytopenia, and high ISI (scores 7-12) were associated with an increased risk of progression to LRTI. Respiratory syncytial virus and human metapneumovirus showed the highest progression risk. Patients with ≥3 independent risk factors or high ISI scores were highly likely to progress to LRTI. We identified novel risk factors for progression to LRTI, including history of multiple transplants and hyperglycemia, suggesting an intervention opportunity with glycemic control. ISI and number of risk factors appear to predict disease progression across several viruses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41409-022-01575-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8853301PMC
April 2022

Interactions among 17 respiratory pathogens: a cross-sectional study using clinical and community surveillance data.

medRxiv 2022 Feb 6. Epub 2022 Feb 6.

Background: Co-circulating respiratory pathogens can interfere with or promote each other, leading to important effects on disease epidemiology. Estimating the magnitude of pathogen-pathogen interactions from clinical specimens is challenging because sampling from symptomatic individuals can create biased estimates.

Methods: We conducted an observational, cross-sectional study using samples collected by the Seattle Flu Study between 11 November 2018 and 20 August 2021. Samples that tested positive via RT-qPCR for at least one of 17 potential respiratory pathogens were included in this study. Semi-quantitative cycle threshold (Ct) values were used to measure pathogen load. Differences in pathogen load between monoinfected and coinfected samples were assessed using linear regression adjusting for age, season, and recruitment channel.

Results: 21,686 samples were positive for at least one potential pathogen. Most prevalent were rhinovirus (33·5%), ( , 29·0%), SARS-CoV-2 (13.8%) and influenza A/H1N1 (9·6%). 140 potential pathogen pairs were included for analysis, and 56 (40%) pairs yielded significant Ct differences (p < 0.01) between monoinfected and co-infected samples. We observed no virus-virus pairs showing evidence of significant facilitating interactions, and found significant viral load decrease among 37 of 108 (34%) assessed pairs. Samples positive with and a virus were consistently associated with increased load.

Conclusions: Viral load data can be used to overcome sampling bias in studies of pathogen-pathogen interactions. When applied to respiratory pathogens, we found evidence of viral- facilitation and several examples of viral-viral interference. Multipathogen surveillance is a cost-efficient data collection approach, with added clinical and epidemiological informational value over single-pathogen testing, but requires careful analysis to mitigate selection bias.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2022.02.04.22270474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8845514PMC
February 2022

Convergent clonal selection of donor- and recipient-derived CMV-specific T cells in hematopoietic stem cell transplant patients.

Proc Natl Acad Sci U S A 2022 02;119(6)

Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109;

Competition between antigen-specific T cells for peptide:MHC complexes shapes the ensuing T cell response. Mouse model studies provided compelling evidence that competition is a highly effective mechanism controlling the activation of naïve T cells. However, assessing the effect of T cell competition in the context of a human infection requires defined pathogen kinetics and trackable naïve and memory T cell populations of defined specificity. A unique cohort of nonmyeloablative hematopoietic stem cell transplant patients allowed us to assess T cell competition in response to cytomegalovirus (CMV) reactivation, which was documented with detailed virology data. In our cohort, hematopoietic stem cell transplant donors and recipients were CMV seronegative and positive, respectively, thus providing genetically distinct memory and naïve T cell populations. We used single-cell transcriptomics to track donor versus recipient-derived T cell clones over the course of 90 d. We found that donor-derived T cell clones proliferated and expanded substantially following CMV reactivation. However, for immunodominant CMV epitopes, recipient-derived memory T cells remained the overall dominant population. This dominance was maintained despite more robust clonal expansion of donor-derived T cells in response to CMV reactivation. Interestingly, the donor-derived T cells that were recruited into these immunodominant memory populations shared strikingly similar TCR properties with the recipient-derived memory T cells. This selective recruitment of identical and nearly identical clones from the naïve into the immunodominant memory T cell pool suggests that competition is in place but does not interfere with rejuvenating a memory T cell population. Instead, it results in selection of convergent clones to the memory T cell pool.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.2117031119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8833188PMC
February 2022

Phylogenomics of SARS-CoV-2 in Emergency Shelters for People Experiencing Homelessness.

J Infect Dis 2022 Jan 29. Epub 2022 Jan 29.

Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA, USA.

Residents and staff of emergency shelters for people experiencing homelessness (PEH) are at high risk of infection with SARS-CoV-2. The importance of shelter-related transmission of SARS-CoV-2 in this population remains unclear. It is also unknown whether there is significant spread of shelter-related viruses into surrounding communities. We analyzed genome sequence data for 28 SARS-CoV-2-positive specimens collected from 8 shelters in King County, Washington between March and October, 2020. We identified at least 12 separate SARS-CoV-2 introduction events into these 8 shelters and estimated that 57% (16 out of 28) of the examined cases of SARS-CoV-2 infection were the result of intra-shelter transmission. However, we identified just a few SARS-CoV-2 specimens from Washington that were possible descendants of shelter viruses. Our data suggest that SARS-CoV-2 spread in shelters is common, but we did not observe evidence of wide-spread transmission of shelter-related viruses into the general population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/infdis/jiac021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8807325PMC
January 2022

Trends in COVID-19 vaccination intent and factors associated with deliberation and reluctance among adult homeless shelter residents and staff, 1 November 2020 to 28 February 2021 - King County, Washington.

Vaccine 2022 01 15;40(1):122-132. Epub 2021 Nov 15.

Department of Medicine, Division of Allergy & Infectious Diseases, University of Washington, Seattle, WA, USA.

Introduction: Little is known about COVID-19 vaccination intent among people experiencing homelessness. This study assesses surveyed COVID-19 vaccination intent among adult homeless shelter residents and staff and identifies factors associated with vaccine deliberation (responded "undecided") and reluctance (responded "no"), including time trends.

Methods: From 11/1/2020-2/28/21, we conducted repeated cross-sectional surveys at nine shelters in King County, WA as part of ongoing community-based SARS-CoV-2 surveillance. We used a multinomial model to identify characteristics associated with vaccine deliberation and reluctance.

Results: A total of 969 unique staff (n = 297) and residents (n = 672) participated and provided 3966 survey responses. Among residents, 53.7% (n = 361) were vaccine accepting, 28.1% reluctant, 17.6% deliberative, and 0.6% already vaccinated, whereas among staff 56.2% were vaccine accepting, 14.1% were reluctant, 16.5% were deliberative, and 13.1% already vaccinated at their last survey. We observed higher odds of vaccine deliberation or reluctance among Black/African American individuals, those who did not receive a seasonal influenza vaccine, and those with lower educational attainment. There was no significant trend towards vaccine acceptance.

Conclusions: Strong disparities in vaccine intent based on race, education, and prior vaccine history were observed. Increased vaccine intent over the study period was not detected. An intersectional, person-centered approach to addressing health inequities by public health authorities planning vaccination campaigns in shelters is recommended. Clinical Trial Registry Number: NCT04141917.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.vaccine.2021.11.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8590934PMC
January 2022

Mathematical Modeling of Within-Host, Untreated, Cytomegalovirus Infection Dynamics after Allogeneic Transplantation.

Viruses 2021 11 16;13(11). Epub 2021 Nov 16.

Fred Hutchinson Cancer Research Center, Vaccine and Infectious Disease Division, Seattle, WA 98109, USA.

Cytomegalovirus (CMV) causes significant morbidity and mortality in recipients of allogeneic hematopoietic cell transplantation (HCT). Whereas insights gained from mathematical modeling of other chronic viral infections such as HIV, hepatitis C, and herpes simplex virus-2 have aided in optimizing therapy, previous CMV modeling has been hindered by a lack of comprehensive quantitative PCR viral load data from untreated episodes of viremia in HCT recipients. We performed quantitative CMV DNA PCR on stored, frozen serum samples from the placebo group of participants in a historic randomized controlled trial of ganciclovir for the early treatment of CMV infection in bone marrow transplant recipients. We developed four main ordinary differential Equation mathematical models and used model selection theory to choose between 38 competing versions of these models. Models were fit using a population, nonlinear, mixed-effects approach. We found that CMV kinetics from untreated HCT recipients are highly variable. The models that recapitulated the observed patterns most parsimoniously included explicit, dynamic immune cell compartments and did not include dynamic target cell compartments, consistent with the large number of tissue and cell types that CMV infects. In addition, in our best-fitting models, viral clearance was extremely slow, suggesting severe impairment of the immune response after HCT. Parameters from our best model correlated well with participants' clinical risk factors and outcomes from the trial, further validating our model. Our models suggest that CMV dynamics in HCT recipients are determined by host immune response rather than target cell limitation in the absence of antiviral treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/v13112292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8618844PMC
November 2021

Human parainfluenza virus evolution during lung infection of immunocompromised individuals promotes viral persistence.

J Clin Invest 2021 12;131(23)

Department of Pediatrics and.

The capacity of respiratory viruses to undergo evolution within the respiratory tract raises the possibility of evolution under the selective pressure of the host environment or drug treatment. Long-term infections in immunocompromised hosts are potential drivers of viral evolution and development of infectious variants. We showed that intrahost evolution in chronic human parainfluenza virus 3 (HPIV3) infection in immunocompromised individuals elicited mutations that favored viral entry and persistence, suggesting that similar processes may operate across enveloped respiratory viruses. We profiled longitudinal HPIV3 infections from 2 immunocompromised individuals that persisted for 278 and 98 days. Mutations accrued in the HPIV3 attachment protein hemagglutinin-neuraminidase (HN), including the first in vivo mutation in HN's receptor binding site responsible for activating the viral fusion process. Fixation of this mutation was associated with exposure to a drug that cleaves host-cell sialic acid moieties. Longitudinal adaptation of HN was associated with features that promote viral entry and persistence in cells, including greater avidity for sialic acid and more active fusion activity in vitro, but not with antibody escape. Long-term infection thus led to mutations promoting viral persistence, suggesting that host-directed therapeutics may support the evolution of viruses that alter their biophysical characteristics to persist in the face of these agents in vivo.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI150506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8631596PMC
December 2021

American Society for Transplantation and Cellular Therapy Series: #3-Prevention of Cytomegalovirus Infection and Disease After Hematopoietic Cell Transplantation.

Transplant Cell Ther 2021 09;27(9):707-719

Division of Infectious Diseases, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, Massachusetts.

The Practice Guidelines Committee of the American Society for Transplantation and Cellular Therapy partnered with its Transplant Infectious Disease Special Interest Group to update its 2009 compendium-style infectious diseases guidelines for the care of hematopoietic cell transplant (HCT) recipients. A new approach was taken with the goal of better serving clinical providers by publishing each standalone topic in the infectious disease series as a concise format of frequently asked questions (FAQ), tables, and figures. Adult and pediatric infectious disease and HCT content experts developed and answered FAQs. Topics were finalized with harmonized recommendations that were made by assigning an A through E strength of recommendation paired with a level of supporting evidence graded I through III. The third topic in the series focuses on the prevention of cytomegalovirus infection and disease in HCT recipients by reviewing prophylaxis and preemptive therapy approaches; key definitions, relevant risk factors, and diagnostic monitoring considerations are also reviewed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtct.2021.05.001DOI Listing
September 2021

Delayed-onset cytomegalovirus infection is frequent after discontinuing letermovir in cord blood transplant recipients.

Blood Adv 2021 08;5(16):3113-3119

Department of Medicine, University of Washington, Seattle, WA.

Cytomegalovirus (CMV)-seropositive umbilical cord blood transplantation (CBT) recipients have a high incidence of CMV-associated complications. There are limited data regarding the efficacy of letermovir for preventing clinically significant CMV infection (CS-CMVi), and the impact of letermovir prophylaxis on delayed-onset CMV reactivation after letermovir discontinuation, in CBT recipients. We compared the cumulative incidence of CS-CMVi and CMV detection in 21 CMV-seropositive CBT recipients receiving letermovir prophylaxis with a historical cohort of 40 CBT recipients receiving high-dose valacyclovir prophylaxis. Letermovir was administered on day +1 up to day +98. The cumulative incidence of CS-CMVi was significantly lower by day 98 in the letermovir cohort (19% vs 65%). This difference was lost by 1 year due to a higher incidence of delayed-onset CMV reactivation in the letermovir cohort. No patients developed CMV disease in the letermovir cohort within the first 98 days compared with 2 cases (2.4%) in the high-dose valacyclovir cohort; 2 patients developed CMV enteritis after discontinuing letermovir. Median viral loads were similar in both cohorts. Thus, letermovir is effective at preventing CS-CMVi after CBT, but frequent delayed-onset infections after letermovir discontinuation mandate close monitoring and consideration for extended prophylaxis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2021004362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405185PMC
August 2021

Genetic variants associated with cytomegalovirus infection after allogeneic hematopoietic cell transplantation.

Blood 2021 10;138(17):1628-1636

Department of Medicine, University of Washington School of Medicine, Seattle, WA.

Human cytomegalovirus (CMV) reactivation is a frequent complication of allogeneic hematopoietic cell transplantation (HCT). Despite routine screening for CMV reactivation and early antiviral treatment, the rates of CMV-related complications after HCT remain high. Genetic variants in both the donor and recipient have been associated with the risk of CMV reactivation and disease after HCT, but these associations have not been validated, and their clinical importance remains unclear. In this study, we assessed 117 candidate variants previously associated with CMV-related phenotypes for association with CMV reactivation and disease in a cohort of 2169 CMV-seropositive HCT recipients. We also carried out a genome-wide association study (GWAS) for CMV reactivation and disease in the same cohort. Both analyses used a prespecified discovery and replication approach to control the risk of false-positive results. Among the 117 candidate variants, our analysis implicates only the donor ABCB1 rs1045642 genotype as a risk factor for CMV reactivation. This synonymous variant in P-glycoprotein may influence the risk of CMV reactivation by altering the efflux of cyclosporine and tacrolimus from donor lymphocytes. In the GWAS analysis, the donor CDC42EP3 rs11686168 genotype approached the significance threshold for association with CMV reactivation, although we could not identify a mechanism to explain this association. The results of this study suggest that most genomic variants previously associated with CMV phenotypes do not significantly alter the risk for CMV reactivation or disease after HCT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2021012153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8554648PMC
October 2021

Cytomegalovirus Viremia and Clinical Outcomes in Kenyan Children Diagnosed With Human Immunodeficiency Virus (HIV) in Hospital.

Clin Infect Dis 2022 04;74(7):1237-1246

Department of Global Health, University of Washington, Seattle, Washington, USA.

Background: Cytomegalovirus (CMV) viremia is common in human immunodeficiency virus (HIV) infection and is associated with worse long-term outcomes. To date, no studies have assessed CMV viremia in children diagnosed with HIV in hospital.

Methods: We studied CMV viremia and clinical outcomes in 163 Kenyan children aged 2 months to 12 years, diagnosed with HIV in hospital. CMV DNA levels in plasma were measured using quantitative polymerase chain reaction (PCR). Regression models were used to assess associations between CMV viremia ≥1000 IU/mL and the risk of continued hospitalization or death at 15 days, duration of hospitalization, and 6-month mortality.

Results: At enrollment, 62/114 (54%) children had CMV viremia, and 20 (32%) were ≥1000 IU/mL. Eleven CMV reactivations were observed after admission. The prevalence and level of CMV viremia were highest in children <2 years and lowest in children ≥5 years old. CMV viremia ≥1000 IU/mL was independently associated with age <2 years (P = .03), higher log10 HIV RNA level (P = .01), and height-for-age z score >-2 (P = .02). Adjusting for age and log10 HIV RNA, the relative risk of death or continued hospitalization at 15 days was 1.74 (95% confidence interval [CI] = 1.04, 2.90), and the hazard ratio of 6-month mortality was 1.97 (95% CI = .57, 5.07) for children with CMV DNA ≥1000 IU/mL compared to lower-level or undetectable CMV DNA. Children with CMV DNA ≥1000 IU/mL were hospitalized a median ~5 days longer than children with lower-level or undetectable CMV DNA (P = .002).

Conclusions: In this nested observational study, CMV viremia was common in hospitalized children with HIV, and levels ≥1000 IU/mL were associated with increased risk of mortality and longer hospitalization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciab604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8994579PMC
April 2022

Comparison of Symptoms and RNA Levels in Children and Adults With SARS-CoV-2 Infection in the Community Setting.

JAMA Pediatr 2021 10 4;175(10):e212025. Epub 2021 Oct 4.

Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle.

Importance: The association between COVID-19 symptoms and SARS-CoV-2 viral levels in children living in the community is not well understood.

Objective: To characterize symptoms of pediatric COVID-19 in the community and analyze the association between symptoms and SARS-CoV-2 RNA levels, as approximated by cycle threshold (Ct) values, in children and adults.

Design, Setting, And Participants: This cross-sectional study used a respiratory virus surveillance platform in persons of all ages to detect community COVID-19 cases from March 23 to November 9, 2020. A population-based convenience sample of children younger than 18 years and adults in King County, Washington, who enrolled online for home self-collection of upper respiratory samples for SARS-CoV-2 testing were included.

Exposures: Detection of SARS-CoV-2 RNA by reverse transcription-polymerase chain reaction (RT-PCR) from participant-collected samples.

Main Outcomes And Measures: RT-PCR-confirmed SARS-CoV-2 infection, with Ct values stratified by age and symptoms.

Results: Among 555 SARS-CoV-2-positive participants (mean [SD] age, 33.7 [20.1] years; 320 were female [57.7%]), 47 of 123 children (38.2%) were asymptomatic compared with 31 of 432 adults (7.2%). When symptomatic, fewer symptoms were reported in children compared with adults (mean [SD], 1.6 [2.0] vs 4.5 [3.1]). Symptomatic individuals had lower Ct values (which corresponded to higher viral RNA levels) than asymptomatic individuals (adjusted estimate for children, -3.0; 95% CI, -5.5 to -0.6; P = .02; adjusted estimate for adults, -2.9; 95% CI, -5.2 to -0.6; P = .01). The difference in mean Ct values was neither statistically significant between symptomatic children and symptomatic adults (adjusted estimate, -0.7; 95% CI, -2.2 to 0.9; P = .41) nor between asymptomatic children and asymptomatic adults (adjusted estimate, -0.6; 95% CI, -4.0 to 2.8; P = .74).

Conclusions And Relevance: In this community-based cross-sectional study, SARS-CoV-2 RNA levels, as determined by Ct values, were significantly higher in symptomatic individuals than in asymptomatic individuals and no significant age-related differences were found. Further research is needed to understand the role of SARS-CoV-2 RNA levels and viral transmission.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamapediatrics.2021.2025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8491103PMC
October 2021

Association of Inherited Chromosomally Integrated Human Herpesvirus 6 with Neurologic Symptoms and Management after Allogeneic Hematopoietic Cell Transplantation.

Transplant Cell Ther 2021 09 7;27(9):795.e1-795.e8. Epub 2021 Jun 7.

Fred Hutchinson Cancer Research Center, Vaccine and Infectious Disease Division, Seattle, Washington; Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, Washington. Electronic address:

Reactivation of human herpesvirus 6 (HHV-6) after allogeneic hematopoietic cell transplantation (HCT) is associated with neurologic complications, but the impact of donor and/or recipient inherited chromosomally integrated HHV-6 (iciHHV-6) on post-HCT central nervous system (CNS) symptoms and diagnostic and therapeutic interventions is not well understood. The aims of the present study were (1) to compare the cumulative incidence of CNS symptoms in the first 100 days following allogeneic HCT among patients with donor and/or recipient iciHHV-6 (iciHHV-6)with that of patients with neither donor nor recipient iciHHV-6 (iciHHV-6) and (2) to assess the role of HHV-6 detection in driving potentially unnecessary interventions in iciHHV-6 patients. We performed a retrospective matched cohort study of 87 iciHHV-6 and 174 iciHHV-6 allogeneic HCT recipients. HHV-6 testing was performed at the discretion of healthcare providers, who were unaware of iciHHV-6 status. The cumulative incidence of CNS symptoms was similar in iciHHV-6 (n = 37; 43%) and iciHHV-6 HCT recipients (n = 81; 47%; P = .63). HHV-6 plasma testing was performed in similar proportions of iciHHV-6 (n = 6; 7%) and iciHHV-6 (9%) patients and was detected in all tested iciHHV-6 HCTs and 2 (13%) iciHHV-6 HCTs. This resulted in more frequent HHV-6-targeted antiviral therapy after iciHHV-6 HCT (odds ratio, 12.8; 95% confidence interval, 1.5 to 108.2) with associated side effects. HHV-6 plasma detection in 2 iciHHV-6 patients without active CNS symptoms prompted unnecessary lumbar punctures. The cumulative incidence of CNS symptoms was similar after allogeneic HCT involving recipients or donors with and without iciHHV-6. Misattribution of HHV-6 detection as infection after iciHHV-6 HCT may lead to unnecessary interventions. Testing for iciHHV-6 may improve patient management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtct.2021.05.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403634PMC
September 2021

Outcomes of Hematopoietic Cell Transplantation in Patients with Mixed Response to Pretransplantation Treatment of Confirmed or Suspected Invasive Fungal Infection.

Transplant Cell Ther 2021 08 5;27(8):684.e1-684.e9. Epub 2021 May 5.

Department of Medicine, University of Washington, Seattle, Washington; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Patients with hematologic malignancy or bone marrow failure are typically required to achieve radiographic improvement or stabilization of invasive fungal infection (IFI) before hematopoietic cell transplantation (HCT) owing to a concern for progression before engraftment. Refractory IFI with a mixture of improvement and progression on serial imaging (ie, mixed response) poses a clinical dilemma, because a delay in HCT may allow for a hematologic relapse or other complications. Furthermore, HCT itself may yield the immune reconstitution necessary for clearance of infection. We sought to describe the characteristics and outcomes of patients who underwent HCT with mixed response IFI. We performed a chart review of all patients who underwent HCT between 2014 and 2020 in whom imaging within 6 weeks before HCT indicated a mixed response to treatment of a diagnosed IFI. Fourteen patients had evidence of a mixed response in low-to-moderate burden of diagnosed IFI by imaging before HCT, including 9 with pulmonary aspergillosis, 2 with hepatosplenic candidiasis (1 also with aspergillosis), and 4 with pulmonary nodules of presumed fungal etiology. Five had refractory severe neutropenia at evaluation for HCT (median, 95 days). All 14 patients showed radiographic stability or improvement in imaging following engraftment; no IFI-related surgeries were required, and no IFI-related deaths occurred. For patients without relapse who underwent HCT more than 1 year earlier, 7 of 8 (88%) were alive at 1 year. Our findings suggest that low-to-moderate burden IFI with mixed response is unlikely to progress on appropriate therapy before engraftment during allogeneic HCT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtct.2021.04.021DOI Listing
August 2021

Viral genomes reveal patterns of the SARS-CoV-2 outbreak in Washington State.

Sci Transl Med 2021 05 3;13(595). Epub 2021 May 3.

Seattle Children's Research Institute, Seattle, WA 98101, USA.

The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has gravely affected societies around the world. Outbreaks in different parts of the globe have been shaped by repeated introductions of new viral lineages and subsequent local transmission of those lineages. Here, we sequenced 3940 SARS-CoV-2 viral genomes from Washington State (USA) to characterize how the spread of SARS-CoV-2 in Washington State in early 2020 was shaped by differences in timing of mitigation strategies across counties and by repeated introductions of viral lineages into the state. In addition, we show that the increase in frequency of a potentially more transmissible viral variant (614G) over time can potentially be explained by regional mobility differences and multiple introductions of 614G but not the other variant (614D) into the state. At an individual level, we observed evidence of higher viral loads in patients infected with the 614G variant. However, using clinical records data, we did not find any evidence that the 614G variant affects clinical severity or patient outcomes. Overall, this suggests that with regard to D614G, the behavior of individuals has been more important in shaping the course of the pandemic in Washington State than this variant of the virus.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/scitranslmed.abf0202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8158963PMC
May 2021

A remote household-based approach to influenza self-testing and antiviral treatment.

Influenza Other Respir Viruses 2021 07 3;15(4):469-477. Epub 2021 May 3.

Department of Medicine, University of Washington, Seattle, WA, USA.

Background: Households represent important settings for transmission of influenza and other respiratory viruses. Current influenza diagnosis and treatment relies upon patient visits to healthcare facilities, which may lead to under-diagnosis and treatment delays. This study aimed to assess the feasibility of an at-home approach to influenza diagnosis and treatment via home testing, telehealth care, and rapid antiviral home delivery.

Methods: We conducted a pilot interventional study of remote influenza diagnosis and treatment in Seattle-area households with children during the 2019-2020 influenza season using pre-positioned nasal swabs and home influenza tests. Home monitoring for respiratory symptoms occurred weekly; if symptoms were reported within 48 hours of onset, participants collected mid-nasal swabs and used a rapid home-based influenza immunoassay. An additional home-collected swab was returned to a laboratory for confirmatory influenza RT-PCR testing. Baloxavir antiviral treatment was prescribed and delivered to symptomatic and age-eligible participants, following a telehealth encounter.

Results: 124 households comprising 481 individuals self-monitored for respiratory symptoms, with 58 home tests administered. 12 home tests were positive for influenza, of which eight were true positives confirmed by RT-PCR. The sensitivity and specificity of the home influenza test were 72.7% and 96.2%, respectively. There were eight home deliveries of baloxavir, with 7 (87.5%) occurring within 3 hours of prescription and all within 48 hours of symptom onset.

Conclusions: We demonstrate the feasibility of self-testing combined with rapid home delivery of influenza antiviral treatment. This approach may be an important control strategy for influenza epidemics and pandemics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/irv.12859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189204PMC
July 2021

Antibodies against vaccine-preventable infections after CAR-T cell therapy for B cell malignancies.

JCI Insight 2021 06 8;6(11). Epub 2021 Jun 8.

Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

BACKGROUNDLittle is known about pathogen-specific humoral immunity after chimeric antigen receptor-modified T (CAR-T) cell therapy for B cell malignancies.METHODSWe conducted a prospective cross-sectional study of CD19-targeted or B cell maturation antigen-targeted (BCMA-targeted) CAR-T cell therapy recipients at least 6 months posttreatment and in remission. We measured pathogen-specific IgG against 12 vaccine-preventable infections and the number of viral and bacterial epitopes to which IgG was detected ("epitope hits") using a serological profiling assay. The primary outcome was the proportion of participants with IgG levels above a threshold correlated with seroprotection for vaccine-preventable infections.RESULTSWe enrolled 65 children and adults a median of 20 months after CD19- (n = 54) or BCMA- (n = 11) CAR-T cell therapy. Among 30 adults without IgG replacement therapy (IGRT) in the prior 16 weeks, 27 (90%) had hypogammaglobulinemia. These individuals had seroprotection to a median of 67% (IQR, 59%-73%) of tested infections. Proportions of participants with seroprotection per pathogen were comparable to population-based studies, but most individuals lacked seroprotection to specific pathogens. Compared with CD19-CAR-T cell recipients, BCMA-CAR-T cell recipients were half as likely to have seroprotection (prevalence ratio, 0.47; 95% CI, 0.18-1.25) and had fewer pathogen-specific epitope hits (mean difference, -90 epitope hits; 95% CI, -157 to -22).CONCLUSIONSeroprotection for vaccine-preventable infections in adult CD19-CAR-T cell recipients was comparable to the general population. BCMA-CAR-T cell recipients had fewer pathogen-specific antibodies. Deficits in both groups support the need for vaccine and immunoglobulin replacement therapy studies.FUNDINGSwiss National Science Foundation (Early Postdoc Mobility grant P2BSP3_188162), NIH/National Cancer Institute (NIH/NCI) (U01CA247548 and P01CA018029), NIH/NCI Cancer Center Support Grants (P30CA0087-48 and P30CA015704-44), American Society for Transplantation and Cellular Therapy, and Juno Therapeutics/BMS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.146743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262349PMC
June 2021

A randomised, placebo-controlled phase 3 study to evaluate the efficacy and safety of ASP0113, a DNA-based CMV vaccine, in seropositive allogeneic haematopoietic cell transplant recipients.

EClinicalMedicine 2021 Mar 19;33:100787. Epub 2021 Mar 19.

Department of Microbiology and Immunology, K.U. Leuven and Department of Hematology, UZ Leuven, Leuven, Belgium.

Background: Cytomegalovirus (CMV) is a complication of allogeneic haematopoietic cell transplantation (allo-HCT). ASP0113, a DNA-based vaccine, contains two plasmids encoding human CMV glycoprotein B and phosphoprotein 65 (pp65). We assessed ASP0113 in CMV-seropositive allo-HCT recipients.

Methods: In this phase 3, randomised, placebo-controlled study, CMV-seropositive allo-HCT recipients were randomly assigned (1:1) via interactive response technology to receive five injections of 1 mL of 5 mg/mL ASP0113 or placebo. The pharmacist and designated staff were unblinded. Masked syringes maintained the blind for patients and study personnel. Efficacy and safety analyses included patients who received ≥1 dose of ASP0113/placebo. The primary efficacy endpoint was the proportion of allo-HCT recipients with composite all-cause mortality and adjudicated CMV end-organ disease (EOD) by 1 year post-transplant. ClinicalTrials.gov: NCT01877655 (not recruiting).

Findings: Patients were recruited between Sept 11, 2013 and Sept 21, 2016. Overall, 501 patients received ≥1 dose of ASP0113 ( = 246) or placebo ( = 255). The proportion of patients with composite all-cause mortality and adjudicated CMV EOD by 1 year post-transplant was 35.4% ( = 87) with ASP0113 and 30•2% ( = 77) with placebo (odds ratio 1.27; 95% confidence interval: 0.87 to 1.85;  = 0.205). Incidence of injection site-related treatment-emergent adverse events (TEAEs) was higher with ASP0113 than placebo. Overall incidence and severity of other TEAEs was similar between groups. T-cell response to pp65 increased over time and was greater with placebo than ASP0113 ( = 0.027).

Interpretation: ASP0113 did not reduce overall mortality or CMV EOD by 1 year post-transplant. Safety findings were similar between groups.

Funding: Astellas Pharma Global Development, Inc .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.eclinm.2021.100787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020145PMC
March 2021

A human coronavirus evolves antigenically to escape antibody immunity.

PLoS Pathog 2021 04 8;17(4):e1009453. Epub 2021 Apr 8.

Basic Sciences and Computational Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.

There is intense interest in antibody immunity to coronaviruses. However, it is unknown if coronaviruses evolve to escape such immunity, and if so, how rapidly. Here we address this question by characterizing the historical evolution of human coronavirus 229E. We identify human sera from the 1980s and 1990s that have neutralizing titers against contemporaneous 229E that are comparable to the anti-SARS-CoV-2 titers induced by SARS-CoV-2 infection or vaccination. We test these sera against 229E strains isolated after sera collection, and find that neutralizing titers are lower against these "future" viruses. In some cases, sera that neutralize contemporaneous 229E viral strains with titers >1:100 do not detectably neutralize strains isolated 8-17 years later. The decreased neutralization of "future" viruses is due to antigenic evolution of the viral spike, especially in the receptor-binding domain. If these results extrapolate to other coronaviruses, then it may be advisable to periodically update SARS-CoV-2 vaccines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.ppat.1009453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8031418PMC
April 2021

American Society for Transplantation and Cellular Therapy Infectious Disease Guidelines: Preface to the Series.

Transplant Cell Ther 2021 02 10;27(2):103-104. Epub 2020 Dec 10.

Hematology and Stem Cell Transplantation Section, Vanderbilt University Medical Center, Nashville, Tennessee.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtct.2020.10.004DOI Listing
February 2021

Risk factors for seasonal human coronavirus lower respiratory tract infection after hematopoietic cell transplantation.

Blood Adv 2021 04;5(7):1903-1914

Vaccine and Infectious Disease Division and.

Data are limited regarding risk factors for lower respiratory tract infection (LRTI) caused by seasonal human coronaviruses (HCoVs) and the significance of virologic documentation by bronchoalveolar lavage (BAL) on outcomes in hematopoietic cell transplant (HCT) recipients. We retrospectively analyzed patients undergoing allogeneic HCT (4/2008-9/2018) with HCoV (OC43/NL63/HKU1/229E) detected by polymerase chain reaction during conditioning or post-HCT. Risk factors for all manifestations of LRTI and progression to LRTI among those presenting with HCoV upper respiratory tract infection (URTI) were analyzed by logistic regression and Cox proportional hazard models, respectively. Mortality rates following HCoV LRTI were compared according to virologic documentation by BAL. A total of 297 patients (61 children and 236 adults) developed HCoV infection as follows: 254 had URTI alone, 18 presented with LRTI, and 25 progressed from URTI to LRTI (median, 16 days; range, 2-62 days). Multivariable logistic regression analyses showed that male sex, higher immunodeficiency scoring index, albumin <3 g/dL, glucose >150 mg/dL, and presence of respiratory copathogens were associated with occurrence of LRTI. Hyperglycemia with steroid use was associated with progression to LRTI (P < .01) in Cox models. LRTI with HCoV detected in BAL was associated with higher mortality than LRTI without documented detection in BAL (P < .01). In conclusion, we identified factors associated with HCoV LRTI, some of which are less commonly appreciated to be risk factors for LRTI with other respiratory viruses in HCT recipients. The association of hyperglycemia with LRTI might provide an intervention opportunity to reduce the risk of LRTI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2020003865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015796PMC
April 2021

Home Spirometry Telemonitoring for Early Detection of Bronchiolitis Obliterans Syndrome in Patients with Chronic Graft-versus-Host Disease.

Transplant Cell Ther 2021 07 26;27(7):616.e1-616.e6. Epub 2021 Mar 26.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington. Electronic address:

Early detection of bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic cell transplantation (HCT) depends on recognition of subclinical spirometric changes, which is possible only with frequent interval spirometry. We evaluated the feasibility of home monitoring of weekly spirometry via a wireless handheld device and a web monitoring portal in a cohort of high-risk patients for the detection of lung function changes preceding BOS diagnosis. In this observational study, 46 patients with chronic graft-versus-host disease or a decline in forced expiratory volume in 1 second (FEV) of unclear etiology after allogeneic HCT were enrolled to perform weekly home spirometry with a wireless portable spirometer for a period of 1 year. Measurements were transmitted wirelessly to a Cloud-based monitoring portal. Feasibility evaluation included adherence with study procedures and an assessment of the home spirometry measurements compared with laboratory pulmonary function tests. Thirty-six patients (78%) completed 1 year of weekly monitoring. Overall adherence with weekly home spirometry measurements was 72% (interquartile range, 47% to 90%), which did not meet the predetermined threshold of 75% for high adherence. Correlation of home FEV with laboratory FEV was high, with a bias of 0.123 L (lower limit, -0.294 L; upper limit, 0.541 L), which is within acceptable limits for reliability. Of the 12 patients who were diagnosed with BOS or suspected BOS during the study period, 9 had an antecedent FEV decline detected by home spirometry. Our data indicate that wireless handheld spirometry performed at home in a high-risk HCT cohort is feasible for close monitoring of pulmonary function and appears to facilitate early detection of BOS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtct.2021.03.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423348PMC
July 2021

American Society of Transplantation and Cellular Therapy Series, 2: Management and Prevention of Aspergillosis in Hematopoietic Cell Transplantation Recipients.

Transplant Cell Ther 2021 03;27(3):201-211

Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas.

The Practice Guidelines Committee of the American Society of Transplantation and Cellular Therapy partnered with its Transplant Infectious Disease Special Interest Group to update its 2009 compendium-style infectious disease guidelines for hematopoietic cell transplantation (HCT). A completely fresh approach was taken with the goal of better serving clinical providers by publishing each standalone topic in the infectious disease series as a concise format of frequently asked questions (FAQs), tables, and figures. Adult and pediatric infectious disease and HCT content experts developed, then answered FAQs, and finalized topics with harmonized recommendations that were made by assigning an A through E strength of recommendation paired with a level of supporting evidence graded I through III. This second guideline in the series focuses on invasive aspergillosis, a potentially life-threatening infection in the peri-HCT period. The relevant risk factors, diagnostic considerations, and prophylaxis and treatment approaches are reviewed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtct.2020.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9088165PMC
March 2021
-->