ABSTRACT
Hematopoietic cell transplant (HCT) recipients are at increased risk of morbidity and mortality from COVID-19. They may have lower SARS-CoV-2-directed antibody levels due to protein loss from the gastrointestinal (GI) tract as a result of preparative regimen-related toxicity and graft-vs.-host disease (GVHD). In fact, previous studies suggested that GI GVHD or diarrhea from other etiologies were associated with a reduction in the half-life of monoclonal antibodies (mAbs). Hence, understanding the pharmacokinetic (PK) profile of mAbs targeting SARS-CoV-2 in this vulnerable population is critical for dose-selection and predicting the duration of protection against COVID-19. This analysis aims to use a population pharmacokinetics (popPK) approach to evaluate the PK of sotrovimab and the effect of covariates in HCT recipients. In a Phase I trial (COVIDMAB), all participants received 500 mg sotrovimab IV prophylactically within one week prior to starting transplant conditioning. Sotrovimab serum concentrations were determined weekly for up to 12 weeks in autologous (n=5) and allogeneic (n=15) HCT recipients (129 observations). Sotrovimb PK and the effect of covariates were analyzed using popPK modeling in NONMEM (version 7.4). GVHD and diarrhea severity data were collected weekly via survey and included as time-dependent covariates during the covariate screening process. The final PK model with covariates was validated using simulation-based validation and goodness of fit plots. PK data were compared to non-transplant patients from 1891 patients with COVID-19 in COMET-ICE, COMET-PEAK, BLAZE-4, and COMET-TAIL and 38 healthy individuals enrolled in GlaxoSmithKline Pharma Study 217653. A two-compartment model best described sotrovimab PK in HCT recipients. In comparison to non-transplant patients, sotrovimab clearance (CL) was 14.0% higher in HCT recipients. Weight was a significant covariate on sotrovimab CL and (Figure Presented) volume of distribution in the central compartment (V2). With every 10 kg increase in body weight, sotrovimab CL and V2 were estimated to increase by 9.5% and 5.5%, respectively. Diarrhea severity was also a significant covariate on sotrovimab CL. HCT recipients with grade 3 diarrhea showed an increase in CL by 1.5-fold compared to those without diarrhea. Based on popPK analyses, sotrovimab CL was higher in HCT recipients compared to non-transplant patients. Higher bodyweight as well as diarrhea resulted in increased sotrovimab CL. There were only 3 patients with GI GVHD, and larger studies are needed to determine whether diarrhea due to GI GVHD or conditioning toxicity was responsible for the observed increase in sotrovimab CL. Further validation of these findings in a larger number of HCT recipients is also warranted to help optimize mAb dosing for COVID-19 prophylaxis and determine whether presence of large-volume diarrhea may require intensified dosing strategiesCopyright © 2023 American Society for Transplantation and Cellular Therapy
ABSTRACT
Background. Respiratory virus infections (RVIs) in adult hematopoietic cell transplant (HCT) candidates have been shown to impact posttransplant outcomes;however, there are few studies in pediatric patients. We sought to evaluate the role of specific viruses and the location of viral infection on post HCT outcomes. Methods. We evaluated allogeneic pediatric HCT recipients receiving myeloablative conditioning from 3/2010-3/2018. All patients had a multiplex PCR for RVIs prior to HCT, regardless of symptoms. Delaying HCT was recommended when feasible for RSV, parainfluenza, metapneumovirus, adenovirus, and influenza, but not routinely for human rhinovirus (HRV) and endemic coronaviruses. We utilized Cox proportional hazards models to evaluate progression to lower respiratory disease (LRD) post HCT and linear regression models to evaluated days alive and out of hospital (DAOH) by 100 days post HCT. Results. Of 310 allogeneic HCT recipients receiving myeloablative conditioning, 133 (43%) were positive for a RVI before HCT. Baseline characteristics were notable for differences for age, recipient CMV serostatus, and delayed HCT (Table 1). The most common RVI was HRV (97, 73%) and 81 (61%) patients were symptomatic at the time of detection. Most patients had a URI (92%) and 11 patients had LRD (3 proven, 8 possible). In univariate analysis, HRV as virus type was associated with fewer DAOH and preHCT URI as location of viral infection (with and without symptoms) trended towards fewer DAOH (Figure 1a). When adjusted for age, preHCT lymphocyte count, cell source, and conditioning regimen, both HRV and preHCT URI showed a trend towards fewer DAOH, but no significant association was found (Figure 1b,c). Twenty patients progressed to LRD after HCT with the same preHCT RVI;no factors, including delay of transplant, were associated with reduced progression to LRD. Conclusion. In this single center study, HRV as virus type and URI as location of viral infection before myeloablative allogeneic HCT were associated with increased hospitalization after HCT, but not inmultivariatemodels. Larger multicenter studies are needed to provide timely evaluation and adequate statistical power to definitivelydetermine role of URI versus LRD and the impact of transplant delay and treatment strategies. (Table Presented).
ABSTRACT
Background. Respiratory virus infections are associated with significant and specific local and systemic inflammatory response patterns, which may lead to reactivation of latent viruses. We examined whether viral upper (URTI) or lower respiratory tract infection (LRTI) with common respiratory viruses increased the risk of CMV viremia after allogeneic hematopoietic cell transplantation (HCT). Methods. We retrospectively analyzed patients undergoing allogeneic HCT between 4/2008 and 9/2018. CMV surveillance was performed weekly and the presence of upper and lower respiratory symptoms were evaluated by multiplex respiratory viral PCR. We used Cox proportional hazards models to evaluate risk factors for development of any CMV viremia or high level CMV viremia in the first 100 days post-HCT. Each respiratory virus infection episode was considered positive for 30 days beginning the day of diagnosis. Results. Among 2,545 patients (404 children, 2141 adults), 1,221 and 247 developed CMV viremia and high level CMV viremia, respectively, in the first 100 days post-HCT. Infections due to human rhinoviruses (HRV, N=476) were most frequent, followed by parainfluenza viruses 1-4 (PIV, N=139), seasonal human coronaviruses (COV, N=134), respiratory syncytial virus (RSV, N=77), influenza A/B (FLU, N=35), human metapneumovirus (MPV, N=37), and adenovirus (ADV, N=61). In adjusted models, RSV LRTI was associated with increased risk of developing CMV viremia at all levels (Figures 1 and 2), and PIV or RSV URTI increased the risk of high level CMV viremia;all other viruses showed no association in univariable models. Figure 1. Model estimates for associations between LRTI and development of any CMV viremia Figure 2. Model estimates for associations between LRTI and development of high level CMV viremia Conclusion. We demonstrated that RSV and PIV infections are associated with an increased risk for development of CMV viremia after allogeneic HCT. This novel association provides the rationale to explore virus-specific inflammatory pathways that may trigger CMV reactivation. CMV viremia may also serve as an endpoint in clinical trials that assess new preventative or therapeutic interventions of RSV or PIV infection.
ABSTRACT
Respiratory viruses are commonly detected in both healthy and immunocompromised children. In most healthy children, respiratory viruses are associated with self-limited upper respiratory tract infections and are not accompanied by significant morbidity. In immunocompromised hosts, including hematopoietic cell transplant recipients, solid organ transplant recipients, and oncology patients, respiratory viruses can be associated with significant clinical manifestations, including prolonged viral shedding, lower respiratory tract disease, the need for supplemental oxygen, late airflow obstruction, and even death. This chapter reviews the major respiratory viruses, including respiratory syncytial virus, human metapneumovirus, influenza, parainfluenza viruses, human rhinoviruses, and human coronaviruses. Other viruses can manifest as pulmonary infection;however, these viruses are discussed elsewhere (see Chapter 17 for discussion of cytomegalovirus and Chapter 22 for discussion of adenoviruses). © 2021 Elsevier Inc. All rights reserved.
ABSTRACT
Background: High morbidity and mortality has been observed with COVID-19 infection;however, there are limited data on clinical characteristics including exposures, coinfections, and antimicrobial use among cancer patients. We aimed to better characterize clinical features and outcomes in this population. Methods: We conducted a retrospective chart review of consecutive patients at the Seattle Cancer Care Alliance diagnosed with SARS-CoV-2 infection by RT-PCR between February 28, 2020 and May 3, 2020. We obtained demographic and clinical data including coinfections, antimicrobial use and outcomes at 30 days after diagnosis. Results: Of 60 patients reviewed, the median age was 62 years (range 22-98) and 43% were male. 34 (57%) patients had solid tumors and 16 (27%) hematologic malignancies. Breast (12%), colorectal (8%) and non-Hodgkin lymphoma (8%) were the most prevalent cancers. 34 (57%) had ≥ 2 comorbidities. The majority of identified exposures were from long-term care facilities (LTCF) (27%) or household contacts (25%) (Fig 1). The most common symptoms at diagnosis were cough (72%), fevers/chills (57%), shortness of breath (38%), nasal congestion/rhinorrhea (35%), and diarrhea (30%). 18 (31%) patients were prescribed at least one course of antibiotics within 30 days of diagnosis;antibiotics were prescribed to 54% of hospitalized patients (Fig 2). 6 (10%) had a documented bacterial infection;of these, 3 were respiratory coinfections. No viral or fungal copathogens were reported. 26 (43%) patients were hospitalized, 9 (15%) admitted to intensive care, and one (2%) required mechanical ventilation. 12 (20%) died within 30 days of diagnosis (Fig 3);of these, 10 (83%) had ≥ 2 comorbidities and 8 (67%) had LTCF exposure.
ABSTRACT
Covid-19 has shocked the world and forced almost all the countries to a dumb-founded state. This virus has minimised the movement of humans, showing changes like never seen before. Positive effects have already been seen in nature and wildlife in the form of pollution control. The adverse effects of lockdown are seen as economic collapse. In this study, all the trauma patients coming to Acharya Vinobha Bhave Rural Hospital, Wardha were included irre-spective of their age and mode of trauma. Period of two weeks before and two weeks after the initiation of lockdown in India from 23rd march 2020 have been taken into consideration. Both the outpatient and emergency patients were included in our study. We have observed a significant fall on overall trauma cases as expected due to the lockdown. There was a fall in the total number of cases by around three times. Our study showed that the demog-raphy of geriatric trauma, which remained almost the same and nearly all of them were old age females. Low-velocity trauma has shown an increase after lockdown from 42% to 64%, while the total numbers of cases are still less as compared to before the lockdown. High-velocity trauma cases have been reduced from 52% to 31% after lockdown, which indicates less road traffic-related injuries. During the lockdown, however, we have seen a significant fall in head neck and face trauma when compared to the upper limb and lower limb trauma.