Researching COVID to enhance recovery (RECOVER) tissue pathology study protocol: Rationale, objectives, and design.

ImportanceSARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or organ dysfunction after the acute phase of infection, termed Post-Acute Sequelae of SARS-CoV-2 (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are poorly understood. The objectives of the Researching COVID to Enhance Recovery (RECOVER) tissue pathology study (RECOVER-Pathology) are to: (1) characterize prevalence and types of organ injury/disease and pathology occurring with PASC; (2) characterize the association of pathologic findings with clinical and other characteristics; (3) define the pathophysiology and mechanisms of PASC, and possible mediation via viral persistence; and (4) establish a post-mortem tissue biobank and post-mortem brain imaging biorepository.MethodsRECOVER-Pathology is a cross-sectional study of decedents dying at least 15 days following initial SARS-CoV-2 infection. Eligible decedents must meet WHO criteria for suspected, probable, or confirmed infection and must be aged 18 years or more at the time of death. Enrollment occurs at 7 sites in four U.S. states and Washington, DC. Comprehensive autopsies are conducted according to a standardized protocol within 24 hours of death; tissue samples are sent to the PASC Biorepository for later analyses. Data on clinical history are collected from the medical records and/or next of kin. The primary study outcomes include an array of pathologic features organized by organ system. Causal inference methods will be employed to investigate associations between risk factors and pathologic outcomes.DiscussionRECOVER-Pathology is the largest autopsy study addressing PASC among US adults. Results of this study are intended to elucidate mechanisms of organ injury and disease and enhance our understanding of the pathophysiology of PASC

Circulating Lymphocyte Counts Early During Radiotherapy are Associated with Recurrence in Pediatric Medulloblastoma

Background Decreased peripheral lymphocyte counts are associated with outcome after RT in several solid tumors, though appear late during or after the radiation course and often correlate with other clinical factors. Here we investigate if absolute lymphocyte counts (ALC) are independently associated with recurrence in pediatric medulloblastoma early during RT. Methods We assessed 202 medulloblastoma patients treated between 2000 and 2016 and analyzed ALC throughout therapy, focusing on both early markers (ALC during week 1 – ALC wk1; grade 3+ Lymphopenia during week 2 – Lymphopenia wk2) and late markers (ALC nadir). Uni- and multivariable regressions were used to assess association of clinical and treatment variables with ALC and of ALC with recurrence. Results Thirty-six recurrences were observed, with a median time to recurrence of 1.6 years (Range 0.2-10.3) and 7.1 years median follow-up. ALC during RT was associated with induction chemotherapy (p<0.001), concurrent carboplatin (p=0.009), age (p=0.01) and high-risk status (p=0.05). On univariable analysis, high-risk disease (HR 2.0[1.06–3.9],p=0.03) and M stage≥1 (HR 2.2[1.1–4.4]) were associated with recurrence risk, as was lower ALC early during RT (ALC wk1 HR 0.28[0.12–0.65],p=0.003; Lymphopenia wk2 HR 2.27[1.1-4.6],p=0.02). Neither baseline ALC nor nadir correlated with outcome. These associations persisted when excluding carboplatin and pre-RT chemotherapy patients, and in the multivariable analysis accounting for confounders lymphocyte counts remain significant (ALC wk1 HR 0.23[0.09–0.57],p=0.002; Lymphopenia wk2 HR 2.3[1.1–4.8],p=0.03). Conclusion ALC during weeks 1 and 2 of RT was associated with recurrence and low ALC is an independent prognostic factor in medulloblastoma. Strategies to mitigate the risk of radiation-induced lymphopenia should be considered