Background The COVID-19 epidemic of 2019-20 is due to the novel coronavirus SARS-CoV-2. Following first case description in December, 2019 this virus has infected over 10 million individuals and resulted in at least 500,000 deaths world-wide. The virus is undergoing rapid mutation, with two major clades of sequence variants emerging. This study sought to determine whether SARS-CoV-2 sequence variants are associated with differing outcomes among COVID-19 patients in a single medical system. Methods Whole genome SARS-CoV-2 RNA sequence was obtained from isolates collected from patients registered in the University of Washington Medicine health system between March 1 and April 15, 2020. Demographic and baseline medical data along with outcomes of hospitalization and death were collected. Statistical and machine learning models were applied to determine if viral genetic variants were associated with specific outcomes of hospitalization or death. Findings Full length SARS-CoV-2 sequence was obtained 190 subjects with clinical outcome data. 35 (18.4%) were hospitalized and 14 (7.4%) died from complications of infection. A total of 289 single nucleotide variants were identified. Clustering methods demonstrated two major viral clades, which could be readily distinguished by 12 polymorphisms in 5 genes. A trend toward higher rates of hospitalization of patients with Clade 2 was observed (p=0.06). Machine learning models utilizing patient demographics and co-morbidities achieved area-under-the-curve (AUC) values of 0.93 for predicting hospitalization. Addition of viral clade or sequence information did not significantly improve models for outcome prediction. Conclusion SARS-CoV-2 shows substantial sequence diversity in a community-based sample. Two dominant clades of virus are in circulation. Among patients sufficiently ill to warrant testing for virus, no significant difference in outcomes of hospitalization or death could be discerned between clades in this sample. Major risk factors for hospitalization and death for either major clade of virus include patient age and comorbid conditions.
Summary:Acute graft-versus-host disease (GVHD) is a complication of bone marrow transplantation (BMT). The histopathologic features used to diagnose GVHD are nonspecific, and may be secondary to chemotherapy or irradiation given before BMT. The presence of apoptotic keratinocytes or activated CTL may distinguish GVHD from conditioning effects. This study investigated the relationship in BMT recipients between keratinocyte apoptosis and the effects of conditioning regimens or immune-mediated GVHD. Inflammatory cells, apoptotic keratinocytes, and CTL expressing TIA-1 (a molecule associated with the lytic granules of CTL) were quantitated in allogeneic and autologous recipients. Allogeneic recipients could exhibit keratinocyte apoptosis secondary to a combination of conditioning effects and immune-mediated GVHD. In contrast, autologous recipients should show conditioning effects only. 'Capped' TIA-1-positive lymphocytes and apoptotic keratinocytes were much more frequent in the allogeneic group than the autologous group (16.1% of total TIA-1 positive lymphocytes vs 4.5%, P = 0.02; and 37.6/mm 2 vs 3.9/mm 2 , P = 0.005, respectively), although there was some overlap in their frequency. Among individual recipients of allogeneic BMT, the number of epidermal lymphocytes or macrophages correlated with the number of apoptotic keratinocytes. A similar, but weaker, correlation was seen between the number of 'capped' TIA-1-positive lymphocytes and apoptotic keratinocytes. No such relationship was seen in autologous recipients. In allogeneic recipients, TIA-1 expressing CTL were seen in intimate contact with apoptotic keratinocytes, some of which also had detectable cytoplasmic TIA-1. No CTL/keratinocyte interactions were identified in autologous recipients. Our results suggest that apoptotic keratinocytes arise in the skin of BMT patients due to both GVHD and conditioning effects, and that the keratinocyte damage in GVHD is mediated by both CTL-dependent and -independent mechanisms. Increased numbers of apoptotic keratinocytes, in the presence of increased epidermal lymphocytes or 'capped' TIA-1-expressing lymphocytes, support a diagnosis
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