CT Imaging of the 2019 Novel Coronavirus (2019-nCoV) Pneumonia
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In The Lancet Gastroenterology & Hepatology, Gwilym Webb and colleagues present a multicentre analysis of outcomes for 151 liver transplant recipients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, with data collected from March 25, 2020, to June 26, 2020.1Webb GJ Marjot T Cook JA et al.Outcomes following SARS-CoV-2 infection in liver transplant recipients: an international registry study.Lancet Gastroenterol Hepatol. 2020; (published online Aug 28.)https://doi.org/10.1016/S2468-1253(20)30271-5Summary Full Text Full Text PDF Scopus (169) Google Scholar The study, which included liver transplant recipients from 18 countries, represents the largest reported series of liver transplant recipients with confirmed SARS-CoV-2 infection to date. The study is also the first to include a comparison with patients with COVID-19 who have not received a liver transplant (n=627), having collected data from the electronic patient records of group of four hospitals in Oxford, UK. Importantly, the report provides an estimation of the risks for liver transplant recipients—who must balance the need for ongoing medical care with the need to remain isolated to reduce exposure to SARS-CoV-2—and also demonstrates the power of international collaboration in solving critical health-care challenges. The study found no difference in the proportion of patients hospitalised between the liver transplant (124 [82%] patients) and the non-liver transplant cohort (474 [76%] patients; p=0·106). Despite an increased need for invasive ventilation support among recipients of liver transplants (30 [20%] vs 32 [5%] in the comparison cohort, p<0·0001), mortality was significantly lower in liver transplant recipients (28 [19%]) than in patients who had not received a liver transplant (167 [27%]; p=0·046). In a propensity score-matched analysis (adjusting for age, sex, creatinine concentration, obesity, hypertension, diabetes, and ethnicity), liver transplantation did not significantly increase the risk of death in patients with SARS-CoV-2 infection (absolute risk difference 1·4% [95% CI −7·7 to 10·4]). COVID-19 lung disease was the main cause of death in both groups and, importantly, there were no liver-related deaths among the transplant recipients. Multivariable analysis showed that factors associated with death among liver transplant recipients included age and creatinine concentration, as well as the presence of non-liver malignancy, whereas time from transplantation and type of immunosuppression were not related to risk of death. In the control population, multivariable analysis showed age, male sex, and diabetes to be the major risk factors for death. An additional notable finding was the higher rates of gastrointestinal symptoms in the liver transplant cohort, with 30% having abdominal pain, vomiting, or diarrhoea at diagnosis compared with just 12% of the control group having abdominal symptoms (p<0·0001). There are some important caveats to the current analysis, such as the significant differences between the two cohorts. Although age, a key risk factor, was higher in the comparison cohort (median 73 years [IQR 55–84]) than the liver transplant cohort (median 60 years [47–66]), the liver transplant group had significantly greater proportions of men (68% vs 52% in the comparison cohort) and patients with diabetes (43% vs 23% in the comparison cohort). In addition, testing rates and thresholds for hospitalisation and admission to an intensive care unit might have differed across different centres and between the cohorts. Furthermore, the liver transplant cohort might have been subject to reporting bias because the data were collected from two registries of clinician-submitted cases; those clinicians might have been more likely to be aware of, and thus submit data on, hospitalised liver transplant recipients with more severe infections (as compared with the comparison cohort, which was drawn from consecutive cases of patients testing positive for SARS-CoV-2). However, this bias would only serve to strengthen the main conclusion that liver transplant recipients are not at a higher risk of death than patients who have not undergone transplantation. It is essential to note that the median time from transplantation in this liver transplant cohort was 5 years (IQR 2–11), and thus the current experience cannot be extrapolated to patients who might acquire SARS-CoV-2 infection in the perioperative period. Despite these limitations, Webb and colleagues' study1Webb GJ Marjot T Cook JA et al.Outcomes following SARS-CoV-2 infection in liver transplant recipients: an international registry study.Lancet Gastroenterol Hepatol. 2020; (published online Aug 28.)https://doi.org/10.1016/S2468-1253(20)30271-5Summary Full Text Full Text PDF Scopus (169) Google Scholar represents the largest experience of SARS-CoV-2 infection in liver transplant recipients to date, and found no adverse effect of liver transplantation on survival following COVID-19 compared with a UK population cohort of patients without liver transplant. A recently published single-centre study of 36 kidney transplant recipients in the USA showed a similar rate of hospitalisation (78%), with a potentially higher rate of death (28%), although, unlike the present series of liver transplant recipients, at least some kidney transplant recipients were within weeks of transplantation.2Akalin E Azzi Y Bartash R et al.COVID 19 and kidney transplantation.N Engl J Med. 2020; 382: 2475-2477Crossref PubMed Scopus (594) Google Scholar A larger multicentre series of 144 kidney transplant recipients, which included only hospitalised patients, found a mortality rate of 32% in a cohort with a median time from transplantation of 5 years, although that study also included some patients with less than 1 year since transplantation.3Cravedi P Suraj SM Azzi Y et al.COVID-19 and kidney transplantation: results from the TANGO international transplant consortium.Am J Transplant. 2020; (published online July 10.)https://doi.org/10.1111/ajt.16185Crossref Scopus (276) Google Scholar Whether there are actually differences in outcome between patients undergoing liver or kidney transplantation, or transplantation of other organs, remains to be determined, although the question is likely to be answered best by large collaborative efforts, as reflected in Webb and colleagues' study.1Webb GJ Marjot T Cook JA et al.Outcomes following SARS-CoV-2 infection in liver transplant recipients: an international registry study.Lancet Gastroenterol Hepatol. 2020; (published online Aug 28.)https://doi.org/10.1016/S2468-1253(20)30271-5Summary Full Text Full Text PDF Scopus (169) Google Scholar Despite the unprecedented challenges imposed by the current pandemic on all aspects of our lives, centres across the globe were able to work together to collect and analyse detailed outcome data for more than 700 patients with SARS-CoV-2 infection, thus providing crucial information on a potentially at-risk population, with an efficiency and scale only possible through international collaboration. We declare no competing interests.
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Interest in a potential role for vitamin D in the prevention or treatment of acute respiratory infections dates back to the 1930s, when cod liver oil was investigated as a means to reduce industrial absenteeism due to the common cold. Meta-analyses of randomised controlled trials conducted from 2007–20 reveal protective effects of vitamin D against acute respiratory infections, albeit these effects were of modest size and with substantial heterogeneity.1Jolliffe D Camargo Jr, CA Sluyter J et al.Vitamin D supplementation to prevent acute respiratory infections: systematic review and meta-analysis of aggregate data from randomised controlled trials.medRxiv. 2020; (published online July 17.) (preprint)https://doi.org/10.1101/2020.07.14.20152728PubMed Google Scholar The striking overlap between risk factors for severe COVID-19 and vitamin D deficiency, including obesity, older age, and Black or Asian ethnic origin, has led some researchers to hypothesise that vitamin D supplementation could hold promise as a preventive or therapeutic agent for COVID-19. From a mechanistic angle, there are good reasons to postulate that vitamin D favourably modulates host responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), both in the early viraemic and later hyperinflammatory phases of COVID-19. Vitamin D metabolites have long been known to support innate antiviral effector mechanisms, including induction of antimicrobial peptides and autophagy. Laboratory data relating to effects of vitamin D on host responses to SARS-CoV-2 specifically are scarce, but one study that screened four compound libraries for antiviral activity has reported an inhibitory effect of the active vitamin D metabolite 1,25-dihydroxyvitamin D (the steroid hormone and biologically active vitamin D metabolite) in human nasal epithelial cells infected with SARS-CoV-2.2Mok CK Ng YL Ahidjo BA et al.Calcitriol, the active form of vitamin D, is a promising candidate for COVID-19 prophylaxis.medRxiv. 2020; (published online June 22.) (preprint)https://doi.org/10.1101/2020.06.21.162396PubMed Google Scholar Vitamin D has also been shown to regulate immunopathological inflammatory responses in the context of other respiratory infections. The finding that these effects were mediated via regulation of the renin-angiotensin system (RAS) in an animal model3Xu J Yang J Chen J Luo Q Zhang Q Zhang H Vitamin D alleviates lipopolysaccharideinduced acute lung injury via regulation of the reninangiotensin system.Mol Med Rep. 2017; 16: 7432-7438Crossref PubMed Scopus (277) Google Scholar has particular relevance in the context of severe COVID-19, where overactivation of RAS associates with poor prognosis. Epidemiological studies investigating links between circulating levels of 25-hydroxyvitamin D (25[OH]D; the biomarker of vitamin D status) and incidence and severity of COVID-19 are currently limited in number. Two ecological studies have reported inverse correlations between national estimates of vitamin D status and COVID-19 incidence and mortality in European countries.4Laird E Rhodes J Kenny RA Vitamin D and inflammation: potential implications for severity of COVID-19.Ir Med J. 2020; 113: 81PubMed Google Scholar, 5Ilie PC Stefanescu S Smith L The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality.Aging Clin Exp Res. 2020; 32: 1195-1198Crossref PubMed Scopus (518) Google Scholar Lower circulating 25(OH)D concentrations have also been reported to associate with susceptibility to SARS-CoV-2 infection6D'Avolio A Avataneo V Manca A et al.25-hydroxyvitamin D concentrations are lower in patients with positive PCR for SARS-CoV-2.Nutrients. 2020; 12e1359Crossref PubMed Scopus (319) Google Scholar and COVID-19 severity.7Panagiotou G Tee SA Ihsan Y et al.Low serum 25-hydroxyvitamin D (25[OH]D) levels in patients hospitalised with COVID-19 are associated with greater disease severity.Clin Endocrinol (Oxf). 2020; (published online July 3.)https://doi.org/10.1111/cen.14276Crossref PubMed Scopus (155) Google Scholar Recently, we have shown that airway diseases are associated with dysregulated vitamin D metabolism,8Jolliffe DA Stefanidis C Wang Z et al.Vitamin D metabolism is dysregulated in asthma and chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2020; (published online March 18.)https://doi.org/10.1164/rccm.201909-1867OCCrossref PubMed Scopus (50) Google Scholar raising the possibility that vitamin D deficiency might arise as a consequence of pulmonary inflammation. Prospective studies can provide insights into the potential for reverse causality, but results from those published to date are conflicting: one retrospective longitudinal study from Israel reported independent associations between low pre-pandemic 25(OH)D levels and subsequent incidence and severity of COVID-19,9Merzon E Tworowski D Gorohovski A et al.Low plasma 25(OH) vitamin D level is associated with increased risk of COVID-19 infection: an Israeli population-based study.medRxiv. 2020; (published online July 3.) (preprint)https://doi.org/10.1101/2020.07.01.20144329Google Scholar but an analogous study in the UK showed no such associations.10Hastie CE Mackay DF Ho F et al.Vitamin D concentrations and COVID-19 infection in UK Biobank.Diabetes Metab Syndr. 2020; 14: 561-565Crossref PubMed Scopus (337) Google Scholar Both of these studies are potentially limited by the use of historic 25(OH)D measurements, which might not reflect concentrations at the time of exposure to SARS-CoV-2. They are also open to residual and unmeasured confounding. Mendelian randomisation studies offer one approach to overcome these problems, but they need to be very large to detect small or moderate effects which might still be of clinical significance. In our view, well powered randomised controlled trials of vitamin D supplementation for the prevention and treatment of COVID-19 are now needed to test for causality. A number of hospital-based treatment trials have been registered to date, but it may prove challenging to detect a signal for vitamin D supplementation in severe COVID-19 for two reasons. First, patients tend to present to hospital in the hyperinflammatory stage of the disease, so it might be too late for them to benefit from any antiviral effects induced by vitamin D supplementation. Second, it could be hard to show the effect of a micronutrient over and above dexamethasone, which has potent anti-inflammatory actions and now represents the standard of care in severe disease. Prevention of SARS-CoV-2 infection also represents an ambitious target, given the highly infectious nature of the pathogen. Perhaps the best hope for showing a clinical benefit lies in a population-based trial investigating prophylactic vitamin D supplementation as a means of attenuating the severity of incident COVID-19, to the extent that it is either asymptomatic or does not result in hospitalisation. The design of such a trial should be informed by findings of meta-analyses of randomised controlled trials of vitamin D to prevent other acute respiratory infections, which suggest that the intervention would work best when given in daily doses of 400–1000 IU to individuals with lower baseline vitamin D status. Pending results of such trials, it would seem uncontroversial to enthusiastically promote efforts to achieve reference nutrient intakes of vitamin D, which range from 400 IU/day in the UK to 600–800 IU/day in the USA. These are predicated on benefits of vitamin D for bone and muscle health, but there is a chance that their implementation might also reduce the impact of COVID-19 in populations where vitamin D deficiency is prevalent; there is nothing to lose from their implementation, and potentially much to gain. NGF has received grant funding from the MRC Epidemiology Unit (MC_UU_12015/5) and NIHR Biomedical Research Centre Cambridge: Nutrition, Diet, and Lifestyle Research Theme (IS-BRC-1215-20014). The MRC were not involved in the writing of this manuscript, or in the decision to submit it for publication. We declare no competing interests.
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A 41-year-old woman with a travel history to Wuhan, China, where the 2019 novel coronavirus (2019-nCoV) was spreading (1), presented with a 4-day history of fever.Laboratory examinations and chest radiographs were negative.Chest CT (Figure ) showed multifocal ground-glass opacities in the perihilar and subpleural regions of both lungs, a common finding of 2019-nCoV-infected pneumonia (2-5).A throat swab was positive for 2019-nCoV on the real-time reverse transcription polymerase chain reaction assay.The patient was immediately isolated for clinical monitoring.Disclosures of Conflicts of Interest: P.L. disclosed no relevant relationships.X.T.
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Although SARS-CoV-2 may primarily enter the cells of the lungs, the small bowel may also be an important entry or interaction site, as the enterocytes are rich in angiotensin converting enzyme (ACE)-2 receptors. The initial gastrointestinal symptoms that appear early during the course of Covid-19 support this hypothesis. Furthermore, SARS-CoV virions are preferentially released apically and not at the basement of the airway cells. Thus, in the setting of a productive infection of conducting airway epithelia, the apically released SARS-CoV may be removed by mucociliary clearance and gain access to the GI tract via a luminal exposure. In addition, post-mortem studies of mice infected by SARS-CoV have demonstrated diffuse damage to the GI tract, with the small bowel showing signs of enterocyte desquamation, edema, small vessel dilation and lymphocyte infiltration, as well as mesenteric nodes with severe hemorrhage and necrosis. Finally, the small bowel is rich in furin, a serine protease which can separate the S-spike of the coronavirus into two "pinchers" (S1 and 2). The separation of the S-spike into S1 and S2 is essential for the attachment of the virion to both the ACE receptor and the cell membrane. In this special review, we describe the interaction of SARS-CoV-2 with the cell and enterocyte and its potential clinical implications.
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