Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes.
TL;DR: The localization of ACE2 expression in the endocrine part of the pancreas suggests that SARS coronavirus enters islets using ACE2 as its receptor and damages islets causing acute diabetes.
Abstract: Multiple organ damage in severe acute respiratory syndrome (SARS) patients is common; however, the pathogenesis remains controversial. This study was to determine whether the damage was correlated with expression of the SARS coronavirus receptor, angiotensin converting enzyme 2 (ACE2), in different organs, especially in the endocrine tissues of the pancreas, and to elucidate the pathogenesis of glucose intolerance in SARS patients. The effect of clinical variables on survival was estimated in 135 SARS patients who died, 385 hospitalized SARS patients who survived, and 19 patients with non-SARS pneumonia. A total of 39 SARS patients who had no previous diabetes and received no steroid treatment were compared to 39 matched healthy siblings during a 3-year follow-up period. The pattern of SARS coronavirus receptor-ACE2 proteins in different human organs was also studied. Significant elevations in oxygen saturation, serum creatinine, lactate dehydrogenase, creatine kinase MB isoenzyme, and fasting plasma glucose (FPG), but not in alanine transaminase were predictors for death. Abundant ACE2 immunostaining was found in lung, kidney, heart, and islets of pancreas, but not in hepatocytes. Twenty of the 39 followed-up patients were diabetic during hospitalization. After 3 years, only two of these patients had diabetes. Compared with their non-SARS siblings, these patients exhibited no significant differences in FPG, postprandial glucose (PPG), and insulin levels. The organ involvements of SARS correlated with organ expression of ACE2. The localization of ACE2 expression in the endocrine part of the pancreas suggests that SARS coronavirus enters islets using ACE2 as its receptor and damages islets causing acute diabetes.
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Ani Nalbandian1, Kartik Sehgal2, Kartik Sehgal3, Aakriti Gupta1, Aakriti Gupta4, Mahesh V. Madhavan1, Claire McGroder1, Jacob S. Stevens1, Joshua R. Cook1, Anna S. Nordvig1, Daniel Shalev1, Tejasav S. Sehrawat5, Neha Ahluwalia6, Behnood Bikdeli, Donald Dietz1, Caroline Der-Nigoghossian7, Nadia Liyanage-Don1, Gregg F. Rosner1, Elana J. Bernstein1, Sumit Mohan1, Akinpelumi A Beckley1, David S. Seres1, Toni K. Choueiri2, Toni K. Choueiri3, Nir Uriel1, John C. Ausiello1, Domenico Accili1, Daniel E. Freedberg1, Matthew R. Baldwin1, Allan Schwartz1, Daniel Brodie1, Christine Kim Garcia1, Mitchell S.V. Elkind1, Jean M. Connors2, Jean M. Connors3, John P. Bilezikian1, Donald W. Landry1, Elaine Wan1 •
TL;DR: A comprehensive review of the current literature on post-acute COVID-19, its pathophysiology and its organ-specific sequelae is provided in this paper, where the authors discuss relevant considerations for the multidisciplinary care of COPD survivors and propose a framework for the identification of those at high risk for COPD and their coordinated management through dedicated COPD clinics.
Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen responsible for the coronavirus disease 2019 (COVID-19) pandemic, which has resulted in global healthcare crises and strained health resources. As the population of patients recovering from COVID-19 grows, it is paramount to establish an understanding of the healthcare issues surrounding them. COVID-19 is now recognized as a multi-organ disease with a broad spectrum of manifestations. Similarly to post-acute viral syndromes described in survivors of other virulent coronavirus epidemics, there are increasing reports of persistent and prolonged effects after acute COVID-19. Patient advocacy groups, many members of which identify themselves as long haulers, have helped contribute to the recognition of post-acute COVID-19, a syndrome characterized by persistent symptoms and/or delayed or long-term complications beyond 4 weeks from the onset of symptoms. Here, we provide a comprehensive review of the current literature on post-acute COVID-19, its pathophysiology and its organ-specific sequelae. Finally, we discuss relevant considerations for the multidisciplinary care of COVID-19 survivors and propose a framework for the identification of those at high risk for post-acute COVID-19 and their coordinated management through dedicated COVID-19 clinics.
2,307 citations
Aakriti Gupta1, Aakriti Gupta2, Mahesh V. Madhavan1, Kartik Sehgal3, Kartik Sehgal4, Nandini Nair1, Shiwani Mahajan2, Tejasav S. Sehrawat5, Behnood Bikdeli2, Behnood Bikdeli1, Neha Ahluwalia6, John C. Ausiello1, Elaine Wan1, Daniel E. Freedberg1, Ajay J. Kirtane, Sahil A. Parikh1, Mathew S. Maurer1, Anna S. Nordvig7, Domenico Accili1, Joan M. Bathon1, Sumit Mohan1, Kenneth A. Bauer3, Kenneth A. Bauer4, Martin B. Leon1, Harlan M. Krumholz2, Nir Uriel1, Mandeep R. Mehra8, Mitchell S.V. Elkind7, Mitchell S.V. Elkind1, Gregg W. Stone6, Allan Schwartz1, David D. Ho9, John P. Bilezikian1, Donald W. Landry1 •
TL;DR: The extrapulmonary organ-specific pathophysiology, presentations and management considerations for patients with COVID-19 are reviewed to aid clinicians and scientists in recognizing and monitoring the spectrum of manifestations, and in developing research priorities and therapeutic strategies for all organ systems involved.
Abstract: Although COVID-19 is most well known for causing substantial respiratory pathology, it can also result in several extrapulmonary manifestations. These conditions include thrombotic complications, myocardial dysfunction and arrhythmia, acute coronary syndromes, acute kidney injury, gastrointestinal symptoms, hepatocellular injury, hyperglycemia and ketosis, neurologic illnesses, ocular symptoms, and dermatologic complications. Given that ACE2, the entry receptor for the causative coronavirus SARS-CoV-2, is expressed in multiple extrapulmonary tissues, direct viral tissue damage is a plausible mechanism of injury. In addition, endothelial damage and thromboinflammation, dysregulation of immune responses, and maladaptation of ACE2-related pathways might all contribute to these extrapulmonary manifestations of COVID-19. Here we review the extrapulmonary organ-specific pathophysiology, presentations and management considerations for patients with COVID-19 to aid clinicians and scientists in recognizing and monitoring the spectrum of manifestations, and in developing research priorities and therapeutic strategies for all organ systems involved.
2,113 citations
Xiaochen Li1, Xiaochen Li2, Shuyun Xu1, Shuyun Xu2, Muqing Yu2, Muqing Yu1, Ke Wang2, Ke Wang1, Yu Tao2, Yu Tao1, Ying Zhou2, Ying Zhou1, Jing Shi2, Jing Shi1, Min Zhou1, Min Zhou2, Bo Wu, Zhenyu Yang2, Zhenyu Yang1, Cong Zhang1, Cong Zhang2, Junqing Yue2, Junqing Yue1, Zhiguo Zhang2, Harald Renz3, Xiansheng Liu2, Xiansheng Liu1, Jungang Xie2, Jungang Xie1, Min Xie1, Min Xie2, Jianping Zhao2, Jianping Zhao1 •
TL;DR: Survival analysis revealed that male, elder age, leukocytosis, high LDH level, cardiac injury, hyperglycemia, and high-dose corticosteroid use were associated with death in patients with severe COVID-19.
Abstract: Background In December 2019, the coronavirus disease 2019 (COVID-19) outbreak occurred in Wuhan. Data on the clinical characteristics and outcomes of patients with severe COVID-19 are limited. Objective We sought to evaluate the severity on admission, complications, treatment, and outcomes of patients with COVID-19. Methods Patients with COVID-19 admitted to Tongji Hospital from January 26, 2020, to February 5, 2020, were retrospectively enrolled and followed-up until March 3, 2020. Potential risk factors for severe COVID-19 were analyzed by a multivariable binary logistic model. Cox proportional hazard regression model was used for survival analysis in severe patients. Results We identified 269 (49.1%) of 548 patients as severe cases on admission. Older age, underlying hypertension, high cytokine levels (IL-2R, IL-6, IL-10, and TNF-α), and high lactate dehydrogenase level were significantly associated with severe COVID-19 on admission. The prevalence of asthma in patients with COVID-19 was 0.9%, markedly lower than that in the adult population of Wuhan. The estimated mortality was 1.1% in nonsevere patients and 32.5% in severe cases during the average 32 days of follow-up period. Survival analysis revealed that male sex, older age, leukocytosis, high lactate dehydrogenase level, cardiac injury, hyperglycemia, and high-dose corticosteroid use were associated with death in patients with severe COVID-19. Conclusions Patients with older age, hypertension, and high lactate dehydrogenase level need careful observation and early intervention to prevent the potential development of severe COVID-19. Severe male patients with heart injury, hyperglycemia, and high-dose corticosteroid use may have a high risk of death.
1,690 citations
Jian-Min Jin1, Peng Bai2, Peng Bai1, Wei He1, Fei Wu2, Xiao-Fang Liu1, De-Min Han1, Shi Liu2, Jin-Kui Yang1 •
TL;DR: While men and women have the same prevalence, men with COVID-19 are more at risk for worse outcomes and death, independent of age.
Abstract: Objective: The recent outbreak of Novel Coronavirus Disease (COVID-19) is reminiscent of the SARS outbreak in 2003. We aim to compare the severity and mortality between male and female patients with COVID-19 or SARS. Study Design and Setting: We extracted the data from: (1) a case series of 43 hospitalized patients we treated, (2) a public data set of the first 37 cases of patients who died of COVID-19 and 1,019 patients who survived in China, and (3) data of 524 patients with SARS, including 139 deaths, from Beijing in early 2003. Results: Older age and a high number of comorbidities were associated with higher severity and mortality in patients with both COVID-19 and SARS. Age was comparable between men and women in all data sets. In the case series, however, men's cases tended to be more serious than women's (P = 0.035). In the public data set, the number of men who died from COVID-19 is 2.4 times that of women (70.3 vs. 29.7%, P = 0.016). In SARS patients, the gender role in mortality was also observed. The percentage of males were higher in the deceased group than in the survived group (P = 0.015). Conclusion: While men and women have the same prevalence, men with COVID-19 are more at risk for worse outcomes and death, independent of age.
1,506 citations
Cites background from "Binding of SARS coronavirus to its ..."
...We have previously reported that high protein expression of ACE2 receptor in specific organs correlated with specific organ failures, indicated by corresponding clinical parameters in SARS patients (11, 12)....
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Weina Guo1, Mingyue Li1, Yalan Dong1, Haifeng Zhou1, Zili Zhang1, Chunxia Tian1, Renjie Qin1, Haijun Wang1, Yin Shen1, Keye Du1, Lei Zhao1, Heng Fan1, Shanshan Luo1, Desheng Hu1 •
TL;DR: To figure out whether diabetes is a risk factor influencing the progression and prognosis of 2019 novel coronavirus disease (COVID‐19), a large number of patients with a history of diabetes will be recruited for this study.
Abstract: Backgound To figure out whether diabetes is a risk factor influencing the progression and prognosis of 2019 novel coronavirus disease (COVID-19). Methods A total of 174 consecutive patients confirmed with COVID-19 were studied. Demographic data, medical history, symptoms and signs, laboratory findings, chest computed tomography (CT) as well the treatment measures were collected and analysed. Results We found that COVID-19 patients without other comorbidities but with diabetes (n = 24) were at higher risk of severe pneumonia, release of tissue injury-related enzymes, excessive uncontrolled inflammation responses and hypercoagulable state associated with dysregulation of glucose metabolism. Furthermore, serum levels of inflammation-related biomarkers such as IL-6, C-reactive protein, serum ferritin and coagulation index, D-dimer, were significantly higher (P Conclusions Our data support the notion that diabetes should be considered as a risk factor for a rapid progression and bad prognosis of COVID-19. More intensive attention should be paid to patients with diabetes, in case of rapid deterioration.
1,061 citations
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...15]), ESR (26 [13-58] vs 8 [7-26]), IL-6 (13....
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References
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TL;DR: The correlation of the model's estimates with patient data accords with the hypothesis that basal glucose and insulin interactions are largely determined by a simple feed back loop.
Abstract: The steady-state basal plasma glucose and insulin concentrations are determined by their interaction in a feedback loop. A computer-solved model has been used to predict the homeostatic concentrations which arise from varying degrees beta-cell deficiency and insulin resistance. Comparison of a patient's fasting values with the model's predictions allows a quantitative assessment of the contributions of insulin resistance and deficient beta-cell function to the fasting hyperglycaemia (homeostasis model assessment, HOMA). The accuracy and precision of the estimate have been determined by comparison with independent measures of insulin resistance and beta-cell function using hyperglycaemic and euglycaemic clamps and an intravenous glucose tolerance test. The estimate of insulin resistance obtained by homeostasis model assessment correlated with estimates obtained by use of the euglycaemic clamp (Rs = 0.88, p less than 0.0001), the fasting insulin concentration (Rs = 0.81, p less than 0.0001), and the hyperglycaemic clamp, (Rs = 0.69, p less than 0.01). There was no correlation with any aspect of insulin-receptor binding. The estimate of deficient beta-cell function obtained by homeostasis model assessment correlated with that derived using the hyperglycaemic clamp (Rs = 0.61, p less than 0.01) and with the estimate from the intravenous glucose tolerance test (Rs = 0.64, p less than 0.05). The low precision of the estimates from the model (coefficients of variation: 31% for insulin resistance and 32% for beta-cell deficit) limits its use, but the correlation of the model's estimates with patient data accords with the hypothesis that basal glucose and insulin interactions are largely determined by a simple feed back loop.
29,217 citations
"Binding of SARS coronavirus to its ..." refers methods in this paper
...Homeostasis model assessment (HOMA) was calculated to estimate insulin sensitivity using the formula: HOMA IR = fasting insulin (lU/ml) 9 fasting glucose (mmol/l)/22.5 [7] ....
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TL;DR: It is found that a soluble form of ACE2, but not of the related enzyme ACE1, blocked association of the S1 domain with Vero E6 cells, indicating that ACE2 is a functional receptor for SARS-CoV.
Abstract: Spike (S) proteins of coronaviruses, including the coronavirus that causes severe acute respiratory syndrome (SARS), associate with cellular receptors to mediate infection of their target cells Here we identify a metallopeptidase, angiotensin-converting enzyme 2 (ACE2), isolated from SARS coronavirus (SARS-CoV)-permissive Vero E6 cells, that efficiently binds the S1 domain of the SARS-CoV S protein We found that a soluble form of ACE2, but not of the related enzyme ACE1, blocked association of the S1 domain with Vero E6 cells 293T cells transfected with ACE2, but not those transfected with human immunodeficiency virus-1 receptors, formed multinucleated syncytia with cells expressing S protein Furthermore, SARS-CoV replicated efficiently on ACE2-transfected but not mock-transfected 293T cells Finally, anti-ACE2 but not anti-ACE1 antibody blocked viral replication on Vero E6 cells Together our data indicate that ACE2 is a functional receptor for SARS-CoV
5,149 citations
"Binding of SARS coronavirus to its ..." refers background in this paper
...SARS-CoV infection is mediated by the binding of its spike (S) protein to a cellular receptor on its target cells, and a recent study proved that ACE2 is a functional receptor for SARS-CoV S protein [4, 5]....
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TL;DR: ACE2 is abundantly present in humans in the epithelia of the lung and small intestine, which might provide possible routes of entry for the SARS‐CoV.
Abstract: Severe acute respiratory syndrome (SARS) is an acute infectious disease that spreads mainly via the respiratory route. A distinct coronavirus (SARS-CoV) has been identified as the aetiological agent of SARS. Recently, a metallopeptidase named angiotensin-converting enzyme 2 (ACE2) has been identified as the functional receptor for SARS-CoV. Although ACE2 mRNA is known to be present in virtually all organs, its protein expression is largely unknown. Since identifying the possible route of infection has major implications for understanding the pathogenesis and future treatment strategies for SARS, the present study investigated the localization of ACE2 protein in various human organs (oral and nasal mucosa, nasopharynx, lung, stomach, small intestine, colon, skin, lymph nodes, thymus, bone marrow, spleen, liver, kidney, and brain). The most remarkable finding was the surface expression of ACE2 protein on lung alveolar epithelial cells and enterocytes of the small intestine. Furthermore, ACE2 was present in arterial and venous endothelial cells and arterial smooth muscle cells in all organs studied. In conclusion, ACE2 is abundantly present in humans in the epithelia of the lung and small intestine, which might provide possible routes of entry for the SARS-CoV. This epithelial expression, together with the presence of ACE2 in vascular endothelium, also provides a first step in understanding the pathogenesis of the main SARS disease manifestations.
4,714 citations
"Binding of SARS coronavirus to its ..." refers background in this paper
...An investigation of ACE2 protein localization in 15 human organs found that ACE2 was abundant in the epithelia of lung and small intestine, where SARS-CoV might enter [9]....
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TL;DR: The organ- and cell-specific expression of ACE2 and its unique cleavage of key vasoactive peptides suggest an essential role for ACE2 in the local renin-angiotensin system of the heart and kidney.
Abstract: ACE2, the first known human homologue of angiotensin-converting enzyme (ACE), was identified from 5' sequencing of a human heart failure ventricle cDNA library. ACE2 has an apparent signal peptide, a single metalloprotease active site, and a transmembrane domain. The metalloprotease catalytic domains of ACE2 and ACE are 42% identical, and comparison of the genomic structures indicates that the two genes arose through duplication. In contrast to the more ubiquitous ACE, ACE2 transcripts are found only in heart, kidney, and testis of 23 human tissues examined. Immunohistochemistry shows ACE2 protein predominantly in the endothelium of coronary and intrarenal vessels and in renal tubular epithelium. Active ACE2 enzyme is secreted from transfected cells by cleavage N-terminal to the transmembrane domain. Recombinant ACE2 hydrolyzes the carboxy terminal leucine from angiotensin I to generate angiotensin 1-9, which is converted to smaller angiotensin peptides by ACE in vitro and by cardiomyocytes in culture. ACE2 can also cleave des-Arg bradykinin and neurotensin but not bradykinin or 15 other vasoactive and hormonal peptides tested. ACE2 is not inhibited by lisinopril or captopril. The organ- and cell-specific expression of ACE2 and its unique cleavage of key vasoactive peptides suggest an essential role for ACE2 in the local renin-angiotensin system of the heart and kidney. The full text of this article is available at http://www. circresaha.org.
2,711 citations
"Binding of SARS coronavirus to its ..." refers background in this paper
...Since its discovery in 2000 [2, 3], ACE2 has been implicated in heart function, hypertension, and diabetes, with its effects being mediated, in part, through its ability to convert angiotensin II to angiotensin 1–7....
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TL;DR: A novel human zinc metalloprotease that has considerable homology to human angiotensin-converting enzyme (ACE) (40% identity and 61% similarity) has been identified.
1,872 citations
"Binding of SARS coronavirus to its ..." refers background in this paper
...Since its discovery in 2000 [2, 3], ACE2 has been implicated in heart function, hypertension, and diabetes, with its effects being mediated, in part, through its ability to convert angiotensin II to angiotensin 1–7....
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