Comorbid Chronic Diseases and Acute Organ Injuries Are Strongly Correlated with Disease Severity and Mortality among COVID-19 Patients: A Systemic Review and Meta-Analysis

The recent outbreak of COVID-19 has been rapidly spreading on a global scale. To date, there is no specific vaccine against the causative virus, SARS-CoV-2, nor is there an effective medicine for treating COVID-19, thus raising concerns with respect to the effect of risk factors such as clinical course and pathophysiological parameters on disease severity and outcome in patients with COVID-19. By extracting and analyzing all available published clinical data, we identified several major clinical characteristics associated with increased disease severity and mortality among patients with COVID-19. Specifically, preexisting chronic conditions such as hypertension, cardiovascular disease, chronic kidney disease, and diabetes are strongly associated with an increased risk of developing severe COVID-19; surprisingly, however, we found no correlation between chronic liver disease and increased disease severity. In addition, we found that both acute cardiac injury and acute kidney injury are highly correlated with an increased risk of COVID-19-related mortality. Given the high risk of comorbidity and the high mortality rate associated with tissue damage, organ function should be monitored closely in patients diagnosed with COVID-19, and this approach should be included when establishing new guidelines for managing these high-risk patients. Moreover, additional clinical data are needed in order to determine whether a supportive therapy can help mitigate the development of severe, potentially fatal complications, and further studies are needed to identify the pathophysiology and the mechanism underlying this novel coronavirus-associated infectious disease. Taken together, these findings provide new insights regarding clinical strategies for improving the management and outcome of patients with COVID-19.

[1]  Matthew Z. Anderson,et al.  Human Genetic Determinants of Viral Diseases. , 2017, Annual review of genetics.

[2]  Hongzhou Lu,et al.  Clinical Features of Patients Infected with the 2019 Novel Coronavirus (COVID-19) in Shanghai, China , 2020, medRxiv.

[3]  Yan Zhao,et al.  Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. , 2020, JAMA.

[4]  Z. Bloomgarden Diabetes and COVID‐19 , 2020, Journal of diabetes.

[5]  Dong Men,et al.  Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely correlated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients , 2020, medRxiv.

[6]  G. Navis,et al.  Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis , 2004, The Journal of pathology.

[7]  Taojiao Wang,et al.  Clinical and immunologic features in severe and moderate Coronavirus Disease 2019. , 2020, The Journal of clinical investigation.

[8]  J. Chan,et al.  Plasma glucose levels and diabetes are independent predictors for mortality and morbidity in patients with SARS , 2006, Diabetic medicine : a journal of the British Diabetic Association.

[9]  Yimin Li,et al.  Clinical findings in critical ill patients infected with SARS-Cov-2 in Guangdong Province, China: a multi-center, retrospective, observational study , 2020, medRxiv.

[10]  J. Xing,et al.  Function of HAb18G/CD147 in Invasion of Host Cells by Severe Acute Respiratory Syndrome Coronavirus , 2005, The Journal of infectious diseases.

[11]  T. Asselah,et al.  Fatal cardiomyopathy associated with pegylated interferon/ribavirin in a patient with chronic hepatitis C. , 2006, European journal of gastroenterology & hepatology.

[12]  Jue Fan,et al.  Specific ACE2 Expression in Cholangiocytes May Cause Liver Damage After 2019-nCoV Infection , 2020, bioRxiv.

[13]  Christian Drosten,et al.  Evidence that TMPRSS2 Activates the Severe Acute Respiratory Syndrome Coronavirus Spike Protein for Membrane Fusion and Reduces Viral Control by the Humoral Immune Response , 2011, Journal of Virology.

[14]  Chuan Qin,et al.  Dysregulation of immune response in patients with COVID-19 in Wuhan, China , 2020, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[15]  Shengqing Wan,et al.  Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations , 2020, Cell Discovery.

[16]  Chang Hu,et al.  Clinical features and short-term outcomes of 221 patients with COVID-19 in Wuhan, China , 2020, Journal of Clinical Virology.

[17]  Hongzhou Lu,et al.  A descriptive study of the impact of diseases control and prevention on the epidemics dynamics and clinical features of SARS-CoV-2 outbreak in Shanghai, lessons learned for metropolis epidemics prevention , 2020, medRxiv.

[18]  G. Herrler,et al.  SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor , 2020, Cell.

[19]  Merlin C. Thomas,et al.  ACE2 deficiency shifts energy metabolism towards glucose utilization. , 2015, Metabolism: clinical and experimental.

[20]  Kai Zhao,et al.  A pneumonia outbreak associated with a new coronavirus of probable bat origin , 2020, Nature.

[21]  World Health Organization,et al.  Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected. Interim guidance , 2020, Pediatria i Medycyna Rodzinna.

[22]  Huan Li,et al.  Risk Factors Associated with Clinical Outcomes in 323 COVID-19 Patients in Wuhan, China , 2020, medRxiv.

[23]  Taojiao Wang,et al.  Caution on Kidney Dysfunctions of 2019-nCoV Patients , 2020 .

[24]  Jing Yuan,et al.  Epidemiological and clinical features of 2019-nCoV acute respiratory disease cases in Chongqing municipality, China: a retrospective, descriptive, multiple-center study , 2020, medRxiv.

[25]  S. Yiu,et al.  Left Ventricular Performance in Patients With Severe Acute Respiratory Syndrome: A 30-Day Echocardiographic Follow-Up Study , 2003, Circulation.

[26]  Bo Li,et al.  Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China , 2020, Clinical Research in Cardiology.

[27]  Zhaofeng Chen,et al.  Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis , 2020, International Journal of Infectious Diseases.

[28]  W. Gong,et al.  Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Wuhan, China. , 2020, JAMA cardiology.

[29]  Taojiao Wang,et al.  Caution on Kidney Dysfunctions of COVID-19 Patients , 2020, medRxiv.

[30]  Suna Wang,et al.  [Clinical characteristics and influencing factors of patients with novel coronavirus pneumonia combined with liver injury in Shaanxi region]. , 2020, Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology.

[31]  Qiang Zhou,et al.  Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2 , 2020, Science.

[32]  Xilong Deng,et al.  Prognostic Factors for COVID-19 Pneumonia Progression to Severe Symptoms Based on Earlier Clinical Features: A Retrospective Analysis , 2020, Frontiers in Medicine.

[33]  Chao Zhang,et al.  Liver injury in COVID-19: management and challenges , 2020, The Lancet Gastroenterology & Hepatology.

[34]  Jie Tian,et al.  Clinical and radiographic features of cardiac injury in patients with 2019 novel coronavirus pneumonia , 2020, medRxiv.

[35]  Liang Liu,et al.  Human Kidney is a Target for Novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection , 2020, medRxiv.

[36]  Ji-yang Liu,et al.  Epidemiological and clinical features of 291 cases with coronavirus disease 2019 in areas adjacent to Hubei, China: a double-center observational study , 2020, medRxiv.

[37]  Jiyuan Zhang,et al.  Pathological findings of COVID-19 associated with acute respiratory distress syndrome , 2020, The Lancet Respiratory Medicine.

[38]  Chang Hu,et al.  Clinical features and outcomes of 221 patients with COVID-19 in Wuhan, China , 2020, medRxiv.

[39]  Zhichao Feng,et al.  Early Prediction of Disease Progression in 2019 Novel Coronavirus Pneumonia Patients Outside Wuhan with CT and Clinical Characteristics , 2020, medRxiv.

[40]  L. Mao,et al.  Neurological Manifestations of Hospitalized Patients with COVID-19 in Wuhan, China: a retrospective case series study , 2020, medRxiv.

[41]  K. Yuen,et al.  Clinical Characteristics of Coronavirus Disease 2019 in China , 2020, The New England journal of medicine.

[42]  Qingling Zhang,et al.  Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS‐CoV) in SARS patients: implications for pathogenesis and virus transmission pathways , 2004, The Journal of pathology.

[43]  Ting Yu,et al.  Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study , 2020, The Lancet Respiratory Medicine.

[44]  Yu Shi,et al.  Host susceptibility to severe COVID-19 and establishment of a host risk score: findings of 487 cases outside Wuhan , 2020, Critical Care.

[45]  Y. Chan,et al.  Short term outcome and risk factors for adverse clinical outcomes in adults with severe acute respiratory syndrome (SARS) , 2003, Thorax.

[46]  P. Drawz,et al.  Masked Hypertension in CKD: Increased Prevalence and Risk for Cardiovascular and Renal Events , 2019, Current Cardiology Reports.

[47]  Hui Chen,et al.  Coronavirus Disease 19 Infection Does Not Result in Acute Kidney Injury: An Analysis of 116 Hospitalized Patients from Wuhan, China , 2020, American Journal of Nephrology.

[48]  C Chen,et al.  [Analysis of myocardial injury in patients with COVID-19 and association between concomitant cardiovascular diseases and severity of COVID-19]. , 2020, Zhonghua xin xue guan bing za zhi.

[49]  Rui Ji,et al.  Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis , 2020, International Journal of Infectious Diseases.

[50]  N. V. Trung,et al.  Tenofovir disoproxil fumarate co-administered with lopinavir/ritonavir is strongly associated with tubular damage and chronic kidney disease. , 2018, Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy.

[51]  Wenwu Sun,et al.  Clinical features and progression of acute respiratory distress syndrome in coronavirus disease 2019 , 2020, medRxiv.

[52]  F. Lai,et al.  Acute renal impairment in coronavirus-associated severe acute respiratory syndrome , 2005, Kidney International.

[53]  W. Jia,et al.  [Changes of liver function in patients with serious acute respiratory syndrome]. , 2003, Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology.

[54]  B. Graham,et al.  Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation , 2020, Science.

[55]  G. Lippi,et al.  Hypertension and its severity or mortality in Coronavirus Disease 2019 (COVID-19): a pooled analysis. , 2020, Polish archives of internal medicine.

[56]  Weifeng He,et al.  [Advances in the research of cytokine storm mechanism induced by Corona Virus Disease 2019 and the corresponding immunotherapies]. , 2020, Zhonghua shao shang za zhi = Zhonghua shaoshang zazhi = Chinese journal of burns.

[57]  Jocelyn Kaiser,et al.  How sick will the coronavirus make you? The answer may be in your genes , 2020 .

[58]  Elizabeth Rea,et al.  Clinical features and short-term outcomes of 144 patients with SARS in the greater Toronto area. , 2003, JAMA.

[59]  H. Nishiura,et al.  Clinical determinants of the severity of Middle East respiratory syndrome (MERS): a systematic review and meta-analysis , 2016, BMC Public Health.

[60]  Ni Zhang,et al.  Clinical and Transmission Characteristics of Covid-19 — A Retrospective Study of 25 Cases from a Single Thoracic Surgery Department , 2020, Current Medical Science.

[61]  F. Tremel,et al.  Chloroquine cardiomyopathy with conduction disorders , 1999, Heart.

[62]  Y. Hu,et al.  Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China , 2020, The Lancet.

[63]  J. Xiang,et al.  Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study , 2020, The Lancet.

[64]  Y. Xiong,et al.  Clinical features and treatment of COVID‐19 patients in northeast Chongqing , 2020, Journal of medical virology.

[65]  C. Yin,et al.  [Study on the damage of liver in patients with SARS]. , 2004, Zhongguo wei zhong bing ji jiu yi xue = Chinese critical care medicine = Zhongguo weizhongbing jijiuyixue.

[66]  Lei Liu,et al.  Clinical characteristics of 51 patients discharged from hospital with COVID-19 in Chongqing,China , 2020 .

[67]  Xin Zhou,et al.  Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China , 2020, The Journal of Emergency Medicine.

[68]  Herbert Y. Lin,et al.  Mechanisms of anemia in CKD. , 2012, Journal of the American Society of Nephrology : JASN.

[69]  Makoto Takeda,et al.  Efficient Activation of the Severe Acute Respiratory Syndrome Coronavirus Spike Protein by the Transmembrane Protease TMPRSS2 , 2010, Journal of Virology.

[70]  Dechang Chen,et al.  Heart injury signs are associated with higher and earlier mortality in coronavirus disease 2019 (COVID-19) , 2020, medRxiv.

[71]  L. Lei,et al.  Clinical characteristics of 51 patients discharged from hospital with COVID-19 in Chongqing,China , 2020, medRxiv.

[72]  Z. Dong,et al.  Hypoxia and Hypoxia-Inducible Factors in Kidney Injury and Repair , 2019, Cells.

[73]  M. Grant,et al.  Role of the ACE2/Angiotensin 1-7 Axis of the Renin-Angiotensin System in Heart Failure. , 2016, Circulation research.

[74]  Su Lin,et al.  Clinical characteristics of non‐ICU hospitalized patients with coronavirus disease 2019 and liver injury: A retrospective study , 2020, Liver international : official journal of the International Association for the Study of the Liver.

[75]  N. Rezaei,et al.  Immune-epidemiological parameters of the novel coronavirus – a perspective , 2020, Expert review of clinical immunology.

[76]  S. Geng,et al.  Clinical Characteristics of Patients with Severe Pneumonia Caused by the 2019 Novel Coronavirus in Wuhan, China , 2020, medRxiv.

[77]  Taojiao Wang,et al.  Clinical and immunologic features in severe and moderate forms of Coronavirus Disease 2019 , 2020, medRxiv.

[78]  I. Olkin,et al.  Meta-analysis of observational studies in epidemiology - A proposal for reporting , 2000 .

[79]  E. Holmes,et al.  Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding , 2020, The Lancet.

[80]  Wu Zhong,et al.  Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro , 2020, Cell Research.

[81]  Shikai Yu,et al.  Clinical characteristics and durations of hospitalized patients with COVID-19 in Beijing: a retrospective cohort study , 2020, medRxiv.

[82]  Dong Men,et al.  Detectable Serum Severe Acute Respiratory Syndrome Coronavirus 2 Viral Load (RNAemia) Is Closely Correlated With Drastically Elevated Interleukin 6 Level in Critically Ill Patients With Coronavirus Disease 2019 , 2020, Clinical Infectious Diseases.

[83]  Y. Chen,et al.  Medical treatment of 55 patients with COVID-19 from seven cities in northeast China who fully recovered , 2020, medRxiv.

[84]  J. Penninger,et al.  SARS‐coronavirus modulation of myocardial ACE2 expression and inflammation in patients with SARS , 2009, European journal of clinical investigation.

[85]  Zhaohui Zheng,et al.  SARS-CoV-2 invades host cells via a novel route: CD147-spike protein , 2020, bioRxiv.

[86]  Reshmi Chatterjee,et al.  An overview of effective therapies and recent advances in biomarkers for chronic liver diseases and associated liver cancer. , 2015, International immunopharmacology.

[87]  N. Alenina,et al.  The ACE2/Angiotensin-(1–7)/MAS Axis of the Renin-Angiotensin System: Focus on Angiotensin-(1–7) , 2017, Physiological reviews.

[88]  Chuanming Li,et al.  The Clinical and Chest CT Features Associated With Severe and Critical COVID-19 Pneumonia , 2020, Investigative radiology.

[89]  Jin-Kui Yang,et al.  Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes , 2009, Acta Diabetologica.

[90]  W. Tu,et al.  Clinical Features and Short-term Outcomes of 102 Patients with Corona Virus Disease 2019 in Wuhan, China , 2020, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[91]  A. Badawi,et al.  Prevalence of comorbidities in the Middle East respiratory syndrome coronavirus (MERS-CoV): a systematic review and meta-analysis , 2016, International Journal of Infectious Diseases.

[92]  J. Penninger,et al.  Loss of Angiotensin-Converting Enzyme 2 Accelerates Maladaptive Left Ventricular Remodeling in Response to Myocardial Infarction , 2009, Circulation. Heart failure.

[93]  M. Crackower,et al.  Angiotensin-converting enzyme 2 is an essential regulator of heart function , 2002, Nature.

[94]  Y. Li,et al.  Altered Lipid Metabolism in Recovered SARS Patients Twelve Years after Infection , 2017, Scientific Reports.

[95]  B. Baban,et al.  Glucocorticoid-Induced Leucine Zipper Promotes Neutrophil and T-Cell Polarization with Protective Effects in Acute Kidney Injury , 2018, The Journal of Pharmacology and Experimental Therapeutics.

[96]  C. Ronco,et al.  Cardiorenal syndrome. , 2014, Heart failure clinics.

[97]  Lijuan Xiong,et al.  Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients , 2020, EBioMedicine.

[98]  Rui Song,et al.  Neutrophil-to-Lymphocyte Ratio Predicts Severe Illness Patients with 2019 Novel Coronavirus in the Early Stage , 2020, medRxiv.

[99]  C. Akdis,et al.  Clinical characteristics of 140 patients infected with SARS‐CoV‐2 in Wuhan, China , 2020, Allergy.

[100]  Jincun Zhao,et al.  A Transmembrane Serine Protease Is Linked to the Severe Acute Respiratory Syndrome Coronavirus Receptor and Activates Virus Entry , 2010, Journal of Virology.

[101]  Y. Hu,et al.  A New Predictor of Disease Severity in Patients with COVID-19 in Wuhan, China , 2020, medRxiv.

[102]  Wei Liu,et al.  Analysis of factors associated with disease outcomes in hospitalized patients with 2019 novel coronavirus disease , 2020, Chinese medical journal.

[103]  M. Londoño,et al.  Recommendations for the treatment of hepatitis C virus infection in chronic kidney disease: a position statement by the Spanish association of the liver and the kidney , 2018, Journal of Nephrology.

[104]  H. Eltzschig,et al.  Hypoxia signaling in human diseases and therapeutic targets , 2019, Experimental & Molecular Medicine.

[105]  T. Roskams,et al.  Human Liver Regeneration: An Etiology Dependent Process , 2019, International journal of molecular sciences.