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SARS-CoV-2 Pathophysiology and Clinical Manifestations

COVID-19 Resources Home Page

 By Matthew E. Levison, MD, Adjunct Professor of Medicine, Drexel University College of Medicine

7/23/2020

 

Pathophysiology: SARS-CoV-2 Host Cell Receptor

Angiotensin-converting enzyme 2 (ACE2), first identified in 2000, is an enzyme attached to the surface of host cells and is the entry point for SARS-CoV-2. ACE2 is widely distributed throughout the body, being expressed on nasal epithelial cells, lung alveolar epithelial cells, small intestinal enterocytes, arterial and venous endothelial cells, and arterial smooth muscle cells in many organs studied. In the kidneys, ACE2 is expressed in the apical brush borders of the proximal tubules, as well as glomerular podocytes; but not in endothelial cells (1).

ACE2 regulates the renin-angiotensin system by catalyzing the hydrolysis of the octapeptide angiotensin II (AngII, a vasoconstrictor) to the heptapeptide angiotensin 1–7 (Ang1-7, a vasodilator). Ang 1-7 also opposes Ang II’s stimulation of the production of proinflammatory cytokines, such as IL-6. ACE2 has been shown to exhibit a protective function in the lung, cardiovascular system, and other organs, and has been evaluated in clinical trials for the treatment of acute respiratory distress syndrome. The consequent depletion of ACE2 following host cell infection leaves Ang II’s pro-inflammatory stimulation and consequent injury to the lung and other organs unopposed (2).

After being primed by the serine protease TMPRSS2, the SARS-CoV-2 spike protein binds to ACE2, followed by the virus’ entry into the host cell. Anti-ACE-2 antibodies and TMPRSS2 inhibitors can prevent SARS-CoV-2 binding to this receptor and its entry into host cells. The wide distribution of ACE2 receptors throughout the body likely explains the multiorgan effects in COVID-19.

Genetic variants in the binding site for the SARS-CoV-2 spike-protein and variation in the level of expression and expression pattern of ACE2 in different tissues may provide a genetic basis for differences in host susceptibility, symptoms, and outcome of SARS-CoV-2 infection (3, 4). Also, ACE2 expression has to been found to vary by age; in a study involving patients with asthma, expression of ACE2 by nasal epithelium was found to be less in younger children (4 to 9 years old) than in older children and people aged 10 to 60 years, and ACE2 expression, after adjusting for sex and asthma, was higher with each subsequent age group, ie, older children (10 to 17 years old), young adults (18 to 24 years old), and adults ≥ 25 years old (5). The lower ACE2 expression in young children relative to adults may help explain why COVID-19 is less prevalent and clinical manifestations are less severe in young children (6), and their frequency of transmission is less (7).

Clinical Manifestations: A Multiorgan System Disease

The lungs are a major target for SARS-CoV-2. However, SARS-CoV-2 also causes injury to many other organ systems, such as the heart, kidneys, and liver. Understanding that COVID-19 is a multiorgan system disease is crucial to its clinical management.

The spectrum of COVID-19’s clinical presentation is wide, from no or minimal symptoms to severe viral pneumonia with respiratory failure, multiorgan system dysfunction, sepsis, and death. Up to 40 to 45% of those infected are asymptomatic when tested for the virus, many of whom remain asymptomatic, but nevertheless shed the virus from the upper respiratory tract and may be capable of transmitting the virus to others (8). Other patients become symptomatic with a mean incubation period of about 5 days, ranging between 2 and 14 days, after exposure (9).

Fortunately, about 80% of those infected will have mild disease, which can be managed on an outpatient basis; 15% with more severe disease (dyspnea, hypoxia, or > 50% lung involvement on imaging) will require hospitalization, and another 5% with critical disease (respiratory failure, shock, or multiorgan system dysfunction) will require ICU admission (10). The case fatality rate globally is about 4%, but it varies based on demographic characteristics of the local population. All ages are susceptible to infection, but the severity and risk of death is increased in older people, in the poor, in Black and Latino populations, and in those with certain pre-existing co-morbidities, such as obesity, diabetes, hypertension, and lung and cardiovascular disease.

Some infected people who are entirely asymptomatic may nevertheless have a low blood oxygen saturation, called “silent hypoxia,” and may have evidence of lung involvement on chest imaging when these studies are done, for example, when seen in an ER for an unrelated problem such as trauma (11). Hypercapnia (elevated blood CO2) is rare in these patients, which may explain why patients with COVID-19 may not complain of shortness of breath until their pulmonary disease is far advanced and hypoxia is severe. Fever, chills, fatigue, dry cough, anorexia, myalgias, diarrhea, and sputum production are common symptoms. Loss of smell (anosmia) and loss of taste (dysgeusia) are also commonly reported. Sore throat, nasal congestion, and rhinorrhea are less common. Some individuals remain afebrile. Others have mild symptoms for 8 to 9 days, until sudden onset or worsening of shortness of breath (dyspnea) prompts an ER visit. Ventilatory support may be needed shortly after the onset of dyspnea (median, 2.5 days).

Cardiac involvement is indicated by elevated levels of troponin and abnormalities on electrocardiograms and heart ultrasounds (12). SARS-CoV-2 infection may destabilize previously asymptomatic coronary atherosclerotic plaques or may cause blood clots to form in coronary vessels, resulting in obstruction of coronary arterial blood flow. Myocarditis due to SARS-CoV-2 has not so far been described.

Some patients develop proteinuria and acute renal insufficiency. About 15% to 30% of patients with COVID-19 in the ICU require renal replacement therapy. On post-mortem exam, proximal acute tubular injury has been seen on kidney histology, with coronavirus-like particles in the cytoplasm of proximal tubular epithelium and podocytes, sites of known ACE2 expression (1). Liver involvement is indicated by elevated levels of serum alanine aminotransferase and aspartate aminotransferase.

COVID-19 frequently is complicated by a coagulopathy, with elevated levels of D-dimer, but unlike disseminated intravascular coagulopathy (DIC) associated with sepsis, bleeding and abnormalities in prothrombin time, partial thromboplastin time, and platelet counts are absent and the fibrinogen level is often increased. Reports describe a high frequency of venous thromboembolism and lung pathology that shows marked microvascular thrombosis and hemorrhage linked to extensive alveolar and interstitial inflammation, which suggests that clotting is contributing to the respiratory failure in these patients.

Neurologic impairment is common in COVID-19. A nationwide study in the UK found COVID-19 patients diagnosed with altered mental status, new-onset psychosis, neurocognitive (dementia-like) impairment, and an affective disorder (13). Patients have also been reported with encephalitis and positive CSF PCR for SARS-CoV-2 (14) and acute necrotising encephalopathy (15). COVID-19 may cause ischemic stroke; such patients have been found to be younger, had worse symptoms, and were at least seven times more likely to die than people who had a stroke not associated with COVID-19 (16). Patients requiring prolonged mechanical ventilation and/or ICU stays may experience symptoms including chronic fatigue, altered cognitive ability, PTSD, and affective disorders.

Lymphopenia is the most common laboratory finding in hospitalized patients with COVOID-19 and has been associated with severe disease. Marked elevation of serum ferritin occurs in patients with severe COVID-19, complicated by “cytokine storm,” which is defined by the excessive and uncontrolled release of pro-inflammatory cytokines (IL-2, IL-6, IL-10, and TNF-α) and inflammatory markers such as C-reactive protein and erythrocyte sedimentation. “Cytokine storm” in COVID-19 appears later in the hospital course reportedly after an initial clinical improvement, and is associated with worsening damage to the lungs, multiorgan failure, and unfavorable prognosis.

Most children are asymptomatic or exhibit mild symptoms when infected with COVID-19, but in late April, some children were first noted to have what has become to be called multisystem inflammatory syndrome in children (MIS-C), a new COVID-19 presentation, which has some features similar to Kawasaki disease (but is seen in an older age group), staphylococcal and streptococcal toxic shock syndromes, bacterial sepsis, and macrophage activation syndromes (17). The children (age 2 to 16 years) have prolonged fever, fatigue, sore throat, headache, abdominal pain and vomiting, with multiorgan involvement (eg, cardiac, gastrointestinal, renal, hematologic, dermatologic, neurologic), which progress rapidly to shock and organ dysfunction. Unlike adults with COVID-19, only a third have respiratory symptoms. Most have left ventricular systolic dysfunction and some have coronary artery dilatation or aneurysms. Lab results show elevated C-reactive protein, lymphopenia and elevated D-dimer, and some have elevated troponin and brain natriuretic peptide (BNP) levels, suggesting cardiac injury. Some have elevated serum creatinine. Some require circulatory or respiratory support or rarely extracorporeal membrane oxygenation. Very few fatalities have been reported among hospitalized cases. Most have had either positive serology or PCR for SARS-CoV-2. Most patients have received intravenous immune globulin treatment, and some were treated with intravenous steroids and heparin. Serology testing should be performed prior to administering IVIG or any other exogenous antibody treatments. Patients younger than 21 years of age who meet the CDC MIS-C criteria (18) should be reported to the local, state, or territorial health department.

Long-term sequelae of COVID-19 in recovering adult and pediatric patients are yet to be determined.

 

References

1. Su H, Yang M, Wan C, et al: Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China. Kidney International 98(1):P219-227, 2020. https://www.kidney-international.org/article/S0085-2538(20)30369-0/fulltext

2. Liu M, Shi P, Sumners C: Direct anti-inflammatory effects of angiotensin-(1-7) on microglia. Journal of Neurochemistry 136:163-171, 2016. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4688174/

3. Stawiski E, Diwanji D, Suryamohan K, et al: Human ACE2 receptor polymorphisms predict SARS-CoV-2 susceptibility. [PREPRINT] bioRxiv April 10, 2020 https://www.biorxiv.org/content/10.1101/2020.04.07.024752v1

4. Cao Y, Li L, Feng Z, et al: Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations. Cell Discovery 6, 11, 2020. February 24, 2020. https://www.nature.com/articles/s41421-020-0147-1

5. Bunyavanich S, Do A, Vicencio A: Nasal gene expression of angiotensin-converting enzyme 2 in children and adults. JAMA 323(23):2427–2429, 2020. doi:10.1001/jama.2020.8707 https://jamanetwork.com/journals/jama/fullarticle/2766524

6. Dong Y, Mo X, Hu Y, et al: Epidemiology of COVID-19 among children in China. Pediatrics https://pediatrics.aappublications.org/content/145/6/e20200702

7. Park YJ, Choe YJ, Park O, et al: Contact tracing during coronavirus disease outbreak, South Korea 2020. Emerging Infectious Diseases October 2020 [early release] July 16, 2020. Accessed July 23, 2020 https://wwwnc.cdc.gov/eid/article/26/10/20-1315-t2

8. Oran DP, Topol EJ: Prevalence of asymptomatic SARS-CoV-2 infection. Annals of Internal Medicine June 3 2020. Accessed July 23, 2020. https://www.acpjournals.org/doi/10.7326/M20-3012

9. Backer JA, Klinkenberg D, Wallinga J: Incubation period of 2019 novel coronavirus (2019-nCoV) infections among travellers from Wuhan, China 20-28 January 2020. Eurosurveillance 25 (5):pii=2000062, 2020. https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2020.25.5.2000062

10. Centers for Disease Control and Prevention: Healthcare workers: Interim clinical guidance for management of patients with confirmed coronavirus disease (COVID-19). June 30, 2020. Accessed July 23, 2020. https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html

11. Levitan R: Opinion: The infection that is silently killing coronavirus patients. New York Times April 20, 2020. Accessed July 23, 2020. https://www.nytimes.com/2020/04/20/opinion/sunday/coronavirus-testing-pneumonia.html

12. Bonow RO, Fonarow GC, O’Gara PT, et al: Association of coronavirus disease 2019 (COVID-19) with myocardial injury and mortality. JAMA Cardiology 5(7):751-753, 2020. https://jamanetwork.com/journals/jamacardiology/fullarticle/2763844

13. Varatharaj A, Thomas N, Ellul MA, et al: Neurological and neuropsychiatric complications of COVID-19 in 153 patients: A UK-wide surveillance study. Lancet Psychiatry June 25, 2020. Accessed July 23, 2020. https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(20)30287-X/fulltext

14. Xinhua: Beijing hospital confirms nervous system infections by novel coronavirus. Xinhuanet. 2020-03-05. Accessed July 30, 2020. http://www.xinhuanet.com/english/2020-03/05/c_138846529.htm

15. Poyiadji N, Shahin G, Noujaim D, et al: COVID-19-associated acute hemorrhagic necrotizing encephalopathy: Imaging features. Radiology 269(2): March 31, 2020. Accessed July 23, 2020. https://pubs.rsna.org/doi/10.1148/radiol.2020201187

15. Yaghi S, Ishida K, Torres J, et al: SARS-CoV-2 and stroke in a New York Healthcare system. Stroke 51(7): 2002-2011, 2020. https://www.ahajournals.org/doi/10.1161/STROKEAHA.120.030335

17. Fornell D: Kawasaki-like inflammatory disease affects children with COVID-19. Diagnostic and Interventional Cardiology May 20, 2020. Accessed July 23, 2020. https://www.dicardiology.com/article/kawasaki-inflammatory-disease-affects-children-covid-19

18. Centers for Disease Control and Prevention: Information for healthcare providers about multisystem inflammatory syndrome in children. May 29, 2020. Accessed July 23, 2020 https://www.cdc.gov/mis-c/hcp/