COVID-19: The Disease

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19 May COVID-19: The Disease

Posted at 16:52h in Insights, Medical Education by

Coronaviruses are named for crownlike spikes on their surface and belong to the Coronavirinae subfamily, which are further classified into 4 groups: the α, β, γ, and δ CoVs by phylogenetic clustering, of which α and β are known to cause infection in humans. The first human CoV (HCoV) was identified in the mid-1960’s  and until 2003, only 2 HCoV species, HCoV-229E and HCoV-OC43, were recognized. Currently, 7 different CoV strains are known to infect humans, including HCoV-229E, HCoV-NL63, HCoV-OC43, and HCoV-HKU1, which generally cause self-resolving infection.  They usually cause mild, self-limiting upper respiratory infections, which account for 15% to 30% of common colds and typically affect young adults but may lead to hospitalization in elderly patients with underlying cardiac and lung disease.

There are also severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East Respiratory Syndrome coronavirus (MERS-CoV), and newly identified SARS-CoV-2, which can cause lethal respiratory infections in humans. Typically, coronaviruses account for a small percentage (less than 5%) of patients hospitalized for acute respiratory illness.

Coronavirus family:

In 2003, a total of 8096 people in 29 countries were reported ill with the SARS infection, starting in Hong Kong, and 774 of them died (around 10%) around the world. It was contained rapidly and ultimately was not as easily transmissible than Covid-19.

The MERS-CoV epidemic emerged in Saudi Arabia in June 2012. The virus transmitted from infected dromedary camels, as the intermediate host, to humans through close contact.  Middle East respiratory syndrome CoV belongs to the β-CoVs group and  Middle East respiratory syndrome CoV spreads from an infected person’s respiratory secretions to others through close contact, with an incubation period of 2 to 13 days. Middle East respiratory syndrome CoV is likely shed into the environment and transferred from environmental surfaces to hands, which then could cause infection through contact. Since 2012, 27 countries have reported cases of MERS including Algeria, Austria, China, Egypt, France, Germany, Greece, Islamic Republic of Iran, Italy, Jordan, but 80% of human cases have been reported by Saudi Arabia. Cases identified outside the Middle East are usually traveling people. As of November 30, 2019, a total of 2494 laboratory-confirmed infections of MERS-CoV have been reported, with 858 associated deaths (case-fatality rate: 34.4%) in 26 countries, with most cases from Saudi Arabia, with 2102 cases with a case-fatality rate of 37%. No vaccine or specific treatment is currently available, Treatment is supportive and based on the patient’s clinical condition.

In December 2019, the health services of Wuhan hospital reported the first cases of Covid-19. It was recognized by WHO in January 2020 and spread from travellers to Italy, Spain and France than USA, Canada and the world. 

The SARS-CoV -19 belongs to the β-CoVs group and binds to the zinc peptidase angiotensin-converting enzyme 2 (ACE2), a surface molecule that is localized on the endothelial cells of arteries and veins, arterial smooth muscle, respiratory tract epithelium, epithelia of the small intestine, respiratory tract epithelium, and immune cells, to enter the host cell. Suppression of ACE2 expression with SARS-CoV -19 infection has been proposed to play a role in the pathologic changes in the lung and contribute to the severe pneumonia and acute lung failure observed with this virus.  This ACE2 binding in the wall of the arteries and veins is the most important cause of coagulation issue, severe lung damage, stroke, clots formation in the legs and other parts of the body. This ACE2 binding does not happen with the other types of viral infection like regular flu, SARS, MERS. New research from all around the world was able to find this exact mechanism through pathophysiology study, on dead patients and sick but alive patients. It took the medical world by surprise as at first the medical community thought it was another similar SARS viral infection, but with the high mortality rate at first, it was evident that it was a different viral mechanism. 

   The virus was confirmed to spread through respiratory droplets from coughs or sneezes with the ability of the host to shed the infection while asymptomatic. Initial symptoms of COVID-19 overlap with other viral syndromes, and include fever, fatigue, headache, cough, shortness of breath, diarrhea, headaches, and myalgias. Much less common with other virulent coronavirus infections such as severe acute respiratory syndrome (SARS) and Middle Eastern respiratory syndrome (MERS-CoV), the COVID-19 has the potential to result in severe illness including systemic inflammatory response syndrome, acute respiratory disease syndrome (ARDS), multi-organ involvement, and shock. Progression to pneumonia is documented by radiological findings and usually occurs 1–2 weeks after the beginning of the symptoms. Although older age and comorbidities such as cardiovascular disease confer a higher risk for severe disease, young and otherwise healthy patients are also at risk for complications .

As of March 3, 2020, per World Health Organization Director-General’s opening remarks, the global mortality rate has been about 3.4%. The overall crude fatality rate varies by location, intensity of transmission, and variations of care. The nationwide mortality rate in China has been around 3.8%.  As of 26 May 2020, COVID-19 has been confirmed in 5,404,512 individuals globally with deaths reaching 343,514 with a morality of 6.4%. By May 1th, 2021, the world is on a third surge with multiple variants of the COVID-19 which has affected 151 millions people and killed 3.2 millions people.

Cytokine Storm:

The “cytokine storm” results from a sudden acute increase in circulating levels of different pro-inflammatory cytokines including IL-6, IL-1, TNF- α, and interferon. This increase in cytokines results in influx of various immune cells such as macrophages, neutrophils, and T cells from the circulation into the site of infection with destructive effects on human tissue resulting from destabilization of endothelial cell to cell interactions, damage of vascular barrier, capillary damage, diffuse alveolar damage, multiorgan failure, and ultimately death. Lung injury is one consequence of the cytokine storm that can progress into acute lung injury or its more severe form ARDS, requiring intensive care admission having a high mortality rate. 

The trigger for CS is an uncontrolled immune response resulting in continuous activation and expansion of immune cells, lymphocytes, and macrophages, which produce immense amounts of cytokines, resulting in a cytokine storm. The CS clinical findings are attributed to the action of the proinflammatory cytokines . Several studies analyzing cytokine profiles from COVID-19 patients suggested that the cytokine storm correlated directly with lung injury, multi-organ failure, and unfavorable prognosis of severe COVID-19 .

Lung injury in coronavirus disease 2019 (COVID-19).

COVID-19 infection causes acute lung injury induced by activation of macrophages, lymphocyte apoptosis, and neutrophils. The macrophages produce cytokines and chemokines and release these mediators into the alveolar space to control infection. COVID-19 induces vascular endothelial damage through activating the complement system that leads to increased permeability and inflammatory thrombus formation. The fibrinolytic system is activated releasing fibrin degradation fragments (D-dimers) in the circulation. Damage in the alveolar space and small arteries is dominant and changes in the blood vessel of the body occurs with the abnormalities of the coagulation.

Coagulation Activation:

SARS-CoV-2 is directly attacking the endothelial cells that line the blood vessels. Endothelial cells harbour the same ACE2 receptor that the virus uses to enter lung cells. And there is evidence that endothelial cells can become infected: researchers from the University Hospital Zurich in Switzerland and Brigham and Women’s Hospital in Boston, Massachusetts, observed SARS-CoV-2 in endothelial cells inside kidney tissue. Dolhnikoff et al reported  fibrinous thrombi (clots) in pulmonary small arteries in areas of both damaged and preserved lung parenchyma. SARS-CoV-2 infects the vessels lining endothelial cells through an angiotensin-converting enzyme 2 receptor and triggers the loss of the normal anticoagulant function of the vascular lumen. The virus seems to activate the complement system, a defence mechanism that sparks clotting. Laurence’s group found that small, clogged vessels in lung and skin tissue from people with COVID-19 were studded with complement proteins.

Since coagulopathy is a common feature of SARS-CoV-2 infection, an increase in d-dimer  (breakdown product from clots ) is the most common finding.  COVID-19-associated coagulopathy ranges from mild laboratory alterations to disseminated intravascular coagulation. Characteristically, high D-dimer levels on admission and/or continuously increasing concentrations of D-dimer is associated with disease progression and poor overall survival. SARS-CoV-2 infection triggers the immune-hemostatic response. Drastic inflammatory responses including, but not limited to, cytokine storm, vasculopathy,  may contribute to an overwhelming activation of coagulation. Hypercoagulability and systemic thrombotic complications necessitate anticoagulant and thrombolytic interventions. 

In addition to the derangement of coagulation/fibrinolysis and platelet function, endothelial dysfunction contributes to the procoagulant change in COVID-19.  One of the larger initial studies found abnormally elevated d-dimer levels in 260 of 560 cases (46.4%). In another series, elevated d-dimers were associated with a poor prognosis. Tang et al. reported increased d-dimers and fibrin degradation products in COVID-19 and they reported that 71.4% of non-survivors fulfilled the criteria of sepsis-induced coagulopathy, while 0.6% of the survivors met the criteria. Among the notable differences between patients who died and those who survived were increased levels of D-dimer and fibrin degradation products. Further, 71% of COVID-19 patients who died fulfilled the International Society on Thrombosis and Haemostasis (ISTH) criteria (29) for DIC, compared with only 0.6% among survivors.  Studies from the Netherlands and France suggest that clots arise in 20–30% of critically ill COVID-19 patients.

Vascular Thrombosis:

Increasing reports have indicated an increased risk of vascular thrombosis and pulmonary embolism in COVID-19 . Cui et al examined thrombosis in non-symptomatic lower limbs by ultrasonography in COVID-19 pneumonia patients treated in ICU and reported that the prevalence was 25% (20/81). In another study in SARS-CoV-1 infected patients, it was reported that 20.5% of patients had deep vein thrombosis, and 11.4% had pulmonary embolism.  Klok et al studied 184 ICU patients and confirmed VTE in 27% and arterial thrombotic events in 3.7% patients. It should be kept in mind that the prevalence of vascular thrombosis and pulmonary embolism is underestimated since the access to contrast-enhanced CT may be limited in critically ill patients for practical reasons. 

Stroke Incidence:

Of a large international study, involving many countries, of the 1916 patients with COVID-19, 31 patients (1.6%) had an acute ischemic stroke. Among the 1683 hospitalized patients with COVID-19, 31 (1.8%) had an acute ischemic stroke; no patients with emergency department  visits had an acute ischemic stroke. Among 1752 patients with COVID-19 who presented to the emergency department with symptoms of a viral respiratory illness, 27 (1.5%) had an acute ischemic stroke, whereas among 998 patients testing positive during a period of universal screening irrespective of symptoms, 19 (1.9%) had an acute ischemic stroke. The median duration from COVID-19 symptom onset to stroke diagnosis was 16 days  (5-28 days). The median age of patients with acute ischemic stroke was 69 years  (66-78 years).

More recently, investigators found that among 3556 patients hospitalized with COVID-19 in New York City, 0.9% had an ischemic stroke. Among the 1916 patients in this study with ED visits or hospitalizations with COVID-19 infection, 1.6% received a diagnosis of ischemic stroke. The rate of ischemic stroke among patients hospitalized with COVID-19 in this study was 1.8%, which is similar to that observed in the Wuhan cohort but higher than that observed in the study by Yaghi et al in New York City. 

Discrepancies in the rate of stroke may be explained across studies by several factors. First, the method of stroke ascertainment varied across studies, and thus some patients with ischemic stroke may have been missed. Second, many hospitalized patients with COVID-19 infection are severely ill, which makes acquiring brain imaging challenging and at times impractical; as a consequence, the threshold to obtain brain imaging may have varied between institutions. Third, the demographic composition of patients included in these cohorts varied, and data suggest that races of color appear to be at heightened risk for severe disease.

Using a retrospective analysis, the group identified 1486 patients with ED visits or hospitalizations with influenza from January 1, 2016, through May 31, 2018. The median age was 62 years (42-78 years), 663 (45%) were men, and vascular comorbidities were common. Symptoms of a viral respiratory illness were present in 1427 patients (96%), including cough (1188 [80%]), fever (833 [56%]), and dyspnea/hypoxia (553 [37%]). There were 48 patients (3%) with severe influenza infection who required mechanical ventilation. Of the 1486 patients with influenza, 3 patients (0.2%) had an acute ischemic stroke. Seasonal influenza is a much different disease than the COVID-19.

Role of prophylactic anticoagulation:

Hospitalized patients with COVID-19 who have respiratory failure or co-morbidities (e.g., active cancer, or heart failure), patients who are bedridden, and those requiring intensive care should receive pharmacological vascular thrombosis prophylaxis, unless there are contraindications. The choice of agents and dosing should be based on available guideline recommendations. The World Health Organization interim guidance statement recommends prophylactic daily low-molecular weight heparins (LMWHs), or twice daily subcutaneous unfractionated heparin (UFH) . Blood-thinning medications are standard of care for patients in the intensive-care unit, and those with COVID-19 are no exception. 

Status on treatment:

The research that helped to develop vaccines against the new coronavirus didn’t start in January 2020. The basic research on DNA vaccines began at least 25 years ago, and RNA vaccines have benefited from 10–15 years of research.  The approach has matured  five years ago, and was very instrumental in the development of current COVID vaccines. For years, researchers had been paying attention to related coronaviruses, which cause SARS (severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome). Conventional vaccines contain viral proteins or disabled forms of the virus itself, which stimulate the body’s immune defences against infection by a live virus. But the first two COVID-19 vaccines for which efficacy was announced in large-scale (phase III) clinical trials used just a string of mRNA inside a lipid coat. The mRNA encodes a key protein of SARS-CoV-2; once the mRNA gets inside our cells, our bodies produce this protein. That acts as the antigen — the foreign molecule that triggers an immune response. The vaccines made by Pfizer and BioNTech and by the US pharmaceutical company Moderna both use mRNA that encodes the  protein, which binds to human cell membranes and allows the coronavirus to invade the cell.

For instance, researchers at the US National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, Maryland, knew from their research on MERS and SARS that it was best to find the RNA sequence to stabilize the resulting  protein to make a vaccine.   That work gave the NIAID team, which worked with Moderna, a head start once SARS-CoV-2 was sequenced in January. 

The third vaccine to show efficacy in phase III clinical trials in November, made by the pharmaceutical firm AstraZeneca with the University of Oxford, UK, does not use mRNA. Instead, a viral vector (or carrier) holds genetic material that codes for the SARS-CoV-2 protein. This, too, benefited from years of research to select the vector; in this case, the firm chose a modified form of adenovirus isolated. Advances in conventional vaccines such as these have also come from research on SARS, MERS, Ebola and malaria.

With large sums given to vaccine firms by public funders and private philanthropists, they could do preclinical and phase I, II and III trials, as well as manufacturing, in parallel instead of sequentially. This meant that companies could work on starting large-scale testing and manufacturing at the same time and  that might not have worked out.  The vaccine science would not have produced such fast results without this funding.  The money  materialized this time because all countries,  wealthy and less wealthy ones, faced large death toll, health care systems overwhelmed and economic devastation caused by the number of sick people and countries lockdown.  

The COVID-19 pandemic should see some permanent changes in vaccine development. For a start, it might establish the use of mRNA vaccines — which had not previously been approved for general use in people — as a speedy approach for other diseases.  This technology is revolutionizing vaccinology, as it can be chemically synthesized in a short period of time  in contrast to the other complicated biotechnology involved in producing proteins in cells. It may be the new way to respond to pandemics in the future. 

What’s more, RNA simplifies the manufacturing as the same facility can be used to make RNA for different diseases. That decreases the investment required and time for production.  Companies should also be ramping up their manufacturing capacities because they still have to make vaccines for measles, polio and other diseases even as they produce COVID-19 immunizations. That could help to meet demand in future.

 

Summary:

The COVID-19 virus belongs to the Coronavirinae subfamily,  of which two are known to cause infection in humans. The first human CoV (HCoV) was identified in the mid-1960’s and  7 different CoV strains are known to infect humans,  which generally cause self-resolving infection.  They are known as the cause of the yearly flu season. They usually cause mild, self-limiting upper respiratory infections, which account for 15% to 30% of common colds and typically affect young adults but may lead to hospitalization in elderly patients with underlying cardiac and lung disease. Typically, coronaviruses account for a small percentage (less than 1%) of patients hospitalized for acute respiratory illness, but suddenly this new COVID virus was causing up to 5% mortality, and much higher in older patients. 

There are also known severe acute respiratory syndrome coronavirus (SARS-CoV): the SARS-Cov form the 2003 infection, the Middle East Respiratory Syndrome coronavirus (MERS-CoV) in 2015, and newly identified SARS-CoV-2 in January 2020. The world was faced with a disease that we did not know much about and we were caught by surprise. China experienced a large amount of death in Wuhan in January, but Europe, mainly Italy, Spain and France were faced with an unprecedented crisis in early 2020. The mortality was high, countries had to lock down as nobody really knew the extend of this crisis. The COVID-19 spread to USA and Canada in February and March of 2020. Progressively other countries were affected and we are now seeing India and Asian countries devastated by this infection. 

We, as the medical society, know how to treat many forms of acute respiratory syndrome and we applied all our knowledge to treat patients with COVID-19. The mortality was still high despite our best effort. Pathophysiology reports and research became more available as the pandemic was raging and we learned that this type of coronavirus was affecting the endovascular cells metabolism, creating in fact  an systemic vasculitis. This systemic vasculitis was causing an inflammatory multi-system vasculitis disease with a disseminated vascular coagulopathy (a systemic effect of the coagulation cascade), leading to intravascular thrombosis and its potential devastating complications. 

The world scientists collaborated 24/7 to understand the virus, its genome and code and went to work in creating several  vaccines, using different approaches such as m-RNA, protein spikes and other vectors. In November 2020, The FDA started to approve temporarily the first vaccine, Pfizer, and then the Astra-Zenica, and the Johnson and Johnson. In the same time, Russia and China were producing their own vaccine. Countries embarked in a massive vaccination program and we may just be able to control  this virus spread,  not just by  measures as wearing mask distancing and lockdown in the worst case scenario, but with herd immunity. What a scientific triumph.

 

References:

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