Сontents

Many studies of COVID-19 are devoted to respiratory and pulmonary manifestations of the disease. SARS-CoV-2 causes respiratory failure, pneumonia, and acute respiratory distress syndrome (ARDS).

With the accumulation of clinical experience in the treatment of the disease, more and more studies of the effect of the disease on other systems of the body began to appear: cardiovascular, hematological, renal, gastrointestinal, neurological, hepatobiliary, endocrinological, ophthalmological, and dermatological.

Pathophysiology of COVID-19

The SARS-CoV-2 virus uses receptor recognition mechanisms similar to the SARS-CoV and MERS coronaviruses to enter healthy target cells.

As an input receptor, the virus uses the membrane receptor angiotensin-converting enzyme 2 (ACE2). The virus’s spike protein interacts with ACE2 using the spike protein of the cellular serine protease TMPRSS2. Joint activation of ACE2 and TMPRSS2 is necessary to complete the process of virus entry into the cell.

A comparative study of coronaviruses revealed that SARS-CoV-2 has a higher affinity for binding to ACE2 than SARS-CoV. This feature can partially explain the increased transmissivity of SARS-CoV-2.

COVID-19 leads to direct viral toxicity, disrupts the regulation of the hormonal system, damages endothelial cells. It also causes inflammation and violation of the immune response, microcirculation dysfunction. Some of these processes may be unique to COVID-19.

Viral Toxicity

Epithelial cells of the respiratory tract have a high level of ACE2 expression. As the disease progresses, the live SARS-CoV-2 virus and viral subgenomic mRNA are detected not only in the upper respiratory tract but also in the lower respiratory tract. The virus multiplies in the cells of the alveolar epithelium of the lung type II in the pulmonary parenchyma in the form of ARDS and pneumonia.

High titers of viral RNA are found in the feces, urine, and blood.

Histopathological studies revealed organotropism of SARS-CoV-2 to neurological, pharyngeal, gastrointestinal tissues, myocardium, and kidneys. RNA studies showed expression of ACE2 and TMPRSS2 in alveolar epithelial cells of the lung type II, secretory goblet cells of the nose, epithelial cells of the gastrointestinal tract, cholangiocytes, colonocytes, esophageal keratinocytes, pancreatic β-cells, podocytes, and cells of the kidneys proximal tubules.

Thus, partial damage to several organs may occur due to direct viral tissue damage. However, the mechanism of extrapulmonary propagation of SARS-CoV-2 is still unclear.

The Damage of Endothelial Cells

The pathophysiological mechanisms of COVID-19 are damage to endothelial cells and subsequent inflammation.

Some studies have demonstrated ACE2 expression in the arterial and venous endothelium of various organs. Histopathological studies have shown the presence of SARS-CoV-2 virus particles in endothelial cells of the kidneys and lungs. The found activated neutrophils and macrophages caused endothelialitis in the vessels of the heart, kidneys, lungs, liver, and small intestine.

Infection-mediated endothelial damage is also characterized by an increased level of the Willebrand factor (a blood plasma glycoprotein that provides platelet attachment to a fragment of a damaged vessel).

Patients with COVID-19 may experience increased thrombin production and inhibit fibrinolysis. It initiates thrombosis, which leads to thrombosis and microvascular dysfunction. In such conditions, the interaction of platelets, neutrophils, and macrophages contributes to the release of cytokines, fibrin synthesis, or the formation of microthrombi. Histopathological studies of patients with COVID-19 confirmed this fact: the presence of fibrinous exudate and microthrombi.

Additional damage to the endothelium causes the formation of extracellular neutrophil traps (NET), which activate external and internal coagulation pathways. A study conducted in the United States showed that increased NET activity is positively correlated with the severity of the disease.

Activation of the HIF-1 signaling pathway (hypoxia-inducible factor 1) and hyperviscosity (caused by acute lung damage by hypoxia) can also exacerbate the prothrombotic condition.

Violation of The Regulation of The Immune Response

Severe manifestations of COVID-19 are also characterized by cytokine release syndrome due to an increased response of innate immunity in the conditions of t-lymphocyte lymphodepletion. Previous studies of coronaviruses have shown that the mediators of inflammation are rapid virus replication and activation of neutrophils and monocytes in terms of impaired functioning of interferon signaling pathways.

For COVID-19, prognostic mortality factors are increased levels of Pro-inflammatory markers in the blood serum, such as interleukin-6 (IL-6), C-reactive protein (CRP), D-dimer, fibrinogen, ferritin, and erythrocyte sedimentation rate.

Violation of the Regulation of the Renin-Angiotensin-Aldosterone System (RAAS)

RAAS is a hormonal system that regulates blood pressure and physiological processes: fluid and electrolyte balance, vascular permeability, and tissue growth.

Under the influence of SARS-CoV-2, ACE2 expression became a counterregulatory of the RAAS pathway. In cleavage by the angiotensin I and II receptor, angiotensin 1-9 is formed, which has vasodilating, antifibrotic, and antiproliferative properties.

Hematological manifestations

Clinical manifestations and epidemiology

Lymphopenia is the primary marker of cellular immunity disorders, which is observed in 67-90% of patients with COVID-19. A decrease in CD4+ and CD8 + lymphocyte subpopulations are associated with severe disease. Also, a negative prognostic marker is a leukocytosis, especially in the form of neutrophilia.

Thrombocytopenia occurs in 5-36% of cases and is observed in a mild form. However, it is also associated with worse outcomes for patients.

Coagulopathy is observed in 46% of hospitalized patients. Increased levels of D-dimer and fibrinogen characterize it. At the same time, at the initial stage of the disease, there are small deviations in the number of platelets, activated partial thromboplastin time, and prothrombin time. It is important to note that increased d-dimer levels are associated with reduced mortality.

Patients with COVID-19 may have several thromboembolic complications and abnormalities in laboratory tests.

Counting cells can reveal lymphopenia, leukocytosis, neutrophilia, and thrombocytopenia. Increased coagulation rates may also be detected: increased prothrombin time and partial thromboplastin time, d-dimer, and fibrinogen levels. Patients may have increased markers of inflammation: IL-6, CRP, ferritin, lactate dehydrogenase, and the rate of erythrocyte sedimentation.

Thrombotic complications are observed in 30% of patients in intensive care units. Arterial complications: ischemic stroke, myocardial infarction, ischemia of the mesentery. Venous: pulmonary embolism, deep vein thrombosis. Catheter thrombosis: thrombosis of venous and arterial catheters, thrombosis of extracorporeal circuits.

It is also possible to develop cytokine release syndrome: multiple organ dysfunction, hypotension, high temperature.

General treatment recommendations: carry out thromboprophylaxis taking into account liver function; use low-molecular-weight heparins or unfractionated heparin instead of oral anticoagulants; global immunosuppression with corticosteroids can help suppress the cytokine storm.

Pathophysiology

The following mechanisms of lymphopenia in COVID-19 are assumed: ACE2-dependent or ACE2-independent virus entry into lymphocytes, lymphocyte depletion mediated by apoptosis, suppression of lymphocyte proliferation by lactic acid, spleen atrophy, extensive destruction of lymphoid tissues.

Leukocytosis and neutrophilia are the results of an inflammatory reaction to SARS-CoV-2 or secondary bacterial infections.

Abnormally high blood levels of fibrinogen and D-dimer reflect inflammation in the early stages of the disease.

Increased expression of ACE2 in endothelial cells contributes to thrombo-inflammation and supports the vicious circle of endothelialitis.

In addition to macrothrombosis, microthrombosis also develops in small vessels. Autopsies of patients who died from COVID-19 showed a high incidence of microvascular and macrovascular thrombosis. Extraordinarily often, thrombosis is observing in the small circle of blood circulation. Microthrombs of alveolar capillaries were 9 times more common in those who died from COVID-19 than in those who died from influenza.

Cardiovascular manifestations

Clinical manifestations and epidemiology

SARS-CoV-2 can cause both direct and indirect cardiovascular consequences: myocardial damage, acute coronary syndromes, cardiogenic shock, cardiomyopathy, acute pulmonary heart disease, arrhythmias, and thrombotic complications.

Myocardial damage occurs in approximately 25% of hospitalized patients with COVID-19. Moreover, if the patients already had cardiovascular diseases, this figure increased to 55%.

It was observed that increased troponin was associated with worse outcomes and more severe disease.

Cardiomyopathy of both ventricles was registered in 7-33% of patients in a severe condition. Isolated insufficiency of the right ventricle was also observed both with and without pulmonary embolism.

Approximately 20% of all patients have cardiac arrhythmias, ventricular arrhythmias, heart block, atrial fibrillation. Among patients in intensive care units, this figure was already 44%.

In New-York, 6% of patients with COVID-19 had an extended QT (more than 500 MS) at the time of hospitalization.

In patients who needed artificial ventilation, atrial arrhythmias were 9 times more common than in patients without a ventilator.

During the COVID-19 epidemic, the incidence of community-acquired cardiac arrest increased by 60%.

Pathophysiology

Cardiovascular manifestations of COVID-19 are caused by multi-factor pathophysiology.

The ACE2 receptor is strongly expressed in cardiovascular tissues. Direct viral damage affects cardiac fibroblasts, endothelial and smooth muscle cells, and cardiac myocytes.

The development of myocarditis in patients with COVID-19 may be associated with a high concentration of the virus. Some autopsy studies have reported the release of virus from myocardial tissue.

Endothelial infection was detected in patients with myocardial infarction and circulatory insufficiency. Viral vascular damage may be the primary mechanism for the development of such severe complications.

Another factor of myocardial damage is a cytokine storm. The systemic inflammatory response is also destructive to blood vessels.

Patients with concomitant cardiovascular diseases are at risk of more severe illness due to possible higher ACE2 levels.

Increased pulmonary vascular pressure occurs due to pulmonary thromboembolism, ARDS, and vascular damage. These factors can cause an isolated malfunction of the right ventricle.

Patients with concomitant coronary heart disease may develop cardiomyopathy, ischemia, or myocardial infarction as a result of tachycardia.

Viral infections increase the risk of myocardial infarction. But taking into account hypercoagulation in patients with COVID-19, this risk increases significantly. An additional danger is a difficulty of diagnosing a myocardial infarction with a rupture of the atherosclerotic plaque. Myocardial infarction is symptomatically similar to myonecrosis in conditions of hemodynamic instability and severe hypoxia (type II myocardial infarction).

Recommendations

Among scientists and doctors, the impact of ACE inhibitors and angiotensin receptor blockers (ARB) on the risk of SARS-CoV-2 infection has not yet been resolved. Some studies show that when taking the appropriate drugs, the lungs are protected. Other studies indicate an increased susceptibility of the body to SARS-CoV-2. Patients with hypertension and heart failure should continue taking these medications.

For patients with St-segment elevation myocardial infarction, percutaneous intervention is preferred. However, if personal protective equipment is not available, then fibrinolytic therapy is appropriate.

Echocardiography can be used to decide catheterization of the heart.

The QT interval should be measured before taking any medications that affect this indicator.

Renal manifestations

Clinical manifestations and epidemiology

A common complication of COVID-19 is acute kidney injury (AKI). It develops more frequently than during the previous SARS-CoV epidemic. AKI can cause death.

The complication is observed in the first two weeks of hospitalization. In China, the complication rate was 0.5-29%. In the US – 37%  where 14% of them required dialysis.

The incidence of AKI in patients with severe conditions was 78-90% in New-York. Hematuria was registered in 50% of cases, proteinuria-in 87%. Renal replacement therapy was required in 31% of patients in intensive care units.

Electrolyte imbalance in the form of acidosis and hyperkalemia was observed even in patients without AKI.

Pathophysiology

Renal abnormality in SARS-CoV-2 has some specific features.

Histopathological studies confirm that SARS-CoV-2 can directly infect kidney cells due to the presence of ACE2 receptors in them. Studies show diffuse aggregation of red blood cells, obstruction of glomerular and peritubular capillary loops, and acute damage to the tubules. Using electron microscopy, the researchers saw individual viral particles with spikes in the podocytes and tubular epithelium.

Second, microvascular dysfunction is secondary to endothelial damage. That is due to the presence in the kidneys, in addition to viral particles, also lymphocytic endothelialitis.

Third, the cytokine stroma that accompanies the severe course of COVID-19 leads to multiple organ failure and viral sepsis. Under the influence of an excessive number of cells of the immune system, glomerular capillaries of the kidneys are damaged, and collapsing focal segmental glomerulosclerosis develops.

Non-specific renal complications are also relevant for patients with COVID-19: interstitial nephritis, rhabdomyolysis, severe albuminuria, and endocytosis defects.

Recommendations

When hospitalizing patients, perform a urine test for the ratio of protein and creatinine.

Individually optimize the fluid balance for each patient. Monitor markers of volume status: hemodynamic parameters, electrolytes in the urine, and serum lactate. Avoid hypervolemia.

During renal replacement therapy, some patients may be the necessary system anticoagulant.

Gastrointestinal manifestations

Clinical manifestations and epidemiology

In patients with COVID-19, gastrointestinal manifestations are observing in 12-61% of cases. Symptoms are associated with a longer duration of illness but are not associated with increased mortality.

In China, anorexia is observed in 21% of cases, diarrhea – in 9%, nausea or vomiting – in 7%, abdominal pain-in 3%. In the US, the same symptoms are more common: anorexia – 35%, diarrhea – 34%, nausea –26%.

Gastrointestinal bleeding is rare.

Pathophysiology

Gastrointestinal manifestations of COVID-19 are probably due to the multifactorial pathophysiology. Direct tissue damage by the virus is possible since the ACE2 receptor is present in the epithelial cells of the intestine. Viral nucleocapsid protein is observed visually using electron microscopy in the epithelial cells of the stomach, duodenum, rectum, and epithelial enterocytes.

Viral RNA is detected in the feces of patients in about half of the cases. Some studies have reported the presence of live viruses in feces even after symptoms have disappeared.

Histopathological studies revealed microvascular damage to the small intestine, which occurred as a result of diffuse endothelial inflammation in the submucosal vessels.

Recommendations

Endoscopic diagnostics should be performed in patients with bleeding in the upper gastrointestinal tract or bile duct obstruction. For non-urgent reasons, diagnostic endoscopy should be abandoned.

In New-York, upper endoscopy was performed with low hemoglobin levels and a large volume of packed red blood cells transfused.

Laboratory markers of gastrointestinal manifestations of COVID-19: increased liver transaminases, increased bilirubin, low serum albumin.

With limited resources, it is preferable to test for SARS-CoV-2 in patients with gastrointestinal and respiratory symptoms.

Hepatobiliary manifestations

Clinical manifestations and epidemiology

Hepatocellular injuries are observed in 14-53% of seriously ill patients. The total prevalence of liver disorders is about 20%. In rare cases, severe acute hepatitis develops.

An increase in aminotransferase levels usually occurs within 500% of normal. Some studies have reported that elevated bilirubin is associated with the severity of the disease and possible progression to a critical condition.

Pathophysiology

The virus can use the ACE2 receptor on cholangiocytes to directly damage the bile ducts.

The liver can also be damaged as a result of systemic inflammation or hypoxia. Ramdevpir, lopinavir, tocilizumab can cause drug-induced liver injury.

Histopathological studies of the liver led to the detection of pathologies: lobular cholestasis, liver steatosis, acute necrosis of liver cells, and сentral vein thrombosis, lymphocytic infiltrates, duct proliferation, portal fibrosis.

Recommendations

Long-term monitoring of liver transaminases is recommended during therapy with remdesivir, lopinavir, tocilizumab.

Endocrinological manifestations

Clinical manifestations and epidemiology

The risk of developing severe COVID-19 is associated with the presence of concomitant diabetes or obesity. According to the US centers for disease control, 24% of hospitalized patients had diabetes. In intensive care units, there were already 32% of such people. In New-York, 36% of those hospitalized had diabetes, and 46% were obese.

Studies conducted in China and Italy show a similar trend: concomitant diabetes is associated with severe disease and death.

In some patients with COVID-19, glucose metabolism abnormalities were observed: diabetic ketoacidosis, increased hyperglycemia, and euglycemic ketosis.

Pathophysiology

Increased levels of cytokines in SARS-CoV-2 can lead to disorders of the pancreatic β-cells, apoptosis, decreased insulin production, and ketosis.

In patients with diabetes with COVID-19, there is an increase in counter-regulating hormones that contribute to a decrease in insulin secretion, insulin resistance, liver glucose production, and ketogenesis.

Obesity reduces lung volume, increases airway resistance, and is often accompanied by diabetes.

Obesity is associated with increased levels of Pro-inflammatory cytokines: IL-6, IL-8, TNF-α, adiponectin, and leptin. They exacerbate the inflammatory response in COVID-19.

Recommendations

For all patients, hemoglobin A1C levels should be evaluated to detect undiagnosed diabetes.

To reduce the risk of infection in medical stuff, conduct remote glucose monitoring using individual monitors.

For patients receiving steroids, it may be necessary to increase the dose of insulin.

Neurological and ophthalmological manifestations

Clinical manifestations and epidemiology

36% of patients have neurological symptoms: ageusia, anosmia, myalgia, headache, dizziness, fatigue, anorexia, confusion. Acute stroke, acute inflammatory demyelinating polyneuropathy, meningoencephalitis, acute necrotic encephalopathy, encephalitis are possible in severe cases.

Ocular manifestations are also possible in the form of conjunctivitis, changes in the retina, and congestion of the conjunctiva.

Pathophysiology

SARS-CoV-2 can infect the Central nervous system by penetrating it through the olfactory bulbs, lattice bone, axons, or through the nasal mucosal epithelium.

Nasal epithelial cells have the highest expression of ACE2 among the cells of the entire respiratory system. Perhaps this feature is the cause of anosmia and ageusia.

Other neurological manifestations are associated with the influence of systemic inflammation on the blood-brain barrier and brain vessels.

Recommendations

To reduce the risk of severe consequences in acute ischemic stroke, ensure that patients have access to thrombectomy and thrombolysis.

It is also recommended to use video monitoring tools to monitor the condition of patients who have suffered a stroke.

If possible, delay immunomodulatory therapy for multiple sclerosis until recovery.

Conduct additional monitoring of the condition of elderly patients with Parkinson’s disease.

Dermatological manifestations

Clinical manifestations and epidemiology

Skin manifestations are registered in about a fifth of hospitalized patients. The form of signs can be different: livedoid or necrotic lesions, erythematous rash, maculopapular rash, blisters, urticaria.

Pathophysiology

Skin manifestations are associated with increased sensitivity to cytokine release syndrome, microthrombosis, and vasculitis.

Histopathological studies most often record dyskeratotic keratinocytes and perivascular dermatitis.

Biopsy of dermatological lesions shows the presence of blood clots in the vessels of the dermis, endothelial inflammation, dense lymphoid infiltrates.

Recommendations

Dermatological manifestations, as a rule, do not require additional therapy and pass independently.

Other features of COVID-19

Children

According to the Center for disease control and prevention of China, children make up about 1% of COVID-19 patients. The disease occurs in a mild or moderate form. Only 1.8% of patients require intensive therapy.

A lighter course of the disease in children is associated with insufficient immune development and weaker Pro-inflammatory activity of cytokines.

Pregnancy

As a result of research, it has not been demonstrated that pregnancy and childbirth affect infection and disease severity. The frequency of intensive care in pregnant women was not higher than in non-pregnant women. There was no increased incidence of complications.

Some studies have found that COVID-19 increases the risk of premature birth and cesarean section.

In pregnant women, vaginal tests for SARS-CoV-2 were negative.

Transmission of the virus to newborns is possible, but studies do not confirm the mass nature of this phenomenon.

Conclusions

SARS-CoV-2 does not only lead to lung complications. The virus affects many vital systems and organs. Doctors should be informed about the clinical manifestations of this complicated disease.

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