Effect of COVID-19 on the Organs

The COVID-19 pandemic that first became apparent in Wuhan, China, is now infecting millions all over the world. This is a review of COVID-19's extensive effects on virtually all the organs. It causes inflammation, endotheliitis, vasoconstriction, hypercoagulability, and edema. Lymphocytopenia, elevated D-dimer, elevated fibrin degradation products (FDPs), and disseminated intravascular coagulation (DIC) are observed. Deep vein thrombosis (DVT), venous thromboembolism, pulmonary embolism (PE), systemic and pulmonary arterial thrombosis and embolism, ischemic stroke, and myocardial infarction (MI) are reported. In the heart it can cause acute coronary syndrome, congestive heart failure, myocarditis, and arrhythmias. Kidney injury is usually secondary to systemic abnormalities. Stroke occurs even in young patients. Delirium and seizures are common. Anosmia and impaired sense of taste are reported. Psychological problems are common among patients as well as providers. Stool may contain virus. Lactate dehydrogenase may be elevated. Various skin manifestations including patchy erythematous rash are reported.


Introduction And Background
The COVID-19 pandemic first became apparent in Wuhan, China. It has rapidly spread to all continents. In persons who develop clinical illness in response to SARS-CoV-2, the respiratory system is the most commonly affected. However, the virus can affect any organ in the body. In critically ill patients, multiple organs are often affected. The virus binds to angiotensin converting enzyme 2 (ACE2) receptors present in vascular endothelial cells, lungs, heart, brain, kidneys, intestine, liver, pharynx, and other tissue [1]. It can directly injure these organs. In addition, systemic disorders caused by the virus lead to organ malfunction. While managing a patient it is essential to evaluate for injury to multiple organs. Disturbances of coagulation and vascular endothelium are common but may not lead to symptoms in early stages. They contribute to injury to multiple organs. Cardiac and renal dysfunction is common among the patients who die. Injury to the organs may become apparent long after the acute infection has subsided. Different organs may be affected at different times. Chronic injury may occur. Rehabilitation can be long and difficult.
cytokine storm, also called as hypercytokinemia or cytokine release syndrome. This maladaptive response can lead to systemic inflammatory response syndrome (SIRS), acute respiratory distress syndrome (ARDS), multi-organ injury, shock, and death. Inflammatory response may continue to increase even when the viral load is diminishing. SARS-CoV-2 infects the endothelial cells in multiple organs and causes diffuse lymphocytic endotheliitis, leading to vasoconstriction [3]. Accompanying inflammation, hypercoagulability, and edema cause hypoperfusion leading to organ ischemia. However, patients with pre-existing immune-mediated inflammatory disease being treated with anticytokine biologics and other immunomodulatory therapies are not at an increased risk due to COVID-19 [4].
Fever and inflammation cause hypercoagulability and impair fibrinolysis. Cytokine interleukin-6 (IL-6) levels correlate with hypercoagulability and disease severity. Elevated antiphospholipid antibodies are associated with thrombosis [11]. The liver increases production of procoagulant substances. Prothrombin time and activated partial thromboplastin time are moderately prolonged. Moderate thrombocytopenia is observed. C-reactive protein is elevated. Cytokine storm and excessive systemic inflammation are associated with lymphocytopenia, elevated Ddimer, elevated fibrin degradation products (FDPs), and DIC. D-dimer levels and DIC are prognostic.
Guidelines recommend thromboprophylaxis [12][13]. Prophylaxis with low-molecular-weight or regular heparin, fondaparinux, or a direct oral anticoagulant such as apixaban or rivaroxaban should be considered. Heparins bind tightly to COVID-19 spike proteins impeding the entry of the virus into cells. Heparins also downregulate IL-6 and reduce immune activation. A nonrandomized study suggests that among patients requiring mechanical ventilation, systemic anticoagulation may be associated with reduced mortality without increasing major bleeding [14]. However, systemic anticoagulation has not proven to be beneficial in ARDS due to other etiologies. After hospital discharge extended prophylaxis may be beneficial.

Pulmonary effects
Autopsy studies indicate that in the acute phase the patients have classic diffuse alveolar damage without organization and fibrosis [15][16]. It is caused by disruption of endothelial and alveolar cells. This leads to fluid and cellular exudation and hyaline membrane formation. Acute fibrinous and organizing pneumonia are also observed [17]. It consists of alveolar fibrin aggregation. Airway inflammation is present. Increased capillary permeability causes alveolar and interstitial edema. Vascular angiogenesis is a distinguishing feature of COVID-19 [18][19].
On chest CT, findings of subpleural and peripheral areas of ground-glass opacity and consolidation are present in patients with COVID-19. Most of the patients have bilateral distribution. On chest radiographs, patchy infiltrates are observed that may be distributed asymmetrically.

Cardiac effects
In COVID-19, cardiac complications can precede and can occur in the absence of pulmonary and other complications [29][30]. Ischemic cardiac injury can occur in patients with established coronary artery disease (CAD), those with latent CAD, and those without CAD. The primary cause of the former two is plaque rupture and thrombosis. The last one is due to inadequate oxygen supply and mimics a MI. For acute coronary syndrome due to plaque rupture, antiplatelet and anticoagulation therapy may be beneficial. Fibrinolytic therapy and percutaneous coronary intervention may be considered. However, the reported incidence of acute MI has declined in the COVID-19 period [31].
Invasion of myocytes by the virus is observed in some patients. Systemic inflammatory response such as cytokine storm can cause myocarditis without direct viral infiltration. It can cause heart failure and arrhythmias. This can occur even after the acute phase of the infection has resolved and in the absence of lung damage.
About one-half of the non-survivors have acute cardiac injury and heart failure. Respiratory failure dominates in the early phases of the disease whereas cardiac injury becomes more critical in the later phases. Vascular risk factors of diabetes, obesity, age, and hypertension have greater association with mortality than does respiratory disease. In Britain one-quarter of the COVID-19 deaths occurred among diabetics, whereas 15% occurred among patients with chronic pulmonary disease.
Heart failure and elevation of brain-type natriuretic peptide (BNP) is observed. Elevated troponin and BNP levels are associated with mortality. PE can cause elevation of troponin as well as BNP. For older patients with existing CAD or hypertension, heart failure may be caused by worsening demand-supply relationship. Myocarditis is more likely the cause in younger patients. Arrhythmias include tachycardia, bradycardia, and asystole. They can be due to inflammation, myocarditis, hypoxemia, metabolic abnormalities, or medications. Cardiovascular complications may occur long after viral clearance and recovery. Inflammation can persist and evolve silently. As an example, dyslipidemia, pulmonary fibrosis, and avascular necrosis evolved over the long term in many survivors of severe acute respiratory syndrome (SARS), which is closely related to COVID-19.
Commonly used medications including angiotensin converting enzyme inhibitors and angiotensin II receptor blockers have not been demonstrated to increase the risk of COVID-19 infection or its complications and should not be discontinued [32].

Renal effects
COVID-19 complicates the management of patients on dialysis and with kidney transplantation [33]. In Britain about 15% of the patients who expired had chronic kidney disease. ACE2 receptors are present in kidneys [34]. The virus is found in glomerular cells, tubular epithelium, and podocytes of kidneys. Acute kidney injury (AKI) is commonly secondary to systemic abnormalities including diabetes, hypertension, chronic kidney disease, hypoxemia, and coagulopathy. Cytokine storms can cause drastic hypoperfusion and AKI.
Acute kidney injury is also caused by rhabdomyolysis due to hyperventilation or medications including antivirals such as remdesivir. In New York, about 90% of patients who were on mechanical ventilation developed AKI [35]. AKI occurs in temporal association with respiratory failure.
Due to shortage of continuous renal replacement therapy and other hemodialysis equipment and supplies, there is greater utilization of peritoneal dialysis. The latter is suboptimal in hospitalized patients, especially if they are unstable. The catheter for peritoneal dialysis is usually placed in the anterior abdomen. It is less effective in patients who are being proned because of respiratory failure. Placing the catheter on the side of the abdomen alleviates the problem.
Among kidney transplant recipients, initially fever is present in only about one-half and diarrhea is present in about one-quarter of the patients [36]. Compared to a matched cohort they have a faster progression of disease and a higher mortality.

Effect on brain
The ACE2 receptors are present in the cerebral cortex and brain stem. Some patients have meningitis and encephalitis indicating viral invasion of the central nervous system (CNS). There is depression of brain stem reflexes including the one that senses oxygen starvation. Neurological manifestations may be the only ones observed or may occur in combination with respiratory or other symptoms [37][38][39]. Neurological manifestations are more common in people with more severe disease. Altered oxygen and carbon dioxide levels may contribute to them. They include dizziness, headache, impaired consciousness including confusion, delirium, and inability to rouse. Delirium is common and can lead to long-term cognitive impairment including memory deficits. Because of a shortage of commonly used sedatives like propofol and dexmedetomidine, benzodiazepines are being used for sedation. They can enhance delirium. Brains of dead patients demonstrate hypoxic changes but encephalitis or other changes due to the virus are rare [40].
Cytokine storm can cause brain inflammation and edema. Some patients have sympathetic storm that can cause seizure-like symptoms. Stroke due to blockage of a cerebral artery can occur even in young patients with no prior history [41]. This is in part because of hypercoagulability and endothelial injury. Cerebral hemorrhage is also observed. Ataxia and seizure may be present. Cranial nerves may be involved. Anosmia and dysgeusia, i.e., impaired sense of taste, are reported [42]. Nerve pain, skeletal muscle weakness and pain, tingling or numbness in the hands and feet are also observed. Rhabdomyolysis may cause elevated serum creatine kinase. Neurological features among patients in ICU with ARDS included encephalopathy, agitation, and confusion [37]. Corticospinal tract signs with enhanced tendon reflexes, ankle clonus, and bilateral extensor plantar reflexes are present in most of the patients.

Effect on eyes
Both ACE2 receptors and TMPRSS2 proteases that are necessary for infection by SARS-CoV-2 are found in ocular surface cells in cornea, inside the eyelids and in the white of the eye [43]. About one-third of hospitalized patients develop ocular abnormalities including conjunctivitis [44]. Conjunctivitis is more common in the sicker patients. Ocular involvement may occur early. Ocular surface cells are portals of entry and reservoirs of the virus. Ocular virus shedding is a source of infection. Infectious virus can persist in the eye for up to three weeks [45].

Gastrointestinal effect
Gastrointestinal (GI) symptoms include loss of appetite, nausea, vomiting, diarrhea, and abdominal pain or discomfort [46][47]. These symptoms might start before or occur with or without other symptoms such as fever, myalgias, and cough. Lower GI tract is rich in ACE2 receptors. Some patients' stool contains intact infectious virus or only RNA and protein fragments of the virus. Patients who have virus in the stool take longer to clear it. Although a small percentage of patients have GI symptoms, up to one-half shed virus in the stool [47]. Virus protein shell is also found in gastric, duodenal, and rectal cells. More than one half of COVID-19 hospitalized patients have elevated lactate dehydrogenase and other liver enzymes indicating injury to the liver or bile ducts. This is likely to be due to an overactive immune system or due to drugs causing liver damage.

Effect on skin
Skin manifestations of COVID-19 are similar to those of other viruses and chronic inflammatory diseases like acne, eczema, psoriasis, and rosacea. Vascular problems associated with skin manifestations can be neurogenic, microthrombotic, or immune complex mediated. Of the patients with skin manifestations, a majority have patchy erythematous rash [48][49]. Some have widespread urticaria or hives. A few also have chickenpox-like fluid-filled vesicles or blisters. They can have measles-like rashes. The most commonly affected area is the trunk. Itching is mild or absent. Some patients have skin eruptions at symptom onset, and others after hospitalization. Lesions usually heal in a few days. Skin manifestations do not correlate with the severity of COVID-19.
Patients may develop livedo reticularis. It is a purplish net-like discoloration of the skin, often a result of blood clotting abnormalities. Lacy, dusky rashes, including dead skin cells are observed on the arms, legs, and buttocks. They are associated with hypercoagulability. Petechiae are present. Nonpruritic blanching livedoid vascular eruption, possibly due to vasoocclusion may be present. They appear as mottled, net-like red, or pink patches. Also present are chilblains, which are purplish, slightly firm and often tender. COVID toes and fingers have frostbite-like areas with red or purple rash or hive-like eruption.

Psychological effects
Because of financial difficulties and social isolation due to COVID-19, many psychological problems can arise. They can be delayed by months. There is an increase in "deaths of despair" from substance abuse or suicide. The risk is greater among persons with dementia, mental illness, and autism. In person and online communication with friends and support professionals is beneficial.
On discharge from ICU, a third of the patients have dysexecutive syndrome consisting of inattention, disorientation, or poorly organized movements in response to command [37]. Some patients who recover from COVID-19 develop mental health problems [50]. These include anxiety, depression, and post-traumatic stress disorder (PTSD). Long term effects can include development of Alzheimer's or Parkinson's disease.

Conclusions
SARS-CoV-2 virus binds to ACE2 receptors present throughout the body and can adversely affect virtually every system of the body. It can cause cytokine storm which can culminate in death. Different organs may be affected in different patients, in a temporal course unrelated to viral load. Inflammation, platelet activation, hypercoagulability, endothelial dysfunction, constriction of blood vessels, stasis, hypoxia, and muscle immobilization contribute to the complications.
The lungs are commonly affected. Acute coronary syndrome, heart failure, and myocarditis may be present. Patients who are on angiotensin converting enzyme inhibitors and angiotensin II receptor blockers should continue taking them. AKI is usually secondary to systemic derangements. Meningitis, encephalitis, encephalopathy, stroke, and delirium are observed. Impaired sense of smell and taste are observed. Eyes are sites of virus entry and can also be sources of infection. Psychological problems are common among patients as well as providers. GI symptoms are observed. Patchy erythematous rash is the most common skin manifestation. Thus, COVID-19 can affect virtually any organ in the body.

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