Complications of COVID-19

19th Nov 2020

It’s well known that the coronavirus attacks the respiratory system. But besides respiratory symptoms, what are the other possible complications of COVID-19? 

 

Cytokine storm in patients with COVID-19

Some COVID-19 patients develop cytokine storm, a devastating overreaction of the immune system. 

Cytokines are small proteins secreted by cells, and they influence the interactions between cells. Cytokines are important in regulating immunity, inflammation, and hematopoiesis.

Cytokines are made by many cell populations, but the predominant producers are immune cells like helper T cells and macrophages. 

Cytokine-producing cell releasing cytokines to target cell. Illustration.

Figure 1. Cytokines are small proteins secreted by activated immune cells in response to inflammation or infection. 

In response to inflammation or infection, these immune cells are activated, and they release cytokines which can go on to promote further inflammatory responses. During an infection, cytokines coordinate the response of immune cells to a specific antigen. 

Cytokines are often produced in a cascade. As one cytokine activates its target cell, it stimulates the cell to make additional cytokines, which subsequently activate additional cells causing further cytokine release. 

Cascade effect of cytokine release activating the next cell in line. Illustration.

Figure 2. Cytokines are often produced in a cascade by which subsequent cells are activated causing further cytokine release, a) cytokine release, b) target cell activated by cytokines, c) target cell stimulation, production, and release of cytokines, d) activation of additional cells, causing further cytokine release.

Here's a short animation of the cytokine cascade:



During a cytokine storm, this cascade gets out of control, and the levels of some cytokines increase far beyond what is needed. Too many immune cells become activated, and they start to attack healthy tissues throughout the body. 

Cytokine storm with one cell releasing cytokines and activating too many cells. Illustration.

Figure 3. Cytokine storm. Sometimes the cytokine cascade gets out of control—this is called a cytokine storm. In this case, too many immune cells become activated and start to attack healthy tissues in the body.

These immune cells will destroy red and white blood cells and damage the liver. Blood vessel walls open to let immune cells into surrounding tissues, but the vessels get so leaky that the lungs may fill with fluid, causing the blood pressure to drop and blood clots form throughout the body. When organs don’t get enough blood, a person can go into shock, risking permanent organ damage or death.

A study conducted in China showed that levels of specific cytokines were increased in those patients who were admitted to the intensive care unit (ICU), compared to those who weren’t admitted to the ICU.1

Several other studies have shown higher levels of certain cytokines, like interleukin-6 (IL-6), are associated with a greater risk of death. This suggests that cytokine storm is associated with more severe coronavirus infections.2–6

In coronavirus infections, cytokine storm can also trigger viral sepsis where ongoing viral replication and excessive systemic inflammation can lead to pneumonitis, acute respiratory distress syndrome (ARDS), respiratory failure, shock, organ failure, secondary bacterial pneumonia, and potentially death.

Possible results of cytokine storm in COVID-19: pneumonitis, acute respiratory distress syndrome (ARDS), respiratory failure, shock, organ failure, secondary bacterial pneumonia, and potentially death. Illustration.

Figure 4. Cytokine storm is associated with more severe coronavirus infections where it triggers pneumonitis, acute respiratory distress syndrome (ARDS), respiratory failure, shock, organ failure, secondary bacterial pneumonia, and potentially death.
 

Other organ systems affected by COVID-19

Due to the systemic nature of a COVID-19 infection, it’s not just the lungs that we must worry about.  

Series of five images depicting those affected by COVID-19: heart, blood vessel, kidney, brain, intestines. Illustration.

Figure 5. In addition to the respiratory system, a number of other organ systems are affected by COVID-19. The heart, blood vessels, kidneys, brain, and intestines can all be affected by the coronavirus infection.

COVID-19 can affect several organs throughout the body. The heart, blood vessels, kidneys, brain, and intestines can all be affected by the coronavirus infection. These organs can be directly affected by the virus or indirectly affected due to the hyperinflammation of the cytokine storm, and the resulting hypoxia and hypercoagulability. 

The effect of COVID-19 infection on the heart

Studies have shown that up to 20% of hospitalized COVID-19 patients had heart damage, and up to 44% had arrhythmias. COVID-19 patients can present with elevated cardiac enzymes, signifying cardiac damage, and electrocardiogram (ECG) findings similar to a heart attack. 

Patient in hospital bed and graph showing 20% heart damage and 44% arrythmia. Illustration.

Figure 6. Hospitalized patients with COVID-19 exhibit heart complications: 20% had heart damage and up to 44% had arrhythmias.

It is not known yet how the virus attacks the heart, but similar to the nose and alveoli, the heart cells are rich in angiotensin-converting enzyme 2 (ACE2) receptors, which the virus needs to enter the cells. The inflammatory damage of a cytokine storm can result in other cardiac symptoms, including swelling and scarring of cardiac tissues, and decreased left ventricular ejection fraction. Given these findings, it’s easy to see why this disease can be even more deadly for patients with preexisting cardiac conditions. 

Three hearts showing swelling, scarring, and decreased left ventricular ejection fraction. Illustration.

Figure 7. The inflammatory damage of a cytokine storm can result in cardiac symptoms including swelling and scarring of cardiac tissues and decreased left ventricular ejection fraction.

Infection with COVID-19 causes clotting abnormalities

COVID-19-associated coagulopathy 

With a COVID-19 infection, some patients experience abnormal clotting, which has recently been named COVID-19-associated coagulopathy (CAC). It is characterized by elevated levels of D-dimer and fibrinogen, and a rise in inflammatory markers such as C-reactive protein (CRP). The coagulopathy can worsen over time and some patients develop disseminated intravascular coagulation (DIC). 

Blood vessel with multiple clots. Illustration.

Figure 8. Disseminated intravascular coagulation (DIC) may develop over time in patients with COVID-19 who experience abnormal clotting, or COVID-19-associated coagulopathy (CAC). 

Clotting abnormalities during a COVID-19 infection can affect the small vessels of many organ systems and result in increased mortality. Two of the most severe outcomes are pulmonary embolism and stroke. 

COVID toes (dermatological symptoms of COVID-19)

Some COVID-19 patients develop swollen, painful, purple, or blue nodules in their fingers or toes. This has become commonly referred to as COVID toes. It is most often seen in pediatric and young adult patients before they develop any other symptoms of the disease. The exact mechanism is not clear, but it has been postulated that it could be related to blood vessel constriction, excessive clotting, or a condition known as purpura fulminans where inflammation secondary to infection causes the body to make micro-clots in the blood vessels of the finger, toes, and nose. 

Two patients with COVID-19 showing COVID toes. Illustration.

Figure 9. Some COVID-19 patients develop what is referred to as COVID toes: swollen, painful, purple, or blue nodules in their fingers or toes. It is most often seen in pediatric and young adult patients before they develop any other symptoms of the disease.

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COVID-19 infection causes blood vessel constriction

It is also thought that blood vessel constriction in the lungs contributes to the extremely low blood oxygen levels seen in some COVID-19 patients. Blood vessel constriction could explain why patients with preexisting damage to their blood vessels, such as those with diabetes or hypertension, are more seriously affected by COVID-19.

Lungs with constricted blood vessel and blood droplet with low oxygen. Illustration.

Figure 10. Pulmonary blood vessel constriction is thought to contribute to extremely low blood oxygen levels seen in some COVID-19 patients.

Kidney damage associated with COVID-19 infection

The kidneys have numerous ACE2 receptors facilitating viral entry into renal cells. So it’s no surprise that COVID-19 patients can present with acute kidney injury, and protein or blood in the urine. 

Two urine collection jars, one with protein, one with blood. Illustration

Figure 11. Patients with COVID-19 can present with acute kidney injury, and protein or blood in the urine.

Close to 50% of COVID-19 patients who are in the ICU develop acute kidney injury. As many as 20–30% of COVID-19 ICU patients require dialysis, and some die from renal failure. 

Patient in hospital bed and graph showing 50% kidney injury, 20–30% dialysis and some deaths. Illustration.

Figure 12. Close to 50% of hospitalized patients with COVID-19 develop acute kidney injury, 20–30% require dialysis, and some die due to renal failure.

However, it’s not just the virus that is compromising kidney function. The use of ventilators and antiviral drugs in COVID-19 treatment also increases the risk of kidney damage. Additionally, cytokine storm can dramatically reduce blood flow to the kidneys resulting in kidney damage. 

COVID-19 affects the brain and the nervous system 

Neurological symptoms or loss of consciousness are present in 5–10% of COVID-19 patients. COVID-19 patients can experience seizures and encephalitis, as well as strokes due to heightened blood clotting. 

Four cartoon people showing neurological symptoms of COVID-19: stroke, encephalitis, unconsciousness, and seizures.

Figure 13. Due to heightened blood clotting, between 5 and 10% of patients with COVID-19 exhibit various neurological symptoms.

It is presumed that the coronavirus enters the brain using ACE2 receptors to cause these effects, and the virus has also been found in the cerebrospinal fluid of infected patients. Cytokine storm is also thought to contribute to brain swelling and other neurological symptoms. 

Loss of smell and taste associated with COVID-19 infection

The transient loss of the sense of smell (i.e., anosmia) and taste (i.e., ageusia) are other neurological findings, but it is not yet known why these occur. Studies suggest that up to 60% of COVID-19-positive patients can experience smell and taste loss. These symptoms are often seen within three days of infection onset in patients with mild cases.

Patient with hamburger thinking of what food it could be. Illustration

Figure 14. Loss of smell or taste has been associated with COVID-19 infection.

Digestive system symptoms associated with COVID-19

Up to 30% of COVID-19 patients can present with diarrhea, vomiting, and abdominal pain. 

Three patients, exhibiting diarrhea, vomiting, and abdominal pain. Cartoon.

Figure 15. Up to 30% of COVID-19 patients can present with diarrhea, vomiting, and abdominal pain. 

This is likely because ACE2 receptors are also abundant in the lining of the gastrointestinal tract. Viral ribonucleic acid (RNA) has been found in around 50% of COVID-19 patient’s stool samples. However, while the virus may be present in fecal matter, the risk of fecal transmission appears to be low.

 

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References

  1. Huang, C, Wang, Y, Li, X, et al. 2020. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet395: 497–506. PMID: 31986264
  2. Mehta, P, McAuley, DF, Brown, M, et al. 2020. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet395: 1033–1034. PMID: 32192578
  3. Shi, S, Qin, M, Shen, B, et al. 2020. Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China. JAMA Cardiol. 5: 802–810. PMID: 32211816
  4. Wadman, M, Couzin-Frankel, J, Kaiser, J, et al. 2020. How does coronavirus kill? Clinicians trace a ferocious rampage through the body, from brain to toes. Sciencehttps://www.sciencemag.org
  5. Wang, D, Hu, B, Hu, C, et al. 2020. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China. JAMA323: 1061–1069. PMID: 32031570
  6. Zhang, JM and An, J. 2007. Cytokines, inflammation and pain. Int Anesthesiol Clin. 45: 27–37. PMID: 17426506