How does coronavirus kill?

Clinicians trace a ferocious rampage through the body, from brain to toes.

By: Meredith Wadman, Jennifer Couzin-Frankel, Jocelyn Kaiser, Catherine Matacic

In: Science.

Apr. 17, 2020

  • How does the virus attack cells around the body?
    • A clear picture is elusive.
  • We don’t understand:
    • Who is vulnerable.
    • Why some people are affected so severely.
    • Why the virus comes on rapidly.
    • Why it is so hard [for some] to recover.
  • The virus acts like no microbe humanity has ever seen.
  • We are still learning, but it’s difficult to find out.
    • No controlled studies.
    • Only small studies, case reports, often not peer-reviewed.
  • Many important unanswered questions.
    • Does blood clotting transform some mild cases into life-threatening emergencies?
    • Is excessive immune responsible for the worst cases?
    • What explains the low blood oxygen in patients who are not gasping for breath?
  • Infection development.
    • Enters the body through nose or throat.
      • Virus requires ACE2 receptors to enter a cell.
        • ACE2 receptors help regulate blood pressure.
      • Many ACE2 receptors in lining of the nose.
    • Once inside the cell, virus replicates and invades new cells.
      • Infected person sheds the virus to others.
      • Symptoms may or may not develop (fever, dry cough, etc.)
  • Issue 1: Cytokine storm: morbidity and mortality of this disease may be driven by the out of proportion inflammatory response to the virus.
    • Overreaction of the immune system.
    • Cytokines normally help guide a healthy immune response.
    • In a cytokine storm, levels of certain cytokines are too high.
    • Immune cells start to attack healthy tissues.
    • Blood vessels leak, blood pressure drops, clots form.
    • Catastrophic organ failure can ensue.
    • Challenge is to figure out to what degree the cytokine level needs to be managed.
  • Issue 2: lung failure: lungs are the primary battle zone.
    • Unless stopped by immune system, virus marches down windpipe.
      • Reaches the lungs.
      • Reaches air sacs (alveoli), rich in ACE2 receptors.
    • Excessive immune system response damages lungs.
      • Fluids created by immune system disrupt oxygen transfer through alveoli.
      • Pathology of pneumonia.
      • Some recover, some worsen.
    • Some develop acute respiratory distress syndrome (ARDS).
      • Driven by hypoxia, hypoxemia.
        • Oxygen levels in the blood plummet.
        • Through V/Q mismatch, shunting, and diffusion abnormalities (See MedCram Update 58).
  • Issue 3: blood clots may also be a major factor in disease severity and morbidity.
    • Not just the lungs are damaged, but also heart and blood vessels.
    • Heart damage is relatively common (differing degrees in different studies).
    • Blood clots are similarly common.
      • Clots can break apart and land in the lungs, blocking vital arteries.
      • Clots can lodge in the brain, causing stroke.
    • Infection may also lead to blood vessel constriction.
      • Reduction in blood flow can lead to swollen, painful digits and tissue death.
      • May explain why some patients with low blood-oxygen levels are not gasping for air.
      • Oxygen uptake may be impeded due to constricted blood vessels, rather than clogged alveoli.
      • Could help explain why patients with pre-existing damage to blood vessels are at higher risk (diabetes, high blood pressure)
      • Most risk factors seem to be vascular: diabetes, obesity, age, hypertension.
      • Mechanism unclear – see also Chinese article on virus affecting vascular biology.
  • Issue 4: renal failure another common cause of morbity.
    • Many patients with kidney failure or damage.
    • Kidney injury = 5x higher likelihood of morbidity.
    • Kidneys have many ACE2 receptors as well, so may be a direct target of the virus.
    • Kidney damage may also be due to use of ventilators or drugs (remdesvir).
    • Or, may be part of whole-body events like plummeting blood pressure.
    • Diabetes or other pre-existing conditions can boost the risk of kidney injury.
  • Issue 5: brain may be struggling as well.
    • Occurrence of strokes, seizures, mental confusion, brain inflammation.
      • Sympathetic storm: brain’s version of a cytokine storm.
    • Unclear under what circumstances the virus penetrates the brain and interacts with ACE2 receptors there.
    • Causal pathway not clear.
  • Other affected areas:
    • Liver:
      • Up to 50% of patients have enzyme levels that signal a struggling liver.
      • Perhaps due to excessive immune system reaction or drugs given.
    • Intestines:
      • Lower gastrointestinal tract is rich in ACE2 receptors.
      • Some 20% or more of patients have diarrhea.
    • Eyes:
      • Conjunctivitis (inflammation of the membrane that lines the front of the eye and inner eyelid) is common in the sickest patients.
    • Nose:
      • Loss of sense of smell.
      • Virus may move up the nose’s nerve endings and damage cells.

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