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  • Only small studies, case reports, often not peer-reviewed.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.