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- Only small studies, case reports, often not peer-reviewed.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.
- Virus requires ACE2 receptors to enter a cell.
- 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.)
- Enters the body through nose or throat.
- 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).
- Driven by hypoxia, hypoxemia.
- Unless stopped by immune system, virus marches down windpipe.
- 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.
- Occurrence of strokes, seizures, mental confusion, brain inflammation.
- 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.
- Liver: