Inflammation – CHRIS DAEL

COVID-19 is a Bad, Weird Disease

In a study released this week in the New England Journal of Medicine (NEJM) researchers in Europe examined 7 lungs from patients who died of COVID-19, 7 lungs of patients with acute respiratory distress syndrome from influenza A (H1N1) and 10 age-matched non-infected control lungs. They examined the lungs using a variety of tools including immunohistochemical analysis, computed tomographic (CT) imaging, and electron microscopy, and measurements of genetic expression among other modalities.

Patients with COVID-19 and influenza can develop a condition known as acute respiratory distress syndrome (ARDS). ARDS is a very severe pulmonary condition that generally leads to worsening blood oxygenation (hypoxemia) that doesn’t respond well to oxygen and often results in patients requiring mechanical ventilation to survive. On x-ray, patients with ARDS can have a ground glass appearance and lung fields can show increasing consolidation to the point of near complete opacification of the x-ray. Histologically, the alveoli (air sacks in the lungs) are diffusely damaged and edematous (filled with protein containing fluid) often with hemorrhage (bleeding) and fibrin deposition (a marker for inflammation and coagulation).

Severe ARDS with ground glass appearance (note: this ARDS is not from COVID-19)/James Heilman, MD / CC BY-SA (https://creativecommons.org/licenses/by-sa/4.0)

The researchers set out to compare the lungs of patients with ARDS from influenza A to those with ARDS from COVID-19. There were some similarities. In general patients with ARDS from COVID-19 and influenza A had diffuse alveolar damage and edema but the edema in the influenza patients was more massive and correlated with the lungs of deceased patients with influenza weighing more than those who died of COVID-19. Both sets of patients had immune cells though there was some difference in the types of T-cells. With respect to measures of inflammation-related gene expression, COVID-19 patients had a total of 79 inflammation-related genes expressed but only 2 genes were uniquely differentially regulated in patients with influenza. The two groups shared an expression pattern for 7 genes.

Significant differences started to arise when the researchers looked at thrombosis and blood vessel pathology. The alveolar capillaries (very small blood vessels where gas exchange of oxygen and carbon dioxide occurs) were 9 times more likely to have microthrombi (small blood clots) and occluded small blood vessels in COVID-19. Additionally, the endothelium (cells that make up the walls of the blood vessels) and endothelial cell membranes of the COVID-19 patients showed significantly more damage from virus present within the cells than similar cells in influenza infected lungs. Finally and most surprisingly, from all of this vascular damage done by SARS-CoV-2 to the lungs of patients with COVID-19, there was significant angiogenesis (development of new blood vessels) in COVID-19 lungs. The combination of increased blood vessel cell damage and microclotting in patients with COVID-19 may be responsible for the lungs working overtime to create new blood vessels to compensate.

This study is small and because of that there could be other reasons for the differences seen between the two groups and the authors concede this. But these findings fit with the experiences of clinicians and researchers who report much higher frequency of clotting abnormalities and dramatic levels of inflammatory response in COVID-19 patients. It’s unknown if the angiogenesis has any effect on survivability either way–further studies may help to elucidate this question.

Thoughts on COVID-19

The Washington Post is reporting that cell phone data tracked by the University of Maryland’s Transportation Institute showed that tens of thousands of people flocked to Georgia after businesses were permitted to open. Over 60,000 more trips into the state were recorded than the week before the opening on April 24. Most of these travelers came from Alabama, South Carolina, Tennessee and Florida. I’ll be keeping an eye on new case data for these five states over the next 2-4 weeks to see if numbers there start to move and will post updates.
This week my home province of New Brunswick, Canada had its first new cases of COVID-19 in two weeks. At least one of the cases is travel related. The positive individuals are in the Saint John and Fredericton areas and come just as the province has begun a phased reopening. By all estimation the province’s public health department has done a superb job managing the pandemic within its borders. The new cases serve as a reminder that the virus isn’t gone and that even in communities who have done almost everything right, it will invariably find its way back in via the path of least resistance.
Though known for a while, there are increasing reports that patients with COVID-19 are suffering from abnormal blood clotting. A study published in the Annals of Internal Medicine found that 58% of 12 post-mortem examinations found deep vein thromboses in patients with COVID-19. There is a growing use of blood thinners to treat the sickest patients in centers around the country. It’s difficult to know at this point whether these clots are part of a well known medical phenomenon related to severe inflammatory states and shock called disseminated intravascular coagulation (DIC). In DIC, extremely ill patients both bleed too much and clot too much at the same time–it’s a clotting system gone haywire and a very difficult problem to manage in critically ill patients. Some of my worst nights during training were spent at a kid’s bedside trying to get them to stop bleeding and clotting, a tragically difficult task. It could also be that there’s something about COVID-19 that specifically causes abnormal clots to develop. Large scale studies are needed to determine the cause and to sort out appropriate treatment but blood thinners seem to be working their way into current standards of care.

Coronary Artery Aneurism in Kawasaki Disease/Wikimedia

http://pediatricimaging.wikispaces.com/file/view/price_lad_angio.jpg/235212558/price_lad_angio.jpg

Doctors in New York have issued an advisory warning of a possible inflammatory complication of COVID-19 in children. Sixty-four kids in New York have developed a condition described as an inflammatory syndrome affecting multiple systems including the heart and blood vessels. The syndrome appears to be similar to another more well-known pediatric condition called Kawasaki Disease. Children with Kawasaki Disease have prolonged fever, rash, enlarged lymph nodes, red lips and tongue, joint pains, swollen hands and feet, and conjunctivitis without discharge or pus. Kids with Kawasaki Disease are at risk for inflammatory changes to the coronary arteries that can cause the heart vessels to develop life-threatening aneurisms. While the new COVID-19 related syndrome affects the heart it’s unclear if it causes the same aneurisms as Kawasaki Disease or instead causes general inflammation of the organ. Some children with the COVID-19 related inflammatory syndrome have develop cardiovascular collapse similar in appearance to Toxic Shock Syndrome, a finding not typically seen in Kawasaki Disease.