Thread by @RafaelPolidoro2

Very excited to share our overview on the pathological development of severe COVID-19 under a conservative systemic inflammation derived from COVID-19 associated lung injury (CALI) two hit model consistent with current data 👇🏾

frontiersin.org/articles/10.33…

On April 4th I started a journey with @Greguialmeida and @ROBERTASANTIS to understand why the circulating levels of IL-6, TNF and IL1 were low in critical patients from Wuhan and still people were insisting in Cytokine Storm as the main cause +

So I read some literature I remembered from pulmonary malaria consequences and convinced @NathanWSchmidt1 that we had some ground to cover using systemic inflammatory response syndrome due to acute lung injury (SIRS-ALI). ALI later came to be covered by SARS definition +

Basically the body responds with two branches when infected by viruses, nicely covered by my hero @VirusesImmunity, the antiviral/antifungal and the inflammatory one. SARS-CoV2 in some patients can block antiviral response and the body respond with CALI +

which consists in increasing paracrine levels of IL-6, TNF, IL8, IL-1 orchestrated by alveolar macrophages and epithelial cells, as amazingly described by another hero @MiriamMerad. Upregulating cell adhesion molecules and permeabilizing the lung endothelium +

at the same time, neutrophils invade the lung (due to IL-8, CAMs and VEGF) and cause harm to the tissue. When proinflammatory cytokines reach liver and bone marrow, it triggers the acute phase response which is proinflammatory and pro-coagulatory +

the bone marrow release immature granulocytes that will return to the lung not differentiated, producing weird cytokines (@VirusesImmunity lab confirmed yesterday) and transcriptional signatures as shown by @IdoAmitLab and others. This second hit is facilitated by comorbidities +

We also believe that alteration of ACE2 levels will augment angiotensin 2 and bradikinin (RAS-KKS systems) levels in the body, leading to increased local inflammation and microthrombosis, a bad addition to the coagulatory response by liver and bone marrow stimulation +

the second hit in the lung results in increased ARDS, diffused alveolar damage, that can result in cytokine storm syndrome, respiratory failure, sustained stimulation of BM and liver and RAS-KKS will lead to coagulopathy and multi-organ failure +

finally, we assumed at the time (April) that after the second hit, viral particles are no longer necessary to maintain the lung-systemic inflammatory loop, making antivirals less effective against mortality. Finally +

we believe that targeting the systemic loop might be a key to reduce need for ICU, mechanical ventilation and mortality. We proposed bisphosphonates, but fingolimod and other immunosupressors can help... dexamethasone... we were happy to see the model being confirmed as we wrote

of note- studies before 2012 showed that systemic inflammatory response syndrome to acute lung injury increases in age and it's predominant in males. Being really low in young people... of course that's not the mechanism, but a readout of systemic sensibility to injury

@threadreaderapp unroll this please