Hi BKP
Not sure if you've seen this but
this Lancet piece is a compelling read. Parenthetically it's nice to see the Journals step up and make recent publications on Covid 19 public domain.
Here's my take on this - And of course one has to confess up front that at the beginning of any scientific puzzle
what you know by definition is way less than what you don't. I think the central scientific puzzle and certainly one with the greatest clinical value is the mortality puzzle –
what characterizes the highly vulnerable to those fatal outcomes. Of course everyone has jumped on the age factor, but the question is what does that mean? You may disagree with my assessment of this admittedly incomplete picture, but of course a spirited and respectful scientific debate can never be a bad thing. And preliminary hypotheses of course are always valuable because they can be falsified and then you can move on to better ideas.
I might tentatively hypothesize that the increased mortality in older groups is another finding related to the work on "inflammaging". This concept has been around for decades (and shows decisive relevance in relationship to Alzheimer's disease in my professional opinion) but in a nutshell it attempts to articulate an age-related tilt in the immune system in which upregulated and even disinhibited innate immunity Is a partial but ultimately unsuccessful compensation for declining adaptive immunity. And I believe it puts the lie to simpleminded notions about inflammation as a unidimensional volume control. It's highly differential and multicomponent, and it looks like in the patients with poorer outcomes there may be a stronger and disinhibited innate immunity response, one that's not only unsuccessful in containing the virus but that may create sepsis and organ failure. The data set in the Lancet piece of course is not conclusive for that because the only cytokine that they indexed is IL-6 which of course is one of the most important ones but they're at least another six or seven that they could've looked at. Of course this exaggerated innate immune response may emerge from greater penetration of the virus into lung and cardiac tissue (which might index another currently completely unknown vulnerability factor possibly even genotypic), and cardiac tissue looks increasingly like it's a target along with vascular tissue, as the biomarkers in the graphic below including not just troponins but also D-dimer might indicate. Intriguingly, the failing patients do not activate lymphocyte production to nearly the same degree and unfortunately they did not index B cell versus T-cell but in any case both are more involved in adaptive immunity than innate immunity. In any case and this part of course is not surprising, the poorer outcomes had sepsis and organ failure in a much higher percentage. A really tempting hypothesis is that the patients with fatal outcomes failed to mount an effective antibody response as their immune systems ramped up to the pathogen, while those with better outcomes gradually achieved increasing and viable adaptive immune resistance. In other words, patients with poor outcomes may be stuck in mostly in innate immunity response with increased damage to bystander tissues, steadily escalating pro-inflammatory cytokines and eventual sepsis, but of course this is just a speculation at this point without adequate date.
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Here's the text from the article Discussion Section that's also quite informative in this regard:
"This retrospective cohort study identified several risk factors for death in adults in Wuhan who were hospitalised with COVID-19. In particular, older age, d-dimer levels greater than 1 μg/mL, and higher SOFA score on admission were associated with higher odds of in-hospital death. Additionally, elevated levels of blood IL-6, high-sensitivity cardiac troponin I, and lactate dehydrogenase and lymphopenia were more commonly seen in severe COVID-19 illness. Sustained viral detection in throat samples was observed in both survivors and non-survivors. Previously, older age has been reported as an important independent predictor of mortality in SARS and MERS.
The current study confirmed that increased age was associated with death in patients with COVID-19. Previous studies in macaques inoculated with SARS-CoV found that older macaques had stronger host innate responses to virus infection than younger adults, with an increase in differential expression of genes associated with inflammation, whereas expression of type I interferon beta was reduced.
The age-dependent defects in T-cell and B-cell function and the excess production of type 2 cytokines could lead to a deficiency in control of viral replication and more prolonged proinflammatory responses, potentially leading to poor outcome.
SOFA score is a good diagnostic marker for sepsis and septic shock, and reflects the state and degree of multi-organ dysfunction. Although bacterial infections are usually regarded as a leading cause of sepsis, viral infection can also cause sepsis syndrome. Previously, we determined that sepsis occurred in nearly 40% of adults with community-acquired pneumonia due to viral infection. In the current study, we found that more than half of patients developed sepsis. Additionally, we found that more than 70% of patients had white blood cell count below 10·0 × 109 per L or procalcitonin below 0·25 ng/mL, and no bacterial pathogens were detected in these patients on admission. Sepsis was a common complication, which might be directly caused by SARS-CoV-2 infection, but further research is needed to investigate the pathogenesis of sepsis in COVID-19 illness. Cardiac complications, including new or worsening heart failure, new or worsening arrhythmia, or myocardial infarction are common in patients with pneumonia. Cardiac arrest occurs in about 3% of inpatients with pneumonia. Risk factors of cardiac events after pneumonia include older age, pre-existing cardiovascular diseases, and greater severity of pneumonia at presentation. Coronary heart disease has also been found to be associated with acute cardiac events and poor outcomes in influenza and other respiratory viral infections.
In this study, increased high-sensitivity cardiac troponin I during hospitalisation was found in more than half of those who died. The first autopsy of a 53-year-old woman with chronic renal failure in Jinyintan Hospital showed acute myocardial infarction (data not published; personal communication with a pathologist from the Chinese Academy of Science). About 90% of inpatients with pneumonia had increased coagulation activity, marked by increased d-dimer concentrations. In this study, we found d-dimer greater than 1 μg/mL is associated with fatal outcome of COVID-19. High levels of d-dimer have a reported association with 28-day mortality in patients with infection or sepsis identified in the emergency department. Contributory mechanisms include systemic pro-inflammatory cytokine responses that are mediators of atherosclerosis directly contributing to plaque rupture through local inflammation, induction of procoagulant factors, and haemodynamic changes, which predispose to ischaemia and thrombosis.
In addition, angiotensin converting enzyme 2, the receptor for SARS-CoV-2, is expressed on myocytes and vascular endothelial cells
so there is at least theoretical potential possibility of direct cardiac involvement by the virus. Of note, interstitial mononuclear inflammatory infiltrates in heart tissue has been documented in fatal cases of COVID-19, although viral detection studies were not reported."
What do you think? Sorry for the long post!