Issue 7, Dott. Francesco Chiappelli, Prof. emeritus UCLA Center for the Health Sciences
Dott. Francesco Chiappelli, Prof. Emer. UCLA Center for the Health Sciences. For comments, questions or the Italian version of these few thoughts, please contact: Chiappelli.research@gmail.com
CoViD-19 pandemic as of 19 June 2020:
Globally – Confirmed Cases: 8,731,700+; Fatalities: 461,430+; New cases (24 h): 27,180+ (0.311%)*
Italia – Confirmed Cases: 238,010+; Fatalities: 34,560+. New cases (24 h): 250+ (0.105%)*
US – Confirmed Cases: 2,290,830+; Fatalities: 121,300+. New cases (24 h): 27,180+ (1.186%)*
California – Confirmed Cases: 168,130+; Fatalities: 5,380+. New cases (24 h): 1,120+ (0.667%)*
Los Angeles County – Confirmed Cases: 78,240+; Fatalities: 3,020+. New cases (24 h): 17 (0.022%)*
Villa Scalabrini Confirmed Cases: 8 Residents, 12 Staff
(publichealth.lacounty.gov)
*: new cases as % of total cases – in a situation that is “flat,” where infection rates are controlled by public health measures, increased testing does not result in increased number of cases and the new cases as % of total cases metric falls, and will eventually approach 0.000..% when the infection spread is controlled. By contrast, in situations where infection is still rising, the metric of new cases as % of total cases rises as well, and can reach 1% and much higher, when the infection is out of control. For example:
Arizona: 6.95%; Brazil: 4.8%; Florida: 4.3%; India: 3.7% Oklahoma: 3.6%; Mexico: 3.4%; Texas: 2.8%; Philippines: 2.3%; Russia: 1.4% US: 1.2%; Portugal: 0.97%; California: 0.7%; UK: 0.5%; World: 0.3%; etc.
vs.
Germany: 0.28%; Belgium: 0.21%; NY State: 0.17%; Norway: 0.14%; Italy: 0.1%; Spain: 0.1%; LA County: 0.02%; Washington State: 0.004%; etc.
-.-.-.
Last December, the first cases of a new pulmonary disease were reported in Wuhan, China. In early January, less than seven months ago, the responsible etiologic agent, the second Corona virus of the SARS strain (SARS-Cov2) was identified and sequenced, and the pathology named the Corona Virus Disease of 2019 (CoViD-19). In the past seven months, CoViD-19 has become a fulminant and deadly pandemic, for which we have no vaccine and no proven treatment, and which we can control only by strict public health measures (i.e., masks and facial covering, and physical distancing; and, when needed, quarantine).
As of today, we know a few things about the virus and the pathology it causes. We know, for example, that the Spike protein (S) of the virus is what binds to ACE2 receptors on human cells, and we know that then enzymes on the cell membrane clip S, allowing the virus to fuse with the membrane and infect the cell. We know that S is covered with sugar moieties, making it a glycoprotein, against which our immune system has great difficulty in building efficient antibodies, which hamper our ability to develop vaccines. We also know that most of the specific antibodies in convalescent plasma is against the virus nucleocapsid protein, not S, rendering even the use of convalescent plasma somewhat unreliable, or at least of unpredictable effectiveness. To be clear, we hear report almost every day of this new vaccine here, that new vaccine there: but de facto, we soon learn that the new antibody species do not bind well to S, are not sustained in time, and therefore are most likely not the ideal candidate for a vaccine. In brief, it may be several months before we can produce and distribute world-wide an efficient long-lasting vaccine.
We also know a bit about the life cycle of the virus: how its RNA is translated into protein, reverse transcribed into DNA for insertion into the host genome, and how it is shed. Therefore, we are actively working at developing new and improved anti-virals. But the fact of the matter is that we have not yet identified the gold standard anti-viral agent specific for SARS-Cov2.
With close to nine million confirmed cases of infection world-wide over the past several months, we have gathered a substantial body of evidence with respect to the disease itself. We know the virus causes a widespread spectrum of pathologies, and several experts are beginning to call it a syndrome, a set of diverse pathologies all sharing one common underlying causative agent (cf., HIV causes the human immunodeficiency syndrome, AIDS).
Whether we speak of CoViD-19 or CoViS-19, the fact remains that, we know, infection with SARS-Cov2 can affect the brain and the central nervous system, the heart and the cardiovascular system, the lungs and pulmonary efficiency, the gastrointestinal tract, the liver and kidneys, as well as certain fundamental physio-biochemical processes, including blood coagulation. Many patients, indeed, die of widespread thrombi (i.e., blood clots) and micro-thrombi throughout the body, consequential to the immune response to SARS-Cov2.
Perhaps because of the very masked nature of the S protein, the anti-viral immune response (i.e., cytotoxic T cells) becomes impaired soon after infection – but impaired in a characteristic manner: the cells do not become non-responsive (i.e., anergic), or dead by necrosis or apoptosis (i.e., programmed cell death), rather they appear “exhausted.” T cells of CoViD-19 patients appear to have exhausted their cellular energy. Yet, the immune system “sees” this viral infection, and must respond. But it now responds, if you will, in an unregulated manner (because the regulatory T cells are incapacitated). Lots of factors, known as cytokines, are produced. Their role is – under controlled conditions – to stimulate and to repress each other as needed to bring about a balanced cellular immune response. When the immune response is not regulated (i.e., inactive regulatory T cells), this cytokine release seemly occurs as a never-ending tsunami of sorts, a storm of very potent factors that are very toxic. It is this cytokine storm that afflicts the patients with most severe CoViD-19 by damaging the lungs often beyond repair, by triggering the blood clotting responsible for multiple thrombi, and by causing the many other pathologies we see in these patients. Even the patients who recover from SARS-Cov2 infection show long-lasting signs and scarring from CoViD-19, from structural destruction of the lung functional architecture, to deficiency of the cardiac muscle, to – most likely, although the evidence is inconclusive at this point – serious and permanent neurological and cognitive dysfunctions. All these long-lasting sequelae of CoViD-19 can be traced back to the destructive effects of the cytokine storm.
Drs. Horby and Landray and their clinical research collaborators from Oxford University reasoned months ago that, since one main problem of CoViD-19 is the cytokine storm, perhaps blunting cytokine production could decrease CoViD-19 morbidity and mortality. Their reasoning was based largely on the extensive body of research on the immune-regulatory role of natural steroids, such as glucocorticoid (GC), that stemmed from the seminal work of Professors Allan Munck and Paul Guyre (Dartmouth Univ.) in the mid-1980’s. They had shown that dexamethasone (DEX), the synthetic form of GC, which is more stable than GC, could effectively regulate cellular immune responses by blocking the production of those cytokines that push the system forward and their receptors on human cells, while boosting the production of those cytokines that suppress the response. In other words, steroids such as GC and DEX could finely regulate cellular immunity: yes, steroids block inflammation, but more than that, they act very specifically to regulate the functional response of immune cells. In fact, research, including mine over several decades, demonstrated that steroids (GC and DEX, and others) are part of a fine immune physiological regulatory loop, now known as neuroendocrine-immune modulation.
The Oxford group ran a Randomized Evaluation of CoViD-19 Therapy (RECOVERY) trial to test whether DEX — which is a widely used in clinical medicine word-wide, is cheap, easily available and (relatively) safe — could be beneficial to CoViD-19 patients. The results are promising, and suggest that DEX can indeed reduce CoViD-19 severity and mortality. Specifically, the study of over 2,000 patients who received low-dose DEX, compared to about 4,000 patients who received standard care, showed that DEX treatment reduced the death rate of CoViD-19 patients on ventilators by about one-third, and reduced the risk of death for patients needing oxygen by close to one-fifth. That means that, in the US alone, DEX treatment could have saved 25,000+ lives over the past three months alone: a staggering fact!
The drug DEX seems, the researchers stated, “to reduce the damage from a hyperactive immune reaction called cytokine storm.”
Quod erat demonstrandum!
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