SARS-CoV-2 infection. A pathobiological view
Abstract
The pandemic is now drawing to a close. In a month or so we will say that it has been tamed. It is already time to discuss the role of the protagonists on a medical level (environmental factors, infectious agent and body defenses) and to make some general considerations.
Coronavirus? Most people perceive it as the best known, feared and hated virus in the world nowadays. Yet the opposite is true. Newborn and not yet well set, coronavirus is currently a mild virus, with the only wish to replicate unhampered in the human upper respiratory tract (as it happens in more than 99 percent of people: healthy carriers, who spread it around the world obliviously). It needs the contribution of the human response to be harmful (and it can be). In fact, the trouble starts in the rare cases (less than one in a thousand?) in which the virus migrates deeply from the upper to the lower respiratory tract, finding a fertile ground. This is exactly when our organism perceives its presence and activates an immune response, perhaps not balanced in favor of the opsonizing immunoglobulins (IgG, IgM) which, unlike IgA, are not useful to expel the virus but try to eliminate it by recruiting the numerous lung macrophages to phagocytosis. In individuals who harbor abundant antigenic material (an important viral population) in the lung, increasing quantities of opsonizing antibodies (occurring 7-14 days after infection, the latency of the primary immune response) induce a serious inflammatory phenomenon indicative of an Arthus-type hypersensitivity. The massive formation of immune complexes together with complement activation triggers the release of pro- inflammatory mediators and simultaneously induces the numerous alveolar macrophages at phagocytosis, causing a huge production of reactive species and a spreading of lysosomal enzymes which overwhelm the valid anti-oxidant and anti-protease defenses of the tissue. A dramatic acute and extensive inflammatory process is therefore generated, which obviously compromises gas exchanges and precipitates the oxygen saturation of the blood, similarly to what happens with shock 1. The danger can lead the doctor to a generous oxygen therapy which, if it is neither well-timed nor well-balanced, can be further toxic (oxygen toxicity) in a tissue already injured by the inflammatory process.
This general pathogenic framework allows validation and / or implementation of the already applied therapeutic interventions, often successful (indeed, recovered cases far exceed deaths), and to identify their most convenient temporal interval along the short and dramatic course of the disease. First of all, both the immune and the antioxidant status of the host before the infection is certainly effective (doctors might perhaps smile but, although they are not considered as drugs, diets rich in healthy colors, from fruits and vegetables, and the administration of complex nutraceuticals may help to strengthen humans against most enemies including coronavirus). Of course, there is ongoing effort to contrast the infection by reducing the infectious load, slowing down its spread in the lung in order to reduce the amount of antigen in the tissue once the immune response is activated. At the onset of the disease, the therapeutic intervention could benefit from a timely, rational use of the following modulators or suppressors of the immune response, single administered or in logical combination:
- controllers of the opsonizing capacity of the anti-coronavirus serum IgG and IgM antibodies (for example, by the administration of high quantities of not specific immunoglobulins G to saturate macrophage receptors);
- lysosomotropic drugs;
- modulators of phagocytosis (for example chloroquine, colchicine);
- anti-inflammatory drugs (steroidal and non-steroidal).
Even at this time, the theory says that the administration of high-dose antioxidant preparations (polyphenols and resveratrol, turmeric, vitamin E) should be able to improve the prognosis, helping to limit the tissue damage caused by the reactive species.
Many other features of the disease deserve a comment from the point of view of the pathologist. The story of patient number one reported by the press deserves a comment on how such a serious disease may suddenly have appeared in a relatively young subject (only 38 years old) who immediately before enjoyed excellent health and active life. The days before hospitalization, he was in China (where he may have had an initial infection); he came back and had an intense social life (he entertained himself for a long time with many friends; were they potential carriers capable of spreading the virus?); then, he played football with friends by making a lot of physical effort (he came into close contact with more people while breathing deeply, probably with his mouth open, in an extremely polluted and cold air). How can we not think of multiple close contagions with additive effects on the infectious load, and even more on the viral share that reached the alveolar level? Did the polypnea of the player favor the arrival of the virus to lungs while primary immunization was taking its course? Walter & Israel provide the classical but accurate description of antibacterial and antiviral traps that effectively (but not completely) protect the respiratory tract and the lung from aero-diffused infections 2. Interestingly, also by analogy with the phenomenon of Arthus, the fact that the patient experienced some prodromal disorders, so that he went to the hospital a few days before the definitive hospitalization, suggests that the antibody response was mounting but had not yet reached the critical level. Of note, the history of the epidemic on the Roosevelt aircraft carrier, which led to the resignation of the commander, shows that multiple cross infections in overcrowded conditions can increase the infectious viral load to the point of causing the disease even in a very young population in an excellent state of health (all able and enlisted soldiers).
The reason why the map of the infection and the severity of the disease exactly overlap the distribution of air pollution by fine particles needs to be further discussed. Many factors can overload the lung with viruses and promote infection 3. Among these, certainly the extent of the infectious charge, but what matters most is the extent of the charge that reaches the lung. Walter & Israel 2 explained that the purification capacity of the respiratory tract is maximally limited (in phylogeny, the function was optimized to deal with dust of a much lower intensity than in the current world), and that our defenses do not distinguish between potentially dangerous biological materials and inert particles, which also exert harmful irritant effects on the muco-ciliary function. It is therefore clear that mixing with high quantities of inert powders can increase the chance of viral particles to evade removal and continue down to the pulmonary alveoli.
Another important point, especially for geriatricians. Why do older people who get sick die more frequently? Theoretically, it cannot be excluded that the reduction in the efficiency of the decontamination mechanisms of the respiratory tract 3 and the small slowdown of the primary immune responses may favor an Arthus-like phenomenon. Certainly, however, the age-related weakening of the reserve capacity of all the functions (respiratory, circulation, renal) to counteract a severe and extensive inflammatory process cannot fail to play a fundamental role. This was masterfully illustrated by J.W. Rowe 4 taking as an example the burn shock mortality according to the age and the burned surface of patients: in case of a burn extended to 30% of the body surface, all patients aged between 5 and 34 years survive while virtually all patients aged 75 to 100 die. If this were indeed the case, why not take into account the patient’s age when adjusting the therapies, and not authorize the presence of a geriatric consultation in intensive care?
Another aspect worthy of consideration. Why is coronavirus infection less severe and dangerous in women? Statistics show that coronavirus mortality in men is four times higher than females), although the average age of women is higher than men. Of course, there can be many causes, and they can exert their effect on several levels, from exposure to the risk of contagion (older women are more likely to live a domestic life, and to a different sociality than male peers) to the ability to damage response (it is well known that for the same age, women are biologically younger, thanks to the greater efficiency of the main protective mechanisms: autophagy and apoptosis 5). However, the effect of anatomical and functional differences between the two sexes relevant to the infection may not be negligible: men inhale greater volumes of air (and therefore greater quantities of particulate pollution and viral particles), and their respiratory tract allows to penetrate more viral particles easily (the section of the respiratory tract is greater in men, while the muco-ciliary purification is a function of the circumference of the duct, and not of its area). Differences between similar genres (although understandably less conspicuous) were found in Taranto for the incidence of respiratory diseases from inert fine particles, which were precisely attributed to the lower exposure of women to environmental risk. The conclusion? It is certainly important that female tissues, better cared for and exposed to less oxidative stress, present with slower biological aging, and therefore better defend themselves from the damage produced by inflammatory diseases.
A final consideration? There is no doubt that the progressively more rigorous application of the scientists recommendations by policy makers has had clear positive effects on the parameters indicative of the immediate mortality of the population, in particular (but not only) of the elderly population. Sociologists and economists will have the task of evaluating the less short-term opportunity of these decisions in light of the indications that statisticians will provide about the effects on mortality (global, including that in the third world) caused by the upcoming global economic depression. The task of longer-sighted people is whether or not to thank a biological enemy who, with little harm, has forced us to adopt more sustainable behaviors that, maintained over time, would certainly save many more lives than those who have been cut short in these days.
References
- Bergamini E. Patologia generale dello shock. Piccin: Padova; 1986.
- Walter JB, Talbot J. Walter & Israel. General pathology, Harcourt Health Sciences. 1997.
- Rowe JW. Textbook of medicine. WB Saunders Company; 1988.
- Bergamini E. Mantenersi in forma per prevenire le malattie. Pisa: ETS 2018 (stampato per conto di Associazione Alberto Sordi & Rotary).
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© Società Italiana di Gerontologia e Geriatria (SIGG) , 2020
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