Why are many patients cured and especially the elderly not?

file 20200327 146705 1fgbj4l
file 20200327 146705 1fgbj4l.jpg?ixlib=rb 1.1
David Pereiras / Shutterstock
Ignacio J. Molina Pineda de las Infantas, University of Granada

It is one of the doubts that most assails us these days. What circumstances cause some people to show mild symptoms of COVID-19, others to suffer severe illness but recover, and others to lose their lives? Is there any explanation? The cause is not unique, and to understand it it is necessary to analyze the complexity of the immune response to the virus.

More entry doors with diabetes and heart disease

Viruses are very dependent microorganisms that, in order to divide, need to invade a cell. To enter, they attach to a receptor on the cell surface that they use as a Trojan horse. In the case of SARS-CoV-2, that receptor is the Angiotensin Convertase Enzyme 2 (ACE2). This molecule is present, among other organs, in the lung cells, which explains the respiratory symptoms of COVID-19.

If the patient suffers from cardiovascular problems or diabetes, the expression of this molecule increases substantially. And that implies that the entry of the virus into the cell is much easier. Hence, these patients are part of the most vulnerable population at this time.

When the virus breaks out, the immune system does not sit idly by. Instead, it responds through the mechanisms of innate or nonspecific immunity, which have multiple cellular and humoral components capable of reacting in a matter of minutes or hours.

If the infection persists – for example, because the viral load is high – then specific immunity kicks in, with CD8+ T lymphocytes at the helm. Although in most cases this second answer is enough to eliminate the infection, in certain patients, especially the elderly, lymphocytes are defeated.

More immunological memory but less repertoire

But why? It must be taken into account that the immune system evolves with age. Young people have fewer memory cells (a consequence of having had fewer infections) but, on the other hand, the repertoire of cells with the capacity to recognize different and/or unknown antigens is greater.

Just the opposite happens in the elderly: memory cells are abundant – useless in the case of SARS-CoV-2, since it is a new virus – and their repertoire is much smaller, which implies a lower response capacity.

Furthermore, aging also entails immunosenescence. This means that the immune system of the elderly acquires a state of latent activation but, paradoxically, the amplitude of the response to each antigen is substantially smaller. In other words, your defenses are alert all the time, but respond with little force. This explains, among other things, the lower capacity to respond to the coronavirus. flu in the elderly. Immunosenescence also causes a decrease in antitumor surveillance and an increase in autoimmune processes.

Who lives and who dies

By comparing the immunological parameters present in patients who survive the infection and those who end up dying, we can deduce some important differences. A recent study performed on a patient who progressed positively and who was analyzed daily, showed a very vigorous immune response to the virus. In his case, 7 days after the onset of symptoms, three types of cells began to be detected in the blood to combat the virus: follicular helper T cells, specialized in cooperating with B lymphocytes to produce antibodies; antibody-producing cells; and cytotoxic T cells.

These last two populations reached a peak on days 8 and 9 after the onset of symptoms, just before hospital discharge on day 10. Three weeks after infection, they had already returned to baseline levels. And at no time were altered levels of proinflammatory cytokines detected. Similar data are found in other series of patients.

Just the opposite happens in patients with a poor prognosis. These usually have a significant decrease in the total number of lymphocytes (lymphopenia, in medical terms), which occurs mainly at the expense of CD8+ T cells, responsible for the specific cellular response to the virus, which are the main ones affected by the loss.

Added to this is that, in the most severe patients, the secretion of proinflammatory cytokines, especially Interleukin-6 (IL-6), is very high. Hyperproduction of IL-6 has an unwanted side effect, since the proinflammatory cytokine cascade causes tissue damage, triggering what is known as a cytokine storm. This phenomenon causes very serious pathologies, and it is suspected that it was the mechanism by which more than fifty million people died in 1917-18 during the sadly remembered pandemic of the spanish flu, which caused lung necrosis (cell death).

The tactic of blocking Interleukin-6

To address the problem, among the treatment strategies there are at least two clinical trials in Madrid hospitals (Ramón y Cajal and Gregorio Marañón) that explore the administration of monoclonal antibodies that directly block IL-6 (Tocilizumab) or the IL-6 receptor. IL-6 (Sarilumab), to verify its positive effect on the recovery of these patients.

What is clear is that to achieve the elimination of the virus it is necessary to mount a powerful and well-coordinated immune response, typical of young individuals without immunosuppression problems. The alterations that immunosenescence entails cause not only a less vigorous response, but also an incorrectly regulated one.The Conversation

Ignacio J. Molina Pineda de las Infantas, Professor of Immunology, Biomedical Research Center, University of Granada

This article was originally published in The Conversation. read the original.