The data was there, from the beginning, but something went unnoticed among so many others. All the studies that included series of patients with COVID-19 told us that the number of men and women suffering from the disease was not equal. Thus, for every 6 men with the disease there were 4 women. Most strikingly, this proportion leaned even more toward men when patients with a severe clinical presentation were grouped, such that 70 percent of the non-surviving patients were men, while only 30 percent of the deceased were women. It therefore appears that women are able to mount a much more effective immune response against SARS-CoV-2 than men.
Uneven response to infectious diseases
This uneven response to infectious diseases based on sex is not unique to COVID-19. We also see it in leishmaniasis, tuberculosis, leptospirosis, meningococcal meningitis or hepatitis A, to indicate some diseases caused by infectious agents. In addition, women, in general, mount a stronger immune response than men after a vaccination process. Without forgetting that there are multiple examples of the same in animals, from birds to invertebrates.
The reasons for these differences are unclear. In principle, everything points to the fact that we must consider the multiple points of contact between the immune system and sex hormones, as well as the genetic – and gene regulation – differences between men and women.
In the case of COVID-19, a very recent study conducted at Yale University examined the different immune responses between men and women, trying to find out what their molecular basis is. For this, 98 patients with a confirmed diagnosis were recruited. Detailed analysis of these patients revealed very important data. Both men and women had an equivalent viral load, from which it is deduced that the virus infects us and reproduces equally in both sexes.
Regarding the level of antibodies produced, it was also indistinguishable in men and women. Therefore, the researchers concluded, the differences must be found in the other two major components of the immune system. That is, innate or nonspecific immunity and cellular specific immunity.
The components of nonspecific immunity respond very quickly, but do the same against all pathogens. The specific response, on the other hand, takes a few days to start up, and is carried out by elements that exclusively recognize that pathogen, and only that one.
Well, following this track it was discovered that men had higher levels than women of certain soluble components (cytokines and chemokines) involved in the inflammatory response. In addition, in men the activation of T lymphocytes, the main cells of the specific immune response, is reduced. And in men, but not in women, the progressive decrease in T-cell activation is strikingly correlated with the worsening of the disease.
At advanced ages, the situation worsens for men, because the decrease in the activation of cytotoxic cells is greater. Finally, as body mass indexes – an indicator of obesity – increase, the disease acquires a worse prognosis in men, but not in women. In summary, being a man, with progressive advanced age and obesity, implies a worse prognosis if SARS-CoV-2 attacks you.
On the contrary, in the case of women, severity is correlated with the increase in pro-inflammatory cytokines that regulate the nonspecific response, specifically those called TNFSF10 and IL15.
Treat COVID-19 in a personalized way
The global analysis of these complex data reveals that the progression of the disease in men is the consequence of a progressive decrease in the specific cellular immune response. On the contrary, in the case of women, the severity of COVID-19 is associated with alterations in the other immune arm, nonspecific immunity. In addition, everything indicates that the poor prognosis in women is not related to a decreased response as it occurs in men. On the contrary, it is linked to an excessive production of pro-inflammatory cytokines of innate immunity. In other words, for the immune system to be able to effectively eliminate the virus, a powerful but strictly coordinated response is needed between all our defense components. And this coordination is broken differently in men and women.
These results could help improve the treatment of COVID-19 patients. Men would need an enhancement of their specific cellular responses, while women would benefit from the opposite, that is, the blocking of innate pro-inflammatory cytokines.
The findings show, once again, that we must treat sick people and not diseases. Walk towards personalized medicine. In the case of COVID-19, it seems that sex could be a key factor in the therapeutic protocol that should, therefore, have different orientations in each case.
Ignacio J. Molina Pineda de las Infantas, Professor of Immunology, Center for Biomedical Research, University of Granada
This article was originally published on The Conversation. Read the original.
