An analysis based on data from 34 countries demonstrated that during the early period of the COVID-19 pandemic, the absolute mortality from all causes among men exceeded that among women. However, relative excess mortality indicators suggest that over time and with the introduction of universal vaccination, the gender gap has significantly narrowed.
A research group led by Katarzyna Doniec from Oxford University conducted the first comprehensive study of gender trends in excess mortality between February 2020 and July 2023. For this, scientists used data collected in 34 high-income countries. Baseline mortality levels were determined based on indicators recorded between 2013 and 2019, and excess mortality was assessed across 136 combinations of age groups and countries.
Overall, during the peak moments of the pandemic, especially before vaccination began, the absolute figures for excess mortality from all causes were higher in men in most countries. However, trends regarding relative mortality suggested that some of these gender differences were due to a higher baseline mortality among men. Before vaccination, in more than half of the studied combinations (60%), scientists recorded noticeably increased mortality among men.
The situation changed in the post-vaccination period: this phenomenon became less frequent, remaining significant in about half of the age group and country combinations (51%). By the start of the epidemic phase (after the global pandemic ended), this trend persisted in only 23% of combinations. Two exceptions were noted: countries with a late start to the pandemic, such as Germany and South Korea, where the unfavorable position of men worsened after vaccination and during the endemic phase for certain age groups (15–64 and 65–74 years in Germany); and countries with an initially low level of excess mortality in both sexes, including Iceland, Finland, Luxembourg, and New Zealand.
When analyzing relative excess mortality (the ratio of actual deaths to expected deaths), changes were observed in the position of men. In the pre-vaccination period, increased excess mortality among men was recorded in only 28% of combinations. In the post-vaccination stage, this figure halved to 14%. In some cases, this indicator was higher in women, for example, in Bulgaria and the USA among people aged 65–74 in the post-vaccination period. In the epidemic period, there were fewer signs of relative gender inequality.
The authors concluded that the unfavorable position of men was evident in the months of high mortality during the pre-vaccination stage. Nevertheless, various statistical methods showed a significant reduction in the gender gap. The Doniec team believes that using both absolute and relative metrics allows for the conclusion that COVID-19 had a negligible impact on long-term changes in gender differences in excess mortality.
Medicine has managed to overcome most infectious diseases through the introduction of vaccination, antibiotics, and sanitary standards. However, sepsis, known to doctors since Hippocrates' time, continues to be one of the leading causes of death worldwide; even in modern intensive care settings, mortality rates for severe forms of sepsis reach 30–50 percent. The history of combating this condition is marked by numerous failures, as many promising drugs failed in clinical trials, and intensive care protocols were revised or discontinued.
Ancient Greeks identified sepsis as a cause of death, using the term 'sepo' (σηπω), meaning 'to rot.' Ancient scholars noted that the condition often occurred after childbirth or injuries, but the true role of infection developing against this background was only established in the 19th century.
The Hungarian obstetrician Ignaz Semmelweis began systematically testing various hypotheses. A key assumption came to him in 1847 after the death of his friend, Professor Jakob Kolletsch, who died of sepsis following a minor finger cut during an autopsy. Semmelweis proposed the theory that doctors and students working in the anatomy theater were transferring 'cadaveric particles' to the maternity ward, causing illness in expectant mothers. He began testing deodorizing agents and eventually resorted to using chlorine lime, noticing a sharp decrease in mortality from 'childbed fever' when hands were treated with the solution.
Concurrently, the concept of antisepsis developed thanks to Joseph Lister. Inspired by Pasteur's work, he suggested treating wounds and instruments with carbolic acid. Lister used creosote, a precursor to carbolic acid, to disinfect wounds, achieving practical success during his lifetime. Despite the successes of Semmelweis and Lister, neither fully understood the true cause of the observed reduction in mortality.
Science was unable to approach sepsis treatment comprehensively for a long time. A breakthrough occurred with the development of microbiology, which allowed for the establishment of a link between sepsis and bacterial infection. The advent of antibiotics in the mid-20th century created the illusion of a complete solution, yet sepsis retained its danger. According to the journal Lancet, over 20 million people die from it annually.
The mechanism of sepsis involves a massive release of pro-inflammatory molecules, such as tumor necrosis factor (TNF-α) and interleukin-1 beta (IL-1β), upon the destruction of bacterial cells. This excess of cytokines triggers an inflammatory response involving the complement system and disruption of the blood clotting cascade, leading to thrombosis.
The inflammatory cascade progresses into a cytokine storm, stimulating the production of nitric oxide, which causes vasodilation and a drop in arterial blood pressure. This results in cardiovascular system failure and organ failure. In severe cases, septic shock develops. The immune system can enter a state of suppression, making the body vulnerable to secondary infections, while inflammation and thrombosis create a vicious cycle that worsens organ function.
Since abnormal blood coagulation is a key element of sepsis, activated protein C, marketed as Xigris, became one of the first candidates. It was approved in the US and Europe in 2001 based on the PROWESS study, which showed a reduction in 28-day mortality despite the risk of bleeding. However, the subsequent PROWESS-SHOCK study did not confirm this effect, and the drug was withdrawn from the market in 2011.
Other attempts to create drugs, including the introduction of endotoxin antibodies to neutralize lipopolysaccharide, also failed: early positive results could not be confirmed in subsequent studies.
The industry shifted focus to removing damaging substances from the blood, leading to the concept of extracorporeal clearance. The Japanese corporation Toray Industries developed Toraymyxin—the first filtration system for septic blood based on immobilized polymyxin B, which binds LPS. This system received approval in Japan in the 1990s and was used in Europe and Asia.
Despite widespread use, large international trials, such as EUPHRATES, did not show significant improvement in patient condition. Researchers hypothesized that hemoperfusion might only be effective in a specific group of patients—those with elevated LPS levels who had not yet reached the irreversible stage of damage. This led to the TIGRIS trial in 2018, which demonstrated the success of Toraymyxin in patients with moderate LPS concentrations, showing a reduction in mortality at 28 and 90 days.
These contradictory data highlighted that sepsis is a heterogeneous condition, not a single disease. Failures in early trials were likely related to the inclusion of overly diverse patient groups. Therefore, different types of sepsis require specific treatments, and biomarkers, such as endotoxin activity analysis, are becoming key to predicting the response to hemoperfusion.
Another approach was proposed by scientists from CytoSorbents Corporation. Instead of targeting LPS, they developed the CytoSorb cartridge, capable of capturing a wide range of medium-sized molecules (up to 60 kilodaltons), including cytokines and inflammatory mediators, regardless of their nature. Initial clinical cases with CytoSorb looked promising, demonstrating a reduction in cytokine levels.
Nevertheless, current guidelines, such as the Surviving Sepsis Campaign (launched in 2002 by the European Society of Intensive Care Medicine), have not included cytokine hemoperfusion in their recommendations due to insufficient evidence, and this method is not recommended in Germany. The limited effectiveness of the method may be related not only to heterogeneity but also to the fact that cytokines reflect an already initiated process, not its cause, as well as the non-selectivity of the procedure.
Currently, extracorporeal therapy is focused on two areas: personalized therapy that accounts for the patient's endotoxin load, and multimodal hemoperfusion, which simultaneously removes several types of harmful molecules. The concept of multimodal therapy has been implemented by the Russian company Efferon and the American company Baxter.
