Text: André Julião, from Agência FAPESP
Every day we inhale thousands of potentially pathogenic fungal spores, but our immune system simply eliminates them. In people who have compromised immunity – such as transplant recipients, patients undergoing cancer treatment or hospitalized in Intensive Care Units (ICUs) –, however, this interaction between pathogen and host can be quite different.
An example is the cases of fungal infections that emerged during the COVID-19 pandemic and potentiated the action of SARS-CoV-2 on the planet. Among patients affected with the severe form of COVID-19 and simultaneously infected by the fungus aspergillus fumigatusmortality reached 80%.
An international group of researchers carried out an overview of the burden of these co-infections (coronavirus and fungi) in the world during the health crisis. The work was published in Nature Microbiology and brings alerts for this and future pandemics.
“The central issue with fungi is that they are an extremely neglected public health problem, with few treatment options. Currently, there are more cases of deaths caused by fungal diseases than by malaria and tuberculosis combined, for example. It is not surprising, therefore, that fungal diseases have taken advantage of so many people hospitalized for COVID-19,” he says. Gustavo Henrique Goldmanprofessor at the Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo (FCFRP-USP) and one of the coordinators of the study, which had support from FAPESP.
In addition to aspergillosis, a disease caused by fungi of the genus aspergillus, two other groups cause concurrent infections with COVID-19. You mucorales are responsible for mucormycosis, which occurs mainly in India and Pakistan. The yeasts of the genus Candidain turn, cause candidiasis and are present in practically the entire planet.
“Aspergillosis associated with COVID-19 [condição denominada CAPA, na sigla em inglês] affects an average of 10% of patients with acute respiratory failure admitted to the ICU. Carriers of this co-infection are twice as likely to have a fatal outcome than individuals infected with SARS-CoV-2 alone”, tells Agência FAPESP Martin Hönigl, a professor at the University of California San Diego, in La Jolla, in the United States, and University of Graz, Austria, first author of the study.
losses and gains
According to the article, aspergillosis can be limited to the upper airways for many days and can be contained with antifungals. Once it invades the blood vessels of the lung, however, mortality is greater than 80%, even if systemic antifungal therapy is administered.
Occurring almost exclusively in ICU patients, candidiasis is no more frequent in COVID-19 patients than in hospitalized patients for other reasons. However, the fungi of a new emerging species, the Candida auris, worry about being able to colonize the skin. They also seem to be the only ones transmitted from one person to another. This species is resistant to all known antifungals and, because it is present in different environments, it can easily reach patients with tubes, respirators and other invasive life support equipment present in hospitals (read more at: agencia.fapesp.br/35923/).
Mucormycosis associated with COVID-19 (CAM) is a serious problem particularly in India, where the number of cases has doubled compared to the period before the pandemic. Reports of this mycosis gained international attention in 2021, when more than 47,500 cases were reported in that country between May and August alone. At the time, considered an epidemic by the Indian government, mucormycosis was erroneously called “black fungus”, due to the appearance of necrotic human tissue resulting from the disease. The black fungi, in fact, belong to another group, relatively distant from the mucorales, and do not cause disease in humans.
In patients with COVID-19, mucormycosis often occurs in the eye and nose region, and can reach the brain. In these cases, the association of the two diseases has a mortality of 14%. Because it causes necrosis, in many cases the infection requires surgeries that disfigure patients. When they survive, they can lose portions of their face, facing various problems for the rest of their lives. When the fungal infection affects the lung or spreads through the body, mortality reaches 80%.
“The prevalence of this mycosis in India was 0.27% in hospitalized patients with COVID-19, although it can often occur in out-of-hospital patients, such as those treated at home with very high doses of systemic corticosteroids that are readily available to the general population. from that country”, says Hönigl.
The use of this and other classes of drugs that decrease immune activity is one of the causes of the increase in fungal infections worldwide. However, the strategy proved successful during the pandemic, with the benefits outweighing the risks. The researchers warn, however, of the importance of avoiding the abusive administration of immunosuppressive drugs.
Alternatively, during the pandemic, some centers with a high risk of aspergillosis have successfully implemented antifungal prophylaxis, with the administration of drugs even before infection with these agents. But as fungi are often resistant to most available drugs and there are not enough clinical studies to evaluate this strategy, it is currently not recommended.
“Immunosuppressants are a great advance in medicine, allowing many people to stop dying from cancer, from autoimmune diseases and even from receiving organs from other people”, explains Goldman.
“As a side effect, its use has greatly increased the incidence of fungal infections. With the exception of some thermotolerant fungi such as A. fumigatusfungi do not normally support mammalian body temperature and are easily countered by our innate immunity, but with reduced immune activity to deal with highly inflammatory diseases such as COVID-19, it opens up a flank for them to attack.” it says.
Global warming also paves the way for many fungi to adapt to higher temperatures, making humans more vulnerable. Therefore, experts agree that the development of new antifungal drugs is urgent. There are currently only four classes of these drugs, compared to dozens of different classes of just antibacterials, for example.
Another problem is the difficulty of diagnosis, which can be very expensive by the standards of low- and middle-income countries or cannot be done at the speed necessary to identify the ideal treatment.
To certify with 100% certainty the presence of aspergillosis, for example, a bronchoscopy exam is necessary – something considered very risky during the COVID-19 pandemic. That’s because the amount of human fluid expelled during the procedure is more than enough to transmit SARS-CoV-2 to medical staff, so testing was avoided. This fact suggests that statistics on this infection are underestimated.
“Fortunately, there is good news for drug development in this area, with several new classes of antifungals in phase 2 and 3 clinical trials,” says Hönigl.
Researchers fear, however, that these new drugs will not reach everyone who needs them and that cutting-edge treatments will remain restricted to rich countries, continuing the existing inequality in the availability of these drugs.
“In this scenario of global warming, few drugs available and diseases that debilitate and cause epidemics and pandemics, new outbreaks of fungal infections will happen again. We need more tools to control them and more researchers to study the different fungi and their mechanisms of action”, concludes Goldman.
The article COVID-19-associated fungal infections is available at: www.nature.com/articles/s41564-022-01172-2.
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