COVID-19 Linked To ‘Alarming Rise’ Of Rare And Highly Lethal Fungal Infection

The COVID-19 pandemic has caused an alarming rise of an aggressive and highly fatal secondary fungal infection among those with active or recovered COVID-19.

Research suggests that the SARS-CoV-2 virus, the overuse of immunosuppressive COVID-19 treatments such as corticosteroids and antibiotics, and the global pandemic response made people more susceptible to coinfections such as COVID-19-associated mucormycosis (CAM).

Mucormycosis, also known as black fungus, is an opportunistic fungal infection that typically affects the sinuses, lungs, and brain. It is caused by a group of molds commonly found in the environment. Before COVID-19, these fungi rarely caused infection because of low virulence, but the second wave of COVID-19 brought tens of thousands of reported cases. Even the Omicron variant, which was generally attributed to mild COVID-19, has been linked to lethal mucormycosis infections in the United States and Asia.

According to the Centers for Disease Control and Prevention, there are several types of mucormycosis:

• Rhinocerebral mucormycosis is an infection of the sinuses that can spread to the brain and is most commonly diagnosed in people with diabetes or in those who have had a kidney transplant.
• Pulmonary mucormycosis is the most common type of mucormycosis, mainly affecting people with cancer or those who have had organ or stem cell transplants.
• Gastrointestinal mucormycosis affects the digestive tract and is more common among children and young adults.
• Cutaneous mucormycosis is the most common form of infection among those without weakened immune systems. It occurs when the fungi enter through a cut, scrape, or surgical incision in the skin.
• Disseminated mucormycosis is where the infection gets into the bloodstream and spreads to the brain and other organs. The mortality rate with this type of mucormycosis is 96 percent.

According to a 2022 paper published in Vaccines, mold spores that cause mucormycosis are found in soil, leaves, or decaying matter. These spores can be dispersed in dust particles and gain entry into the human body through the respiratory tract, skin, or a weakness in the mucosal barrier. Once inside the body, the fungal spores can germinate and multiply, leading to infections such as cutaneous necrotizing fasciitis and disseminated mucormycosis.

The symptoms of mucormycosis vary depending on the patient, their underlying medical conditions, and the organs affected by the infection. Early symptoms may include nasal pain, vision loss, headache, fever, blackish nasal discharge, facial pain on one side, and mouth swelling. The infection primarily affects the nose, sinuses, lungs, eyes, and brain but can disseminate through the blood to other areas of the body.

According to a 2023 paper published in Travel Medicine and Infectious Disease, mucormycosis strikes patients within 12 to 18 days after COVID-19 recovery, and nearly 80 percent require surgery. A delayed or untreated diagnosis can result in a mortality rate as high as 94 percent.

COVID-19-Associated Mucormycosis Is a ‘Worldwide Phenomena’

In a 2022 review published in The Lancet, researchers analyzed 80 cases of COVID-19-associated mucormycosis from 18 countries, including eight cases from the United States, and found mucormycosis infection can be a serious complication of severe COVID-19, especially for those with diabetes and hyperglycemia, or high blood sugar.

Additionally, the authors noted that systemic corticosteroid treatment can reduce mortality in people with severe COVID-19, but the treatment, combined with immunological and other clinical factors, can also predispose patients to secondary fungal diseases like mucormycosis. This particular infection is associated with high morbidity and mortality, even in those with mild COVID-19 cases. The same is true for COVID-19 patients who received intensive antibiotic treatment.

Of the 80 cases analyzed by researchers, 74 patients were hospitalized for COVID-19 after receiving a mucormycosis diagnosis. In six cases, patients had COVID-19 before hospitalization for mucormycosis-associated symptoms—four of whom were hospitalized for COVID-19 within one to three months before a mucormycosis diagnosis.

Researchers identified 59 patients with rhino-orbital cerebral disease, 20 with pulmonary disease, and one had gastrointestinal mucormycosis. With cerebral mucormycosis, the fungus initially invades the nasal cavity and paranasal sinuses, presenting similarly to acute sinusitis. It can then lead to angioinvasion, where tumor cells get through blood vessel walls and cause blood clots. The infection rapidly spreads to orbital and brain sites and is associated with high morbidity and mortality.

Nearly 50 percent (39 patients) died. The median survival time from the day of the mucormycosis diagnosis was 106 days for rhino-orbital cerebral disease and only nine days for patients with pulmonary mucormycosis. Among survivors, 46 percent (19 patients) lost their vision.

The researchers noted several underlying health conditions among the patients with mucormycosis in addition to COVID-19, including uncontrolled or poorly controlled diabetes, hypertension or high blood pressure, chronic kidney disease, and cancer. Those with diabetes were more likely to have rhino-orbital mucormycosis and mild to moderate cases of COVID-19. Those without diabetes were more likely to have other manifestations of the infection and severe COVID-19. Researchers found that pulmonary mucormycosis almost exclusively occurred in the ICU setting.

The Lancet paper’s corresponding author, Dr. Martin Hoenigl, is an associate professor of translational mycology at the Division of Infectious Diseases at the Medical University of Graz, Austria, and the current president of the European Confederation of Medical Mycology.

“Our study outlines that COVID-19-associated mucormycosis, although more prevalent in parts of the world that have traditionally higher mucormycosis rates due to higher levels of environmental exposure (e.g., India, Pakistan, Iran, Egypt, China), is a worldwide phenomenon,” Dr. Hoenigl told The Epoch Times in an email.

“Our study has been performed early during the COVID pandemic before the extent of the COVID-19 associated mucormycosis crisis in India was recognized/came into the public focus, and raises attention to this serious, often deadly complication that can be very difficult to diagnose and requires aggressive treatment for a chance of successful outcome,” he said.

Numerous countries observed a sudden increase in CAM cases in 2021 during the second wave of the pandemic. India, a “hot spot” for the deadly infection, typically diagnosed 50 cases of mucormycosis each year but had already observed 28,252 cases as of June 2021. The number of mucormycosis cases has been increasing since.

Deadly Fungal Infection More Common With COVID-19

Dr. Hoenigl told The Epoch Times that mucormycosis is more common with COVID-19 than other infectious diseases due to specific risk factors that emerged with the pandemic and its management, as well as specific immunological mechanisms that predispose patients with severe COVID-19 to developing the condition.

“In terms of clinical risk factors, the increased population of undiagnosed or uncontrolled diabetes (driven by reduction of routine healthcare services during the early COVID pandemic) was an important driver of COVID-19 associated mucormycosis, as was overuse of systemic corticosteroids for COVID-19 treatment that happened in some countries where steroids were available for purchase over the counter, and at the same time, there was a lack of availability of supplemental oxygen,” Dr. Hoenigl said.

“In terms of immunological mechanisms, conditions such as hyperglycemia, steroid overuse, and high levels of iron and ketone bodies, but also COVID-19 itself via the virus-induced endoplasmic reticulum stress cascade are upregulating the expression of glucose-regulated protein 78 (GRP78), which, besides acting as a cofactor in viral entry, binds to spore-coating CotH3 invasin on the fungal surface and favors invasion of nasal epithelial cells by mucorales, resulting in rhino-orbital cerebral mucormycosis,” he explained.

The endoplasmic reticulum (ER) is a large structure within a cell that performs many functions, including calcium storage, protein synthesis, and lipid metabolism. GRP78 plays a significant role in regulating the ER. It is often upregulated in patients with COVID-19, which predisposes people to getting mucormycosis.

GRP78 helps regulate the ER’s stress response, can form a complex with the spike protein and the angiotensin-converting enzyme 2 (ACE2) to encourage entry and infection of SARS-CoV-2, and acts as a host receptor that allows molds that cause mucormycosis to enter cells and cause disease.

“There are other important immunological mechanisms as well that explain how severe COVID-19 can predispose patients to develop mucormycosis,” Dr. Hoenigl added.

Other Studies Identify Mucormycosis Risk Factors

In a 2021 review published in the Journal of Infection and Public Health, researchers found that hyperglycemia, impaired immunity, acidosis, raised ferritin—which is often indicative of higher iron levels, inflammation, or infection—glucocorticoid therapy, and COVID-19-specific factors were implicated in the pathogenesis of CAM.

In a 2022 study published in Cureus, researchers followed 62 patients with cerebral mucormycosis for up to 12 weeks to evaluate the risk factors, symptoms, and impact of various interventions on the disease outcome. All participants reported being symptomatic with flu-like illness during the two months preceding their diagnosis, with 58 of the 62 subjects testing positive for COVID-19 and 54 of the 58 patients receiving treatment.

“COVID-19 patients are more susceptible to opportunistic fungal infections due to the immune dysregulation caused by iatrogenic immunosuppression (via corticosteroids or undefined antibiotic treatment), uncontrolled diabetes mellitus, use of invasive or noninvasive ventilation, and other pre-existing conditions,” the paper’s authors wrote.

The researchers found that COVID-19 and diabetes mellitus were significant risk factors for developing mucormycosis. Common signs and symptoms of mucormycosis often appeared within a few weeks of COVID-19, although neurological symptoms were either absent or appeared later. The most common initial symptoms included ptosis—a drooping eyelid—or severe headache.

The median time between COVID-19 infection and the first noticeable symptom of mucormycosis was 16 days. The mean time between the first symptom of mucormycosis and the first neurological symptom was 19 days. The most common initial neurological symptom was hemiparesis—a weakness or inability to move one side of the body.

The study found that 18 (29 percent) patients were symptomatic for mucormycosis even before the resolution of their COVID-19. At the end of 12 weeks, only 18 patients had completely recovered without any residual symptoms, while 19 had persistent symptoms.

Of the 62 subjects, 53 required surgical intervention, eight patients needed their eyes extracted, 21 patients died, 37 survived, and four were lost at follow-up. The higher-than-expected survival rate was attributed to the study occurring in a hospital facility with access to prompt antifungal treatments.

In a January review of 20 papers on mucormycosis and COVID-19, researchers discovered numerous fungal coinfections in COVID-19 patients, 0.3 percent of which were related to mucormycosis.

The researchers attributed CAM to hyperglycemia from previously existing diabetes or excessive use of steroids, increased ferritin levels due to the “inflammatory cascade” initiated by COVID-19, immunological and inflammatory phenomena that occur with SARS-CoV-2 infection, immunosuppression from steroid use or other therapies, germination of fungal spores due to reduced white cell counts in those with COVID-19, and hypoxia—or insufficient oxygen levels which promote growth of the fungus.

Researchers also found that fungal infections were greater in critically ill COVID-19 patients, those requiring mechanical ventilation, and those hospitalized for more than 50 days.

According to the paper, medical management of the disease includes antifungal treatments and surgical debridement of the associated lesions. This is challenging for COVID-19 patients because many are given immunosuppressive therapies, such as steroids, and withdrawing immunosuppressive medications used to treat COVID-19 is part of the treatment for mucormycosis. They further suggest using hyperbaric oxygen therapy for hypoxia and acidosis.

To prevent mucormycosis in those with COVID-19, researchers suggest taking a detailed medical history to assess risk factors, using a controlled steroid regimen, sterilizing water in humidifiers, halting excessive antibiotics, and controlling blood sugar.

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