COVID-19-Associated Mucormycosis: Triple Threat of the Pandemic
Consider a scenario in which cells of the respiratory tract that are already infected with SARS-CoV-2 come in contact with fungal spores that sprout branch-like filaments (hyphae), invade blood vessels and cause death to surrounding tissues. Throw in an underlying condition, like diabetes, that further compromises the host’s immune system, and a serious triple threat unfolds.
Unfortunately, this scenario is far from hypothetical. Mucormycosis, a fungal infection caused by ubiquitous environmental molds, such as Rhizopus arrhizus, Rhizomucor pusillus, Apophysomyces variabilis and Lichtheimia corymbifera, is surging as a COVID-19-associated infection at unprecedented rates throughout India and raising alarm bells around the world. From May 5-July 12, 2021, 41,512 cases and 3,554 deaths were attributed to this rare, but life-threatening fungal infection. The majority of those cases occurred during active SARS-CoV-2 outbreaks in India, prompting the Central Government of India to declare a mucormycosis epidemic on May 10, 2021.
During a timely World Microbe Forum session about emerging pathogens, Dr. Ilan Schwartz summarized the threat. "Hospitals are going from seeing maybe 2 patients with mucormycosis in a month to 500-600 patients being admitted concurrently. This is unprecedented. We’ve never seen a fungal infection with this kind of rapid surge and this much devastation," he said. While Schwartz acknowledged that the reasons for the surge are complicated and not completely understood, characteristics of the causative microbes, their unwitting hosts and the relationships between them do provide important context to this story.
Mucor Molds, the Fungi
Mucormycosis is caused by molds belonging to the order Mucorales, which are commonly found in the soil, on plant surfaces, decaying fruits, veggies and animal manure. Most mucor molds are incapable of infecting humans because they do not grow at body temperature. However, thermotolerant species, such as those isolated from COVID-19-associated mucormycosis (CAM) cases in India, can cause opportunistic infection; and when they do, it’s serious.
Mucormycosis, the Disease
"Possibly the most feared infection in all of infectious diseases is mucormycosis," Schwartz provocatively stated. "It’s an extremely morbid and deadly fungal infection, but it’s caused by ubiquitous, environmental molds that we’re breathing in all the time. If your immune system is functioning as it should, this is not a problem; but a range of different immunodeficiencies can predispose someone to invasion [by] the inhaled spores."
If the fungus takes hold, those spores germinate to produce hyphae that invade blood vessels and surrounding tissue, blocking blood flow and causing tissue death as they spread. Most commonly, infection occurs in the sinuses and brain. However, cancer patients and those who have undergone organ transplant are at an increased risk of lung infection, and infants are more susceptible to gastrointestinal mucormycosis. Alternatively, organisms that cause mucormycosis may enter the body through cuts or burns in the skin and cause cutaneous necrosis (tissue death), or the infection may become disseminated and spread through the bloodstream to infect other parts of the body. Reports of orbital mucormycosis (infection of sinus passages near the eyes) are particularly common with CAM cases.
Symptoms include one-sided facial swelling, pain, headache, fever, blindness and black lesions where necrotic tissue is visible. Without aggressive interventions, such as antifungals and removal of dead tissue (which is disfiguring and invasive), mucormycosis is rapidly fatal. Prior to its association with COVID-19, the overall mortality rate of mucormycosis was estimated to be 54%, and disseminated mucormycosis was nearly 96% fatal. However, the type of mold, site(s) of infection and underlying condition of the patient or recent history of disease, such as COVID-19, all affect the outcome of infection.
Immunocompromised Hosts Are Predisposed to Mucormycosis
Immunocompromised hosts are significantly predisposed to mucormycosis. Key risk factors include cancer, organ or bone marrow transplantation, burns and other traumatic injuries that cause breaks in the skin, treatment with corticosteroids, neutropenia and uncontrolled diabetic ketoacidosis.
India is second only to China when it comes to the number of people living with diabetes, and a systematic review of CAM cases that occurred before May 13, 2021 found that 80% of cases occurred in patients with pre-existing diabetes mellitus (DM), 14.9% of which experienced accompanying ketoacidosis, a serious complication that occurs when high levels of blood acids, called ketones, are produced.
As a result, patients in diabetic ketoacidosis may experience further dysregulation to immune cells in the bloodstream. Neutrophils, phagocytic cells that make up 40%-70% of white blood cells in humans, are amongst the first responders to inflammation and are essential to the innate immune response. They are responsible for engulfing and killing pathogenic microbes, and are therefore key to the inhibition of fungal spore proliferation. However, phagocytic chemotaxis and intracellular killing are both disrupted during diabetic ketoacidosis, likely due to hyperglycemia and low pH resulting from the production of excess acid in the blood. And patients who lack phagocytes (neutropenia) or have impaired phagocytic function are particularly vulnerable to fungal infection resulting in mucormycosis.
But that is still only part of the story. As Schwartz aptly pointed out, the main factors precipitating the mucormycosis epidemic include, "COVID-19 in most of the patients that are infected, underlying poorly controlled diabetes, in some cases unmasked by COVID-19, and the liberal prescribing of corticosteroids [to treat COVID-19] outside of their indication." What happens when Mucor spp. meet coronavirus in an already immunocompromised host?
Complex Host-Microbe Interactions Drive COVID-19-Associated Mucormycosis (CAM)
It is well-known that immunodeficiencies, like diabetes, not only create immune imbalances that allow fungal infections to thrive, but also predispose patients to severe COVID-19. Furthermore, the SARS-CoV-2 virus employs some unique strategies to avoid detection during early infection, which ultimately suppress the immune system further.
Dr. Benjamin tenOever highlighted these strategies in another World Microbe Forum session about the short and long-term consequences of SARS-CoV-2 infection. In response to an invading pathogen, the properly functioning immune system initiates 2 main cellular responses, which tenOever referred to as the "call to arms" and the "call for reinforcements." The call to arms induces Type-1 interferons, which acts as a warning to neighboring cells that an active infection is taking place and prepares those cells to ward off the virus as it attempts to spread. The call for reinforcements relies on the transcription factor nuclear factor kappa B (NF-κB) to induce secreted proteins that have chemoattractant properties, which recruit cells of the innate and adaptive immune response, including T cells, B cells, monocytes, neutrophils and natural killer (NK) cells, to help neutralize the threat at the site of infection.
SARS-CoV-2 is unique in that it induces NF-κB while blocking INF-1, allowing SARS-CoV-2 to replicate uninhibited, without a call to arms, while continuing to call for reinforcements. A significant amount of immune infiltrate (immune cells and cytokines in fluid) is generated, as a result, with neutrophil infiltration being one of the more noteworthy pathologies of the SARS-CoV-2 infected. These infiltrates are proinflammatory in nature. And as they accumulate, they begin to act on their own inflammatory environment, which ultimately generates the "cytokine storm" that is associated with severe COVID-19. Finally, the combination of infiltrate and the blocked induction of interferon, which typically stops the virus from spreading and causing excess cell death, can lead to respiratory distress.
Direct damage to airway epithelial cells and blockage of INF-1 pathways increase susceptibility to fungal invasion. Corticosteroids, like dexamethasone, may be administered to control inflammation. However, corticosteroid use is a risk factor of mucormycosis, and increased blood sugar is a known side effect of the treatment. If an underlying diabetic condition exists, that risk greatly intensifies.
COVID-19-Associated Mucormycosis (CAM) Exploits Systemic Vulnerabilities
As scientists continue to dissect the complex causes of this mucormycosis epidemic, it is becoming clear that, true to the opportunistic nature of these fungi, mucor molds took full advantage when host defenses were down and the world was distracted by a pandemic. As clinicians were triaging massive SARS-CoV-2 outbreaks, steroids were prescribed in quantities and for durations that far exceed World Health Organization (WHO) recommendations, likely compromising patients' immune systems, increasing blood sugar levels and leaving patients, with and without underlying diabetic conditions, more susceptible to fungal invasion.
One thing is certain: CAM has exposed a number of medical vulnerabilities that warrant further attention. For starters, few treatments exist for fungal diseases like mucormycosis. This is partly because similarities between fungi and human cells make the development of antifungal therapies that are not toxic to the host particularly challenging, and antimicrobial resistance continues to threaten the viability of the limited number of antifungals that are available.
One of the treatments for mucormycosis, amphotericin B, targets sterols, lipids found in cell membranes of both human and fungal cells. Ergosterol, a component of fungal cell membranes, is more sensitive to this antifungal medication than cholesterol, but administration of amphotericin B is limited by infusion-related toxicity that, once again, is likely the result of proinflammatory cytokine production. Furthermore, corticosteroid use during treatment with amphotericin B is known to cause metabolic imbalances like hypokalemia, further complicating medical intervention during CAM.
There is still much to learn about the triple threat that has emerged from the pandemic, but moving forward, it will be especially important to carefully monitor blood-glucose levels and thoroughly discuss any underlying medical conditions with patients before beginning corticosteroid use to treat COVID-19. This page will be updated as new information about this complex and developing situation is available.
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