Mucormycosis: A Secondary Infection in COVID-19

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The mucormycosis fungus, commonly known as the zygomycosis fungus, causes black fungal disease. The fungus can cause a variety of diseases. In immunocompetent people, the fungi responsible are typically non-pathogenic since they are common environmental organisms. Infarction and necrosis of the host tissues are symptoms of mucormycosis, which is caused by hyphae invading the vasculature.

Mucormycosis can manifest as a number of syndromes depending on the anatomic location involved, including rhino-orbital-cerebral, pulmonary, cutaneous, and Gastrointestinal, and disseminated diseases. However, in immunocompromised people, these apparently harmless organisms might turn into a deadly and difficult-to-treat infection. Infections can manifest themselves in a variety of ways, including rhinocerebral, gastrointestinal, pulmonary, cutaneous, and dissemination. Mucormycosis is on the high rise along with the second wave of COVID-19 in India, patients suffering from COVID-19, and the patients on immunosuppressants like diabetes mellitus, hematological malignancy, solid organ transplants, and corticosteroid treatment are among the long list of infectants. It is important to reduce the chances of contracting mucormycosis for individuals with compromised immune systems. Preventive measures seem to be the only way out of the crisis.

The mucormycosis fungus, nowadays commonly known as the black fungus. Mucormycetes are members of Mucoromycotina-subphylum, Mucorales-order, zygomycosis-family (Table 1) [1,4]. Mucorales contain 11 genera and 27 species that have been linked to human infections (Table 2). The most common cause of mucormycosis worldwide is Rhizopus arrhizus, followed by Lichtheimia, Apophysomyces, Rhizomucor, Mucor, and Cunninghamella bacteria. When people come into contact with fungal spores in the atmosphere, they develop mucormycosis. Mucormycosis is most common in individuals that have health issues or who take medications that reduce the body's capacity to combat disease. After the fungus reaches the skin through a slash, scratch, burn, or other forms of skin trauma, mucormycosis may also develop [2,3,5]. Mucormycosis has become more prominent in modern decades, due to an increase in the number of severely immunocompromised people [1]. As of the current scenario, Mucormycosis is on high rise in India, patients suffering from COVID-19 and the patients on immunosuppressants like diabetes mellitus, hematological malignancy, solid organ transplants, and corticosteroid treatment are among the long list of infectants, hence are subjected to a high mortality rate (30-50%) [4,5].

Table 1. Classification of Mucormycosis

Kingdom Fungi
Subphylum Mucoromycotina
Order Mucorales
Family Mucoraceae
Genera Rhizopus Mucor Cunninghamella Apophysomyces Lichtheimia Saksenaea Rhizomucor

Table 2. Infection frequency of various genera

Genera Infection Frequency
Rhizopus 47%
Mucor 18%
Cunninghamella 7%
Apophysomyces 5%
Lichtheimia 5%
Saksenaea 5%
Rhizomucor 4%

 

2 TYPES OF MUCORMYCOSIS

Mucormycosis is categorized into five major types based on anatomic location: rhino-orbital-cerebral mucormycosis (ROCM), pulmonary, cutaneous, gastrointestinal (GI), disseminated mucormycosis [4].

2.1 Rhino-Orbital-Cerebral Mucormycosis (ROCM)

Rhinocerebral mucormycosis is the most frequent form of mucormycosis, and it primarily affects the nasomaxillary complex [7]. Mucormycosis of the sinuses and brain, that can spread into the palate, oral mucosa, bone, orbit, and brain. People with uncontrolled diabetes and others who have undergone a transplant as well as immunocompromised hosts are more likely to get this kind of mucormycosis. Rhino-orbital-cerebral mucormycosis has about 25–39% cases [4,6]. 

The rapid development is due to the complex pathogenesis. Fungal hyphae entering blood vessel walls cause endothelial injury. As a consequence, intravascular thrombus and vascular occlusion form, causing ischemia and necrosis in the host tissues. The fungus flourishes in necrotic tissues and spreads to other parts of the body through blood vessels. Thrombosis of the sphenopalatine and internal maxillary arteries causes necrosis of the maxilla in rhinocerebral mucormycosis. It can rapidly propagate to the orbit and brain via these vessels, resulting in death [7,8]. Rhino-orbital-cerebral mucormycosis has about 25–39% cases with the mortality rate increase, with recent estimates ranging from 25% to nearly 80% [7,9].  Mucormycosis is a rapidly spreading, potentially fatal disease that necessitates timely diagnosis and aggressive treatment.

Rhino-orbital cerebral mucormycosis is a medical and surgical emergency that requires immediate attention. It's difficult to get a definitive diagnosis early on because delaying the therapy can worsen morbidity and mortality, while the early antifungal treatment and thorough surgical debridement can be done on a trial-and-error basis. Its symptoms are fever, headache, facial & nasal inflammation, periorbital swelling, and black nasal or palatine mucosa eschar [7].

2.2 Pulmonary Mucormycosis

Pulmonary mucormycosis is an uncommon but dangerous fungal disease that normally develops when the immune system is compromised [10,11]. Pulmonary mucormycosis is the second most common type of mucormycosis [12]. Diabetes, hematologic malignancy, and strong organ and stem cell transplant are the most important risk factors [5,13]. Fungus can rapidly infiltrate lungs, nerves, and lymphatics, causing thrombosis and infarction, and the respiratory tract has been identified as the portal of entry for them. Infection can increase rapidly to integrate and masses and can involve both lungs. Pulmonary necrosis is a common scenario due to the angioinvasive nature of the disease, delays in treatment lead to gradual pulmonary dysfunction, fungal sepsis, and/or hemoptysis which are associated with a greater mortality rate. Early diagnosis and proper treatment are critical when pulmonary mucormycosis is suspected but studies have shown that fluconazole, amphotericin B is the most effective medical antifungal treatment [14]. Its symptoms are fever, cough, chest pain, and shortness of breathing.

2.3 Cutaneous Mucormycosis

Cutaneous mucormycosis is a form of mucormycosis that develops after a wound or a break in the skin and can be seen in an immunocompetent host [15]. It can be categorized as a localized infection, a deep expansion, or a part of a disseminated infection, depending on the degree of the invasion. Localized infection occurs in 32–56 percent of cases, and it is normally limited to the cutaneous and subcutaneous tissue without spreading to other areas. The deep extension applies to muscle, bone, and tendon penetration, which occurs in 24–52 percent of patients. The infection also manifests as necrotizing fasciitis with erythematous necrotic eschar in these patients. Cutaneous mucormycosis is a form of disseminated infection that affects non-contiguous sites in addition to the cutaneous site and is seen in 16–20% of cutaneous infections [16-18].

If cutaneous mucormycosis is left untreated, it can lead to a deep tissue infection affecting muscle, bone, and fascia. Necrotizing fasciitis is a serious complication of cutaneous mucormycosis and, through vigorous surgical debridement and antifungal treatment, has a poor prognosis. Immediate aggressive surgical debridement is the most preferred mode of treatment in the case of cutaneous mucormycosis, along with a long-term and slow systemic antifungal therapy as an alternative. Its symptoms are ulcers, black infected area, pain, warmth, excessive redness, or swelling around a wound.

2.4 Gastrointestinal Mucormycosis

Gastrointestinal (GI) mucormycosis is the most difficult to diagnose due to non-specific symptoms. Gastrointestinal mucormycosis is more prevalent in young children than in adults, especially in premature and low-birth-weight children or who are immunosuppressed [19,20,21]. It accounts for 5-13 percent of all mucormycosis cases. The major risk factors include solid organ transplants, hematological malignancies, and neutropenia diabetes mellitus, chronic alcoholism, malnutrition, peritoneal dialysis, and the use of broad-spectrum antibiotics [5,20]. The most prominent site of infection is the bowel, which comprises the esophagus, stomach, small intestine, and large intestine [20,22]. The most common site of infection in infants is the small and large intestine wherein the adult stomach is the most common site of infection. Other organs that are affected are the liver, pancreas, abdominal wall, and urinary bladder. This disease has an 85% case fatality rate. Increased knowledge would lift awareness about the disease which could aid in early detection and can be treated with the combination of surgical debridement and antifungal therapy (fluconazole, voriconazole, posaconazole, itraconazole) or micafungin [20]. Its symptoms are abdominal pain, Nausea, vomiting, and gastrointestinal bleeding.

2.5 Disseminated Mucormycosis

When a mucormycosis fungus spreads through the bloodstream to another part of the body, it causes disseminated mucormycosis. The infection usually affects the brain, but it may also affect the spleen, heart, and skin. The most prominent place of transmission is the lung, followed by the central nervous system, sinus, liver, and kidney [5,23]. The major risk factors involve solid organ transplant and hematological malignancy [5,24]. Disseminated mucormycosis has 13% of cases among all the types of mucormycosis. Its symptoms are not well known, but disseminated mucormycosis infect the brain can developmental status changes or coma.

3. MUCORMYCOSIS AND COVID-19

COVID-19 is linked to a high rate of secondary infections, both bacterial and fungal, most likely as a result of immune dysregulation. Furthermore, the extensive use of steroids, monoclonal antibodies, and broad-spectrum antibiotics as part of the COVID-19 armamentarium can result in the production or exacerbation of pre-existing fungal diseases [25]. Mucormycosis as a secondary or co-infection that can be caused by a number of causes, including pre-existing diseases such as diabetes mellitus, prior respiratory pathology, immunosuppressive treatment, the risk of hospital-acquired infections, and systemic immune alterations caused by COVID-19 infection itself [26]. COVID-19 patients have elevated levels of inflammatory cytokines such as interleukin [IL]-2R, IL-6, IL-10, and tumor necrosis factor (TNF-α), as well as a weakened cell-mediated immune response, affecting all CD4 + T and CD8 + T cells. As a result, there is an increased susceptibility to fungal coinfections [27].

In the recent scenario, Mucormycosis is declared as an epidemic in India. There are various cases where patients suffering from COVID-19 infection develop mucormycosis during their treatment, and claiming a lot of lives.

4. MINIMIZING THE RISK OF MUCORMYCOSIS

Mucormycosis causing fungus is so abundant in the atmosphere, it's impossible to prevent inhaling fungal spores. Mucormycosis has no vaccine. It is important to reduce the chances of contracting mucormycosis for individuals with compromised immune systems.

When a diabetic patient (uncontrolled diabetes) is associated with steroid use and a COVID-19 positive status, one is at a high risk of contracting this infection. As a result, diabetics must constantly track and regulate their blood sugar levels. Patients that are Covid positive who have a mild form of the infection should avoid taking steroids. Steroids are worthless in the treatment of moderate COVID-19 infection. Whereas on the other hand, they raise the risk of secondary infections like Mucormycosis. Therefore, after recovering from COVID-19, there is a high chance of fungal infection. Surplus steroids are also a source of concern because it has a significant impact on the immune system directly. Masks must be worn at all times. Airborne fungal spores can quickly penetrate the body through the nose. This makes masking up even more critical in terms of infection prevention. Preventive measures seem to be the only way out of the crisis [28,29,30].

5. CONCLUSION

Mucormycosis is on the rise in India, along with the second wave of COVID-19. Patients with COVID-19 and those on immunosuppressants, such as diabetes, hematological malignancy, strong organ transplants, and corticosteroid therapy, are among the infectants. The infection is already declared as an epidemic in India with more than 5500 cases and over 200 deaths since last month. Doctors and healthcare workers are on high alert and taking preventive measures to curb further infections. Hygiene and cleanliness of the hospitals and COVID wards should be maintained. While discharging COVID patients should be checked for early symptoms of the fungal infections and advised for further care and hygiene to prevent the mucormycosis infection. Surgery being the major treatment, preventive measures and early diagnosis seems to be the only ways to curb the high rise of mucormycosis in hospitals and COVID centers.

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