As the human-to-human transmitted disease, coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been an emergency global public health event [1,2]. SARS-CoV-2 is responsible for lower respiratory infection and can cause Acute Respiratory Distress Syndromes (ARDS) [3]. Besides, the diffuse alveolar damage with severe inflammatory exudation, COVID-19 patients always have immunosuppression with a decrease in CD4 + T and CD8 + T cells [4]. Critically ill patients, especially the patients who were admitted to the Intensive Care Unit (ICU) and required mechanical ventilation, or had a longer duration of hospital stays, are more likely to develop fungal co-infections [5]. Hence, it is important to notice that COVID-19 patients can develop further fungal infections during the middle and latter stages of this disease, especially severely ill ones [6]. 

Mucormycosis (previously called zygomycosis) is a serious, sporadic but cosmopolitan, rare opportunistic fungal infection caused by a group of molds called mucormycetes. These molds live throughout the environment. Mucormycosis mainly affects people with serious underlying diseases such as diabetic acidosis and acute leukemia and in patients treated with corticosteroids or cytotoxic drugs [7]. It most commonly affects the sinuses or the lungs after inhaling fungal spores from the air. It can also occur on the skin after a cut, burn, or other type of skin injury. Generally, these infections are broken down into five presentations: rhinocerebellar, pulmonary, cutaneous, gastrointestinal, and disseminated [8].

Case Reports

Four cases of mucormycosis were found, in COVID recovered patients, at our institute within interval of one month.

First was a 60-years female, with known case of diabetics mellites (DM) and hypertension (HTN) and post- COVID day-15. She presented in ENT department, with the complainst of nasal blockage and breathlessness, since 1 week. On examination, nasal mass was present in right nasal cavity. 

Second was 58-years female, also known case of DM and was COVID recovered, for one month. She came with the palatal perforation, pansinusitis and blindness. 

Third patient was 60-years female, recovered from COVID, from 15 day and a known case of DM, came with extensive paranasal infection. 

Fourth case was of 45-years non-diabetic male, came with post-COVID orbital swelling and sinusitis.

Turbinectomy was done in the Department of ENT in all these cases and specimen was sent to the Department of Pathology for Histopathological examination. Specimen received were multiple, blackish coloured tissue pieces aggregating to 2 X 1 cm, along with a bony part of size 1.5 X 0.5 cm.

Microscopic examination revealed abundant necrosis along with chronic inflammatory cells and giant cell reaction. Plenty of right angle branching broad hyphae of mucormycosis along with spores were also noted.

Periodic Acid Schiff (PAS), special stain for fungus, was done subsequently, in all the five cases. Thus, confirming the diagnosis.

Even as the world is grappling with the continuing effects of the COVID-19 pandemic, a new health issue appears to be quickly reaching the potential of an outbreak in India. Mucormycosis, a type of rare but deadly black fungal infection has been found in patients recovering from COVID-19 and is being referred to as COVID-19 triggered mucormycosis in this context.

Reports suggest that ENT surgeons at Delhi’s Sir Ganga Ram Hospital (SGRH) have found 13 cases in the last fortnight and around half the patients lost their eyesight as a result. Cases have also reportedly emerged in Ahmedabad and Mumbai, with 44 patients (nine out of whom passed away) having been recorded at the Ahmedabad Civil Hospital.

Mucormycosis is a fungal infection caused by certain types of mold, known as mucormycetes. They are found throughout nature (ubiquitous) and can be found in the soil and decaying organic matter like decaying vegetation. In individuals with a weakened or compromised immune system, they can cause severe, even life-threatening, infection.

Figure 1: Microphotograph Showing Broad Fungal Hyphae (40x, H and E)

Figure 2: Microphotograph Showing PAS Staining Fungal Hyphae (40x)

Most people develop this infection by breathing in mold spores [8]. Several clinical forms of mucormycosis are recognised [9,10]. Disseminated mucormycosis is a rare form often seen in individuals who are severely immune-compromised. In this form, the infection spreads to other areas of the body and becomes widespread. Other areas that can be affected include the brain, heart, spleen, skin, and other organs [8]. Rhinocerebral mucormycosis begins as a fulminant infection of the nasal cavity, paranasal sinuses and soft tissues of the orbit. Once established, it is difficult to treat and is rapidly fatal [7]. In rare instances, mucormycosis can affect or spread to affect the kidneys, the inner lining of the chambers of the heart and the heart valves (endocarditis) and the bone (osteomyelitis) [8]. 

Signs and symptoms of disseminated mucormycosis vary greatly depending upon the organ system involved.

There are people who are at a greater risk of developing mucormycosis, include those who have low levels of neutrophils (neutropenia), that help to fight off infection, and are receiving broad-spectrum antibiotics and drugs that suppress the activity of the immune system (immunosuppressive drugs). Other conditions increasing the risk of developing mucormycosis include kidney insufficiency, HIV/AIDS, use of contaminated medical equipment near or in open wounds, long-term use of corticosteroids, skin trauma including burns or other injury to the skin; extreme malnutrition; and illegal drug use involving needles. Premature newborns can be at a greater risk to infection including mucormycosis as well. In rare instances, there is no any identifiable risk factor [8].

Researchers have determined that mucormycosis infection has a high affinity for the blood vessels. Invasive opportunistic infections are characterised by tissue infraction. Infarcts are caused by thrombosis complicating hyphal invasion of arteries and veins. Angioinvasion may also lead to hematogenous dissemination [7].

COVID-19 patients with trauma, diabetes mellitus, GC use, prolonged neutropenia, allogeneic hematopoietic stem cell transplant, solid organ transplant, hemopoietic malignancy are more likely to develop mucormycosis [11]. Mucormycosis is usually suspected based on results of direct microscopy or plus fluorescent brighteners from clinical specimens such as sputum, bronchoalveolar lavage fluid and skin lesions that Mucorales hyphae are non-septate or pauci-septate with a variable width of 6–16 µm. To confirm the diagnosis, non-pigmented hyphae showing tissue invasion should be shown in tissue sections stained with hematoxylin–eosin (HE), PAS or GMS [12]. Culture of specimens is strongly recommended for identification of genus and species, also AST. What’s more, it is suggested to be cultured at 30⁰C and 37⁰C separately that typically cottony white or grayish black colony usually will be found, afterward morphological identification of fungi or DNA sequencing based on bar code genes, such as 18S, ITS, 28 s, or rDNA. MALDI-TOF identification is just moderately supported because it depends mainly on in-house databases, and many laboratories do not have this capacity [13]. Further, it is promising to detect fungi DNA, in serum as well as in other body fluids, even in paraffin-embedded tissue, however, because of lack of standardization supported it is only with moderate strength. 

The treatment recommendations can be supported by the global guideline for the diagnosis and management of mucormycosis in 2019 by European Confederation of Medical Mycology (ECMM) and Mycoses Study Group Education and Research Consortium that the therapeutic and alternative medication of mucormycosis have been given more detailed guidance opinions [11]. Generally, it strongly supports an early complete surgical treatment for mucormycosis whenever possible, in addition to systemic antifungal treatment. In neutropenic patients, those with graftversus-host disease or high-risk factor, primary prophylaxis with posaconazole may be recommended. Amphotericin B lipid complex, liposomal Amphotericin B and posaconazole oral suspension are treated as the first-line antifungal monotherapy, while isavuconazole is strongly supported as salvage treatment. There are no convincing data to guide the use of antifungal combination therapy of polyenes and azoles or polyenes plus echinocandins [14]. 

One estimate based on a study in the San Francisco area placed the incidence at 1.7 people per every 1,000,000 in the general population. According to the medical literature, the incidence of mucormycosis is increasing. Mucormycosis has been reported all over the world. This infection can potentially affect individuals of any age, including premature newborns [8].

A diagnosis of mucormycosis is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. A diagnosis of mucormycosis is challenging because the symptoms are common to many conditions including other types of infection. A diagnosis is made by identifying mold in affected tissue and sometimes can be confirmed by fungal culture. A prompt diagnosis is important so treatment can begin as early as possible.

A diagnosis of mucormycosis can be suspected when affected individuals who have been identified as having a fungal infection do not respond to antifungal medications that target Aspergillosis. 

Samples can include fluid from the respiratory system or mucus coughed up from the lungs (sputum) if lung infection is suspected. Surgical removal of a small sample of skin tissue can be taken in cutaneous mucormycosis.

A tissue sample can then be taken and used for a fungal culture, which can determine the presence and type of fungal infection. However, sometimes a fungal culture does not reveal a fungal infection despite the presence of infection. Thus, a negative result on a fungal culture does not rule out mucormycosis.

If a histopathology study is positive for infection, but a fungal culture is negative, a test called polymerase chain reaction (PCR) may be used, that can identify the causative species of the infection.

Imaging techniques such as computerized tomography (CT) scanning may be used to determine the exact location and extent of an infection.

Mucormycosis is a rare infection, which when detected early can be controlled by systemic anti-fungal chemotherapy with amphotericin B and radical debritment or excision of devitalised tissue, along with control of underlying immunosuppressive condition or disease. Hence, greater awareness, for opportunistic infections can be great help to reduce the morbidity and mortality. Histopathological confirmation and fungal culture are of significant use in diagnosis of the infections.

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