Infection follows different signs and symptoms 7, 8, 9 (Figure 2).

Introduction of Mucormycosis in human body with its signs and symptoms are as follows:

Occasionally, there is bluish discoloration of the skin near the sinuses or the eye socket, which occurs due to a lack of oxygen (cyanosis). Sometimes, there can be the development of blurred vision or double vision. If unrecognised and untreated, notable tissue death can occur, and the infection can cause significant damage to facial structures.

The first case of mucormycosis was reported in the year 1885 by Paltauf. 10 In 1943, a publication by Gregory et al. the first time reported observation of rhino-orbital cerebral mucormycosis. 11 In 1955, Harris reported the first case with cerebro-rhino orbital mucormycosis, who survived the disease. 12 There is little change in the diagnosis and outcome of this disease. Even though mucormycosis isof many forms – cerebral, cutaneous, rhino cerebral, intestinal, or pulmonary – it is still a rarity. It should be suspected in patients who are diabetic or immuno compromised. 13

The standard treatments for mucormycosis –

Zygomycetesare a class of fungus that causes Mucormycosis. The most repeated species isolated from patients are Apophysomyces (A. variabilis), Cunninghamella (C. bertholletiae), Lichtheimia [Absidia] (L. corymbifera, L. ramosa), Mucor(M. circinelloides), Rhizopus (R.arrhizus (oryzae) R. microsporus), Rhizomucor (R. pusillus), and Saksenaea (S. vasiformis). These are common environmental organisms that are not harmful to immuno competent humans. Immuno compromised patients (i.e., transplant patients, HIV, patients of chronic steroids or disease-modifying anti-rheumatic medications, leukemia, or other cancer patients) can present with rapidly progressive necrotizing infection (Figure 3). Describes the Growth of Sporangiospores in human body followed by spreading of infection through blood stream ). Likewise, uncontrolled diabetics (particularly those with a history of diabetic ketoacidosis) are also at high risk. Mucormycetes are the moldsthat cause fungal infection and lead to mucormycosis. They are found ubiquitous. Therefore,they can be found in the soil and decaying organic matter like decaying vegetation.

Usually they do not cause problems, as these molds are found commonly all over nature. However, those individuals who have weak and compromised immune systems, these molds can cause severe, and even life-threatening infections. Breathing in mold spores increases the chance of developing infection. Cuts or open wounds can also contribute to the development of infection.

In the case of uncontrolled diabetes, the patient is at a high risk of developing mucormycosis, and in the end, they may develop diabetic ketoacidosis. Ketoacidosis is a complication in which any individual having poorly- controlled Diabetes in which the body produces high levels of blood acids termed as ketones. Ketoacidosis is a diabetes complication that leads to a variety of symptoms.

People who are at greater risk of developing mucormycosis are:

Following fungi cause mucormycosis –

i. Rhizopus species

ii. Mucor species

iii. Rhizomucor species

iv. Syncephalastrum species

v. Cunninghamellabertholletiae

vi. Apophysomyces species

vii. Lichtheimia (formerly Absidia) species.

Graphical overview for healthcare associated risk factors in Mucormycosis is presented in (Fig4 :

Figure 4

The diagnosis is made based on the patient's medical history, including a physical examination and the patient's risk factors for a fungal infection. Although some tests, such as CT or MRI 23, may assist in characterizing the degree of infections or tissue loss, a precise diagnosis is challenging. Mucormycosis is diagnosed utilizing histology and/or the identification of the organism by culture from afflicted sites. In the absence of particular biomarkers, the isolate is recognized at the species level. No accurate serological or blood test exist. A biopsy (tissue collected by surgical removal or endoscopes with biopsy instrument) of infected tissue, together with specific tissue stains looking for distinct structural components, may help identify the fungus and aid in the ultimate diagnosis. 24

Although there is no circulating antigen detection test for mucormycosis, it is commonly noticed that the 1,3-β-d-glucan detection test is negative in Mucorales infections. On the other hand, these two tests can help rule out invasive aspergillosis, which is the most common differential diagnosis, as well as mixed Aspergillus and Mucorales infections. There is currently no standardized blood polymerase chain reaction (PCR) test. As a result, biological specimens from clinically affected locations must be analyzed for diagnosis. Obtaining tissue biopsies for histopathology and culture should be a top priority. 25

The treatment for mucormycosis needs to be fast and aggressive. The need for urgency derives from the fact that the patient has usually already sustained permanent tissue damage by the time a presumptive diagnosis is made.

Mucormycosis is treated with a multimodal approach that includes antifungal agents, surgical debridement, and correction of the underlying condition that predisposes the patient to the disease. In mucormycosis, it is crucial to keep the underlying problems under control. Uncontrolled Diabetes necessitates immediate treatment of metabolic imbalances.

Recent therapeutic advances may improve mucormycosis outcomes. Amphotericin B lipid complex (ABLC) has emerged as the cornerstone of primary therapy for mucormycosis. Table 1 depicts possible First and Second line treatments of mucormycosis. Posaconazole may be effective as salvage therapy. However, based on the existing data, it cannot be recommended as first-line therapy for mucormycosis. Preclinical and limited retrospective clinical data suggest that combining ABLC and echinocandin therapy may improve mucormycosis survival. A definitive trial is required to confirm these findings. In animal models of mucormycosis, combining ABLC with the iron chelator deferasirox improved outcomes. 27, 28

As of 7 June 2021, India is facing a dangerous increase in coronavirus disease 2019 (COVID19) cases during its second wave, with a total of 28, 996, 949 cases and 351, 344 deaths, which is growing by the day. 29 Mucormycosis is another fatal infection that highly affects the COVID sufferer. Black fungus is the common name given for Mucormycosis. The fight from COVID is not yet over. India has been facing another deadly challenge of mucormycosis.

Steroid preparations such as Dexamethasone, Methylprednisolone, or prednisolone are administered by patients with moderate to severe COVID infection. Even various antimicrobial agents are also prescribed to prevent and treat pulmonary infections that may cause pneumonia.

Numerous COVID patients have been suffering from comorbid conditions. India being an epicenter of Diabetes with enormously more than 50 million diabetics, 30 is of particular importance in the present scenario of the COVID pandemic. COVID therapy with Steroids and immune-suppression predisposing conditions such as old age, cancer chemotherapy or radiotherapy, organ transplant recipients on immune-suppressors, or any disease requiring steroid treatment are well-recognized comorbid conditions.

The immuno suppressive state becomes very profitable for opportunistic fungal infections. Aspergillus being ubiquitous in the atmosphere and Candida being inhabitant of human body are most frequent fungal infections that wait for the host to be immune-suppressed. Mucor is the next fatal and challenging life-threatening infection. Mucormycosis is also called Black Fungus due to black bruises it forms in the infected area. Mucor infects deeper tissues starting from the sinus and then expanding its effect to the eyeball, including bone and the soft tissues, and ultimately reaches brain tissues. Mucormycosis is so terrible and gruesome that it may cause rapid deterioration of the eyes, leading to perpetual loss of vision. Once Mucor goes in for infecting the brain, the patient declines rapidly, leading to paralysis, organ failure, other related complications, and eventually death.

Every COVID patient recovered and discharged from the hospital should be warned to be watchful of the early symptoms of Mucormycosis. Symptoms involve blood-stained or black discharge from the nose, localized pain, redness over the cheek bone or palate, redness of the eye, headache, and fever.

Mucor infection is generally rigidly established, which makes early diagnosis difficult. The choice of extensive apparent surgical intervention is not all the time possible, especially if the infection has reached the brain. The best approach is to start antifungal drugs immediately, and if possible, surgical- intervention should be carried out. If there is advancing infection to the brain, the only remaining option will be aggressive treatment with appropriate antifungal drugs. The plan of action should be to give effective antifungal Drugs as early as possible with the best dose for the optimum duration until the infection is eradicated.

According to Global Guidelines on Treatment of Mucormycosis by the European Confederation of Medical Mycology, the choice of anti-Mucor drugs is limited to three molecules –

(1) Amphotericin B

(2) Isavuconazole

(3) Posaconazole

In case of pre-existing renal compromise, Isavuconazole and Posaconazoleare exceedingly recommended.

Amphotericin B, which is a potent broad-spectrum fungicidal, is used for the treatment of mucormycosis. Fig 5 present comparative study of mortality rate with different modes of therapy. The treatment of mucormycosis should be initiated with a high dose of Amphotericin B. Considering the dose-related toxicity and nephrotoxicity, the first choice is liposomal Amphotericin B. In India, there are following two forms of liposomalformulations:

A. Liposomal Amphotericin B Suspended in Dextrose: This form of the formulation is recommended at the daily dose of 5-10 vials.

B. Liposomal Amphotericin B in Saline: A dose of 1-3 vials per day is recommended.

The replacement of Dextrose by Saline has been reported to contribute to reducing nephrotoxicity. The lower dose of drug prepared in Saline makes the treatment economical too.

As development of mucor takes place on high blood sugar levels, it more frequently occurs in Diabetics. Diabetic COVID patients, treated with steroids may have further raised levels of sugar which favorsmucor growth.Therefore, Liposomal Amphotericin B in Saline will be a better option to resist mucor maturation and thus influential effective treatment.

The effective use of steroids and antimicrobials in COVID patients, early diagnosis, and early start of treatment with Liposomal Amphotericin B and its prolongation till the clearance of infection can save many lives. 31

Figure 5

Folowing are some precautions33 that can be taken to minimise the risk of infection :

Do's

Don'ts

Mucormycosis, often known as Black Fungus, belongs to the order Mucorales and the subphylum Mucormycotinea. Mucormycosis  has been found to be contagious in persons with impaired immune systems. This is often reported to be seen in people with a history of Diabetes, haematological malignancies, organ transplantation, and so on. Desferrioxamine medication increases the risk of Mucormycosis, and several steroid formulations, such as Dexamethasone and Mehtylprednisolone, used in patients with severe to moderate COVID-19 infection, are also susceptible to Mucormycosis infections. Along with the drug therapy used for COVID treatment, many patients with a history of diabetes and other disorders, as well as old age, increase their risk of mucosmycosis infection. This complicates the recovery of infected individual and reduces the likelihood of total recovery.

While fighting the battle with covid-19, a new deadly infection also spread, which is more dreadful for the COVID sufferers. The treatments used for COVID patients include a risk of infection therefore patients should be monitored by professionals, if possible or kept under watch for the various early symptoms of mucormycosis like blood-stained or black discharge from nose, localized pain, redness over the cheekbone or palate, redness of eye, headache and fever. CT or MRI are the two tests that are convenient for the scanning of mucormycosis. Amphotericin B, Isavuconazole, Posaconazole are the Drug of choice for Mucor infection. Regions like India which is an epicentre for diabetic patients have higher risks and so the first line of treatment preferably is liposomal Amphotericin B which is a potent broad spectrum fungicidal.