Mucormycosis is an uncommon emerging life-threatening fungal infection that occurs in people whose immune system doesn’t function well (immune-compromised) including people with uncontrolled diabetes mellitus, people who have low levels of neutrophils, a type of white blood cell that helps the body fight off infection and heal itself (neutropenia), or people whose immune system is being suppressed by medications (immunosuppression) as part of their treatment for blood cancer (hematological malignancy), hematopoietic stem cell transplantation, or solid-organ transplant, with high morbidity and mortality.
Mucormycetes of the order Mucorales, subphylum Mucoromycotina infections are usually acquired when spores from the molds are breathed in (inhaled) or, less commonly, enter the body through a cut in the skin. The infection is not contagious; it cannot be spread from one person to another. Seasonal variations affect the incidence of mucormycosis, with most infections occurring from August to November Due to the rarity of the disease, it is almost impossible to conduct large randomized clinical trials and most available data on epidemiology, diagnosis, and treatment from case reports. Mucormycetess. The ketone reductase, enzyme allows Rhizopus to thrive under acidic and high glucose environment. Serum from healthy individuals inhibits growth of Rhizopus, whereas diabetic ketoacidosis individuals serum stimulates their respective growth.
Treatment with glucocorticoids, Diabetes mellitus, particularly with ketoacidosis, Hematologic malignancies,Hematopoietic cell transplantation, Solid organ transplantation, AIDS, Injection drug use ,Trauma/burns ,Malnutrition predisposes to the infection and influences the clinical presentation of invasive mucormycosis.
Rhino-orbital-cerebral and pulmonary mucormycosis are acquired by the inhalation of spores. Cilia transport these inhaled spores to the pharynx which are cleared through the gastrointestinal tract in healthy individuals. The infection usually begins in the nasal turbinates or the alveoli in susceptible individuals. The agents of mucormycosis are angioinvasive; thus, infarction of infected tissues is a hallmark of invasive disease. Deferoxamine and iron overload
By boosting development and pathogenicity, deferroxamine, which chelates both iron and aluminium, raises the risk of mucormycosis. The deferoxamine-iron chelate feroxamine is a siderophore for Rhizopus species, boosting iron uptake by the fungus, stimulating fungal growth and tissue penetration. In the absence of deferoxamine medication, iron excess may predispose to mucormycosis. Furthermore, people with diabetic ketoacidosis have higher levels of free iron in their blood, which encourages Rhizopus oryzae development at an acidic pH but not at an alkaline pH. Patients who have received several blood transfusions and are treated with this chelating drug for iron overload are currently at risk for deferoxamine-associated mucormycosis. Other iron chelating drugs, such as deferasirox and deferiprone do not act as siderophores are not as effective as deferoxamine and therefore do not increase the risk of mucormycosis
Coronavirus disease 2019-associated
Mucormycosis has been reported in a number of patients with coronavirus illness in 2019. (COVID-19). Individuals with diabetes mellitus who took COVID-19 steroids prior to being diagnosed with mucormycosis make up the bulk of cases. Facial pain, facial or orbital edema, headache, and/or nasal eschar are the most common symptoms of rhino-orbital-cerebral mucormycosis. Individuals with COVID-19 who experience inexplicable worsening pulmonary status or problems have been shown to have pulmonary mucormycosis infections. Mucormycosis of the gastrointestinal tract has also been reported. In case studies from India, overall mortality ranged from 15% to 31%.
Infarction and necrosis of host tissues are hallmarks of mucormycosis, which is caused by hyphae invasion of the vasculature. The infection normally progresses quickly, but there have been a few reports of infections that progress slowly.
T he most common clinical manifestation of mucormycosis is rhino-orbital-cerebral infection, which is thought to begin with spore inhalation into a susceptible host's paranasal sinuses. The most prevalent underlying disease is hyperglycemia, which is usually accompanied with metabolic acidosis. Acute sinusitis, with fever, nasal congestion, purulent nasal discharge, headache, and sinus pain, is the most common symptom. All of the sinuses become involved, and spread to contiguous structures, such as the palate, orbit, and brain, usually progresses rapidly over the course of a few days over the course of weeks. The most common clinical manifestation of mucormycosis is rhino-orbital-cerebral infection, which is thought to begin with spore inhalation into a susceptible host's paranasal sinuses. The most prevalent underlying disease is hyperglycemia, which is usually accompanied with metabolic acidosis. Acute sinusitis, with fever, nasal congestion, purulent nasal discharge, headache, and sinus pain, is the most common symptom. Facial numbness is frequent and results from infarction of sensory branches of the fifth cranial nerve. Spread of the infection from the ethmoid sinus to the frontal lobe results in obtundation. Spread from the sphenoid sinuses to the adjacent cavernous sinus can cause cranial nerve palsies, sinus thrombosis, and carotid artery involvement. Unless the patient has an underlying hematologic malignancy with neutropenia, hematogenous dissemination to other organs is uncommon. R. oryzae is the most common cause of rhino-orbital-cerebral mucormycosis.
Pulmonary mucormycosis is an illness that develops quickly after spores are inhaled into the bronchioles and alveoli. The infection can spread to nearby structures, such as the mediastinum and heart, or distribute hematogenously to other organs, resulting in pneumonia with infarction and necrosis. The majority of patients have a fever and hemoptysis, which can be severe at times. Hematologic malignancies, treatment with glucocorticoids or deferoxamine, and solid organ transplantation are the most common underlying diseases; pulmonary infection is less common than rhino-orbital-cerebral infection in diabetics.
Although unusual, mucormycosis of the gastrointestinal tract may occur as the result of ingestion of spores. The stomach was the most common site, followed by the colon. The ileum and esophagus were rare sites of involvement. The underlying diseases of patients with gastrointestinal mucormycosis have been diabetes mellitus, solid organ transplantation, treatment with glucocorticoids, and prematurity and/or malnutrition in infants. Patients present with abdominal pain and hematemesis. The gastrointestinal lesions are necrotic ulcers that can lead to perforation and peritonitis. Bowel infarctions and hemorrhagic shock can result from gastrointestinal mucormycosis, and the prognosis for all patients is poor.
Inoculation of spores into the dermis is the most common way for mucormycosis agents to infect the skin and soft tissues. As a result, cutaneous mucormycosis is virtually usually linked to wounds or trauma. Fungi can enter the dermis by seemingly harmless injuries such as the site of an intravenous catheter insertion, spider bites, and insulin injection sites. Contaminated traumatic wounds, bandages and splints, burns, and surgical sites have all been linked to infection. When infection is coupled with tiny skin cracks, the host typically has an underlying condition such as diabetes, organ transplantation, neutropenia, or severe prematurity. Infections linked to major trauma or contaminated dressings have been discovered in apparently healthy people. Cutaneous mucormycosis is a fungal infection that appears as a single, painful, indurated area of cellulitis that progresses into an ecthyma-like lesion. Patients suffering from trauma with an open wound further contaminated with spores can develop rapidly progressive tissue necrosis, depicting the presence of ischemic infarction. Dissemination and deep tissue involvement further complicates cutaneous mucormycosis.
Isolated involvement of the kidneys with mucormycosis is presumed to occur via seeding of the kidneys due to an episode of fungemia. Almost all patients with isolated renal mucormycosis have risk factors for fungemia, including an intravenous catheter, intravenous drug use, or AIDS.Patients with renal mucormycosis usually present with flank pain and fever. Involvement can be either unilateral or bilateral.
Isolated CNS involvement
Mucormycosis of the central nervous system (CNS) is usually caused by a paranasal sinus infection. Infection is hypothesised to be caused by seeding of the brain during a fungemia episode, similar to how renal involvement causes infection. More than two-thirds of individuals with isolated CNS mucormycosis were intravenous drug users who likely administered fungi-contaminated material directly into the bloodstream. In addition to drug use, some of the patients with isolated CNS mucormycosis had HIV infection. Most of the patients with isolated CNS mucormycosis have presented with lethargy and focal neurologic deficits, with the vast majority having involvement of the basal ganglia. Isolated involvement of the frontal lobe has also been described.
Disseminated mucormycosis is rare and occurs most commonly in severely immunocompromised patients, burn patients, premature infants, and individuals who have received deferoxamine . The mortality rate in patients with disseminated mucormycosis was 96 percent.
The identification of organisms in tissue by histopathology, followed by culture confirmation, is used to diagnose mucormycosis. However, when culture fails to produce growth, histopathologic identification of an organism with a Mucorales-like structure may be the only indication of infection. In order to establish a diagnosis as soon as possible, a therapist must consider this entity in the appropriate clinical situation and undertake invasive tests. Mucormycosis agents, on the other hand, can invade the airways or be contaminants in cultures, and isolation of these fungi in a culture does not always mean infection To evaluate if antifungal therapy should be provided, the culture findings must be interpreted in the context of the patient's signs and symptoms as well as the underlying condition. In individuals suspected of having an invasive fungal infection, serum tests such as the 1,3-beta-D-glucan assay and the Aspergillus galactomannan assay are being employed more frequently. The agents of mucormycosis do not share these cell wall components and neither test is positive in patients with mucormycosis. Investigational studies have demonstrated the feasibility of using polymerase chain reaction (PCR)-based techniques on histologic specimens. The PCR-based technique used in this study appears promising for establishing the diagnosis of mucormycosis when cultures are negative.In addition to traditional culture techniques and PCR with sequencing, matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry can be used to identify the causative species from culture specimens.
Mucormycosis should be suspected in high-risk patients, specifically those with diabetes and metabolic acidosis who have sinusitis, abnormal mentation, and/or infarcted tissue in the nose or palate.Endoscopic evaluation of the sinuses should be performed to look for tissue necrosis and to obtain specimens. The specimens should be inspected for characteristic broad, nonseptate hyphae with right-angle branching using calcofluor white and methenamine silver stains. The presence of the characteristic hyphae in a clinical specimen provides a presumptive diagnosis that should prompt further evaluation. When the clinical picture is highly suggestive of mucormycosis, the absence of hyphae should not deter doctors from making the diagnosis. Imaging is used to determine the extent of sinus involvement as well as to assess neighbouring structures such as the eyes and brain. As the initial imaging study, a computed tomography (CT) scan is recommended because it can frequently be done rapidly and is more sensitive than magnetic resonance imaging (MRI) in detecting bony erosions.
Focused consolidation, masses, pleural effusions, or numerous nodules may be seen on chest radiographs or CT scans. Angioinvasive fungi have a halo sign (ground-glass attenuation around a nodule), but a reversed halo sign (a focal area of ground-glass attenuation surrounded by a ring of consolidation) has also been observed. The typical broad nonseptate hyphae can be seen in sputum or bronchoalveolar lavage (BAL) specimens, which is often the initial sign of mucormycosis.On a lung biopsy, hyphae can also be seen. Endoscopic biopsies of lesions with the characteristic hyphae can be used to diagnose gastrointestinal mucormycosis. Percutaneous biopsy or nephrectomy can be used to diagnose isolated renal involvement. Urine cultures nearly seldom turn out to be sterile. CT imaging of the kidneys can reveal ill-defined areas of low attenuation and reduced enhancement, which can indicate pyelonephritis, or many tiny foci, which can indicate abscesses.Treatment of mucormycosis involves a combination of surgical debridement of involved tissues rhinocerebral infection, debridement to remove all necrotic tissue can often be disfiguring, requiring removal of the palate, nasal cartilage, and the orbit. and antifungal therapy. Hyperglycemia, metabolic acidosis, deferoxamine use, immunosuppressive medications, and neutropenia are all predisposing conditions for infection that must be avoided. The medicine of choice for initial therapy is intravenous (IV) amphotericin B (lipid formulation). Patients who have responded to amphotericin B are given posaconazole or isavuconazole as a step-down therapy. For patients who do not respond to or cannot tolerate amphotericin B, posaconazole or isavuconazole can be used as salvage therapy; whether to use oral or IV posaconazole or isavuconazole for salvage therapy depends on the patient, whether an initial course of amphotericin B was able to be administered, and whether the patient has a functioning gastrointestinal (GI) tract. Because of the lack of randomised trials evaluating the efficacy of antifungal treatments for mucormycosis,
The starting dose is 5-10 mg/kg daily of liposomal amphotericin B or amphotericin B lipid complex, There are anecdotal reports of using combination therapy with amphotericin B and either posaconazole or an echinocandin. In severe cases in which there is little residual renal function, nephrectomy with antifungal therapy (using an amphotericin B formulation, posaconazole, or isavuconazole) for two weeks appears to be a reasonable course of action.
Posaconazole and isavuconazole are broad-spectrum azoles that are active in vitro against the agents of mucormycosis and that are available in both parenteral and oral formulations. Posaconazole or isavuconazole can be used as an oral step-down therapy for patients who have responded to a lipid formulation of amphotericin B. We keep giving amphotericin B to the patient until he or she shows indications of improvement, which usually takes a few weeks. We recommend using posaconazole delayed-release tablets (300 mg every 12 hours on the first day, then 300 mg once daily) with food if possible when switching to oral posaconazole. We don't utilise posaconazole oral suspension because it's not very bioavailable and requires fatty diet to absorb. When using isavuconazole, loading doses are necessary for the first 48 hours. Loading doses of 200 mg (ie, two capsules) of oral isavuconazole (equivalent to 372 mg of the prodrug isavuconazonium sulfate) should be given every 8 hours for six doses, followed by 200 mg orally once daily starting 12 to 24 hours after the last loading dose. Patients were treated with isavuconazole IV or orally. Patients with primary mucormycosis received treatment for 102 days, those with refractory mucormycosis for 33 days, and those with intolerance to other antifungal therapy for 85 days. These findings imply that isavuconazole has some therapeutic efficacy in the treatment of mucormycosis, but due to the nonrandomized trial design and small sample size, strong conclusions cannot be drawn.
For patients who do not respond to or cannot tolerate amphotericin B, we employ posaconazole or isavuconazole as a salvage therapy. Patients who must be shifted from amphotericin B before they have had a positive response or who are unable to absorb oral drugs should receive the IV version of posaconazole or isavuconazole. Therapy should be continued until the signs and symptoms of infection have resolved clinically, as well as the radiographic evidence of current disease; therapy should also be continued until the underlying immunosuppression has been reversed, if possible. If immunosuppression cannot be addressed, some individuals will be on medication for the rest of their lives.
Other possible therapies
Larger studies are needed to establish whether combination therapy is beneficial. Although the echinocandins (eg, caspofungin) have no in vitro activity against the agents of mucormycosis , R. oryzae, the most common cause of mucormycosis, expresses the target enzyme for echinocandins, suggesting that these agents may have clinical utility. The above observations, however, have a number of flaws. Because of the small number of patients and the fact that they all had surgical debridement, determining the influence of antifungal medication on outcomes was difficult. Furthermore, the patients were mostly non-neutropenic. Because modulation of the host neutrophil response is thought to occur when echinocandins are used to treat infections with filamentous fungus, this could have altered the response to antifungal therapy. Voriconazole, fluconazole, and flucytosine, among other antifungal medications, are ineffective against Mucorales.
Studies in mice with mucormycosis found that these agents might actually be beneficial (eg, improve survival and reduce the tissue fungal burden). Deferasirox, on the other hand, has not been sufficiently investigated in people as an additional treatment for mucormycosis and should not be utilised. Small studies have looked into the potential utility of adjunctive deferasirox, with conflicting results. One possible explanation for the poorer outcomes in patients who got deferasirox is that the drug was given to more individuals with hematologic malignancy, neutropenia, and/or pulmonary involvement, all of which are linked to poor outcomes. Deferasirox's potential benefits and risks will need to be investigated further.
Hyperbaric oxygen has been used in some patients with mucormycosis, but the benefit of this therapy has not been established.
The prognosis for recovery from mucormycosis is dismal, despite early diagnosis and vigorous combination surgical and medicinal therapy. The cutaneous involvement, which seldom disseminates, is an exception. Disseminated infection, renal failure, and infection with Cunninghamella species are all independent risk factors for death. The following are some of the precautions that can be taken to avoid contracting the yellow fungus:
I Keep your room, home, and surroundings as clean as possible; ii) Remove stale food and faeces as soon as possible to prevent bacteria and fungus growth; iii) Control the humidity in your room and home to prevent bacteria growth. Maintaining clean air flow inside the room and residence is essential, just as it is for Covid patients. iv) Patients who test positive for the coronavirus must begin treatment right away to avoid consequences like yellow fungus.
- Corey KE, Gupta NK, Agarwal S, Xiao HD. Case records of the Massachusetts General Hospital. Case 32-2013. A 55-year-old woman with autoimmune hepatitis, cirrhosis, anorexia, and abdominal pain. N Engl J Med 2013; 369:1545.
- Shields JA, Shields CL. Eyelid, Conjunctival, and Orbital Tumors: An Atlas and Textbook, 3rd ed, Lippincott Williams & Wilkins, Philadelphia 2016.
- Placik DA, Taylor WL, Wnuk NM. Bronchopleural fistula development in the setting of novel therapies for acute respiratory distress syndrome in SARS-CoV-2 pneumonia. Radiol Case Rep 2020; 15:2378.
- Kanwar A, Jordan A, Olewiler S, et al. A Fatal Case of Rhizopus azygosporus Pneumonia Following COVID-19. J Fungi (Basel) 2021; 7.
- Monte Junior ESD, Santos MELD, Ribeiro IB, et al. Rare and Fatal Gastrointestinal Mucormycosis (Zygomycosis) in a COVID-19 Patient: A Case Report. Clin Endosc 2020; 53:746.
- Mekonnen ZK, Ashraf DC, Jankowski T, et al. Acute Invasive Rhino-Orbital Mucormycosis in a Patient With COVID-19-Associated Acute Respiratory Distress Syndrome. Ophthalmic Plast Reconstr Surg 2021; 37:e40.
- Werthman-Ehrenreich A. Mucormycosis with orbital compartment syndrome in a patient with COVID-19. Am J Emerg Med 2021; 42:264.e5.