| Abstract|| |
Mucormycosis is an invasive fungal infection that has been increasing in incidence over the years. Increase in the number of diabetics, malignancy patients, and use of immunosuppressants has mainly led to this gradual upward surge. Mucormycosis has various clinical forms, including rhino-orbito-cerebral, pulmonary, gastrointestinal, and cutaneous. Fungi belonging to Mucorales are thermotolerant and ubiquitous, found growing on organic substrates such as bread, decaying fruits and vegetables, crop debris in soil, compost, and animal excreta. During this second wave of the COVID-19 pandemic, the number of cases of mucormycosis has increased manifold in a short span of time. Associated comorbidity of diabetes mellitus, increased use of higher doses and prolonged duration of systemic corticosteroids, the glucogenic and prothrombotic propensity of the virus, hypoxic environment, COVID pneumonia, increased hospitalization, ICU admissions, and mechanical ventilation have all contributed toward this high rise in numbers. The rhin-orbito-cerebral form is the commonest manifestation of mucormycosis in COVID. Rhizopus oryzae, the main species causing mucormycosis, is identified by hyaline, sparsely-septate, broad, ribbon-like hyphae with irregular right-angle branching ribbon-like hyphae with rhizoids. For the early diagnosis of this infection, 10% KOH mount is very important. These fungi are very rapidly growing and thus can be differentiated from their main ally, Aspergillus. Treatment is mainly in the form of extensive surgical debridement along with liposomal amphotericin B. Posaconazole and isavuconazole are second-line agents, which can also be used for maintenance. Control of diabetes and COVID-19, along with judicious use of antibiotics and systemic corticosteroids, are equally important as management strategies in these pandemic times.
Keywords: Amphotericin B, COVID-19, cutaneous, mucormycosis, rhino-orbito-cerebral, Rhizopus
|How to cite this article:|
Vasudevan B, Hazra N, Shijith K P, Neema S, Vendhan S. Mucormycosis: The Scathing Invader. Indian J Dermatol 2021;66:393-400
| Introduction|| |
Mucormycosis is the third-most important fungal infection worldwide next to candidiasis and aspergillosis. Cases of mucormycosis have been showing a gradual increase in the last two decades mainly due to an increase in the number of patients on immunosuppressive medications and widespread use of polymicrobial antibiotics. However, the second wave of COVD-19 has brought an unprecedented number of mucormycosis cases to the forefront. This review is an attempt to give an insight into various aspects of this devastating angio-invasive fungal infection that has already resulted in a lot of mortality and morbidity.
A systematic search of the literature was conducted on the electronic databases of PubMed and Google scholar for the period from January 1, 2000 to April 30, 2021 using keywords Mucormycosis, Mucor, Rhizopus, and COVID-19. Discussion related to the Mucormycosis infection and also the surge in cases due to COVID-19 were given priority in the review.
| Taxonomy|| |
Mucormycosis is an opportunistic fungal infection caused by a group of filamentous molds belonging to the zygomycete family. Zygomycetes are classified into two main orders, namely Mucorales and Entomophthorales. Mucormycosis causing human infection mostly belongs to the order Mucorales. Fungi belonging to Mucorales are thermotolerant and ubiquitous, found growing on organic substrates such as bread, decaying fruits and vegetables, crop debris in soil, compost, and animal excreta. Mucoraceae, Cunninghamellaceae, Mortierellaceae, Saksenaceae, Syncephalastraceae, and Thamnidaceae are the families in this order. The most common genera in the family Mucoraceae are Rhizopus, Mucor, Absidia (Lichtheimia), and Apophysomyces. Among all the species, Rhizopus oryzae is responsible for 70% of all mucormycosis cases. Other common species include Rhizopus microsporus, Cunninghmaella bertholletiae, Apophysomyces elegans, and Saksenaea vasiformis. These are thermotolerant fungi found mainly in soil and decaying matter.
| Epidemiology|| |
There has been a rising trend of these infections, especially in the 21st century with each progressing year. This rise is mainly attributed to the increasing number of immunocompromised patients globally and better availability of diagnostic methods. The prevalence of mucormycosis in developing countries is 80 times higher than in developed countries. The prevalence of mucormycosis is approximately 0.1–2 cases per million worldwide, while studies from India have reported a prevalence of approximately 140 cases per million, which contributes to most of the cases globally., Globally rise in hematological malignancies and use of immunosuppressive medications have been incriminated as the reason for the increase, while in India, it is mainly due to an increase in the number of diabetic patients and secondarily due to inoculation through trauma. Further, the rhino-orbito-cerebral form is more common in diabetics, while the pulmonary form is more commonly found among patients with hematological malignancies., It is more common in males and at a mean age of 60 years., The main mode of acquiring infection is the result of inhalation of sporangiospores or inoculation of wounds. Rarely ingestion of contaminated food can lead to the gastrointestinal form. Nosocomial mucormycosis is attributed to contaminated wound dressings, catheter insertion, and needle pricks.
| Risk Factors|| |
Major risk factors for mucormycosis are uncontrolled type 2 diabetes mellitus especially with ketoacidosis, use of systemic corticosteroids and polymicrobial antibiotics, organ transplantation, neutropenia, malignant hematologic disorders, HIV, desferrioxamine therapy in patients receiving hemodialysis, malnutrition, trauma, and burns., Post-tuberculosis sequelae and chronic kidney disease play an important role in developing countries., Use of voriconazole for suppressing Aspergillus infections in transplant patients has been blamed in few studies. India has a high prevalence of type 2 diabetes mellitus, which is a risk factor for developing the infection.
| Pathogenesis (The Angio-Invader)|| |
The pathogenesis of mucormycosis is attributed to impaired neutrophil migration and impaired macrophage function, which is aggravated by poorly controlled blood glucose, acidic pH, and hyperglycemia of ketoacidosis., Prolonged high-dose corticosteroids and immunosuppressive agents play an important role resulting in impaired migration of neutrophils or ingestion by phagolysosome fusion in macrophages.
Free iron in serum plays a critical role in predisposing patients with diabetic ketoacidosis to mucormycosis as it supports the growth of Rhizopus oryzae at acidic pH., Patients receiving desferrioxamine are susceptible to mucormycosis as it strips ferric iron from transferrin and attaches itself to the mold through an inducible receptor that helps in transferring iron into the fungal body., Fungi can obtain iron from the host by using high-affinity iron permeases or low-molecular-weight iron chelators (siderophores). Rhizopus secretes rhizoferrin, a siderophore that supplies Rhizopus iron through a receptor-mediated and energy-dependent process. Use of heme from the host especially if receiving blood transfusions is probably another method for acquiring iron. Thus, an increase in serum glucose, iron, and ketone bodies can lead to an increase in the growth of Mucorales.
The fungus causes extensive angioinvasion, leading to vessel thrombosis and subsequent tissue necrosis. Damage and penetration through endothelial cells or extracellular matrix proteins lining blood vessels is an important step in the pathogenesis., This angioinvasion could be the result of interaction between the spore-coating protein family known as CotH on the fungal surface with glucose regulator protein 78 (GRP78) receptor expressed on the endothelial cell surface, leading to injury to endothelial cells and later hematogenous dissemination. The ischemic necrosis in the infected tissues also prevents the soldier leukocytes from helping in defense and also antifungal agents from reaching the focus.
| Clinical Manifestations (The Body Invader)|| |
Mucormycosis can have various clinical forms, which include rhino-orbito-cerebral, pulmonary, gastrointestinal, cutaneous, renal, and disseminated. Infection of bones, heart, ear, parotid gland, uterus, urinary bladder, and lymph nodes have also been reported., Rhino-orbito-cerebral (39%) is the commonest form, followed by pulmonary (24%), skin (19%), brain (9%), gastrointestinal tract (7%), and disseminated disease (6%). A much higher proportion of skin and soft tissue involvement has been reported in immunocompetent patients.
As it is a fungus with low virulence, it may inhabit the nasal mucosa in healthy people as a commensal. Once the patient is immunosuppressed, the fungus can sporulate within the paranasal sinuses and then spread to nearby orbit or intracranially, thus explaining the common occurrence of the rhino-orbito-cerebral form.
Clinically, rhino-orbito-cerebral mucormycosis can present initially with blocked nose, nasal crusting, epistaxis, facial pain, and edema. Later, they can progress to signs and symptoms of sinusitis (headache and fever), proptosis, ptosis, chemosis, ophthalmoplegia, and various neurological signs and symptoms when complications such as cavernous sinus thrombosis and neurological extension occur [Figure 1]. A black eschar in the nasal cavity or hard palate region is an early marker of definite mucormycosis, though it may be present in only 50% of cases. Poor prognostic markers include delay in treatment, evidence of intracranial extension, bilateral involvement, and invasion of palate.
|Figure 1: Rhino-orbito-cerebral form of Mucormycosis manifesting as periorbital edema on the right side|
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The pulmonary alveolar macrophages are inefficient in handling the fungus in immunosuppressed patients. Manifestations of pulmonary involvement are difficult to differentiate from that of aspergillosis and include fever, hemoptysis, dyspnea, and pleural pain. Endobronchial and tracheal invasion along with the involvement of great vessels could lead to fatal hemoptysis.
Gastrointestinal mucormycosis can involve the large intestine, stomach, small intestine, and esophagus, and patients present with abdominal pain, gastrointestinal bleed, abdominal distension, or diarrhea. It is common in neonates.
Endocarditis is the commonest cardiac manifestation. Isolated renal involvement is rare. Disseminated forms mainly include lungs, central nervous system, liver, and kidney.
Cutaneous mucormycosis is not uncommon and occurs as a result of disruption of the skin barrier, which acts as a host defense against the infection. Major predisposing factors contributing to the cutaneous form include penetrating trauma, contamination of burns or open wounds with soil or decaying matters as a result of motor vehicle accidents, natural disasters, IV drug abuse, insect bites, and scratches., Acquired infection in the hospital care setting occurs as a result of contaminated dressings, needles, and surgeries. Outbreak of cutaneous mucormycosis as a result of contaminated elastoplastic bandages in 1970 had helped us to look into this mode of transmission more seriously.
Cutaneous mucormycosis can be classified based on its extent as localized, which is restricted to the cutaneous and subcutaneous tissue without involving the adjacent tissues, and deep extension, which refers to the invasion of muscles, bones, and tendons, or as a part of disseminated infection. The characteristic cutaneous lesion of mucormycosis is a necrotic eschar with surrounding erythema and induration [Figure 2]. The localized form can manifest as bullae, pustules, ulcers, abscesses, zosteriform lesions, granulomatous pyoderma, annular plaques, or erythema multiforme-like lesions. There may be associated pain, redness, and swelling. A cotton-like growth can be seen on the surface in extensive lesions giving rise to the terminology "hairy pus." Cutaneous manifestations can also be a part of disseminated infection and are seen in 16%–20% of cases.
|Figure 2: Cutaneous form of Mucormycosis manifesting as eschar on the left side of the mouth|
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Clinical diagnosis criteria as given by Smith and Kirchner in 1950 remains the gold standard for diagnosis of Mucormycosis:
- Necrotic black turbinate
- Bloody nasal discharge with ipsilateral facial pain
- Indurated and discolored, soft periorbital or perinasal swelling
- Eyelid ptosis, eyeball proptosis, and ophthalmoplegia
- Multiple cranial nerve palsies with no documented cause.
The fungus is rapidly and extremely invasive and can result in mortality rates from 33.3%–80% to 100% in disseminated infections. A delay in diagnosis even by 12 hours is considered to be fatal in this angio-invasive infection. Early diagnosis of cutaneous mucormycosis may be responsible for the lower rate of mortality associated with cutaneous forms.
| Mucormycosis in COVID-19 (The Corona Invader)|| |
COVID 19 has been a very difficult pandemic to manage mainly because of the pneumonia and thrombosis aspects.,, Secondary infections of both bacterial and fungal nature have been reported in the COVID pandemic ever since it started in December 2019. Mucormycosis has been known to increase in incidence following natural disasters such as the tsunami in 2004 in India or the Missouri tornado in 2011. During the SARS-CoV pandemic in 2003 as well, fungal infection was the main cause of death in patients with severe acute respiratory syndrome, accounting for 25%–73.7% of deaths.
However, the exponential increase during the coronavirus pandemic has been unprecedented. In the first wave, patients were mainly managed with home isolation and steroids in few cases. However, with the second wave, many patients required steroids in higher doses and for longer durations and they also required high-flow oxygen for a long duration due to hypoxia. A lot more patients required mechanical ventilation.
Diabetes as a common comorbidity, pre-existing alveolo-interstitial lung disease, higher use of steroids and other immunosuppressives, covid pneumonia, higher chances of nosocomial infection, prolonged ICU stays, hospitalization, mechanical ventilation, and immune alterations of Covid-19 infection have contributed to this increase in cases of mucormycosis.,
Diabetes itself being a predisposing factor for not only fungal infections but also more severe covid infection is probably the biggest factor. Uncontrolled diabetes increases the risk manifold. Renal involvement in diabetes is another problem factor.
Pancreatic involvement by the coronavirus can cause islet cell injury, leading to impaired insulin secretion and thereby glucose intolerance. Virus entry into beta islet cells leads to downregulation of angiotensin-converting enzyme 2 (ACE2), producing increased angiotensin levels, which impairs insulin secretion. This could add to the increased incidence of diabetes in such patients.
The proportionately higher and prolonged use of systemic steroids might have contributed to this cause in another large percentage. Steroids are not only immunosuppressive but also increase levels of blood sugar, both contributing to the increased susceptibility. Many of the mucormycosis cases occurred in patients who were discharged from hospitals and were in their third or fourth week of COVID infection, meaning that the longer use of steroids had a role to play. In diabetics, even 5–14 days of oral corticosteroid therapy was found to predispose patients to mucormycosis.
Overexpression of inflammatory cytokines and impaired cell-mediated immunity (decrease in both CD4+ T and CD8+ T cells) in COVID-19 might be another contributing factor. GRP78 receptor, which is utilized by the SARS-Cov2 virus to gain entry into the endothelial cell, is upregulated in COVID19 infection. Alveolo-interstitial involvement in covid pneumonia can also predispose to mucor involvement of lungs and sinuses.
Mucorales spores thus have an ideal environment to germinate in patients with COVID-19 due to the hypoxia, high levels of glucose, acidic medium provided by diabetic or metabolic acidosis, high iron levels, and decreased immunity due to diminished phagocytic activity, along with risk factors of prolonged hospitalization and mechanical ventilation. Covid-19 infection also causes endothelial damage and thrombosis, facilitating the spread of Mucor. Thus, the glucogenic effect of the virus and hypercoagulable prothrombotic state of the covid patients are also being considered as probable predisposing factors.
Patients of severe COVID having ARDS or MODS cannot be sent for radiological investigations frequently and this may preclude early diagnosis. Also, with the hospital services being heavily loaded with managing COVID per se, the situation may be suboptimal for management of mucormycosis.
India being heavily endemic for mucormycosis poses a much higher risk of this infection to its citizens. Unclean water in the humidifier, use of high-flow oxygen, and modification by zinc levels are other proposed causes with presently no evidence.
It has been found that rhino-orbito-cerebral involvement is the commonest manifestation of mucormycosis in COVID-19 with sinus involvement occurring in 100% cases, orbital in 43%, and cerebral in 9%.
| Investigations|| |
Laboratory diagnosis of mucormycosis includes direct microscopy on Giemsa stain [Figure 3]a or KOH mount [Figure 3]b, which is an inexpensive yet invaluable tool in rapid identification of the fungi., Nasal swabs obtained during diagnostic nasal endoscopy are particularly sensitive specimens. Mucorales generally produce typically nonpigmented, wide (6–25 μm), flat, thin-walled, nonseptate, ribbon-like hyphae with right-angled irregular branching.,
|Figure 3: (a) Smear mount from the biopsy showing the typical ribbon-like broad aseptate hyphae of Rhizopus oryzae (200×, Giemsa stain) and (b) 10% KOH mount showing the aseptate hyphae|
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Biopsy of the lesion can be taken and sent for histopathological examination where fungal hyphae typical of Mucorales can be demonstrated. Histology shows fungal infiltration of blood vessels, vasculitis, thrombosis, tissue infarction, hemorrhage, perineural invasion, and an extensive neutrophilic infiltrate [Figure 4]. Hematoxylin and eosin stain may sometimes show only the cell wall with no structures inside or occasionally very degenerate hyphae. Special stains such as Grocott-methenamine silver and periodic acid-schiff stain can then be used to visualize the fungi.
|Figure 4: High power view on histopathology showing the ribbon-like hyphae of Mucor spp phagocytosed by foreign body giant cells (400×, H and E)|
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Culture is an important tool for the diagnosis of mucormycosis as it can aid in identifying the genus and species responsible for the infection and for antifungal susceptibility testing. Culture has low sensitivity as it can be falsely negative in 50% of the cases., Mucorales grow rapidly within 3–7 days on most fungal culture media such as Sabouraud agar and potato dextrose agar when incubated at 25–55°C, and this can be used to distinguish it from the closely resembling Aspergillus [Figure 5] and [Figure 6]. The hyphae are fibrous or "cotton candy-like." Other characteristic features are light coloration, usually yellow on the reverse of the plate, and multicolored sporulating colonies ranging from white to black. Species of the fungus can be differentiated by the presence of rhizoids, stolons and columella, visualized on lactophenol cotton blue mounts [Figure 7].
|Figure 5: Rapid growth of the Mucor on Sabouraud's Dextrose agar. (a) Multiple Candida colonies with one early colony of Mucormycetes (at 4 hours). (b) 8–10-h-old colony. (c) 24-h-old colony. (d) 48-h-old colony|
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|Figure 6: Aspergillus spp colony morphology on the left to show how it differs from the image of Mucor colony on the right (Saborauds dextrose agar with Chloramphenicol media)|
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|Figure 7: (a and b) Lactophenol cotton blue mount with additional scotch tape mount demonstrating sporangiophores of Rhizopus spp bearing sporangia. The "rhizoids" are visible at the point of origin of the sporangiophores. The light brown color denotes older aerial hyphae (LCB mount, 400×)|
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Molecular methods such as PCR-based techniques can be used to identify the fungus with good specificity. A quantitative multiplex polymerase chain reaction-based 18S rRNA can detect the fungus very early in the infection. Molecular identification by internal transcribed spacer sequencing is strongly recommended as a future technique.
For rhino-orbito-cerebral mucor, nasal endoscopy in initial stages of sinusitis and noncontrast CT of paranasal sinuses are the first-line investigations, and gadolinium-enhanced MRI is better suited for diagnosing intra-orbital or intracranial extension. Sinus opacification, focal bony erosions, extrasinus spread, the black turbinate sign due to cavernous sinus involvement, and intracranial extension strongly indicate mucormycosis [Figure 8] and [Figure 9].
|Figure 8: NCCT PNS and orbits in 3 different cases of invasive rhino-orbital mucormycosis demonstrating mucosal thickening in paranasal sinuses with pre-septal and post-septal left orbital inflammatory changes and associated deformity and proptosis of the globe|
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|Figure 9: Post-contrast fat-suppressed T1W coronal images of MRI in 3 different cases demonstrating "Black Turbinate" sign, invasive rhinosinusitis with orbital extension in right (a) and left (b and c) side respectively. Pre and post-septal extension of inflammatory changes leading to deformity of the globe in fat-suppressed T2WI (d) giving "Guitar pick sign" (e) and associated proptosis (f) demonstrated in FLAIR axial images|
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Pulmonary mucormycosis findings on CT scan include nodules or mass, halo sign, reversed halo sign (area of ground-glass opacity surrounded by a ring of consolidation), consolidation, central necrosis, air-crescent sign, and occlusion of pulmonary vessels on CT angiogram.
| Treatment|| |
The successful management of mucormycosis depends on early suspicion, timely diagnosis, and correction of the predisposing factors. Surgical debridement of the lesion combined with early antifungal therapy helps to improve clinical outcome. Extensive surgical debridement of necrotic areas and surrounding small normal areas is especially important for the rhino-oculo-cerebral form with repeated surgeries required in most cases. This can lead to improvement in a significant number of cases.
Amphotericin B, posaconazole, and isavuconazole are the therapeutic armamentarium available, with amphotericin B being foremost. Polyene liposomal amphotericin B is preferred to amphotericin B deoxycholate as there is reduced nephrotoxicity and intolerance. Amphotericin exerts its antifungal activity by binding to sterols, preferentially ergosterol, which provides structure and rigidity to fungal cells. Dosage of 5–10 mg/kg/day for at least 3 weeks and titrating with PCR is ideal. However, the duration can be varied based on individual response, and maintenance with triazoles can be considered as well. CNS and disseminated forms will need 10 mg/kg doses and longer treatments. The total cumulative dose for the entire therapy ideally is 2.5–3 g. Amphotericin B deoxycholate is cheaper and more easily available and is therefore a viable choice. Serum potassium and renal parameters need constant monitoring during therapy.
Triazoles posaconazole and isavuconazole are considered the second line and salvage therapy for patients intolerant to amphotericin B., IV and oral posaconazole have become recently available and may change treatment in the future considering that present use is mainly in syrup form. It may also be considered for prophylaxis. The standard dose schedule for posaconazole is 200 mg 6 hourly or 400 mg 12 hourly. Isavuconazole is still in the initial stages of use and therefore not prescribed widely though its high bioavailability, linear pharmacokinetics, and broad-spectrum may find favor in the future. A loading dose of 200 mg 8 hourly for 2 days followed by 200 mg once a day is presently the regimen followed.
Itraconazole, terbinafine, voriconazole, and caspofungin have not been found to be effective against mucormycosis. Hyperbaric oxygen, iron chelation with nondesferrioxamine chelators, and granulocyte-macrophage colony-stimulating factor are few other treatment options that have been tried.
| Conclusion|| |
Mucormycosis is an invasive fungal infection that has been steadily increasing in incidence over the years mainly due to an increase in diabetes, malignancies, and use of immunosuppressives. The COVID-19 pandemic has brought it to the limelight with a large number of cases in a short span. Early diagnosis and aggressive management with surgical debridement and antifungal therapy remain the cornerstone of treatment. However, good control of diabetes and COVID-19 infection along with optimum use of steroids will form the best defense against this invader. Prevention of diabetes and COVID-19 infection will form the final fortress, which the fungus will find difficult to breach.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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