Insult to injury: COVID-19-associated mucormycosis
By Warren Heymann, MD
June 9, 2021
Vol. 3, No. 23
As America unmasks this Memorial Day, COVID-19 is ravaging India. The scenes of desperation stemming from the overwhelmed heath system, poverty, and funeral pyres are almost unfathomable. In the midst of the devastation, doctors in India have observed an increasing number of patients with COVID-19 who developed mucormycosis concurrently or post-recovery. (1)
Mucormycosis is an emergent angio-invasive mycosis caused by opportunistic fungi classified in the phylum Mucoromycota (formerly Zygomycetes). The most frequently isolated species causing cutaneous disease is Rhizopus arrhizus (formerly R. oryzae). Mucormorales are ubiquitous saprophytes gaining entry through the nasal, respiratory, and palatal mucosa, and through skin abrasion or loss of the skin barrier. In their review of 115 cases of cutaneous mucormycosis, Bonifaz et al demonstrated that 18 cases were primary and 97 secondary. Primary cutaneous mucormycosis was most frequently associated with adhesive bands (44.4%) and trauma from traffic accidents (33.3%), presenting as extensive and deep necrotic ulcers. Secondary cutaneous mucormycosis cases were rhino-cerebral with uncontrolled diabetes (81.4%), most frequently presenting as necrosis of the eyelid and the nose (65.9%). The most effective treatment was the combination of amphotericin B with surgical debridement. Clinical and mycological cure was achieved in 31.0% of primary cases and 44.4% of secondary cases. (2)
Garg et al detailed the case of a 55-year-old man with diabetes and end-stage renal disease who was diagnosed with pulmonary mucormycosis 21 days following admission for severe COVID-19 infection. He was treated successfully with liposomal amphotericin B. The authors reviewed 8 cases of COVID-19-associated mucormycosis (CAM) reporting that diabetes mellitus is the most common risk factor. Three of the 8 patients had rhinocerebral disease. In addition to diabetes, classical risk factors for mucormycosis include hematological malignancies and iatrogenic immunosuppression in transplant patients. Interestingly, 3 subjects had no risk factor other than glucocorticoid therapy for COVID-19. (3)
John et al reviewed 41 cases of CAM. The majority of cases (71%) were from India. CAM was typically seen in patients with diabetes mellitus (DM) (94%) especially patients who were poorly controlled (67%) and severe or critical COVID-19 (95%). The presentation was typical of mucormycosis seen in diabetic patients (mostly rhino-orbital and rhino-orbital-cerebral presentation). (4)
According to Alekseyev et al: “In rhinocerebral mucormycosis, the disease’s hallmark is attributed to tissue necrosis from angioinvasion and subsequent thrombosis. This presents as notoriously black, necrotic eschars. The fungi gain entry via inhalation into the paranasal sinuses and may ultimately spread to the sphenoid sinus, palate and cavernous sinus. Patients may complain of blurry vision, inflammation around the orbit, sinusitis, facial pain or numbness, headache, proptosis, ophthalmoplegia, or even periorbital cellulitis.” (5) The diagnosis is confirmed by imaging (CT, MRI) of the brain, sinuses, and orbit; biopsy (demonstrating inflammation, edema, thrombosis, necrosis, and coenocytic hyphae accentuated by PAS and/or GMS stains), culture, and/or PCR. (1,5).
Regarding pathogenesis of CAM, steroid therapy, which can be life-saving in viral pneumonia, may be a “double-edged sword,” predisposing patients to secondary bacterial and fungal infections. (6) CAM may be related to the “endothelialitis” observed in severe COVID-19 infections. John et al opine: “Interestingly, acidemic states and hyperglycemia induce the enthodelial receptor glucose-regulated protein (GRP 78) and the Mucorales adhesin spore coat protein homologs (CotH), creating a “perfect storm” for increased adhesion and penetration of Mucorales to the endothelium. Of interest, GRP 78 has been postulated as one of the receptors responsible for SARS-CoV-2 entry.” (4) Importantly, many families are self-medicating (presumably at least some with steroids) and applying oxygen therapy at home without proper hygiene. (1) These practices could predispose patients to CAM.
The paradox between the United States and India regarding COVID-19 could not be starker. I hope that by the time you read this commentary the situation in India has vastly improved, both in terms of vaccination rate and COVID-19 prevalence.
Point to Remember: Patients with severe COVID-19 infection, especially those who are diabetic, have an increased risk of developing mucormycosis. Any complaints related to the rhino-cerebral-orbital region must be assessed immediately to thwart this devasting infection.
Our expert's viewpoint
Arun C Inamadar MD, FRCP(Edinburgh)
Department of Dermatology
Vijayapura – 586103, Karnataka, India
India is witnessing a downswing in the second wave of COVID-19 at present after a steady decline in fresh infections. Unfortunately, India is now swamped with mucormycosis cases as a post-COVID-19 infection complication. In our own university hospital almost 70 cases of mucormycosis underwent treatment. Only one had secondary cutaneous mucormycosis as evidenced by eschar over nose and peri-orbital area. They were all managed by a team of otolaryngologists, maxillofacial surgeons, and intensivists with surgical debridement and with drugs specific for mucormycosis; there was hardly a role for dermatologists.
The issues faced by dermatologists in India are twofold. One being teaching-learning with residents training at various medical institutes and universities and the other involving a huge chunk of practicing dermatologists.
As the outpatient and inpatient visits and admissions dwindled due to pandemic and lockdowns, teaching-learning was mainly dependent upon teledermatology, online social media, and platforms like Zoom. Most of the teaching-learning activities were conducted as webinars to update ourselves, while cancelling all the offline CMEs and conferences. Evaluation of residents was also done on virtual mode in many university exams. Case scenarios were discussed in place of live case demonstrations. As dermatology is a visual specialty, the transformation to such teaching-learning was easy. Contributions of both the residents and teachers of dermatology as first-line warriors of the pandemic are being utilized by COVID care hospitals.
The initial wave of COVID-19 till this day still affects a large contingent (almost 10K) of practicing dermatologists, notably: running a safe dermatology practice, managing inflammatory disorders with immunosuppressive agents, and appropriately performing procedural dermatology, including laser use and aesthetic procedures. Guidelines developed by professional societies were published on a war footing to guide the specialty based on available literature on the COVID-19 virus. Online consultation platforms were used by many to cater to the needs of medical dermatology patients. Challenges of prescribing immunosuppressive and biologics were unfolded as the literature started pouring about correct use of them and the window period to wait in case of associated COVID infections.
There were challenges to diagnose and manage the initial cutaneous manifestations of COVID-19 infections like the COVID toe (chilblain-like), first reported condition in western literature was not that common in India (presumably because of the less severe winter compared to Europe and USA). The commonest manifestations were a morbilliform rash (like any viral exanthema), varicelliform eruptions, urticaria, and pityriasis rosea (PR)-like eruptions. Surprisingly, there was increased incidence of herpes zoster (HZ). After the first wave declined, aesthetic and laser procedures were added to treat the patients with whatever strict guidelines were advised by local associations and even international literature on guidelines.
When the Indian government started inoculating all health care workers, few vaccine-related skin manifestations were noted such as a PR-like rash, cutaneous small vessel vasculitis-like lesions, and HZ. As vaccination was administered to many health care workers, gradually outpatient service was started till the second wave of COVID-19 hit India with a vengeance! Dermatology practice again became standstill, with online consultations and direct patient care for only for patients with severe inflammatory conditions like pemphigus, severe psoriasis, systemic lupus, etc.
Another issue faced by dermatologists was offering guidance to patients who are on prolonged immunosuppressive agents such as steroids, methotrexate, or rituximab regarding vaccination, once the government of India started vaccinating persons above 45 years of age. Guidelines helped us accordingly.
In a nutshell, Indian dermatologists have faced — and are still facing — the pandemic with many issues: care of common dermatology ailments taking the backseat, the resistant dermatophyte infection epidemic continuing without guidance of treatment complicated by patient self-medication, social stigma attached with vitiligo continuing with non-availability of expert advice and necessary phototherapy, etc. The fear of managing chronic inflammatory conditions like psoriasis with “poor man’s biologic” methotrexate and rituximab use in pemphigus has raised huge question marks in the prevailing pandemic.
This pandemic has made us think how all the medical fraternity in general, and dermatologists in particular, can be prepared for such medical disasters. We are fortunate being a visual specialty where digital solutions can assist us in managing patients from afar.
Bonifaz A, Tirado-Sánchez A, Hernández-Medel ML, Kassack JJ, Araiza J, González GM. Mucormycosis with cutaneous involvement. A retrospective study of 115 cases at a tertiary care hospital in Mexico. Australas J Dermatol. 2021 May;62(2):162-167. doi: 10.1111/ajd.13508. Epub 2020 Nov 22. PMID: 33222179.
Garg D, Muthu V, Sehgal IS, Ramachandran R, Kaur H, Bhalla A, Puri GD, Chakrabarti A, Agarwal R. Coronavirus Disease (Covid-19) Associated Mucormycosis (CAM): Case Report and Systematic Review of Literature. Mycopathologia. 2021 May;186(2):289-298. doi: 10.1007/s11046-021-00528-2. Epub 2021 Feb 5. PMID: 33544266; PMCID: PMC7862973.
John TM, Jacob CN, Kontoyiannis DP. When Uncontrolled Diabetes Mellitus and Severe COVID-19 Converge: The Perfect Storm for Mucormycosis. J Fungi (Basel). 2021 Apr 15;7(4):298. doi: 10.3390/jof7040298. PMID: 33920755; PMCID: PMC8071133.
Alekseyev K, Didenko L, Chaudhry B. Rhinocerebral Mucormycosis and COVID-19 Pneumonia. J Med Cases. 2021 Mar;12(3):85-89. doi: 10.14740/jmc3637. Epub 2021 Jan 19. PMID: 33984095; PMCID: PMC8040444.
Ahmadikia K, Hashemi SJ, Khodavaisy S, Getso MI, Alijani N, Badali H, Mirhendi H, Salehi M, Tabari A, Mohammadi Ardehali M, Kord M, Roilides E, Rezaie S. The double-edged sword of systemic corticosteroid therapy in viral pneumonia: A case report and comparative review of influenza-associated mucormycosis versus COVID-19 associated mucormycosis. Mycoses. 2021 Feb 16:10.1111/myc.13256. doi: 10.1111/myc.13256. Epub ahead of print. PMID: 33590551; PMCID: PMC8013756.
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