Dear Sir,
We read the recent article titled "Paranasal Mucormycosis in COVID-19 Patient" by Saldanha M et al. [1] with great interest. The authors did a fantastic job highlighting the importance of a fatal disease at this crucial time. We would like to draw attention to a spike of mucormycosis in COVID-19 suffered or recovered patients. Immunocompromised COVID-19 patients are vulnerable to rhino-orbital-cerebral mucormycosis, which is a life-threatening opportunistic invasive fungal infection caused by mucoromycetes [2, 3]. The mortality rate even with the treatment is around 50% [4]. A high index of suspicion, a low threshold for diagnosis, immediate and accurate management with aggressive surgical debridement and systemic antifungal therapy remains the standard of care. The targeted points for attention are described below which might be helpful for the halt of this epidemic.
At-Risk Population
Those with uncontrolled diabetes mellitus and diabetic ketoacidosis, history of treatment with corticosteroids therapy [5], organ or bone marrow transplant, other forms of metabolic acidosis, neutropenia [6], increased serum iron levels [7], deferoxamine or iron chelation therapy in patients of hemodialysis [8], and malignant hematologic disorders [8].
COVID-19 Related Immunosuppression
This viral infection causes significant immunosuppression due to lymphopenia, reduced CD4 and CD8 T cells [9,10,11]. There is a huge inflammatory cytokine surge, increased neutrophils, and endotheliolitis [11]. It induces a prothrombotic state by directly invading the endothelium and causing diffuse endothelial inflammation [10,11,12]. It also induces pre-diabetic state [13].
Corticosteroids Related Immunosuppression
They are the mainstay in COVID-19 management and are used for immunomodulation-related lung damage. Being no definitive treatment for COVID-19, only systemic corticosteroids have shown improved survival [14], but at the cost of an exhausted immune response. It induces hyperglycemia [15] with impaired neutrophil migration and phagolysosome fusion [16, 17]. According to Indian guidelines moderate cases should get systemic methylprednisolone 0.5-1 mg/kg/day or dexamethasone 0.1–0.2 mg/kg for three days within 48 h of admission, if inflammatory markers are raised or need for mechanical ventilation is present. Severe cases should get systemic methylprednisolone 1-2 mg/kg/day or dexamethasone 0.2–0.4 mg/kg for 5–7 days [12].
Uncontrolled Gycemic Index
Those with diabetes are at an increased risk of complication and mortality than non-diabetics [18]. A rapid diagnosis can result in lowering mortality. Impaired neutrophil function causes defective chemotaxis, transmembrane migration, and reduced superoxide production [19]. Reduced binding of transferrin to iron in acidotic conditions favors the growth of mucor [20]. Increased expression of endothelial receptors GRP-78 will result in dysfunction of polymorphonuclear cells leading to defect in chemotaxis and intracellular apoptosis [21]. Increase GRP-78 mediates invasion and damage of human endothelial cells by Rhizopus oryzae [22]. Structural and functional modifications of platelets results in defective membrane properties and alterations of nitric oxide metabolism [23]. Active ketone reductase system in uncontrolled diabetes favors growth in the acidic and glucose-rich environment [24].
Preventive Measures
Judicious use of corticosteroids, antifungals, and broad-spectrum antibiotics is recommended. One should not initiate early and high-dose corticosteroid therapy. They are recommended at titrated doses with strict sugar monitoring. The target to control hyperglycemia during the management of COVID-19 and after recovery should be kept in mind. Stringent follow-up is necessary in high-risk COVID-19 patients [12]. Drugs like tocilizumab should be discouraged as they reduce immunity [25]. High-risk patients should be advised to wear a mask all the time after recovery and change it regularly, avoid dusty and soil areas, gardening and maintain personal hygiene. A separate set of instruments and endoscope for the debridement of mucormycosis. Adequate sterilization of endoscope, instruments, and operating room to prevent cross-infection.
Measures for Early Detection
An extensive examination of COVID-19 patients and not ignoring the red flag symptoms that can detect the dreaded disease at the earliest. Diagnostic nasal endoscopy and biopsy for KOH smear in high-risk patients such as those admitted in ICU, on steroids therapy, more than 50 days of hospital stay, on mechanical ventilation, or high levels of IL6 and ferritin [26]. The high-risk patients when undergoing HRCT thorax may be advised for added scans of the nose, paranasal sinuses, and brain for early detection.
Alarming Signs of Mucormycosis
Development of nasal obstruction, nasal crusting, foul or bloody nasal discharge, unilateral facial or orbital pain, facial palsy, facial numbness, blackening of nose or cheek, headache, toothache, loosening of tooth, palatal eschar, periorbital swelling, diplopia, blurred vision, ptosis, proptosis, reduced vision, focal seizures [27].
Goals of Management of Mucormycosis
A delay of even 6 days in beginning the treatment raises the mortality from 35 to 66% [12]. To minimize the mortality, the three main goals are reversal of the underlying immunosuppression. Aggressive debridement to reduce fungal load and for faster penetration of antifungal therapy. Systemic antifungals are paramount in the management with surgical debridement [12].
Finally, I thank the authors and hope that they and readers find some of this information useful.
References
Saldanha M, Reddy R, Vincent MJ (2021) Paranasal Mucormycosis in COVID-19 Patient. Indian J Otolaryngol Head Neck Surg. 22:1–4. https://doi.org/10.1007/s12070-021-02574-0
Lin E, Moua T, Limper AH (2017) Pulmonary mucormycosis: clinical features and outcomes. Infection 45:443–448
Peng M, Meng H, Sun Y, Xiao Y, Zhang H, Lv K et al (2019) Clinical features of pulmonary mucormycosis in patients with different immune status. J Thorac Dis 11:5042–5052
Werthman-Ehrenreich A (2020) Mucormycosis with orbital compartment syndrome in a patient with COVID-19. The Am J Emerg Med 42:264.e5-264.e8
Waizel-Haiat S, Guerrero-Paz JA, Sanchez-Hurtado L, Calleja-Alarcon S, Romero-Gutierrez L (2021) A case of fatal rhino-orbital mucormycosis associated with new onset diabetic ketoacidosis and COVID-19. Cureus 13(2):e13163
Serris A, Danion F, Lanternier F (2019) Disease entities in mucormycosis. J Fungi 5(1):23
Ibrahim AS, Spellberg B, Walsh TJ, Kontoyiannis DP (2012) Pathogenesis of mucormycosis. Clin Infect Dis 54:1–7
Hirabayashi KE, Idowu OO, Kalin-Hajdu E et al (2019) Invasive fungal sinusitis: risk factors for visual acuity outcomes and mortality. Ophthalmic Plast Reconstr Surg 35:535–542
Yang W, Cao Q, Qin L, Wang X, Cheng Z, Pan A et al (2020) Clinical characteristics and imaging manifestations of the 2019 novel coronavirus disease (COVID-19): a multi-center study in Wenzhou city, Zhejiang, China. J Infect 80:388–393
Gangneux JP, Bougnoux ME, Dannaoui E, Cornet M, Zahar JR (2020) Invasive fungal diseases during COVID-19: we should be prepared. J Mycol Med 30:100971
Liu J, Li S, Liu J et al (2020) Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARSCoV- 2 infected patients. EBioMedicine 55:102763
Sen M, Lahane S, Lahane TP, Parekh R, Honavar SG (2021) Mucor in a viral land: a tale of two pathogens. Indian J Ophthalmol 69:244–252
Müller JA, Groß R, Conzelmann C et al (2021) SARS-CoV-2 infects and replicates in cells of the human endocrine and exocrine pancreas. Nat Metab 3:149–165
The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group (2020) Association Between administration of systemic corticosteroids and mortality among critically Ill patients with COVID-19: a meta-analysis. JAMA 324(13):1330–1341
Tamez-Pérez HE, Quintanilla-Flores DL, Rodríguez-Gutiérrez R, González-González JG, Tamez-Peña AL (2015) Steroid hyperglycemia: prevalence, early detection and therapeutic recommendations: a narrative review. World J Diabetes 6(8):1073–1081
Hoang K, Abdo T, Reinersman JM, Lu R, Higuita N (2020) A case of invasive pulmonary mucormycosis resulting from short courses of corticosteroids in a well-controlled diabetic patient. Med mycol case rep 29:22–24
White PL, Dhillon R, Cordey A et al (2020) A national strategy to diagnose COVID-19 associated invasive fungal disease in the ICU. Clin Infect Dis. https://doi.org/10.1093/cid/ciaa1298
Apicella M, Campopiano MC, Mantuano M, Mazoni L, Coppelli A, Del Prato S (2020) COVID-19 in people with diabetes: understanding the reasons for worse outcomes. Lancet Diabetes Endocrinol 8(9):782–792
Shetty N, Thomas B, Ramesh A (2008) Comparison of neutrophil functions in diabetic and healthy subjects with chronic generalized periodontitis. J Indian Soc Periodontol 12(2):41–44
Simcox JA, McClain DA (2013) Iron and diabetes risk. Cell Metab 17(3):329–341
Sabirli R, Koseler A, Goren T, Turkcuer I, Kurt O (2021) High GRP78 levels in COVID-19 infection: A case-control study. Life Sci 265:118781
Liu M, Spellberg B, Phan QT, Fu Y, Fu Y, Lee AS, Edwards JE Jr, Filler SG, Ibrahim AS (2010) The endothelial cell receptor GRP78 is required for mucormycosis pathogenesis in diabetic mice. J Clin Invest 120(6):1914–1924
Kaur R, Kaur M, Singh J (2018) Endothelial dysfunction and platelet hyperactivity in type 2 diabetes mellitus: molecular insights and therapeutic strategies. Cardiovasc Diabetol 17(1):121
Anand VK, Alemar G, Griswold JA Jr (1992) Intracranial complications of mucormycosis: an experimental model and clinical review. Laryngoscope 102:656–662
Kimmig LM, Wu D, Gold M, Pettit NN, Pitrak D, Mueller J et al (2020) IL-6 inhibition in critically Ill COVID-19 patients is associated with increased secondary infections. Front Med (Lausanne). 7:583897
Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H et al (2020) Clinical course and outcomes of critically ill patients with SARSCoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med 8:475–481
Honavar SG (2021) Code mucor: guidelines for the diagnosis, staging and management of Rhino-Orbito-Cerebral mucormycosis in the setting of COVID-19. Indian J Ophthalmol 69:1361–1365
Acknowledgements
This manuscript is original and it, or any part of it, has not been previously published; nor is it under consideration for publication elsewhere. There exists no conflict of interest among the authors and there are no financial disclosures to be made. Being a Letter to the Editor, it is exempted from the ethical requirements of the institutional review board.
Funding
Nil.
Author information
Authors and Affiliations
Contributions
BS Conceptualization of the article and revising it critically for important intellectual content. MC Conception and drafting of article, formal analysis and final approval of the version. NS Manuscript preparation and update the references, final approval of the version.
Corresponding author
Ethics declarations
Conflicts of interest
Nil.
Ethical Approval
This manuscript is exempted from the ethical requirements as it does not contain any human or animal research.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Solanki, B., Chouhan, M. & Shakrawal, N. Mucor Alert: Triad of COVID-19, Corticosteroids Therapy and Uncontrolled Glycemic Index. Indian J Otolaryngol Head Neck Surg 74 (Suppl 2), 3075–3077 (2022). https://doi.org/10.1007/s12070-021-02801-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12070-021-02801-8