CASE SERIES

https://doi.org/10.5005/jp-journals-10071-24025
Indian Journal of Critical Care Medicine
Volume 25 | Issue 11 | Year 2021

Mucormycosis in COVID Diabetic Patients: A Horrifying Triad!

Parshika Panwar1https://orcid.org/0000-0003-0582-5426, Anish Gupta2https://orcid.org/0000-0002-4704-6271, Amit Kumar3https://orcid.org/0000-0002-6491-5010, Bhavna Gupta4https://orcid.org/0000-0002-3108-0408, Shiv C Navriya5https://orcid.org/0000-0003-4859-3979

1Department of General Medicine, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India

2Department of CTVS, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India

3Department of ENT, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India

4Department of Anaesthesia, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India

5Department of Urology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India

Corresponding Author: Shiv C Navriya, Department of Urology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India, Phone: +91 9958365510, e-mail: drshivnavriya2004@gmail.com

How to cite this article: Panwar P, Gupta A, Kumar A, Gupta B, Navriya SC. Mucormycosis in COVID Diabetic Patients: A Horrifying Triad! Indian J Crit Care Med 2021;25(11):1314–1317.

Source of support: Nil

Conflict of interest: None

ABSTRACT

Infectious diseases with the coronavirus disease-2019 (COVID-19) can be linked to various microbial and fungal coinfections. Mucormycosis is an invasive opportunistic infection that enters as inhalation of fungal spores through the nose or paranasal sinuses in diabetic and immunocompromised patients. We present our experience of managing seven cases of recent COVID-19 infection with uncontrolled diabetes who developed rhino-orbital mucormycosis. All patients were diagnosed by clinical examination and imaging and managed by emergency surgical debridement and liposomal amphotericin-B. A lethal triad of impaired immunity due to COVID-19 infection, state of hyperglycemia, increased use of steroids, or rampant broad-spectrum antimicrobials works as fertile soil and may assist in the growth or alleviation of a fungal infection. Healthcare professionals must be aware of the potential of secondary invasive fungal infections in diabetic patients with moderate to severe category of COVID-19 infectious disease, especially on steroid therapy.

Keywords: COVID, Diabetes mellitus, Hyperglycemia, Mucormycosis, Steroid.

INTRODUCTION

Coronavirus disease-2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, can induce a range of symptoms that vary from minor to life-threatening pneumonia. Numerous bacterial and fungal coinfections can be caused by preexisting morbidities (diabetes and lung diseases) or develop as a hospital-acquired infection.1 We present seven cases with known diabetes and recent moderate to severe COVID-19 infection who developed rhino-orbito-maxillary mucormycosis during their treatment for COVID-19 pneumonia.

CASE SERIES

We have described the seven cases with rhino-orbito-maxillary mucormycosis and COVID-19 infection, which we have come across in the last 2 weeks from May 1, 2021, to May 15, 2021, at our dedicated COVID tertiary care center. Demographic and clinical details of these cases are summarized in Table 1. All patients in our series had moderate to severe COVID pneumonia based on CT severity score and diabetes mellitus (DM) with uncontrolled blood sugars, five being the chronic diabetics and two recently diagnosed. Four patients were referred with features of mucormycosis and three developed evidence of sinusitis during their hospital stay for COVID treatment. Six patients had received broad-spectrum antibiotics, only three patients received steroids as per guidelines, and five patients who were managed in intensive care unit (ICU) were required oxygen support. Facial pain with swelling, eyelid edema, and nasal blockade were the commonly presented symptoms. Blood investigations revealed raised serum ferritin in two patients, HbA1c of >10 in two patients, and urine ketone positive without acidosis in one patient. All patients were diagnosed based on history, clinical examination, radiological imaging (Figs 1 to 4) and managed by a multidisciplinary team (consisting of ENT specialist, treating physician, critical care expert) approach. All patients underwent emergency surgical debridement (Figs 1 to 4), received intravenous amphotericin-B (5 mg/kg body weight), injection insulin for DM along with the care of COVID pneumonia. All patients were doing well in the first week of postoperative period.

Table 1: Demography and clinical profile of COVID-associated mucormycosis cases
Parameter Case 1 Case 2 Case 3 Case 4 Case 5 Case 6 Case 7
Age (in years)/sex 58/F 59/M 69/M 54/M 65/M 50/M 72/F
Presenting complaints Left eyelid edema, ptosis, and eye prominence Left-side facial heaviness, pain, and watering eyes Right infraorbital facial swelling Redness of right eye with decreased vision Swelling of right eye with vision loss Drooping right eyelid with right nasal obstruction Altered mental status × 2 days
Day after COVID-positive 4 15 5 4 21 14 17
Severity of COVID Moderate Severe Severe Moderate Moderate Severe Severe
Broad-spectrum antibiotics Yes Yes No Yes No Yes Yes
Requirement of oxygen Yes 6 L/minute Yes, 8 L/minute No No Yes, 8 L/minute Yes, 12 L/minute Yes, 15 L/minute
Experimental therapy None None None None None None None
History of steroid use, dose, and duration Dexamethasone 6 mg OD—3 days Methyl prednisolone 16 mg BD—5 days None None None Methyl prednisolone 8 mg BD–5 days None
Comorbidity T2DM for 5 years T2DM (Recent dx) T2DM 8 years T2DM T2DM, HTN T2DM (Recent dx) T2DM
Blood sugars (at the time of admission) 370 mg/dL 405 mg/dL 403 mg/dL 310 mg/dL 234 mg/dL 219 mg/dL 312 mg/dL
Management of DM Insulin Insulin Insulin Insulin Insulin Insulin Insulin
Other abnormal investigations D-dimer 1.16 mg/L Urine ketone positive, no acidosis CRP—52.45 mg/L, IL-6—45.75 pg/mL Swab microscopy—filamentous fungi Ferritin 731.8 HbA1c 13.2 HbA1c 10.7 D-dimer 1.23 HBA1c 11.2 Ferritin 4063
Imaging CT PNS and brain MRI PNS CT PNS CT PNS   CT PNS  
Antifungal agent Liposomal amphotericin-B Liposomal amphotericin-B Liposomal amphotericin-B Liposomal amphotericin-B Liposomal amphotericin-B Liposomal amphotericin-B Liposomal |amphotericin-B
Intervention Left medial maxillectomy with debridement through lateral rhinotomy incision left medial maxillectomy via Weber-Ferguson incision with lynch extension Emergency surgical debridement Right medial maxillectomy + right orbital decompression Right medial maxillectomy + right orbital decompression Right medial maxillectomy with debridement Left total maxillectomy with orbital exenteration + tracheostomy
Outcome (in the first week of postoperative period) Improved Improved Improved Improved Improved Improved Stable

Figs 1A to C: (A) Axial CT image showing ground glass opacities in bilateral lung fields suggestive of COVID pneumonia; (B) Axial CT image showing obliteration of left maxillary ostiomeatal complex, maxillary, and ethmoid sinusitis with no bony erosion; (C) Intraoperative field images after debridement of unhealthy tissue with black discoloration (bold yellow arrow) and raised skin flaps for the procedure (bold blue arrow)

Figs 2A to D: (A) Intraoperative photograph showing maxillary sinus invaded by mucor, bold yellow arrow; (B) Photograph after debridement and removal of sinuses; (C) and (D) Specimen of total maxillectomy with dead necrosed tissue

Figs 3A and B: (A) MRI brain with orbit showing enhancing mucosal thickening with significant soft tissue edema involving left maxillary, ethmoidal, and sphenoid sinuses (bold red arrow) without the involvement of brain; (B) Clinical photograph showing edematous left cheek and eyelid, prominent left eye with chemosis

Figs 4A to D: (A) T2-weighted coronal magnetic resonance imaging showing obliteration of left maxillary sinus with surrounding soft tissue edema; (B) T2-weighted axial magnetic resonance imaging showing heterogeneous enhancement of ethmoid sinus suggestive of sinusitis; (C) Postoperative photograph showing incision line and approach; (D) Hematoxylin and eosin (H&E X400) photomicrograph showing broad nonseptate fungal hyphae, accompanied by numerous neutrophils and histiocytes in necroinflammatory background

DISCUSSION

The most common Mucorales of Zygomycetes class causing deadly fungal infection mucormycosis is Rhizopus oryzae belonging to Mucoraceae family can be found in soil and rotting organic matter like spoiled foods, leaves, compost piles, or rotten wood.2 Paultauf described the mucormycosis first in 1885 and classified it into six types based on symptomatic presentation and site of involvement including rhino-orbito-cerebral, pulmonary, cutaneous, gastrointestinal, disseminated, and miscellaneous.3 Inhaling fungal spores from the air often affects the sinuses or lungs or allows the fungus to penetrate the skin through cuts, scrapes, burns, or other open wounds that may cause infection. Rhino-orbito-cerebral mucormycosis and pulmonary mucormycosis are the two common forms of COVID-19 associated mucormycosis.1

Mucormycosis mainly affects people who have comorbidities or are taking medications that cause immunosuppression. COVID-19 is linked to a high rate of secondary infections, both bacterial and fungal, most likely due to immune dysregulation. COVID-19 infection is associated with reduced numbers of T lymphocytes, CD8+T and CD4+T cells, altered innate immunity predisposing to opportunistic invasive fungal infection.4,5 Mononuclear and polymorphonuclear phagocytes are the first line of defense preventing the inhaled spores of Mucorales invading into deeper tissues via producing oxidative metabolites and cationic peptide defensins.6 Steroids and hyperglycemia cause impairment in the ability of phagocytes responding to invading organisms resulting in impaired chemotaxis, dysfunctional phagocytes, and defective intracellular killing.7 Furthermore, it has been demonstrated that ketoacidosis associated with uncontrolled diabetes potentiates the mucormycosis by two mechanisms. Firstly, Rhizopus arrhizus produces the ketoreductase enzyme in diabetic patients, allowing to use ketone bodies of patient.8 Secondly studies have shown that Mucorales utilize iron for growth and ketoacidosis favors the release of iron from protein-bound form.2,9 Patients with impaired cellular or humoral immunity have inadequate defense leading to invasion by Mucorales in paranasal sinuses. Fungus further invades into deeper tissues and arteries causing thrombosis, ischemia, and necrosis. The widespread use of steroids, monoclonal antibodies, and broad-spectrum antibiotics as part of the COVID-19 armamentarium can result in the development or exacerbation of preexisting fungal diseases.4 Our experience highlights the significant association of uncontrolled blood sugars with the emergence of mucormycosis even in the absence of steroid therapy; similar findings were noted in recently published case series by Sarkar et al. in which all patients were diabetic with raised blood sugars and all received steroids as per guidelines.10

Diagnosis and Management

High index of clinical suspicion and appropriate imaging of the involved part with CT or MRI is needed to diagnose mucormycosis. Definitive diagnosis almost always needs histopathological examination as microscopy, culture, or imaging has limitations.10 Unfortunately, delayed diagnosis in mucormycosis is associated with fatal outcomes. Management of mucormycosis includes timely diagnosis, emergency surgical debridement, correction of underlying predisposing factors, and antifungal agents. European Confederation of Medical Mycology (ECMM) group has developed the global guidelines for the management of mucormycosis and recommends urgent medical and surgical intervention in suspected or confirmed cases because of the progressive nature of the infection. For medical management intravenous liposomal amphotericin-B is recommended as first line therapy, intravenous isavuconazole, and oral or intravenous posaconazole is preferred if first-line therapy is contraindicated or not responding.11

Recently Indian council of Medical Research (ICMR) also issued evidence-based advisory regarding the emergence of mucormycosis with COVID-19. It recommends a multidisciplinary team approach with extensive surgical debridement, control of blood sugars and ketoacidosis, aim to discontinue steroid rapidly, antifungal therapy with intravenous liposomal amphotericin-B 5–10 mg/kg body weight without slow escalation and adequate hydration.12

Remedies for Prevention

The increase in mucormycosis among COVID-19 patients is due to poorly controlled blood sugars and immune dysregulation. Steroid use may potentiate both these predisposing factors so it should be used sparingly in COVID-19 therapy as per standard protocols.4,5,12 In our series also uncontrolled blood sugar was the most important factor leading to the development of mucormycosis. The inclusion of any medication entails an additional responsibility to comprehend its impact on the unanticipated adverse sequel. While receiving steroid treatment, it is imperative to strictly control blood sugars on insulin as continuing the patients on OHA (particularly biguanides) may add to metabolic insult by being unpredictable and having lactic acidotic potential.13 If the COVID-19 patient is on oxygen assistance, the humidifier for oxygen therapy should be filled with distilled water, fill up to about 10 mm below the maximum fill line, should be changed daily and the humidifier should be washed in mild soapy water, dried in air before reuse.14

The COVID-19 patient’s overall cleanliness should be preserved; any fresh complaints especially facial pain, swelling or numbness, orbital pain or swelling, blurred or double vision must be acknowledged and evaluated as soon as possible. In presence of warning sign or symptoms, should not hesitate to get early aggressive investigations. Patients are instructed to wear mask and to cover body part with proper clothes at the time of discharge; they should be educated regarding early signs and symptoms of mucormycosis.14 There should be no time lag between discussion and decision!

  1. Diabetic status: strict control

  2. Dose and duration of steroids: Strike hard (in crisis) and wean quickly (till crisis)

  3. De-escalation of the scenario (steroid stewardship)

  4. Device’s cleanliness care (indwelling catheters, central line, or any dressing or humidifiers are often the nidus of infection ).

CONCLUSION

Physicians should be aware of the possibility of invasive secondary fungal infections in patients with COVID-19 infection, especially in poorly controlled diabetics. The use of therapeutic agents including steroids and antibiotics should be closely controlled to achieve the best possible therapeutic result at the lowest possible dosage and for the shortest possible time. Timely detection of invasive fungal infection and treatment with antifungal agents as well as operative intervention can reduce the mortality and morbidity.

ORCID

Parshika Panwar https://orcid.org/0000-0003-0582-5426

Anish Gupta https://orcid.org/0000-0002-4704-6271

Amit Kumar https://orcid.org/0000-0002-6491-5010

Bhavna Gupta https://orcid.org/0000-0002-3108-0408

Shiv C Navriya https://orcid.org/0000-0003-4859-3979

REFERENCES

1. Mehta S, Pandey A. Rhino-orbital mucormycosis associated with COVID-19. Cureus 2020;12(9):e10726. DOI: 10.7759/cureus.10726.

2. Bouza E, Muñoz P, Guinea J. Mucormycosis: an emerging disease? Clin Microbiol Infect 2006;12(7):7–23. DOI: 10.1111/j.1469-0691.2006.01604.x.

3. Viterbo S, Fasolis M, Garzino-Demo P, Griffa A, Boffano P, Iaquinta C, et al. Management and outcomes of three cases of rhinocerebral mucormycosis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2011;112(6):e69–e74. DOI: 10.1016/j.tripleo.2011.04.048.

4. Garg D, Muthu V, Sehgal IS, Ramachandran R, Kaur H, Bhalla A, et al. Coronavirus disease (Covid-19) associated mucormycosis (CAM): case report and systematic review of literature. Mycopathologia 2021;186(2):289–298. DOI: 10.1007/s11046-021-00528-2.

5. Gangneux JP, Bougnoux ME, Dannaoui E, Cornet M, Zahar JR. Invasive fungal diseases during COVID-19: we should be prepared. J Mycol Med 2020;30(2):100971. DOI: 10.1016/j.mycmed.2020.100971.

6. Waldorf AR. Pulmonary defense mechanisms against opportunistic fungal pathogens. Immunol Ser 1989;47:243–271. PMID: 2490078.

7. Chinn RY, Diamond RD. Generation of chemotactic factors by Rhizopus oryzae in the presence and absence of serum: relationship to hyphal damage mediated by human neutrophils and effects of hyperglycemia and ketoacidosis. Infect Immun 1982;38(3):1123–1129. DOI: 10.1128/iai.38.3.1123-1129.1982.

8. Pandey A, Bansal V, Asthana AK, Trivedi V, Madan M, Das A. Maxillary osteomyelitis by mucormycosis: report of four cases. Int J Infect Dis 2011;15(1):e66–e69. DOI: 10.1016/j.ijid.2010.09.003.

9. Spellberg B, Edwards J Jr, Ibrahim A. Novel perspectives on mucormycosis: pathophysiology, presentation, and management. Clin Microbiol Rev 2005;18(3):556–569. DOI: 10.1128/CMR.18.3.556-569.2005.

10. Sarkar S, Gokhale T, Choudhury SS, Deb AK. COVID-19 and orbital mucormycosis. Indian J Ophthalmol 2021;69(4):1002–1004. DOI: 10.4103/ijo.IJO_3763_20.

11. Global guideline for the diagnosis and management of mucormycosis: an initiative of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium. Lancet Infect Dis 2019;19(12):e405–e421. DOI: 10.1016/S1473-3099(19)30312-3.

12. RECOVERY Collaborative Group, Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, et al. Dexamethasone in hospitalized patients with Covid-19. N Engl J Med 2021;384(8):693–704. DOI: 10.1056/NEJMoa2021436.

13. https://www.mohfw.gov.in/pdf/Clinical Guidance on Diabetes Management at COVID19 patient Management Facility.pdf.

14. https://www.icmr.gov.in/pdf/covid/techdoc/Mucormycosis_ADVISORY_FROM_ICMR_In_COVID19_time.pdf.

________________________
© The Author(s). 2021 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted use, distribution, and non-commercial reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.