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 Table of Contents  
CASE SERIES
Year : 2021  |  Volume : 23  |  Issue : 2  |  Page : 219-224

Risk factor profile of Mucormycosis in COVID 19 patients: A Case series


1 Classified specialist Medicine and Neurologist, Department of Medicine, Base Hospital, New Delhi, India
2 Classified specialist Medicine and Geriatrician, Department of Medicine, Base Hospital, New Delhi, India
3 Resident Medicine, Department of Medicine, Base Hospital, New Delhi, India
4 Resident Department of Pathology, Army Hospital, Research and Referral, New Delhi, India
5 Classified specialist Department of Radiology, Base Hospital, New Delhi, India
6 Clinical Biochemistry, Delhi, India

Date of Submission27-Jun-2021
Date of Decision05-Aug-2021
Date of Acceptance01-Sep-2021
Date of Web Publication07-Oct-2021

Correspondence Address:
Lt Col (Dr) Rahul Soni
Base Hospital, Delhi Cantt, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jmms.jmms_97_21

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  Abstract 


Coronavirus disease-19 (COVID-19)-infected patients are at risk to develop severe opportunistic infections, especially fungal infections. The incidence of mucormycosis has increased in patients who are recovering from COVID-19 and now it has become an epidemic in India. In the background of the COVID-19 pandemic, we present a case series of seven patients with mucormycosis and their risk factor profile. Six of our patients had nonketotic poorly controlled glycemic status. All patients were mild or asymptomatic as far as COVID-19 clinical symptoms are concerned, but they had high inflammatory markers such as interleukin 6 (IL-6), ferritin, and D-dimer, which are commonly seen in a cytokine storm. Hyperglycemia and COVID-19 infection were consistent features in our patients. We found that COVID-19 patients with poor glycemic control and high inflammatory markers are at high risk for mucormycosis infection. However, the duration from the diagnosis of COVID-19 and the development of symptoms of mucormycosis was varied from 1 to 12 days (mean- 5.71). There was no correlation of the level of IL-6 or D-dimer with the early onset of mucormycosis. We also did not find any correlation of mucormycosis with other proposed risk factors such as oxygen therapy, steam inhalation, or prolonged steroid therapy, since four of our patients had never received steroids in any form and three had received only mild dosages of steroid. The sample size for statistical analysis was inadequate. However, a randomized clinical trial or larger observational study is needed to establish this observation.

Keywords: COVID-19, D-dimer, hyperglycemia, interleukin 6, mucormycosis, steroids


How to cite this article:
Soni R, Nauhwaar D, Kumar A, Patil A, Saha M, Debnath J. Risk factor profile of Mucormycosis in COVID 19 patients: A Case series. J Mar Med Soc 2021;23:219-24

How to cite this URL:
Soni R, Nauhwaar D, Kumar A, Patil A, Saha M, Debnath J. Risk factor profile of Mucormycosis in COVID 19 patients: A Case series. J Mar Med Soc [serial online] 2021 [cited 2021 Dec 3];23:219-24. Available from: https://www.marinemedicalsociety.in/text.asp?2021/23/2/219/327562




  Introduction Top


Coronavirus disease 19 (COVID-19) causes mild to life-threatening pneumonia with respiratory failure and became pandemic in 2020. The disease is more aggressive in the presence of other comorbidities such as diabetes mellitus, chronic obstructive pulmonary disease, malignancies, chronic kidney disease, and individuals on immunosuppressant drugs such as MMF. These patients are more likely to receive corticosteroids and biologicals (Tocilizumab). These subsets of patients are already at risk to develop severe opportunistic infections, especially fungal infections. In the background of the COVID-19 pandemic, we present a case series of seven patients with mucormycosis and their risk factor profile. Rhizopus, Mucor, Rhizomucor, Cunninghamella, and Absidia are types of mucormycosis.[1] These fungi cause life-threatening and angioinvasive diseases causing high mortality even in treated patients. In the pre-COVID-19 era, the prevalence of mucormycosis was approximately 0.14 cases per 1000.[2] Song G and colleagues have found that out of all post-COVID-19 patients who presented with a fungal infection, 5% had developed Aspergillus and 7% Mucor infection.[3] The incidence of mucormycosis has increased in patients who are recovering from COVID-19 and now it has become an epidemic in India with about 10,000 cases reported in the past few weeks.


  Methodology Top


This case series is from Base Hospital Delhi Cantt. We reviewed the records of patients admitted to the COVID wards of Base hospital Delhi Cantt in May to June 2021 and then studied all suspected or diagnosed mucormycosis patients. We reviewed seven patients who were diagnosed as mucormycosis on KOH mount and were admitted to the COVID-19 ward. We have retrospectively studied the patient's clinical profile, blood investigations, radiological imaging, and histopathological reports. Most of the patients were diagnosed on the basis of radiological picture and fungal stain obtained from tissue biopsy/nasal swabs. No fungal culture report was available. Details of the clinical profile of all seven COVID-19 patients are described in [Table 1]. Details of clinical profile, hematological, hepatic, and renal parameters, radiological profile, microbiological profile, and inflammatory markers of same COVID-19 patients with mucormycosis at the time of hospitalization are described in [Table 2]. The data were described as continuous or categorical and appropriate statistical analysis in form of mean or median. The patients were treated with weight-adjusted injection amphotericin (liposomal/plain) and were later on shifted to oral posaconazole depending on the renal parameters and drug availability. The patients with invasive and bulky disease underwent endoscopic debridement as per the treating surgeon's assessment. The patients were discharged or transferred to other hospital once they became COVID negative.
Table 1:Clinical and Risk Factor profile of Covid -19 patient

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Table 2: Symptomsand Biochemical profile of patients

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  Discussion Top


In our case series, 5 (71%) patients were male and 2 (29%) were female. The duration from the diagnosis of COVID-19 and the development of symptoms of mucormycosis was 3–12 days in four patients. Three (43%) patients presented with mucormycosis-related symptoms and found to be COVID-19 positive. The mean duration from the onset to symptoms of mucormycosis in our patients was 5.7 days. Six (85%) patients presented with moderate to severe frontotemporal headache, cheek pain, and nasal congestion. Headache is because of the involvement of the paranasal sinus (PNS) and orbits. Five (71%) patients had monocular or binocular blurring of vision due to involvement of optic nerve swelling. Most of our patients had a fever or sore throat. One patient had lateral rectus palsy associated with confusion as presenting feature.

Diabetes mellitus is the most common risk factor for mucormycosis, with an overall mortality of 46%.[4] In our case series, we found that 6 (85%) patients had hyperglycemia on initial evaluation. This was similar to another case series described by Singh et al.[5] Two (28.5%) patients were old cases of diabetes and they were on metformin. Rest 4 (57%) patients were freshly detected to have hyperglycemia at the time of hospitalization. Although both known diabetic patients were on the oral hypoglycemic drugs, their glycemic control was poor as evident by high HbA1c and high random blood sugar [Table 1]. Hyperglycemia causes increased expression of the endothelial receptor GRP78, which results in leukocyte dysfunction, impaired chemotaxis, and intracellular killing. Diabetic ketoacidosis (DKA) also causes an increase in free iron in the serum. This endogenous iron is taken up by the fungi through siderophores or iron permeases, which enhances its growth. Hyperglycemia also delays interferon gamma response with a prolonged hyperinflammatory state with low CD4 and CD8 cell counts.[6] However, none of our patients developed DKA at the time of hospitalization or even after steroid therapy for COVID-19.

In COVID-19 infection, lymphopenia is documented and this could increase the risk of developing invasive mucormycosis.[7] None of our patients had lymphopenia at the time of COVID-19 infection [Table 2]. Critically ill patients are subjected to emergency invasive procedures, mechanical ventilation, continuous renal replacement therapy (CRRT), and prolonged hospital stays, which increase chances of mucormycosis infection. None of our patients was supported by mechanical ventilation or CRRT prior to the diagnosis of mucormycosis. One patient was an old case of non-Hodgkin lymphoma and chronic kidney disease postrenal transplant on immunosuppressant and oral prednisolone for the last 1 year.

Post-COVID-19 patients develop secondary bacterial and fungal infections due to dysregulation of the innate immune response, ciliary dysfunction, cytokine storm, thromboinflammation, microvascular coagulation, and eventual immune exhaustion.[8] Prothrombotic phase is evidenced by the increased incidence of the thrombotic phenomenon. These thrombi provide a good intravascular growth media for fungus, especially angioinvasive fungus-like Mucor. In all of our patients, interleukin 6 (IL-6) (mean: 272.83 ng/mL) and D-dimer (mean: 1633 ng/mL) were significantly raised. This was similar to case series published by Singh and colleagues.[5] However, in our case series, the mean D-dimer level was much lower. However, there was no correlation of the level of IL-6 or D-dimer with early onset of mucormycosis (statistical analysis not possible due to small sample size). Serum ferritin was also significantly increased in 4 (57%) patients. Patients who require oxygen therapy or steam inhalation are at risk for fungal infection. In our case series, only 1 (14%) patient required four to six liter/min of oxygen support with a face mask and none of the patients gave a history of excessive or prolonged steam inhalation therapy.

Recovery trial has recommended the use of dexamethasone for patients with moderate to severe COVID-19 illness as it had shown mortality benefit.[9] However, in the clinical real-world scenario, higher doses and early and longer durations have been used in cases with a severe disease without strict monitoring of glycemic levels, which has led to poor glycemic control. Prolonged steroids also cause neutrophilic leukocytosis and have inhibitory effects on cytokines and chemokines, ingestion, and phagolysosome fusion.[10] This leads to a reduction in leukocyte migration to the site of inflammation. Steroids also cause lymphopenia of both T and B cells. Hence, it increased the risk of infections in patients on prolonged use of glucocorticoids. These effects are amplified by the use of immunosuppressant drugs. The use of corticosteroid (pulse/prolong therapy) with anti-IL-6 directed treatment strategies and high fungal spore counts in the environment increases the risk of infection. Five (71%) patients received steroids prior to diagnosis of mucormycosis, out of which 4 (57%) had received oral dexamethasone for a short duration and one was on oral prednisolone (14%) for a long duration. None had received injection methylprednisolone or other immunomodulators like tocilizumab. These patients were never hospitalized earlier to any other hospital with COVID-19-related symptoms.

The most important manifestations are rhino-orbital-cerebral and pulmonary. Mucormycosis is clinically presented as discharge from the nasal or oral cavity and necrotic lesion. Our patients presented with unilateral headache, periorbital pain, and paresthesias over the face, and blurring of vision. One (14%) patient had altered sensorium with left lateral rectus palsy. None of our patients presented with eschar or discharge in the nasal or oral cavity and necrotic lesion.

Computed tomography and magnetic resonance imaging (MRI) are one of the important tools in the diagnosis of rhinocerebral mucormycosis. In MRI images, there will be opacified T2 hyperdensities of maxillary, ethmoid, frontal, and sphenoid sinuses associated with nodular mucosal thickening. There will be no fluid level in the sinuses.[11] However, there may be hypointensities due to the presence of iron or manganese in fungal tissue.[12] Deep soft-tissue infiltration by fungi leads to obliteration of infratemporal fossa, pterygopalatine fossa, pterygomaxillary fissure, and periantral fat. It can also involve the orbital apex and cavernous sinus. Lack of enhancement of intracranial vessels is suggestive of vasculitis and thrombosis.[13] Mycotic emboli can cause infarcts or may cause abscesses. Mucor infection of the PNSs can lead to osteomyelitis of cancellous bone of the cranial vault, e.g., frontal bones. In our case series, MRI brain was done in 5 (71%) patients and NCCT head was done in 2 (29%) patients [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]. All patients (100%) had involvement of PNS and 4 (57%) of them have orbital involvement. None of them has the involvement of the brain. One patient had an altered sensorium. Cerebrospinal fluid (CSF) was done, which showed one lymphocyte, glucose of 50 mg/dL (random blood sugar 140 mg/dL), and protein was 68 mg/dl. CSF was negative for potassium hydroxide (KOH) mount and no organism seen on staining.
Figure 1: Coronal section of noncontrast computed tomography PNS showing hypodense soft tissue thickening involving the right maxillary and anterior ethmoid sinus-associated widened maxillary ostium

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Figure 2: Ill-defined hypodense soft tissue thickening is noted involving the right anterior and posterior ethmoid air cells with breach of right lamina papyracea. The contiguous extension of soft tissue thickening is noted across lamina papyracea into the medial extraconal compartment of right orbit

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Figure 3: Axial post contrast T1 weighted image at the level of mid-orbital plane shows enhancing soft tissue thickening in bilateral anterior and posterior ethmoid air cells and sphenoid sinus with extension into medial extraconal compartment of right orbit

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Figure 4: Coronal T2 weighted image magnetic resonance imaging PNS showing mucosal thickening involving bilateral maxillary sinus and anterior ethmoid sinus. The medial wall of right maxillary sinus and uncinate process are not visualized suggestive of erosion

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Figure 5: Axial section of noncontrast tomography of paranasal sinus showing hypodense soft tissue thicking involving the right maxillary sinus

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Rapid diagnostic methods of a fungal infection include KOH mount staining. All patients were positive for KOH mount [Figure 6] and [Figure 7]. The biopsy is again a good diagnostic tool. Three (43%) of our patients underwent biopsy. Mucormycosis is difficult to routinely culture and it takes weeks. Treatment in suspected mucormycosis patients should be initiated early and should not be delayed for culture reports because it is very invasive fungi and result in poor outcomes.
Figure 6: KOH mount of nasal tissue sample, showing broad aseptate fungal hyphae

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Figure 7:KOH mount with Calcofluor white shows Broad pauciseptate /aseptate fungal hyphae under fluorescent microscope

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Treatment of mucormycosis is surgical debridement and prolonged liposomal amphotericin. Surgical debridement, if done earlier, results in a better outcome. The European Confederation of Medical Mycology recommends liposomal amphotericin B (5–10 mg/kg per day) as first-line treatment for all patterns of organ involvement. In case renal toxicity develops, the dose can be reduced, but doses below 5 mg/kg/day have inconsistent benefit. Amphotericin B lipid complex 5 mg/kg/day is an alternative for patients without CNS involvement. Isavuconazole is recommended for salvage therapy. It can be used as first-line therapy in individual not tolerating amphotericin B. Posaconazole oral suspension and posaconazole delayed release tablets and infusion are other alternatives for first line or salvage treatment. No benefit noted in use of antifungal combination therapy. Limiting factor for use of amphotericin B formulations is renal toxicity and for the azole class is hepatic toxicity.[14]

All our patients were treated with intravenous amphotericin and 3 (43%) underwent surgical debridement. None had repeat surgery. The most common and important adverse effects of amphotericin are hypokalemia and azotemia. Sometime, patients require renal replacement therapy in view of acute kidney failure. Three (43%) of our patients had worsening renal dysfunction after starting amphotericin. However, none of them required dialysis.


  Conclusion Top


This case series presents mucormycosis infection in COVID-19 nonketotic poorly controlled diabetic patients. All patients were mild or asymptomatic as far as COVID-19 clinical symptoms are concerned, but have high inflammatory markers which are commonly seen in a cytokine storm. This study tried to establish other postulated risk factors for the development of mucormycosis like steam inhalation etc apart from steroid Abuse and immunosuppressants . However no consistent correlation was established between other risk factors being postulated and mucormycosis infection apart from COVID-19 infection and poor glycemic control. Diabetic COVID-19 patients with poor glycemic control and high inflammatory markers are at high risk for mucormycosis infection. Hyperglycemia and COVID-19 infection were consistent features in our patients. We did not find any correlation between mucormycosis with other proposed risk factors such as oxygen therapy, steam inhalation, or prolonged steroid therapy. Although no correlation was established between steam inhalation, steroid use, or oxygen therapy and the only risk factors were hyperglycemia and COVID-19 infection, a randomized clinical trial is needed to establish this observation.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for 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.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Revannavar SM, Supriya PS, Samaga L, Vineeth KV. COVID-19 triggering mucormycosis in a susceptible patient: A new phenomenon in the developing world? BMJ Case Rep 2021;14:e241663.  Back to cited text no. 1
    
2.
Skiada A, Pavleas I, Drogari-Apiranthitou M. Epidemiology and diagnosis of mucormycosis: An update. J Fungi (Basel) 2020;6:E265.  Back to cited text no. 2
    
3.
Jeong W, Keighley C, Wolfe R, Lee WL, Slavin MA, Kong DC, et al. The epidemiology and clinical manifestations of mucormycosis: A systematic review and meta-analysis of case reports. Clin Microbiol Infect 2019;25:26-34.  Back to cited text no. 3
    
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Song G, Liang G, Liu W. Fungal co-infections associated with global COVID-19 pandemic: A clinical and diagnostic perspective from China. Mycopathologia 2020;185:599-26.  Back to cited text no. 4
    
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Singh Y, Ganesh V, Kumar S, Patel N, Aggarwala R, Soni KD, et al. Coronavirus disease-associated mucormycosis from a tertiary care hospital in India: A case series. Cureus 2021;13:e16152.  Back to cited text no. 5
    
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Hodgson K, Morris J, Bridson T, Govan B, Rush C, Ketheesan N. Immunological mechanisms contributing to the double burden of diabetes and intracellular bacterial infections. Immunology 2015;144:171-85.  Back to cited text no. 6
    
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Pasero D, Sanna S, Liperi C, Piredda D, Branca GP, Casadio L, et al. A challenging complication following SARS-CoV-2 infection: A case of pulmonary mucormycosis. Infection 2020;Dec 17 :1-6.  Back to cited text no. 7
    
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Felsenstein S, Herbert JA, McNamara PS, Hedrich CM. COVID-19: Immunology and treatment options. Clin Immunol 2020;215:108448.  Back to cited text no. 8
    
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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;384:693-704.  Back to cited text no. 9
    
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Ronchetti S, Ricci E, Migliorati G, Gentili M, Riccardi C. How glucocorticoids affect the neutrophil life. Int J Mol Sci 2018;19:E4090.  Back to cited text no. 10
    
11.
Gamba JL, Woodruff WW, Djang WT, Yeates AE. Craniofacial mucormycosis: Assessment with CT. Radiology 1986;160:207-12.  Back to cited text no. 11
    
12.
Press GA, Weindling SM, Hesselink JR, Ochi JW, Harris JP. Rhinocerebral mucormycosis: MR manifestations. J Comput Assist Tomogr 1988;12:744-9.  Back to cited text no. 12
    
13.
Kilpatrick C, Tress B, King J. Computed tomography of rhinocerebral mucormycosis. Neuroradiology 1984;26:71-3.  Back to cited text no. 13
    
14.
Cornely OA, Alastruey-Izquierdo A, Arenz D, Chen SC, Dannaoui E, Hochhegger B, et al. 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:e405-21.  Back to cited text no. 14
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
 
 
    Tables

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