|Ahead of print
|Mucormycosis in the setting of the Covid-19 pandemic in patients without exposure to steroids and oxygen: A case series from a tertiary care center in North India
Sachin Gautam1, Mradul Kumar Daga2, Govind Mawari1, Naresh Kumar1, Ishan Rohatgi1, Maryam Hussain1, Vaishali Vinod Ramteke1, Sandeep Garg1, Suresh Kumar1, Sarika Singh3, Ishwar Singh4
1 Department of Medicine, Maulana Azad Medical College, New Delhi, India
2 Department of Internal Medicine and Infectious Disease, Institute of Liver and Biliary Sciences, New Delhi, India
3 Department of Pathology, Maulana Azad Medical College, New Delhi, India
4 Department of ENT, Maulana Azad Medical College, New Delhi, India
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|Date of Submission||23-Nov-2021|
|Date of Decision||19-Dec-2021|
|Date of Acceptance||20-Dec-2021|
|Date of Web Publication||21-Mar-2022|
Background: Sudden surge of mucormycosis cases in India needs an urgent attention as multiple factors have been implicated. However, diabetes mellitus remains to be one of the most important and modifiable factors. Methodology: We prospectively followed 11 patients with mucormycosis in May 2021 and June 2021, admitted to our hospital to study the possible etiologies. Results: Out of the 11 patients, six were males and five were females, with an average age of 52.45 years. Type 2 diabetes mellitus was the ubiquitous comorbidity, and every patient presented with uncontrolled hyperglycemia (six out of them were in diabetic ketoacidosis). Glycated hemoglobin levels ranged from 10.2% to 15.1%. Out of 11 patients, four patients were non-COVID, whereas five patients had a history of COVID-19 infection. All these five post COVID-19 patients presented approximately 20 days after recovery, out of which one patient had severe infection who was hospitalized. The remaining two patients were COVID-19-positive. Out of 11 patients, 10 patients had rhino-orbital mucormycosis at presentation, among which four patients had cerebral involvement, and one out of them later developed invasive disease. However, one patient had only pulmonary mucormycosis at presentation. Serum ferritin was raised in all the patients, and six had serum zinc levels below the reference range. Serum flow cytometry showed leukopenia with normal CD4:CD8 ratio in seven patients. In the clinical outcome, six patients expired, whereas five patients responded to the treatment and were discharged on oral posaconazole therapy. Conclusion: From our study, it is quite evident that uncontrolled diabetes and its complications such as diabetic ketoacidosis were an important risk factor for the occurrence of mucormycosis in COVID-19 patients as well as non-COVID-19 patients, even without exposure to steroids or oxygen. Thus, blood glucose levels should be kept at optimum level during the management of COVID-19 patients.
Keywords: Debridement, diabetes, immunosuppression, liposomal amphotericin B, mucormycosis, non-COVID, posaconazole, post-COVID-19, steroids
|How to cite this URL:|
Gautam S, Daga MK, Mawari G, Kumar N, Rohatgi I, Hussain M, Ramteke VV, Garg S, Kumar S, Singh S, Singh I. Mucormycosis in the setting of the Covid-19 pandemic in patients without exposure to steroids and oxygen: A case series from a tertiary care center in North India. Indian J Med Spec [Epub ahead of print] [cited 2022 May 28]. Available from: http://www.ijms.in/preprintarticle.asp?id=339999
| Introduction|| |
Mucormycosis is a rare, opportunistic, angioinvasive fungal disorder, caused by ubiquitous filamentous fungi of the order Mucorales. These include Rhizopus, Mucor, Rhizomucor, Cunninghamella, and Absidia., Due to angioinvasion by fungal hyphae, necrotizing vasculitis sets in which later leads to thrombosis and subsequent tissue infarction. The prevalence of mucormycosis in India is estimated to be 0.14 cases/1000 population. Multiple risk factors have been identified such as immunocompromised states, uncontrolled diabetes mellitus, diabetic ketoacidosis, treatment with immunosuppressive drugs like corticosteroids, bone marrow, or organ transplant, neutropenia, trauma, deferoxamine therapy, and malignant hematological conditions.,, Due to a recent surge of mucormycosis cases after COVID-19 infection, a new entity, COVID-19-associated mucormycosis (CAM) has come into the limelight. CAM is mostly considered a secondary infection among patients who had previously been infected with SARS-CoV-2 and have risk factors such as diabetes mellitus or steroids., Hence, we prospectively followed 11 patients of mucormycosis from May 16, 2021, to June 20, 2021, who were admitted to COVID-19 wards of our hospital to study the possible causes which lead to a sudden surge of mucormycosis cases in our hospital amid COVID-19 crisis.
| Case Series|| |
Eleven patients were included in this study, out of which six were males (55%) and five were females (45%); average age of males was 53.8 years and females was 50.8 years. The clinical and laboratory profile of the patients have been tabulated in [Table 1] and [Table 2]. Type 2 diabetes mellitus was the most common comorbidity, which was present in all patients, followed by hypertension which was the next common comorbidity being present in six patients, hypothyroidism in two, whereas chronic kidney disease and coronary artery disease were seen in one patient each, respectively. All patients had poor glycemic control with an initial random blood glucose level of more than 300 mg/dl and glycated hemoglobin level ranging from a minimum of 10.2% to a maximum of 15.1%. Diabetic ketoacidosis was present in six patients. Out of 11 patients, four patients had no history of COVID-19 infection and all of them reported negative for SARS-CoV-2 on presentation, whereas five patients had a history of COVID-19 infection, out of which only one had severe infection who was hospitalized and needed steroids and oxygen support. All these five post COVID-19 patients presented approximately 20 days after recovery with a RT-PCR for SARS-CoV-2 reported negative on this presentation. Among the remaining patients, two patients were COVID-19 positive on presentation. Serology for HIV, hepatitis B, and C were negative for all patients. Majority of the patients had eye complaints such as six patients had periorbital swelling, redness, and headache, five had retro-orbital pain, and four had diminutions of vision. Ear, nose, and throat (ENT) complaints such as history of nasal congestion along with blackish discharge were present in four patients, whereas two patients had gum and throat pain. Ophthalmological examination revealed that the majority of the patients had decreased visual acuity as seen in seven, complete ophthalmoplegia with loss of direct and indirect light reflexes in six, and ptosis in four patients. ENT examination revealed nasal congestion along with blackish necrotic crusting and ulcers in nasal and oral cavity in four patients. Facial features of few patients are shown in [Figure 1]. Nasal swabs were taken from all patients, and a 10% to 20% potassium hydroxide wet mount was performed, which was reported positive for branched aseptate hyphae in 10 of them, as shown in [Figure 2]. Contrast-enhanced magnetic resonance imaging or contrast-enhanced computed tomography of the brain, orbit, paranasal sinuses, and chest was performed, which revealed rhino-orbital mucormycosis at presentation in 10 patients, among which four patients had cerebral involvement and one out of them later developed invasive disease with pulmonary and cutaneous involvement. One patient had only pulmonary mucormycosis at presentation. Radiological imaging showing different types of involvement is shown in [Figure 3]. Functional endoscopic sinus surgery (FESS)-guided biopsy of the involved site was performed in 10 patients, and biopsy images of the specimens are shown in [Figure 2]. Biopsies in these patients were consistent with mucormycosis showing aseptate branched fungal hyphae with silver methenamine stain. During hospital stay, complications such as sepsis were seen in six patients, hypokalemia or anemia in three patients, transaminitis in three patients, and pulmonary tuberculosis, bilateral lower respiratory tract infection, and acute stroke were seen in one patient each. Serum ferritin was raised in all the patients and six patients had serum zinc levels below the reference range (52–286 μg/dL). Serum flow cytometry showed leukopenia along with absolute B and T subset lymphopenia with normal CD4:CD8 ratio in one COVID-19 infected, four post COVID-19 infected, and two non-COVID patients. In treatment, intravenous liposomal amphotericin B (5 mg/kg/day) was given to every patient, dose was escalated to 10 mg/kg/day in patients with systemic involvements such as cerebral or pulmonary mucormycosis along with the addition of intravenous vancomycin in disseminated cases and standard antimicrobials such as injection piperacillin-tazobactam combination were used. Strict control of blood glucose levels was maintained through insulin infusions, along with proper hydration to prevent acute kidney injury and maintain optimum levels of serum electrolytes. FESS-guided local debridement was done on an alternate day basis in eight patients. Out of the two COVID-19-positive Mucor patients, only one patient required oxygen through nonrebreathing mask, injection remdesivir, and dexamethasone. Duration of hospital stay was <10 days in two patients, minimum of 4 days, five patients had more than 20 days and maximum of 32 days. Six patients expired, three of them had rhino-orbital with cerebral involvement, and two had only rhino-orbital, and one had rhino-orbital with cerebral, pulmonary, and cutaneous involvement. The remaining five patients (45.45%) were discharged on oral posaconazole therapy.
|Figure 1: Facial features of patients with mucormycosis. (a) Blackish crust over the right eye with ptosis and periorbital swelling in the left eye and redness in bilateral eye. (b) Periorbital swelling, redness, and blackish crust below the right eye with extension to the right nasolabial fold along with left side|
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|Figure 2: (a and b) Fungal KOH mount showing aseptate branched fungal hyphae. (c) 1–10, broad aseptate fungal hyphae with right-angle branching. Mucormycosis (Hematoxylin and eosin, × 200). (d) 1–8, fungal hyphae highlighted with silver methenamine stain (Silver methenamine, × 200)|
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|Figure 3: (a) Chest radiograph of pulmonary mucormycosis patient showing increased bronchopulmonary markings in bilateral lung fields with inhomogeneous opacity in the left middle zone. (b-d) Contrast-enhanced computed tomography paranasal sinuses with ORBIT: showing rhino-orbital mucormycosis. (e and f): Contrast-enhanced computed tomography chest: showing patchy areas of consolidation with necrotizing pneumonia, findings suggestive of pulmonary mucormycosis|
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| Discussion|| |
Clinically mucormycosis can present as (1) rhino-cerebral, (2) pulmonary, (3) cutaneous, (4) gastrointestinal, and (5) disseminated forms. In the present case series, all cases were biopsy-proven except for one where only radiological evidence was there. In our series, 10 patients had rhino-orbital involvement, among which four had cerebral involvement at the presentation and one out of them later developed pulmonary and cutaneous involvement. One patient had isolated pulmonary mucormycosis, who was later on diagnosed with pulmonary tuberculosis as well.
Diabetes mellitus has been recognized as the most common risk factor for mucormycosis in Indian population, whereas hematological malignancies and transplant recipients are seen in Western population.,, Diabetes mellitus tends to alter the immune response in host body by reducing chemotaxis and phagocytic efficiency. Moreover, in diabetic ketoacidosis fungi such as Rhizopus oryzae produce an enzyme ketoreductase, which helps in utilizing host's ketone bodies. As we found out in our series, diabetes mellitus was the most common comorbidity, and uncontrolled hyperglycemia was seen in every patient. Diabetic ketoacidosis was present in six patients and metabolic acidosis due to chronic kidney disease in one non-COVID patient, which itself is an independent risk factor to it. Hence, diabetes mellitus was the primary risk factor for mucormycosis in our case series.
In a recent review by “Pal et al.,” pooling data retrieved 99 cases of CAM globally; majority of cases of CAM had been found in India (72%), where 78% were males, and 85% had a history of diabetes mellitus. Here, 37% of patients had a history of COVID-19 infection in the past, and an average duration between COVID-19 diagnosis and the first evidence of mucormycosis was found to be 15 days. In the present case series, five patients were post–COVID-19, presenting almost 20 days after recovery with fresh eye ENT complaints, among which only one required steroid and oxygen therapy for COVID. SARS-CoV-2 infection may cause hyperglycemia through different mechanisms such as beta-islet cell damage leading to reduced insulin release, cytokine storm, and interleukin-6 (IL-6) which contributes to insulin resistance.,, Apart from this, due to acidic environment in diabetic ketoacidosis, free unbound iron is increased due to displacement of ferric ions from transferrin, which further adds to pathogenesis of mucormycosis. In a case series by “Nair et al.,” on 127 CAM patients found 6 immunocompetent patients without history of steroids or immunomodulator drug intake developed new-onset diabetes mellitus after COVID-19 infection and presenting as mucormycosis after an average duration of 14.2 days after COVID-19 diagnosis. This again reflects upon diabetogenic role of SARS-CoV-2. Similarly, in our study, newly diagnosed type 2 diabetes mellitus was seen in two COVID-negative, one COVID-19-positive, and two post-COVID-19 infected patients, who prior had no clue or screened for diabetes.
Hyperferritinemia is seen in severe COVID-19 infection, which leads to increased intracellular iron along with IL-6 which further stimulates ferritin synthesis and reduces iron export out of the cell causing reactive damage to the hepatocytes. Furthermore, upon tissue damage, ferritin is released into bloodstream which loses its iron content, producing raised free serum iron levels. However, hyperferritinemia was seen in all patients in our case series, which could possibly be elevated falsely due to being an acute phase reactant. However, serum iron was within normal limits in seven patients and reduced in four patients.
Irrational usage of broad-spectrum antibiotics, apart from steroid, have led to increased secondary bacterial or fungal infections in coronavirus-positive or -recovered patients. Usage of reusable oxygen humidifiers without proper care may further add to the risk. Moreover, there could be other logistic factors too which need to be identified.
COVID-19-induced endotheliitis and immunosuppression are well known along with glucocorticoid-induced lymphopenia, hyperglycemia, and immunosuppression, which all contribute to the pathogenesis of mucormycosis., Here, in the present series, steroid was only given in one post-COVID-19 infected patient and one COVID-19-positive patient, the rest of the patients did not receive steroids. Uncontrolled diabetic status was seen in every patient as a single most important risk factor. History of COVID-19 infection past or current was present in seven cases, whereas four were non-COVID patients. In contrast to this, one Indian study showed no incidence of mucormycosis cases in 1027 COVID-19 patients admitted to ICU and their postdischarge follow-up, from March 2020 to May 2021, even with low-dose protocol-based corticosteroid therapy, which was given in 915 along with strict blood glucose control in 417 diabetic cases. Hence, the rise of mucormycosis cases during the second wave of COVID-19 in India could not just merely be an incidental association rather a strong involvement of environmental and other factors too. Like in a review by “Chandra and Rawal,” it has been mentioned that increased expression of GRP78 due to dexamethasone, diabetic ketoacidosis, and high serum iron could possibly explain the rise of mucormycosis in India during the second wave, as increased binding to GRP78 both by prevalent SARS-CoV-2 variant (B.1.1.7 and B.6.117) and mucormycosis as a portal of entry into host cells.
Profound lymphopenia due to multiple factors remains to be an important immunological factor promoting mucormycosis. Serum flow cytometry was performed for 10 patients, which showed absolute B and T-cell leukopenia with normal CD4 to CD8 ratio in four post-COVID-1– infected patients, two COVID-19-negative patients, and one COVID-19-positive patient, however, others showed normal lymphocyte subsets. As seen in our study, lymphopenia could be attributed to uncontrolled diabetic status in every patient. Moreover, COVID-19 infection past or current is itself an added risk factor to it.
Apart from this, zinc supplementations were also given in most of the patients during COVID-19 second wave in India. Studies have shown that zinc deficiency and zinc chelators such as clioquinol or phenanthroline have an inhibitory effect on fungal growth., Hence, serum zinc level was done in all patients. However, on contrary to available literature, it was found in our series that serum zinc levels were lower in six patients and normal in five patients. To look for the association of serum zinc levels, serum iron studies, and serum flow cytometry, a large study is required, especially in comparing CAM and COVID-19-negative mucormycosis patients. Hence, a risk-based approach with initial serum zinc levels and serum flow cytometry to show lymphopenia is needed. Keeping in mind the ongoing pandemic and its future implications, there is a need for a validated score for considering mucormycosis risk to be developed or updated at earliest to be applied on presentation among patients who are suspected of mucormycosis on clinical basis.
| Conclusion|| |
From our study, it is quite evident that uncontrolled diabetes and its complications such as diabetic ketoacidosis were an important risk factor for the occurrence of mucormycosis in COVID-19 patients as well as non-COVID-19 patients, even without exposure to steroids or oxygen. Moreover, lymphopenia due to multiple causes must also be looked upon. Thus, blood glucose levels should be kept at the optimum level during the management of COVID-19 patients. Hence, clinicians need to be vigilant to look for mucormycosis symptoms frequently not only in post-COVID-19 infected cases but also in COVID-19-positive and non-COVID cases during the pandemic, as it is possible that non-COVID–infected patients during a pandemic may have other unidentified factors contributing to the occurrence of mucormycosis.
Informed consent from all the patient participants.
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.
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Conflicts of interest
There are no conflicts of interest.
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Mradul Kumar Daga,
Internal Medicine and Infectious Disease, Institute of Liver and Biliary Sciences, New Delhi
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]
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