Introduction
COVID- 19 infection does not stop at acute phase. There are many post covid complications like opportunistic infections especially mucormycosis. This is possibly the most feared infection of all the opportunistic infections. Several cases are reported, especially from India.
Prevalence of mucormycosis worldwide is 0.005%. In India the incidence is 80 times more than the rest of the world.1 Opportunistic infections in COVID-19, especially mucormycosis is associated with underlying diabetes, especially in patients with ketoacidosis, high ferritin levels and decreased white blood cell (WBC) and phagocytic activity. There is a need for relook at these patients because of high morbidity and mortality associated mucormycosis. We reviewed our cases of COVID-19 associated mucormycosis, its association with co morbidities and drugs used during COVID-19 infection and the histological patterns in tissues.
Mucormycosis was first described by Platauf in 18852 and the term mucormycosis was coined by Baker in 1957. Mucormycosis is a serious fungal infection caused by a group of molds called Mucoromycetes. Mucormycosis is commonly seen in immunosuppressed people. Diabetes is the most common cause of mucormycosis. India has the second largest population of diabetics worldwide. Poorly controlled diabetes and steroid induced hyperglycaemia secondary to treatment of COVID-19 with steroids are a potent combination for creating a favourable environment for the growth of mucormycosis. Diabetes is an independent risk factor, and in association with COVID-19 infection, especially poorly controlled diabetes, is a fertile ground for occurrence of mucormycosis.
Materials and Methods
Material for this study is from a tertiary care hospital in South India. This study included patients who were diagnosed as mucormycosis on biopsy over a period of four months associated with resurgence of COVID-19 in India. Post COVID-19 status was defined as greater than two weeks after being first detected with COVID-19 by polymerase chain reaction (PCR) and a subsequent PCR negative result.
Biopsies from patients in post COVID-19 or ongoing COVID-19 infection were included in the study.
Depending on the site, patients presented with varied signs and symptoms. Patients presented with facial pain, orbital pain and /or decreased vision and sinusitis. Patient with gastric lesion was an ongoing covid patient with dyspeptic symptoms. Lung lesion presented with cough and imageology revealed thick-walled cavity in the upper lobe of lung. Tracheal lesion was seen in a post-transplant, post COVID-19 patient with difficulty in breathing and cough. Biopsies were sent in 10% buffered formalin. 4-micron thin sections were studied. Routine Haematoxylin and Eosin (H&E) stains were done and Gomori’s methenamine silver (GMS) was done in all cases. Diagnosis was based on histomorphological features.
Results
Twenty-three cases of mucormycosis were diagnosed. Eighteen cases were diagnosed post covid period. Age of the patients ranged from 30 years to 74 years. Male to Female ratio was 1:1.1. Mean age of the patients was 51 years.
In post COVID-19 patients, symptoms developed after two to four weeks after covid illness. Four cases were diagnosed in ongoing covid cases. Mean age of onset of symptoms of mucormycosis after a PCR diagnosis of COVID-19 was 21 days. All patients were diabetic (100%). Ketoacidosis was seen in three patients (13.0%). All the patients were treated with steroids (100%), Remdisivir was used in 16 patients (72.7%). One patient received Baricitinib and four patients received Tocilizumab (27.2%) as second immunomodulator drugs in addition to the steroids due to high inflammatory markers. Ten cases were from rhino-orbital area (43.47%), nine cases from sinuses (39.13%), one each from gastric wall (4.34%), trachea (4.34%) and 2 cases from lung (8.68%) were diagnosed. (Table 1)
Panel of investigations done in these patients included CRP, IL-6, D-Dimer, ferritin, and complete blood counts. (Table 2).
MRI of the brain, orbits and paranasal sinuses revealed soft tissue swelling in the pre-septal, premaxillary and retrobulbar regions with pan sinusitis. (Figure 1)
Figure 1
Axial and Coronal T1 post contrast images show poorly marginated non enhancing area (necrotic tissue) noted in the right ethmoidal sinus involving nasal septum, middle turbinate, meatus, and cribriform plate. Maxillary sinus shows mucosal thickening
Table 1
Showing clinical details, site of involvement, treatment and prognosis in patients in the study
Table 2
Showing values of various inflammatory markers
Histologically, In all these cases broad aseptate filamentous hyphae with irregular branching was seen. (Figure 2 A&B) There was infarction and necrosis due to angioinvasion with neutrophilic infiltration in all cases (Figure 2 B&C). Granulomatous inflammation was seen in seven cases (Figure 2 D). Melanin pigment was seen in two cases. Sections through the exenterated orbits (Figure 3 A) revealed periorbital tissue necrosis, inflammation and in one case fungal hyphae were seen extending into the pigment layer. (Figure 3 B) These hyphal structures were GMS positive. (Figure 3 C) Pigment was identified as melanin by Masson Fontana stain.(Figure 3 D) Sporangia and sporangiophores were seen in two sino-nasal mucosal lesions.
Figure 2
A): Section showing characteristic ribbon like aseptate branching hyphae. (H&E X 200); B: Section showing areas of infarction with fungal elements. (H&E X100); C: Sections showing dense neutrophilic infiltration forming abscesses with fungal filaments. (H&EX100); D: Sections showing granulomatous reaction with giant cells showing fungal elements. (H&EX200)
Figure 3
A: Gross specimen of exenterated eyeball with periorbital tissue; B: Section showing pigment layer of orbit with dense neutrophilic infiltration with fungal elements. (H&EX200); C: Section showing broad hyphae with right angle branching. (GMSX 200); D: Section showing sporangia with sporangiophore with brownish black pigment. (H&EX200)
After the course of Amphotericin B, these patients were started with Posaconazole delayed release tablet form 300 mg twice daily for two doses followed 300 mg daily for 3-6 months in immunocompetent patients.
Discussion
COVID- 19 viral infection is not limited to acute respiratory syndrome. It is associated with many opportunistic infections including bacterial and fungal infections. Mucormycosis is described in these patients and more so from India. Diabetes is the most common risk factor for mucormycosis in India. India has the second largest population of diabetics. Large number of diabetic population and steroid induced hyperglycaemia in patients treated with steroids were two important factors for high incidence of mucormycosis in India. Mucormycosis is an airborne infection, and it starts in the upper airways. Mucormycosis is described in diabetics, hematological and other malignancies, organ transplantation, immunosuppression and steroid therapy, iron overload and desferrioxamine therapy, AIDS patients, intravenous drug abusers and malnutrition.3 In COVID-19 patients, factors which facilitate the spores of mucorales to cause infection are many. Spores germinate to produce hyphae that invade the blood vessels and adjacent tissue, this blocks the blood flow to the tissues causing extensive infarction and necrosis. High glucose levels, low pH is a fertile media for mucormycosis. Decreased phagocytic activity of white blood cells enhances the expression of glucose regulator protein (GRP-78) of endothelial cells. This enables angio-invasion and hematogenous dissemination.4 The level of unbound serum iron in an acidic environment is an important predisposing factor in growth of mucormycosis. Increase in serum concentration of ferritin causes insulin resistance. Reduced iron binding and excess free iron is taken up by the fungus and further enhances the growth and virulence.5 Increase in cytokines in patients with COVID-19 mainly IL-6, increases free iron levels.
Hence, all the parameters were evaluated, and we found good correlation in COVID-19 patients who developed mucormycosis.
It is an angioinvasive fungus, histologically, there will be infarction, necrosis, and neutrophilic infiltration of these areas. Few patients develop a granulomatous reaction.
The management of covid patients is predominantly supportive. There is an exaggerated immune response causing multiorgan failure.6 There is a cytokine storm described and this led to the use of immunomodulator drugs like Tocilizumab and Baricitinib. Inhibition of IL-6 has adverse consequences as shown in experiments in mice. There is decreased immunity to opportunistic infections7 including mucormycosis.
The overall mortality rate of mucormycosis as described in literature for India is 36.5%.8 In our series, one patient who had bilateral orbital involvement expired, as he refused treatment, patient with gastric involvement of mucormycosis also expired constituting 8.6% mortality rate. All the other patients recovered and are on follow up.
Conclusion
In early diagnosis of COVID-19, judicious use of steroids, good control of diabetes during on-going COVID-19 treatment and post COVID-19 period, high index of suspicion for mucormycosis and prompt initiation of anti-fungal therapy with aggressive debridement are essential for successful management of COVID-19 associated mucormycosis. Though morbidity was there in the form of loss of vision in our series, overall survival was 91.4%.
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