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Varied presentation of post Covid mucormycosis in a tertiary care centre in Northern India

Aims and Objectives : To study the cytomorphological presentation of post covid mucormycosis. Materials and Methods: A retrospective observational study was conducted at a tertiary care center in Northern India for a period of six months, in patients with post covid mucormycosis. Results: The study included 50 cases with post covid mucormycosis. Males with 28 cases (56.0%) were more commonly affected than females. Nose comprising of 36 cases (72.0%) was the most commonly affected area, with nasal cavity showing 24 cases (48.0%) being most common site within the nose. 36 cases (72.0%) were positive exclusively for Mucormycosis. 10.0% cases of mucor showed superadded bacterial infection. Candida was seen in 03 cases (6.0%) and aspergillosis in 02 cases (4.0%). There were 6.0% cases of mucormycosis with associated chronic osteomyelitis. All the patients had a history of steroid use throughout their coronavirus treatment. Conclusions: A rare but fatal fungal infection (mucormycosis) has a strong association with covid-19 infection, in active as well as recovered patients, particularly in those with co-morbid medical conditions and treated with high doses of corticosteroids. This is an Open Access (OA) journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.


Introduction
Coronavirus disease 2019 (Covid- 19) is an infection caused by severe acute respiratory syndrome (SARS-CoV-2). The Covid-19 symptom have increased since the initial days of the disease's presentation, to begin with it included only dry cough and high grade fever, however it now includes varied multisystemic problems as well. It has also been associated with a wide range of opportunistic bacterial and fungal infections. 1 Several cases of Covid related mucormycosis have been emerging world-wide, particularly from India. The primary reason thought to be facilitating Mucorales spores to germinate in covid patients is an ideal environment of high glucose (diabetes, new-onset hyperglycaemia, steroidinduced hyperglycaemia), low oxygen, increased levels of ferritin, acidic medium (metabolic acidosis, diabetic ketoacidosis),and decreased phagocytic activity of white blood cells due to immunosuppression combined with considerable other shared risk factors including prolonged hospitalization with or without mechanical ventilators. 2 Mucormycosis is a rare yet fatal fungal infection affecting patients with weakened immunity. Patients include those with uncontrolled diabetes mellitus, acquired immunodeficiency syndrome, iatrogenic immunosuppression and haematological malignancies, and those who have undergone organ transplantation. 3 Rhizopus Oryzae, a filamentous microfungus, belonging to the family Mucoraceac, is known to be the most common type, accountable for approximately 60.0% of mucormycosis cases in humans and is also responsible for 90.0% of the Rhino-orbital-cerebral (ROCM) form. 4 Here the mode of contamination occurs through inhalation of fungal spores.
The characteristic features of mucormycosis includes the presence of hyphal invasion of sinus tissue and a duration of less than four weeks. 5,6 Clinically, it can present with few atypical signs and symptoms like complicated sinusitis with crusting and nasal blockade, proptosis, ptosis,facial pain and oedema, ophthalmoplegia with fever, headache and other neurological signs and symptoms if intracranial extension is present. 7,8 A black eschar may be seen in the nasal cavity or over the hard palate region, but is not characteristic. 9 A rapid progression of the disease is seen without prompt intervention. Sometimes, even after swift diagnosis, treatment, aggressive medical and surgical intervention, management is often ineffective, resulting in an extension of the infection and ultimately death. 10 Here, we present our recent experience of 50 cases of mucormycosis seen over a time period of just six months in Covid-19 positive cases.

Materials and Methods
A retrospective observational study was undertaken at Jawaharlal Nehru Medical College, AMU, Aligarh, India, over a period of six months, from May to November 2021 in 50 clinically suspected cases of rhino-orbital mucormycosis received in the Department of Pathology.
The samples were received in normal saline and crush/imprint smears were prepared and stained with H&E, PAP and PAS stains for rapid evaluation. The patient's presentation details, imaging findings, co-morbidities, management details and follow-up information were obtained, recorded and analysed.

Results
Our study included a total of 50 cases of Mucormycosis. The most common age group of presentation was bimodal between 31-40 and 51-60 years, with 15 cases (30.0%) in each decade. Males comprised 28 cases (56.0%) and 22 cases (44.0%) were females (Tables 1 and 2). Nose seemed to be the most common site for the development of Mucormycosis, comprising of 36 cases (72.0%), followed by maxilla with 06 cases (12.0%). Within    On Cytology, of all the patients showing positivity, 36 cases (72.0%) were positive exclusively for Mucormycosis, with thick broad aseptate hyphae and spores (Figure 1).
There were also 6.0% cases which were associated with chronic osteomyelitis (Table 5).

Discussion
The Covid-19 infection has been associated with a wide range of disease patterns, ranging from mild cough to lifethreatening pneumonia. 11 Although, the chances of healthy individuals contracting mucormycosis is extremely rare, a   complex interplay of factors such as as diabetes mellitus, use of immunosuppressive therapy, previous respiratory disorders risk of hospital-acquired infection can lead to secondary infections. 12 The sites favoured by mucormycosis may includes nose, sinuses, orbit, CNS, GIT, lung, jaw, heart and mediastinum, however ROCM is considered to be the most common variety seen world-wide. 13 Here, ROCM refers to the entire spectrum ranging from limited sinonasal disease (tissue invasion), limited rhino-orbital disease (progression to orbits) to rhino-orbital-cerebral disease (CNS involvement). 13 On microbiological examination, mucormycosis hyphae can be differentiated from other fungal infections based on the diameter, branching angle (right or acute branching), presence or absence of septa and pigmentation. Smith and Krichner 14 in 1950 laid out the criteria for clinical diagnosis of mucormycosis including: (i) Blood-tinged nasal discharge and facial pain, both on the same side, (ii) Black, necrotic turbinate's easily mistaken for dried, crusted blood, (iii) Ptosis of the eyelid, proptosis of the eyeball and complete ophthalmoplegia (iv) Soft peri-orbital or peri-nasal swelling with discoloration and induration and (v) Multiple cranial nerve palsies unrelated to documented lesions.
Patel et al conducted a study in June 2021 with 465 cases of Mucormycosis without covid-19 and showed that rhinoorbital presentation was most commonly seen (67.7%), followed by pulmonary presentation (13.3%) and cutaneous type (10.5%). Among Indians, diabetes mellitus (73.5%), malignancy (9.0%) and organ transplantation (7.7%) were the most common predisposing factors for the development of disease. 15 Song et al. conducted a study in April 2020 where the association between Covid-19 and invasive fungal sinusitis was examined which led to the conclusion that a large number of patients affected by or recovered from Covid-19 are at an increased risk of developing invasive fungal diseases. 16 Another study conducted by White et al. comprising of 135 adults with Covid-19 infection, reported an incidence of 26.7% for invasive fungal infections. 17 In a recent review, 8.0% of coronavirus-positive or recovered patients had secondary bacterial or fungal infections during hospital admission, with widespread use of broad-spectrum antibiotics and steroids. 18,19 Ideally, surgical debridement of the infected area should be performed as soon as possible once the diagnosis is confirmed. Although surgery alone is reported not to be curative,an aggressive surgical approach has been shown to improve survival. 20 Amphotericin-B deoxycholate remains the anti-fungal treatment of choice to start, with its liposomal preparations preferred because of decreased nephrotoxicity. Prognosis remains poor even with aggressive surgery and intravenous anti-fungal therapy, with reported mortality rates of 33.3-80 per cent, going up to 100 per cent in disseminated infections. 21

Conclusions
Covid-19 is associated with a significant incidence of secondary infections both bacterial and fungal due to weakened/altered immunity. Additionally, the rampant use of corticosteroids and high prevalence of diabetes in India are two of the main factors aggravating the illness. If infected, early surgical intervention and intravenous antifungal treatment is the current mainstay for management, with a good prognosis and less severe disease course in cases of post-coronavirus mucormycosis.