key: cord-1034038-0xfei2l6
authors: Muraleedharan, Manjul; Panda, Naresh Kumar; Angrish, Prerna; Arora, Kanika; Patro, Sourabha Kumar; Bansal, Sandeep; Chakrabarti, Arunaloke; Rudramurthy, Shivaprakash Mandya; Bakshi, Jaimanti; Mohindra, Satyawati; Gupta, Rijuneeta; Virk, Ramandeep Singh; Verma, Roshan Kumar; Ramavat, Anurag Snehi; Nayak, Gyanaranjan
title: As the virus sowed, the fungus reaped! A comparative analysis of the clinico‐epidemiological characteristics of rhino‐orbital mucormycosis before and during COVID‐19 pandemic
date: 2022-04-08
journal: Mycoses
DOI: 10.1111/myc.13437
sha: 369f55570b2eeac83de3e11ab7fd0e6bc2879ef7
doc_id: 1034038
cord_uid: 0xfei2l6

BACKGROUND: The sudden surge of mucormycosis cases which happened during the second wave of COVID‐19 pandemic was a significant public health problem in India. OBJECTIVES: The aim of this study was to analyse the clinico‐epidemicological characteristics of the mucormycosis cases to determine the changes that had occurred due to COVID‐19 pandemic. METHODOLOGY: A retrospective cross‐sectional study was conducted at the Department of Otolaryngology Head and Neck Surgery, PGIMER, Chandigarh, India. Patients diagnosed with rhino‐orbital mucormycosis were categorised into the following groups: Pre‐pandemic(May 2019 to April 2020), Pandemic Pre‐epidemic (May 2020 to April 2021) and Epidemic (1 May 2021 to 12 July 2021). The epidemiological, clinical and surgical data of all the patients were retrieved from the hospital records and analysed. RESULTS: The epidemic period had 370 cases, compared with 65 during pandemic period and 42 in the pre‐pandemic period. Diabetes mellitus was seen in 87% of cases during epidemic period, 92.9% in the pre‐pandemic period and 90.8% in the pre‐pandemic pre‐epidemic period. The proportion of patients suffering from vision loss, restricted extra‐ocular movements, palatal ulcer and nasal obstruction was higher in the pre‐epidemic groups, and the difference was significant (p, <.01). There was no history of oxygen use in 85.9% of patients and no steroid use in 76.5%. The death rates were the lowest during epidemic (10%). CONCLUSION: COVID‐19 has caused a statistically significant increase in the number of mucormycosis infections. The mortality and morbidity which showed an increase during the first wave of COVID‐19 decreased significantly during the epidemic period.

SARS-CoV-2 by RT PCR and never had previous history of infection. A total of 26/65 was diagnosed with COVID-19 for the first time at admission or within a week before the date of admission (suggestive of a recent infection). Very few (3, 4 .6%), who had been treated for COVID-19 (before 2 weeks of presentation), developed mucormycosis.

During the epidemic period, a total of 370 fresh cases of mucormycosis were diagnosed and were taken for immediate surgical debridement. The majority 313 (84.6%) were positive for SARS-CoV-2 infection (became positive on testing at admission or detected positive within a week after admission to our hospital), whereas 34 (9.2%) were negative for SARS-CoV-2. The post-COVID cases stood at 23 (6.2%). TA B L E 1 Comparison of socio-demographic profile of study participants amongst three groups 

The association of the COVID-19 infection with mucormycosis was statistically significant with a p-value of <.01. (Table 1 ).

Diabetes mellitus was undoubtedly the single most comorbidity predisposing to the infection. In total, 92.9% of patients with mucormycosis had diabetes in the pre-pandemic period, while almost a similar percentage (90.8%) had diabetes during the pandemic preepidemic period but slightly lower (87%) during epidemic period

The other significant comorbidity was hypertension (32.1%). There was no significant difference in the proportion of cases having associated hypertension over the years. No statistically significant changes in the comorbidity profile could be seen over the study period.

The other comorbidities present in the study group were haematological malignancies, chronic kidney disease, tuberculosis, HIV, chronic liver disease and interstitial lung disease. There was a statistically significant difference in the association with haematological malignancies, CKD and tuberculosis across the three periods, as they were very rare and not found uniformly across all the study periods ( Table 2 ).

The major presenting complaints of the patients with rhino-orbital mucormycosis included diminished or loss of vision, restricted extraocular movements, peri-orbital/facial swelling, palatal ulcer, nasal obstruction and facial skin changes ( Table 3 ).

The most common presenting symptom over the years has been 

The other complaints were palatal ulcer, nasal obstruction, facial swelling and skin ulceration. Both the groups in pre-epidemic era had greater proportion of patients suffering from these symptoms individually.

On the contrary, it is also interesting to note the co-existence of these symptoms at the time of presentation. 40.5% and 41.5% of patients presented with four or more of these symptoms in the two pre-epidemic groups, while during the epidemic, the proportion of patients presenting with four or more of these symptoms was 9.2%.

Thus, the proportion of patients suffering from vision loss, restricted extra-ocular movements, palatal ulcer and nasal obstruction was higher among the pre-epidemic groups and this difference was statistically significant (Table 3) . Similarly, the higher number of patients having more than four symptoms was also statistically significant (<0.01).

An overwhelming 318 patients had no history of oxygen use (85.9%), and 283 (76.5%) had no history of steroid usage. It is also noteworthy that 80.8% (n = 299) had no history of hospitalisation prior to being infected with Mucorales ( Table 4) .

Of the 87 patients who had history of steroid usage, 71 patients have taken it either orally or as intravenous preparations under monitoring in a hospital setting, whereas16 of them had it at home without any blood sugar monitoring.

The ethmoid sinuses were the most commonly affected sinus across all the periods with the percentage involvement being 97.6%, 89.2% and 88.5% during the pre-pandemic; pandemic pre-epidemic; and epidemic groups respectively. The palatal involvement during the epidemic with 32.1% showed palatal ulceration, while in the preepidemic period, it was seen in 61.7% of patients and the difference was statistically significant (p, <.01). The maxillary sinus was surprisingly involved in a similar manner during the pre-pandemic and epidemic periods with 61.9% and 58.1% respectively. During the first wave of COVID-19, significantly more number of patients (83.1% p = .01) had involvement of the maxillary sinus.

The intra-orbital involvement as evident intra-operatively showed a statistically significant decrease during the epidemic period compared with the pre-epidemic period (p, <.01). The orbital involvement was the highest during the pandemic period before the epidemic with 65.1% of patients affected. The epidemic period showed only 25.6% of patients having orbital involvement.

There was an increase in the percentage of patients with disseminated rhino-orbital mucormycosis, specifically with intra-cranial and lung involvement during the epidemic period. While 22.7% of the patients during the epidemic had intra-cranial (n = 82) and pulmonary (n = 2), the percentages during the pandemic pre-epidemic and prepandemic periods were 12.3% and 14.2% respectively. The difference was not statistically significant ( Table 5 ).

The surgical management of mucormycosis involved the debridement of the affected sinuses and the tissues. We had classified the procedures into the following types, signifying the extent of the disease.

The procedures most commonly performed were total/ extended total maxillectomy, partial maxillectomy, orbital exenteration, debridement of the sinuses, debridement of facial skin and drainage of facial abscess.

Total maxillectomy, indicative of an extensive disease, was performed in 45.2% in the pre-pandemic group and 49.2% in the pandemic pre-epidemic group. Thus, rate of total maxillectomy in the epidemic period was 12.4%. The difference was statistically significant (p, <.01).

Orbital exenteration also showed a statistically significant reduction (p, <.01) in the epidemic period. 193 patients underwent exenteration in the two months after epidemic (36%). The rates were 52.4% and 66.2% during the previous years.

There has been but an increased number of patients requiring debridement of the facial skin and subcutaneous tissue during the epidemic period (p, <.01). The involvement usually occurred on the cheek along the distribution of the inferior orbital nerve. Approximately half of the patients required debridement of the skin (n = 180, 50.6%) while the percentages were 11.9% and 20% in the pre-epidemic periods.

The number of these different procedures an individual patient undergoes as part of debridement can be considered as being indicative of the extensiveness of the disease. An analysis of this aspect points out to the fact that the proportion of patients undergoing more than 3 of these procedures was the highest among the pandemic pre-epidemic group with 63.1% of the patients undergoing extensive procedures. In the pre-pandemic group, it was 45.2%, while in epidemic group, it was 48.9%. The difference was not statistically significant though ( Table 6 ).

The percentage of endoscopic procedures went down drastically during the pandemic pre-epidemic period when it consisted just 7.7% of the procedures. The difference between the three groups was not statistically significant though ( Table 7) . 

As the long-term follow-up data of the epidemic period are not available, the treatment outcomes on a short-term basis have been analysed based on whether the patients could be discharged or not. The intrahospital death rates during the three periods were 16.7%, 30.8% and 10% during the pre-pandemic, pre-epidemic; pandemic, pre-epidemic;

and epidemic periods respectively. Thus, the epidemic period showed the least death rates (Table 8 ).

Of the 42 patients treated in the pre-pandemic group, follow-up data of 32 are available. 4.8% had recurrences and underwent repeat procedures (n = 2). 23 are still alive after 2 years, thus bringing the survival rate among the ones who could be followed up to 71.9%.

Among the pandemic pre-epidemic group, 6/65 were lost to follow-up. Of the remaining 59, the recurrence rates were 7.7%, and death rate was 40.7%.

It has to be noted that deaths on follow-up include the in-hospital deaths during admission and also deaths which are due to reasons other than mucormycosis. It is of particular importance that the pandemic pre-epidemic period saw the most morbidity and mortality (statistically significant, p < .01; Table 9 ).

The world in general and India in specific was entering into a phase history of oxygen support. The use of industrial grade oxygen so as to overcome the sudden crunch in oxygen availability also came under scanner and was held by many as being responsible for the fungal crisis. The mean age was found to be 51.9 years.

Another study by Bhanuprasad et al. 3 into the risk factors associated with the mucormycosis epidemic studying 164 patients (132 COVID and 32 non-COVID-Mucor cases) concluded that there was a high association with steroid use (71%). Oxygen use was found to be present only in minority of the cases. Diabetes mellitus again was the most significant predisposing factor in both COVID and non-COVID cases. The mean age was 51 years with a male predisposition. 

There is overwhelming evidence that COVID-19 infection, especially in the second wave, is strongly associated with the spike in the mu- 

In two papers from the Institute published 18 years apart, it is evident that the risk factors have not changed much. 1, 6 Uncontrolled diabetes was the most common cause, and rhino-orbital mucormycosis remained the most common type. The mortality rates were 48% in 2001, while in 2018, it remained similar at 46.7%. In another study involving 27 patients with rhino-orbito-cerebral mucormycosis, the survival rate in people undergoing surgery for at least the rhino-orbital part followed by medical management with amphotericin (conventional) was 78.3%. 7 In unoperated ones, the condition was fatal with 100% death rates.

Our data for the three years showed comparable survivals.

The management principles based on radical debridement, regular wound examination and revision debridement, and medical man- The early presentation of patients was evident from the statistically significant fall in the intra-orbital involvement of the disease. More than 50% of the patients usually presented with extension of the disease to the orbits (52.4% in the pre-pandemic and 65.1% in the pandemic pre-epidemic period). The percentage was the lowest during the epidemic period with just a quarter of the patients presenting with the orbital involvement (25.6%). The initial studies showed up to 72% orbital involvement, but this may be attributed to the fact that it was a study based on ophthalmology practice. The previous reports of mucormycosis occurring in otherwise

Investigation (equal)

Resources (equal)

Naresh Panda: Conceptualization (lead); Formal analysis (lead)

Supervision (lead)

Prerna Angrish: Data curation (equal)

Kanika Arora: Data curation (equal)

Sourabha Kumar Patro: Formal analysis (equal)

Sandeep Bansal: Supervision (equal)

Arunaloke Chakrabarti: Supervision (equal)

Shivaprakash Mandya Rudramurthy: Supervision (equal)

Jaimanti Bakshi: Supervision (equal)

Satyawati Mohindra: Supervision (equal)

Rijuneeta Gupta: Supervision (equal)

Writing & editing (equal)

Singh Virk: Supervision (equal)

Writing -review & editing (equal)

Supervision (equal)

Writing & editing (equal)

Supervision (equal); Writing -review & editing (equal)

Writing -review & editing (equal)

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As the virus sowed, the fungus reaped! A comparative analysis of the clinico-epidemiological characteristics of rhino-orbital mucormycosis before and during COVID-19