Post-COvId -19 Invasive Fungal Sinusitis: A Case Series from Southern India

Acute Invasive Fungal Rhinosinusitis (AIFR) is a serious condition with aggressive course and high mortality rates. There is an upsurge in the incidence of invasive fungal rhinosinusitis in post COvId-19 patients. We have come across 20 AIFR cases in post COvId-19 patients. On retrospective exploration of the patient’s records, we found that 30% patients had received steroids and 90% had diabetes. All the patients were managed by administration of Iv amphotericin B and local debridement of infected tissues. The mortality rate was as low as 15 %. We conclude that combined approach of Antifungal therapy with debridement of infected tissues improves the prognosis and survival of AIFR patients.


INTROduCTION
The coronavirus disease 2019 (COVID-19) pandemic has caused several parallel challenges on a global scale.In the midst of this pandemic, there has been a new epidemic of acute invasive fungal rhinosinusitis (AIFR) infections. 1 The recent spate of COVID-19-associated AIFR cases have earned global attention.
There has been a substantial increase in the incidence of AIFR of the maxillofacial region, namely mucormycosis and aspergillosis. 2 In India, many states have reported more than 30,000 cases of AIFR, rendering it a notifiable disease. 3IFR is defined as the presence of fungal hyphae within the sino-nasal mucosa, submucosa, vasculature, or bone with 1 month or less of sinusitis symptoms. 4AIFR is a serious infection and is considered the most aggressive subtype of fungal sinusitis with subsequent serious morbidity and mortality. 5he primary objective of the present study was to establish AIFR in relation to the COVID-19 pandemic and illustrate its characteristic clinical, microbiological, radiological, and histopathological profile and management at our institute, Sri Devaraj Urs Medical College (SDUMC), Kolar, Karnataka, India.

Study design
This is a retrospective analytical study.

Setting
Department of Microbiology and Department of Otorhinolaryngology, R. L. Jalappa Hospital & Research Center, a tertiary care teaching hospital

Ethical approval obtained
This study was approved by the

Statistical analysis
Data from 20 patients were collected and entered into Microsoft Excel, and descriptive data were analyzed.

Case series
This is a retrospective case series analysis of post-COVID-19 patients with AIFR admitted at our hospital and managed by the Department of Microbiology and the Department of Otorhinolaryngology from May to June, 2021.
Patients were diagnosed based on characteristic clinical manifestations, radio imaging, microbiological analysis (microscopy/ culture), and histopathological examination of the sinonasal specimens.
We analyzed the patient demographic details, clinical presentations, comorbidities, laboratory results, imaging findings, and management and clinical outcomes.
In our study, only six (30%) patients received steroids during their COVID-19 treatment, and three (15%) patients received remdesivir as antiviral and antifungal treatment in 70% of patients.Oxygen was used in managing seven (35%) patients, and 90% and 30% of the patients had diabetes and hypertension as comorbidities, respectively; two patients had no comorbidity.
Regarding KOH reports, 11 cases were positive and fungal culture isolates with Rhizopus and Aspergillus species predominant; two cases were reported with co-infections as shown in Figure 1, 2 and 3 (Aspergillus niger and Rhizopus and A. niger and Candida species, respectively).Of the 20 cases, 14 were confirmed via histopathological examination as shown in Figure 4 and Table 2.
In our study, we identified Rhizopus species in eight patients, Mucor in five patients, Aspergillus fumigatus in four patients, A. niger in three patients, and A. flavus in one patients; one patient was infected with Candida (co-infection with A. niger).
The clinical outcome with treatment was considered to be good because there was only 15% mortality (three cases); four patients were discharged against medical advice, and 13 patients  were discharged after successful treatment.
There was compelling evidence of lymphopenia in the majority of patients, as seen in the CBC reports of 12 (60%) patients, consistent with the findings of a few previous studies.Nineteen patients underwent imaging tests (n = 20).Inflammatory marker (serum ferritin, lactate dehydrogenase, D-dimer (in some patients), and IL-6 marker (in one patient)) levels were examined as shown in Figure 5.

dISCuSSION
AIFR is a rapidly progressive and lifethreatening infection of the nasal cavity and paranasal sinuses. 6AIFR is known to occur in patients with neutrophil dysfunction or neutropenia such as hematological malignancies, uncontrolled diabetes, aplastic anemia, and hemochromatosis and in patients receiving immunosuppressive drugs. 7ommon clinical features noted in AIFR are fever, nasal congestion, acute onset of facial pain, and extension of pain into surrounding structures, such as the paranasal soft tissues, orbit, and cranial vault.Orbital involvement can result in attenuation of vision, whereas sinus or intracranial extension can be associated with proptosis or neurological impairment, respectively. 8here is extensive angioinvasion and hypercoagulability in COVID-19 patients, which act via ACE2 receptor inhibitors (ACE2 receptors are present in numerous organs, including the lungs, kidneys, blood vessels, and heart). 9The causal link between COVID-19 and AIFR remains a mystery.
Many factors contribute to causing this unholistic syndemic.SARS-CoV-2 infection causes impaired cell-mediated immunity, lymphopenia, and associated reduction in CD4 T and CD8 T cell counts. 10The use of steroids in COVID-19 treatment has further led to the inadvertent consequences of steroid-induced hyperglycemia and immunosuppression. 5To add to the existing problem, errant diabetes control leads to endothelial damage, and endotheliitis and thrombosis also predispose patients to fungal infections. 11,12 h e e f f e c t s o f c o r t i c o s t e r o i d microangiopathy on diabetes patients and the possible peripheral microthrombi in COVID-19 patients could contribute to the increase in AIFR infections in post-COVID-19 patients. 13SARS-CoV-2 causes upper and lower respiratory tract  infections, similar to previous SARS-COV and MERS infections. 14ncontrolled diabetes mellitus and extensive use of steroids are the two main factors exacerbating AIFR; both of these must be effectively managed. 15Therefore, the successful management of this fatal infection requires early identification of the disease and aggressive and prompt medical and surgical management to prevent fatality. 16In our study, 80% of the patients had diabetes with high HbA1c levels, which supported the findings.
In our case series, the possibility of a correlation between COVID-19 and AIFR infections was analyzed.Lymphopenia was noted in 12 of the 20 patients (60%) with COVID-19.
Viral replication stresses the role of inflammatory response and neutrophil and monocyte influx in the bloodstream and impaired neutrophil-lymphocyte ratio, thereby making the patient susceptible to systemic fungal infections. 17Phagocytic cells are the major host defense mechanisms against mucormycosis.Hyperglycemia and acidosis in diabetes patients are known to impair the ability of phagocytes to move toward and kill pathogens by both oxidative and nonoxidative mechanisms. 18,19mphotericin-B is the treatment of choice for AIFR.It is available as amphotericin-B deoxycholate.Treatment should be started with liposomal amphotericin-B because it is less nephrotoxic. 20or refractory/intolerant cases for longterm maintenance, posaconazole/other azoles should be used as an alternative treatment option. 21,22ur case series highlights the association of fungal sinusitis occurrence with post-COVID-19 in patients.

CONCluSION
AIFR cases are continually increasing in the COVID-19 pandemic.This emphasizes the need for the early clinical diagnosis of AIFR in patients with COVID-19, which is essential for good treatment outcomes. 23A combination of medical management using antifungal treatment and surgery for the debridement of infected tissues improves the prognosis and survival of these patients. 24

Table 1 .
Clinical presentation of patients

Table 2 .
Microbiological and pathological findings