Rhino-orbital-cerebral Mucormycosis and Aspergillosis Post-COVID-19: Contrariety in Terms of Prevalence Severity Management and Prognosis at a Tertiary Care Centre in Western Rajasthan

INTRODUCTION

COVID-19 that was declared as a global pandemic by World Health Organization in March 2020 continues to be a health concern directly or indirectly. With the upsurge of cases with the commencement of second wave of COVID-19 infection, a myriad of potential complications are being noted, most commonly including secondary bacterial and fungal infections which can be attributed to the immune dysregulation related to COVID-19. These infections mostly have a possible association with concomitant medical conditions, such as diabetes mellitus, decompensated pulmonary functions, and the widespread use of immunosuppressive agents. These patients presented with features, such as headache, localized pain, nasal discharge, sinusitis, orbital cellulitis and diminution of vision which is characteristic of rhino-orbital fungal infection.^1,2

Rhino-cerebral-orbital mucormycosis and aspergillosis are both opportunistic invasive fungal infections. Their spores are found in the environment, inhalation of which normally does not cause any harmful effects but results in serious infections in people with a weak immune system. Mucormycosis is caused by the family Mucoraceae which is divided into the subspecies Absidia, Rhizopus, and Mucor. Invasive aspergillosis is caused by Aspergillus fumigates but the infection occurs in noninvasive form as well as like allergic Aspergillus sinusitis and aspergilloma. Rhino-orbital cerebral mucormycosis (ROCM) and invasive aspergillus infections starts in the nose and paranasal sinuses (PNS) are infltrating the orbit or the brain over the orbital apex or the cribriform plate by bony destruction and angioinvasion. Aspergillosis being first, mucormycosis is the second most frequent mycosis caused by filamentous fungi.³ But rhino-orbital aspergillosis is a relatively infrequent entity.⁴ The detection of mucormycosis an uncommon opportunistic invasive fungal infection has been declared as notifiable disease under Epidemic Diseases Act 1897 on May 19, 2021 in India.

Looking at all of these patients, we try to fathom the common link between these patients, that is, the most frequently associated risk factors, understand their clinical picture and how the radiological, microbiological and pathological investigations aid the diagnosis of the disease.

In our knowledge, rhino-orbital aspergillosis infection post-COVID-19 is not talked about in any articles because of the probable overshadowing by the overwhelming occurrence of ROCM .So here in our study, we aim to highlight the contrasting features of patients diagnosed with ROCM and rhino-orbital aspergillosis in terms of prevalence, presentation and course of management. Also to see the sensitivity of KOH reports, the investigation that forms the grounds for our diagnosis.

MATERIALS AND METHODS

The study involved 71 patients admitted from May to July 2021 at the Department of Otorhinolaryngology, M.D.M. Hospital, Jodhpur, Rajasthan, India. All included patients were tested positive for invasive fungal sinusitis by KOH mount/fungal culture of nasal biopsy or gingival biopsy or palatal scrapings.

A minimum follow-up period of 1 month was taken. History was sought for diabetes, steroid use, immune deficiency, and chemotherapy. Individual charts were reviewed to note the clinical picture, the ophthalmology opinion taken for intraorbital involvement, visual acuity and ocular movements, neurosurgical opinion were sought to rule out any intracranial extension. Brain + orbit + PNS MRI scans with gadolinium contrast done in all the patients to see the extent of the disease. Surgical debridement was done within 24 h and a revision surgery done as and when indicated. As soon as the diagnosis of mucormycosis was established, intravenous liposomal amphotericin B 5 mg/kg (350 mg) after pre-hydration with 500 mL normal saline was started, liposomal amphotericin 350 mg is diluted with D5% 500 mL + 8 units of human insulin regular (HIR) and given over 4–6 hours. Every alternate day, kidney function and daily serum electrolytes were monitored and accordingly the dose of amphotericin B was modulated. Nasal endoscopy was done daily and gelfoam soaked with ointment povidone iodine was kept locally at the surgically debrided area.

Study location: the Department of Otorhinolaryngology, M.D.M. Hospital, Dr. S.N. Medical College, Jodhpur, Rajasthan, India.

Study design: A retrospective observational study.

RESULTS

The study included 71 patients between the age 24 and 79 years out of which 19 were females and 58 were males. A total of 53 patients were diagnosed with mucormycosis, 18 with aspergillus infection. We observed that the most common underlying risk factor was Diabetes mellitus which was seen as in 63 out of 71 patients. As poor glycemic control is associated with poor prognosis, we noted that around 30% of total patients had HbA1C value >12 gm%. It was seen that out of 53 patients of mucormycosis,50 had DM type 2 and 48 were recently diagnosed whereas out of 18 patients of aspergillosis, 14 had DM type 2 and only 5 were recently diagnosed.

A total of 45 patients had a history of steroid intake during COVID-19 management, out of which 34 took it by parenteral route and 11 in the form of oral formulations.

B/l pneumonitis seen in a total of 35 patients and other comorbidities like hypertension/CAD were seen associated with 17 patients.

About 38 patients were diagnosed with mucormycosis within 2 months of COVID-19 positivity whereas only two patients of aspergillosis had prior COVID-19 infection.

Presentation of various risk factors and relationship of HbA1C value with the different infections is depicted in Figures 1 and 2, respectively.

Most commonly these patients presented with the complaint of facial paresthesia (36 patients). Around 25 patients presented with orbital involvement which has a spectrum of manifestations, including chemosis, proptosis, ptosis, and loss of vision seen in 11 patients. About 21 patients had complaints of headache. And 15 patients presented with involvement of maxilla either seen radiologically or the loosening of tooth/blackening of the hard palate present, 12 patients presented with nasal discharge. Intracranial involvement was seen in six patients. Skin involvement was seen in one patient.

The stages of presentation as recommended by Singh et al.⁵ in an article in 2018 are depicted in Table 1.

On nasal endoscopy, around 42 out of 53 mucormycosis and 2 out of 18 aspergillosis patients showed necrosed middle turbinate. Others either had mild secretions around the turbinates or a healthy picture of the nasal cavity.

The KOH mount report was compared with the fungal culture report of the nasal endoscopic biopsy sample to yield the results of sensitivity and positive predictive value (PPV) of KOH mount being 91% and 98%, respectively.

Radiological evaluation revealed mucosal thickenings in the PNS as a unanimous finding and rest are enlisted in Table 2. Bilateral disease presentation was seen in 27 patients, 1 of them being aspergillosis and the rest being mucormycosis.

A total of 20 mucormycosis patients and 3 aspergillosis patients required aggressive surgical intervention during their first surgery either in the form of total/partial maxillectomy or orbital exenteration (Figs 3 and 4).

Around 8 out of 58 patients of mucormycosis (13%) and 5 out of 18 patients of aspergillosis (27%) required revision surgery. Out of these, 6 out of 8 patients (75%) of mucormycosis and all 5 patients of aspergillosis (100%) required aggressive surgical intervention during second surgery as opposed to re-debridement alone (Figs 5 and 6).

Along with the surgical management, medical management in the form of intravenous liposomal Amphotericin B was given. The cumulative dosage varied according to the renal function tests with average being around 4.5 gm. After discharge, patients were given tablet posaconazole 300 mg OD with the aim of continuing it for 90 days. After a follow-up period of minimum 1 month, a total of 10 patients died. And all of these patients were mucormycosis diagnosed (Figs 7 and 8).

DISCUSSION

The incidence of invasive fungal disease was more common in males than females with the ratio being 3:1 and this preponderance has been documented as early as in 1990s in an article by Bhide et al.⁶ In our opinion, this can be linked to the higher rates of smoking habits in males which in turn leads to poor pulmonary reserve that might have increased the susceptibility of COVID-19 and hence the invasive fungal infections.

The incidence of these infections have seen an upsurge in these post-COVID-19 times and mucormycosis has been the leading face. In our study, Rhino-orbital aspergillosis prevalence was seen much less as compared with mucormycosis.

Our study showed that DM was associated in about 88% cases and steroid use during the previous COVID-19 management was noted in 64%. The documentation of these two with rhinocerebral fungal infections has been done as early as in 1960s in an article by Abramson et al.⁷

Likewise, Jiang et al. has described DM as an independent risk factor for rhino-orbital-cerebral mucormycosis and commonest underlying condition with 40% association and Swati et al. concluded that uncontrolled diabetes was the major risk factor for precipitating mucormycosis in the times of COVID-19 (96.7%).^8,9

Most of the patients of mucormycosis were recently diagnosed with diabetes which might be the reason of poor glycemic control as patients were not aware of the diabetes so were not taking any medication. Also HbA1c was noted to be mostly moderately high in aspergillosis as apposed to mucormycosis.

It has been seen that hyperglycemia can impair a wide range of functions involved in the process of bacterial and virus cells phagocytosis, including recognition, adherence and chemotaxis in neutrophils, monocytes, and macrophages. It also seems to affect the immunologic response of T cells. Local factors like decreased blood flow and nerves damage might also be in a way a contributing factor. Drozdowska and Drzewoski emphasized on the influence of hyperglycemia on the third component of complement (C3).¹⁰ It is advocated that glycation of C3 hinders its attachment to the bacterial surface and thereby impairs opsonization, which is a crucial part of phagocytosis. Galletti et al. in their study mentioned that fungus has the ability to express proteins on its surface which are structurally and functionally homologous to complement receptors on mammalian phagocytes. Chronic hyperglycemia induces their expression that in turn leads to the attachment of C3 to them and results in a lack of fungus recognition as a pathogen. This particular kind of molecular mimicry contributes to easier colonization and infection.¹¹

Our study shows that facial parethesia and pain were the most common presenting complaints and this has been advocated by many authors like in an article by Dhiwakar et al. perinasal cellulitis/paresthesia was found to be the most frequent early clinical sign of disease and Spellburg et al. highlighted that the initial symptoms of rhinocerebral mucormycosis are consistent with either sinusitis or periorbital cellulitis.^{12, 13} Now, this is probably due to the anatomical location of the maxillary sinuses which underlie the cheeks and that leads to facial paresthesia/pain.

And our radiological findings resonate with this as well since maxillary sinuses were found to be the most commonly involved sinuses (as a part of pansinusitis or isolated involvement). Likewise, Abdollahi et al. in his study proposed that the maxillary sinuses were the most frequently involved sites (66.7% of the cases) followed by the ethmoid sinus.¹⁴

The nasal endoscopy revealed the presence of necrotic tissue, mostly involving the middle turbinates either partially or completely and this classical finding of black necrotic eschar tissue that sometimes resembles dried blood has also been described by Singh et al.⁵

KOH fungal staining is a quick diagnostic tool that yields results as early as about 6 hours and rhino-orbital mycosis that has been proven to be a deadly infection can be life-threatening in a very short span of time and herein lies the importance of early diagnosis so that the prompt institution of antifungal chemotherapy is started ensuring a favorable outcome. In our study, KOH fungal staining gave 50 patients mucormycosis positive, 14 patients aspergillosis positive and fungal culture gave 50 + 03 patients as mucormycosis positive, 13 + 04 patients aspergillosis positive. When considering fungal culture as gold standard, sensitivity and PPV of KOH fungal staining was calculated as 90% and 98%, respectively as compared with a study by Garg et al. who highlighted that in 9 of 10 cases (90%), KOH mount and giemsa stain could provide opinion correlating with fungal culture.¹⁵

As mentioned by Balai et al., it has now been established that the definitive management of invasive rhino-orbital mycosis is the combined surgical management and intravenous antifungal therapy.¹⁶ And in our study, it was seen that the need of aggressive surgical approach during the presentation of the patients was mostly needed in mucormycosis followed by aspergillosis. The surgical debridement along with intravenous liposomal amphotericin B was sufficient for disease control in majority of the patients. But a few patients presented with recurrence and a subsequent need for revision surgery. The revision surgery depended upon the fact that whether there was any residual disease left or extension of the disease has occurred. And it was noted that re-debridement was not enough for any aspergillosis patient and all of them underwent either maxillectomy or orbital exenteration.

Since 60 years, amphotericin B has been the gold standard for the treatment of invasive fungal infections and improved tolerability has been seen with its lipid formulations as they have a similar spectrum of activity and a more favorable safety profile.¹⁷ and liposomal amphotericin B was the drug of choice in our patients as well; its efficacy has been documented long back as Bhide et al. in 1996 reported that in his study, an average total dose of 1.2–1.5 grams spread over a period of 5–6 weeks was used though the total dose advocated is 2–4 grams. Ten patients who showed favorable response and who are surviving to this date had received 1.2–1.5 grams as the total dose of amphotericin.⁶

But in our patients, the average dose was 4.5 grams and 2 patients with intracranial extension even received a cumulative dose as high as 9.5 grams and as of now, both are alive and healthy. Posaconazole was also widely used mainly as oral formulation but also intravenously when abnormal renal functions limited the use of amphotericin B.

In a study by Carvalhaes et al., Posaconazole displayed potency greater than or equal to the other azoles against the Mucorales group and also, posaconazole and other mold-active azoles showed good activity against Aspergillus spp. causing invasive mycosis.¹⁸ Dannaoui also in his study documented that posaconazole is effective against some species of zygomycete.¹⁹

CONCLUSION

In this study, we noted a male preponderance in our patients that can be linked to the similar preeminence in smoking habits and thus susceptibility for COVID-19 infection. DM and steroid intake were the most commonly associated risk factors. Facial paresthesia being the most common presentation resonated with maxillary sinus involvement being the most common radiological involvement. Nasal endoscopy proved to be an excellent screening procedure and necrotic middle turbinate seen predominantly in mucormycosis that suggests fast progression as opposed to aspergillosis and hence bilaterality was seen in cases of mucormycosis. KOH fungal staining proved to be an excellent diagnostic tool by being precise and time sensitive as well. Signs of extensive disease at presentation were seen much more in mucormycosis than aspergillosis and hence the need for aggressive surgical intervension. For revision surgery, re-debridedment alone was not enough for aspergillosis which again can be correlated to the rather slow progression of aspergillus as compared with mucormycosis. Since mucormycosis patients already underwent maxillectomy/eye exenteration, re-debridement will suffice. The safe upper limit of liposomal amphotericin B was noted to be 9.5 gm. Posaconazole proved to be a good alternative as an antifungal.

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