Effect of the staging of rhino-orbital-cerebral mucormycosis on its management and clinical outcome

India has tackled the aggressive and furious second wave of coronavirus-19 (COVID-19). Amidst that, the country had witnessed another fatal disease called rhino-orbital-cerebral mucormycosis (ROCM), which showed an exponential hike in the COVID-19 era.[1] During the second wave of COVID-19 in India, about 81% of cases of ROCM were reported to be associated with this, and it was declared a notifiable disease by the Government of India.[2] Mucormycosis is caused by the fungal class Mucoromycotina and is an opportunistic infection caused by mold fungi of the genus Rhizopus.[3] Mucormycosis is a potentially lethal fungal infection predisposed by uncontrolled diabetes mellitus, corticosteroids, immunosuppressive therapy, acquired immunodeficiency syndrome (AIDS), trauma/burns, hematologic and solid organ malignancies, transplantation, and iron overload.[1] The surge of ROCM was seen during the second wave of COVID-19 when excessive hypoxic events were reported with uncontrolled glycemic status, high ferritin levels, immunosuppression by the virus itself, corticosteroid and tocilizumab use. These factors are highly conducive to the germination and proliferation of the fungal spores.[2] This fungal infection starts from the sinonasal mucosa by inhaling the fungal spores from the contaminated environment and then through angioinvasion, it shows rapid progression of the disease with eventual involvement of the orbit with necrosis of blood vessels leading to blindness.[4] Angioinvasion of blood vessels such as the internal carotid artery or the cavernous sinus by hyphae causes dry gangrene in the eye, leading to cerebral infarctions, aneurysms, and hematogenous dissemination.[5] If it reaches the brain, chances of mortality increase and it carries poor prognosis. There is an old, ill-defined staging that shows overlapping of various clinical manifestations, according to which it is staged as follows: Stage 1 – infection of the nasal mucosa and paranasal sinuses, stage 2 – orbital involvement leading to superior orbital fissure syndrome and orbital apex syndrome, stage 3 – cerebral involvement leading to cavernous sinus thrombosis, occipital and frontal lobe infarctions.[6] In the COVID era, due to the influx of a high volume of ROCM patients, a working staging system was required to help in triaging these patients for customized care. Honavar[7] proposed a simple staging system of ROCM based on the anatomic progression from the nasal mucosa onto the paranasal sinuses, orbit, and brain and its severity in each anatomic location. This staging system attempted to plug in the symptoms, signs, and preferred diagnostic tools for each of these stages based on the anatomic progression from the point of entry. The next logical step is its validation, proposing the preferred management for each stage, and correlating the outcomes. A retrospective analysis of proven cases of ROCM was conducted to assess the effect of the new staging system to customize its management and outcome. The demographic details and clinical characteristics of those patients are shown in Table 1.Table 1: Demographics and baseline variablesIn this study, the orbital involvement was divided into 3 A, up to 3D for defining the symptoms and management in the vicinity of the orbit, and 4A onward to evaluate its extension to the brain for its prognostication and the patient’s survival according to the classification devised by Honavar et al.[7] [Table 2]. Depending upon the staging of ROCM, a multidisciplinary team approach was followed. Up to stage 3A, otorhinolaryngologists managed cases by surgical debridement, functional endoscopic sinus surgery (FESS), sinus irrigation, and partial or total maxillectomy. Along with this, intravenous injection of liposomal amphotericin B (AMB) 5–10 mg/kg/day was given as per the institutional protocol for 2–4 weeks depending upon the response of the therapy. Proper monitoring was done as AMB is nephrotoxic. Blood urea nitrogen (BUN) and serum creatinine were closely observed and if BUN was found to be raised to 50 mg/dl and serum creatinine to 3 mg/dl, then it was tapered and switched to oral posaconazole. As prediagnosed chronic kidney disease was seen in 42 (20.89%) patients, AMB was given cautiously. Oral posaconazole 300 mg once daily was given for a period of 1–3 months. About 65 (32.33%) patients received transcutaneous retro-orbital AMB (TRAMB) at a dose of 3.5 mg/ml as an adjuvant therapy to restore vision. Treatment monitoring was done based on the clinicoradiologic regression or progression. The visual acuity of these patients was monitored very closely. Exenteration was indicated for the eyes with extensive orbital involvement including apex with no perception of light or with central retinal artery occlusion (CRAO) or disfigured or protruded eye with exposure keratitis or sloughed out cornea or progressive disease despite repeated sinus debridement with AMB lavage.Table 2: Relationship of various variables with the staging of ROCMThe clinical outcome variables were the visual outcome, globe salvageability, and survival of the patients. The visual outcome was the visual acuity at the latest follow-up of the patient; globe salvageability was considered compromised if exenteration was done. These patients were followed up for at least 6 months. The predisposing factors such as COVID-19 and chronic kidney disease showed a statistically significant relationship with ROCM staging. The visual outcome at the maximum follow-up and globe salvageability showed a statistically significant relationship with ROCM staging. The staging of ROCM also showed a significant relationship with the survival of the patient, with a P value of 0.05. Various management strategies such as FESS and exenteration showed a significant relationship with the survival of the patients, with a P value of 0.00 each, which demonstrates the significant effect of globe salvageability on the survival of ROCM patients [Table 3].Table 3: Effect of various variables on the survival of the patientsComorbidities, such as diabetes, and steroid usage led to excessive risk of ROCM among COVID-19 patients.[8] In the present study, 67.16% of patients were diabetics and this was in agreement with the findings of Ponnaiah et al.,[8] who reported diabetes as a predisposing factor in mucormycosis to the tune of 71%. Corzo-León et al.[9] and Dolatabadi et al.[10] performed a study on Mexican and Iranian populations and demonstrated a prevalence of 72% and 75.4% mucormycosis in diabetic patients, respectively. In the Indian scenario, indiscriminate use of steroids was found to be predominant in the COVID era due to a lack of awareness and their over-the-counter use.[11] In addition to these comorbidities, hypertension and chronic kidney disease can be responsible for ROCM. In the current study, 20.89% had deranged renal function tests and 44.27% were hypertensive. A total of 133 (66.16%) patients were reported to be post-COVID with an average gap of 27 days between the onset of COVID-19 infection and diagnosis of ROCM, which is consistent with the results of Ramaswami et al.[12] There is a new system of staging based on the general anatomic progression, which was put forward by Honavar[7]to divide ROCM through its course from nose to brain in four stages. This staging can be helpful for management, monitoring the outcome, and even prevention of this fatal entity. In the current study, 46.77% of patients developed stage 3D and 13.43% of patients presented with cranial involvement of cavernous sinus with stage 4D. A total of 136 (67.66%) cases showed orbital and ophthalmic involvement predominantly with orbital cellulitis, periorbital swelling, cranial nerve involvement, diplopia, pain, orbital apex syndrome, and a diminution of vision. The same trend of 60% of orbital cellulitis was reported by Swati et al.[13] A total of 24 (11.94%) patients presented with denied perception of light, which was mainly due to CRAO in 20 (83.33%) patients. Cornely et al.[14] reported that 46.77% of cases involved the orbit and ocular tissues. Microbiologically, the ROCM infection was confirmed showing aseptate hyphae by KOH–calcofluor mount in all cases. All the patients received intravenous liposomal AMB. AMB may be nephrotoxic, so these patients were monitored for electrolytes and renal function tests, which is consistent with Ramaswami et al.[12] Keeping in view the safety profile of the drug, liposomal AMB was used for the patients in this study as it is less nephrotoxic compared to conventional sodium deoxycholate AMB which can cause acute kidney injury. TRAMB was given to the cases that showed orbital involvement. In the management part of this study, we have modified the treatment strategies after looking into the classification system. In the present study, 74.62% of cases underwent surgeries in the form of FESS, partial or total maxillectomy to salvage the globe and orbit, which is on the higher side of the report by Swati et al. who reported that 62.2% of their cases underwent surgery.[13] This can be explained by the fact that surgical management may differ due to the staging pattern in that study. In 14 (6.97%) cases, exenteration was done to save the life of the patients to avoid its extension into the cerebral tissue, and it shows its significant impact on the survival of ROCM patients. This study is one of its kind with its focus on the effect of staging of ROCM on the visual acuity, globe salvageability, and survival outcomes. The sample size is also large enough to justify the generalizability of the study. To conclude, the staging of ROCM is associated with predisposing factors such as diabetes, steroid usage, chronic renal disease, and COVID-19. It shows its impact on clinical management and outcomes such as visual outcome, globe salvageability, and survival of the patients. The staging helps in framing the treatment protocols, predicting outcome, and prognostication of ROCM.