key: cord-1053362-ro9r2p8j
authors: Sekaran, Anuradha; Patil, Nayana; Sabhapandit, Swapnali; Sistla, Srinivas Kishore; Reddy, Duvvur Nageshwar
title: Rhino-orbito-cerebral mucormycosis: An epidemic in a pandemic
date: 2021-12-24
journal: IJID Regions
DOI: 10.1016/j.ijregi.2021.12.009
sha: 4c943e4e34bbbe4c6e7eed3b7bb2d9b524fe5356
doc_id: 1053362
cord_uid: ro9r2p8j

Introduction With the severe COVID-19 disease, opportunistic infection of Rhino-orbito-cerebral mucormycosis(ROCM) is increasing in India. Aim To study the laboratory parameters, histopathological features of sinus mucosal biopsies and exenterated orbits and clinical aspects of patients with ROCM. Materials and methods We retrospectively analysed nasal and sinus debridement biopsies and orbital exenteration specimen of 30 patients, along with their laboratory parameters, clinical history of predisposing conditions and medication history during COVID-19 infection. Results All patients were either in post COVID-19 recovery period or having ongoing COVID-19 infection. Most patients were diabetic with increased glycosylated hemoglobin (HbA1c). Steroids and antibiotics were used in most patients. 30 sinonasal mucosal debridement from various sites along with 9 orbital exenterations and one frontal decompression craniectomy specimen were examined. Mucor was densely seen in necrotic tissue and presence of vessel and nerve invasion was documented. There were four mortality. Conclusion ROCM is a life-threatening disease. High index of suspicion with prompt aggressive surgical and medical management by multi-disciplinary team can be life saving. Efforts to maintain optimal glycemic index is likely to be helpful in preventing ROCM. Judicious use of steroids is mandatory to control the collateral epidemic of ROCM in India.

Hospital. 123

We retrospectively reviewed case records of 30 patients with ROCM whose nasal and sinus 125 debridement biopsies and orbital exenteration were done during April 24 to May 24, 2021 in 126 AIG Hospital. The medical records were retrieved for relevant clinical history, in particular, 127 date of COVID-19 positivity by reverse transcriptase polymerase chain reaction (RT-PCR), 128 treatment given with specific note on usage of antibiotics, steroids (type, dosage and duration 129 of use), Remdesivir, Tocilizumab, multivitamin supplements, oxygen therapy, hospitalization 130 and ventilation history. Presence of co-morbid conditions like hypertension, DM, cancer and 131 immunosuppression because of any chronic illness were documented with available 132 information, followed by telephonic conversations. Contrast enhanced magnetic resonance 133 imaging (MRI) were reviewed for involvement of paranasal sinuses (PNS), orbit and brain. 134

Complete blood picture (CBP) was documented. Most of the cases did not have laboratory 135 investigations like interleukin-6 (1L-6), C-reactive protein (CRP), lactate dehydrogenase 136 (LDH), Ferritin and D-dimer and hence, could not be analysed. Fungal filaments on 137 potassium hydroxide (KOH) mount and growth on culture media such as potato dextrose agar 138 (PDA), Sabouraud's dextrose agar (SDA) from samples taken during sinus and nasal 139 debridement were also documented. 140

Tissue samples from the sinuses and nasal turbinates were entirely processed. All exenterated 141 eyeballs had a sample of orbital apex tissue sent separately along with the main specimen. 142

The eye balls were grossed according to the department protocol on par with the CAP 143 protocol meant for grossing oncosurgical specimen of eyeball. After orbital nerve cut end 144 was sampled, 2 vertical sections on either sides of cornea were made through the entire 145 eyeball and the 3 parts obtained were further bread loafed and processed (Fig 1) . 146

Haematoxylin and eosin ( H&E) stained slides were prepared, which were examined for 147 presence and type of fungi and density of necroinflammation. Grocott methenamine-silver 148 (GMS) and periodic acid-Schiff (PAS) special stains were further examined for confirmation 149 of the fungal organisms and also to demonstrate their presence in low fungal density areas. 150

Blood vessel and neural invasion was documented wherever detected. 151 152

We received a total of 30 specimen. Among them, 26 were from male and 4 from female 154 patients. Age range was 24-73 years, while 5 cases were less than 35 years of age. (Fig 2a  155 and 2b). 156 19 cases were in post-COVID-19 recovery period ranging from 15 days to 2 months. 157 However, 11 cases had ongoing COVID-19 infection (approximately day 7 to day 9 from 158 onset of COVID-19 symptoms) (Fig.3) . 159 27 patients had history of steroid intake (Methyl prednisolone 40 mg or Dexamethasone-6mg 160 followed by tapering doses for overall duration of 12 days) during COVID-19 infection. Few 161 patients had history of steroid intake for almost 3 weeks. 3 patients did not give reliable 162 history of steroid intake. These three patients had high blood sugar levels. All patients 163 however had received antibiotics (Doxycycline/ Azithromycin). 3 patients had received 164 Tocilizumab and 3 patients received Remdesivir. All cases had received multivitamin 165 supplements including zinc, vitamin C and vitamin D. 166 17 cases had history of DM. 5 patients were de-novo cases of DM. In the remaining 8 cases, 167

proper history could not be elicited. However, 29 patients had deranged blood sugar levels in 168 2 or more occasions and HbA1c tested in 14 patients was high (more than 9% in 11 cases) 169 with values ranging from 6.8-15. One patient had high blood sugar levels after surgery for 170 ROCM. Hence all 30 patients were finally diagnosed as diabetic. There were 8 hypertensive 171 patients, all of whom also had DM. Of these, one patient had acute kidney injury and another 172 had previous history of pancreatitis and cerebrovascular accident. 16 cases had received 173 oxygen therapy, of which 8 cases also required mechanical ventilation. Cycle threshold (CT) 174 score of RT-PCR in ongoing COVID-19 infection patients ranged from 26.7 to 33.9. 175

Most predominant symptoms were facial pain (22 cases, 73.3%), headache (16 cases, 53.3%), 176 followed by swelling of eyelid (6 cases, 20%), loss of vision (6 cases, 20%), eyelid drooping 177 (4 cases, 13.3%), nose block (4 cases, 13.3%), proptosis (4 cases, 13.3%), restricted eye 178 movements (1 case, 3.3%), epistaxis (1 case, 3.3%) and palatal eschar (1case, 3.3%). (Fig 4) . 179

Duration of symptoms ranged from 8 to 20 days before they availed medical care. The 180 demographic and clinical features of the patients are given in Table 1 . 181

Complete blood picture (CBP) showed leucocytosis in 19 cases, with presence of neutrophilia 182 (22 cases) and lymphopenia (7 cases). Other cases had normal hemogram. The 183 haematological values are shown in Table 2 . Neutrophil to lymphocyte ratio (NLR) was 184 raised in most patients (25 cases). Mean ± SD for PT-INR was 1.05 ± 0.14. D-dimer was not 185 done in most cases. 186

Contrast enhanced MRI of PNS, orbits and brain (Fig 5) was done in most cases. Orbital 187 cellulitis, orbital apex involvement along with involvement of corresponding optic nerve 188 were diagnosed in 9 cases. (Fig 6) . Cavernous sinus involvement was seen in 4 cases, while 189 1 case had changes of pachymeningitis over right fronto-temporal lobe, extending along right 190 cavernous sinus. 6 cases also had cerebral involvement. All 30 cases had involvement of one 191 or more nasal/sinus mucosa. documented. Presence of Charcot-leyden crystals, eosinophilic aggregates and fungal 209 elements were noted. All cases with fungi were evaluated further based on morphology, 210 presence or absence of necrosis, nerve invasion and vascular invasion. (Fig 7) . All 30 cases 211 showed inflammation predominantly lymphoplasmacytic with neutrophilic infiltrates around 212 fungus. 23 cases showed necrosis, 8 cases showed perineural fungal invasion and 10 cases 213 showed vascular invasion by fungal elements. 214

All cases had broad, pauci-septate or non-septate, wide, ribbon like hyphae with irregular 215 branching, mostly at 90° (Fig 8 a-d) . Most samples were subjected to KOH and culture 216 studies. Culture showed fluffy, white, brown or greyish colonies on Sabouraud's dextrose 217 agar/ potato dextrose agar. Some of the cases were culture and KOH negative (3 cases) but 218 fungi were detected in histopathology sections. In 5 cases, no fungal growth occurred on 219 culture but KOH showed pauciseptate broad fungal hyphae. One case (Fig 8d) had co-220 infection with Aspergillus species having septate hyphae with acute angle branching and 221 fruiting bodies (Fig 8d-Inset) along with the Mucor species. Most common species that was 222 isolated on culture was Rhizopus, while 1 case showed Lichtheimia corymbifera (Absidia). 223

The radiological and microbiological results of these cases are given in Table 2 , while the 224 histopathological findings are mentioned in Table 3 . For patients with complete resolution of infection, confirmed clinically (endoscopically) and 235 on imaging, a custom exenteration prosthesis will be fitted as part of rehabilitation. This is 236 planned after a mean interval of 6 to 9 months following orbital exenteration. The prosthesis 237 is either a stick-on adhesive type or magnetic or spectacle mounted based on patient 238 preference and socket healing. 239

No radical maxillectomies were performed. Only partial / subtotal were done and no further 240 reconstruction surgery were done in these patients. In cases where inferior maxillectomy was 241 done, in the initial first 6months an acrytic palatal obturator was given and after 6months 242 permanent dentures were given to patient. our study, all 30 cases had nasal/sinus mucosal involvement, 9 had orbital involvement and 1 338 had cerebral involvement (Fig-1) . 339

A recent staging of this fungal disease is as follows-340

Stage 1-Involvement of the nasal mucosa, 341

Stage 2-Involvement of the paranasal sinuses, 342

Stage 3-Involvement of the orbit (3a-Naolacrimal duct, medial orbit; 3b-diffuse 343 orbital involvement; 3c-central retinal artery or ophthalmic artery occlusion, 344 involvement of orbital apex, loss of vision; 3d-Bilateral orbital involvement) 345

Stage 4-Involvement of the central nervous system [Honavar SG,2021] . 346 Direct microscopy of deep or endoscopy guided nasal swab and paranasal sinuses or orbital 347 tissue using KOH mount maybe helpful for rapid diagnosis and has 90% sensitivity. Culture 348 helps in genus and species identification and antifungal susceptibility testing. However In our study, Mucormycosis was found in all 30 cases. One case had co-infection with 372

Aspergillus species (Fig 3d) . 

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