SUBMITTED 24 NOV 21 1 REVISION REQ. 30 JAN 22; REVISION RECD. 6 FEB 22 2 ACCEPTED 6 MAR 22 3 ONLINE-FIRST: MARCH 2022 4 DOI: https://doi.org/10.18295/squmj.3.2022.025 5 6 Successful Management of Rhino-Orbital-Cerebral Mucormycosis in a 7 Child with Acute-on-Chronic Kidney Disease and Malnutrition 8 Case report and literature review 9 *Mohammed Al Reesi,1 Taleb Al Muqbali,2 Ahmed Al Ajmi,3 Varna Menon4 10 11 Departments of 1Paediatrics, 2Ears, Nose & Throat, 3Oral Maxillofacial Surgery and 12 4Laboratory, Suhar Hospital, Suhar, Oman. 13 *Corresponding Author’s e-mail: alreesimohammed@gmail.com 14 15 Abstract 16 Mucormycosis is a very rare fungal infection in children. It is caused by opportunistic fungi, and 17 mainly affects immunocompromised patients. Early diagnosis is very important for a good 18 outcome. Successful management requires the reversal of the underlying predisposing risk 19 factors, surgical debridement and prompt administration of active antifungal agents, with 20 liposomal amphotericin B being the first line therapy. This case, to the best of the authors’ 21 knowledge, is the first rhino-orbital-cerebral mucormycosis to be reported on among Omani 22 children. We highlight the importance of early diagnosis and prompt surgical and medical 23 interventions in achieving a satisfactory outcome and we review the published literature in regard 24 to the management. 25 Keywords: Mucormycosis; Sinusitis; Proptosis; Liposomal amphotericin B; Rhizopus; 26 Posaconazole; Malnutrition. 27 28 Introduction 29 Mucormycosis is a very rare fungal infection in children. It is caused by opportunistic fungi, and 30 mainly affects immunocompromised patients.1 Early diagnosis is very important for a good 31 outcome.2 Successful management requires the reversal of the underlying predisposing risk 32 mailto:alreesimohammed@gmail.com factors, surgical debridement and prompt administration of active antifungal agents, with 33 liposomal amphotericin B being the first line therapy.3,4 This case, to the best of the authors’ 34 knowledge, is the first rhino-orbital-cerebral mucormycosis to be reported on among Omani 35 children. We highlight the importance of early diagnosis and prompt surgical and medical 36 interventions in achieving a satisfactory outcome and we review the published literature in regard 37 to the management. 38 39 Case Report 40 We present a six-year-old Omani girl who was referred to a tertiary care hospital in Oman from 41 a local health centre in 2016 with sudden onset facial swelling, left periorbital skin rash and 42 reduced oral intake for one day. She had no history of fever, nasal congestion, ear pain or 43 toothache. There was no history of allergy, preceding trauma or insect bites. She was not a 44 diabetic and had no history of haematological malignancy or recurrent infections. She was 45 operated on for meningomyelocele in the neonatal period. That was complicated by reflux 46 nephropathy, chronic kidney disease and paraplegia. She had normal speech, vision and hearing. 47 48 The patient was very thin and weighed just 9 kilograms. She was tachypneic with acidotic 49 breathing and she had a respiratory rate of 40 per minute, a pulse rate of 120 beats per minutes, 50 and Blood pressure (BP) of 100/80 mmHg, Spo2 of 100% with 10 L of O2 via non-rebreathing 51 mask. She had mild proptosis of the left eye, left sided facial swelling of the left orbit with 52 multiple pustular lesions on the left eye brow, left side of forehead and nasal bridge (Figure 1). 53 She was not able to see from her left eye, but she had a normal ocular motility and fundus. An 54 oral cavity examination showed multiple dental caries. Her left palatal mucosa was coated by a 55 very thick white lesion opposite her upper first and second left molars, measuring 2x2 cm and 56 with central dark discoloration (Figure 2-A). Neurologically, she was conscious and oriented. 57 She was hypotonic in both upper and lower limbs with brisk reflexes (her baseline). Other 58 systemic examinations were unremarkable. 59 60 An initial laboratory investigation showed a haemoglobin of 6.84 g/dl, a white blood cell count 61 of 38.8 X 103 with mainly neutrophils (35.35 X 103) and platelets count of 1078.00 X 103. Her 62 C-reactive protein was very high (342 mg/L). Her venous blood gas showed metabolic acidosis 63 with bicarbonate of 7.8 nmol/L and base excess of -22 mmol/L. She had acute-on-chronic kidney 64 disease. Her urea was 22.6 mmol/L, her creatinine was 150.66 umol/L, while other electrolytes 65 were within normal limits. Her random blood glucose was 6.27 mmol/L and glycosylated HB 66 (%HBA1C) was 4.42%. Her chest radiograph was normal. 67 68 She was initially admitted into the general paediatric ward and a diagnosis of periorbital cellulitis 69 was made. A few hours later, she was shifted to a paediatric intensive care unit after she 70 developed hypotension (BP: 48/40 mm Hg), which was corrected by two boluses of normal 71 saline. A bicarbonate infusion was also given to correct her metabolic acidosis. She was given 72 cefotaxime, amikacin, metronidazole and cloxacillin intravenously. Contrasted Computed 73 topography (CT) of the orbits and brain revealed pan maxillary and ethmoid sinusitis (more on 74 the left side) with subtle rarefaction of the left lamina paprychea. There was an inflammatory 75 phelgmon of the medial and inferior wall of the left orbit measuring 28 x 7 mm. There was no 76 evidence of bone destruction or intracranial involvement. (Figure 3). Multidisciplinary teams 77 (MDTs) were consulted urgently, including paediatric infectious diseases, ophthalmology, Oral 78 Maxillofacial surgery (OMFS) and Ear, Nose and Throat (ENT) teams. The antimicrobial 79 regimen was changed to renal-adjusted doses of intravenous ceftazidime, clindamicin and 80 ciprofloxacin to cover the most likely causative organisms, including staphylococcus aureus, 81 anaerobes and pseudomonas aeruginosa. In addition, an invasive fungal infection, such as 82 mucormycosis was strongly suspected. Therefore, a diagnostic nasal endoscopy was performed 83 within 24 hours of her being admitted, which showed necrosis of the left maxillary wall and 84 upper part of the left inferior turbinate. Urgent KOH staining of the biopsy specimen showed 85 aseptated cylindrical fungal hyphae. Subsequently, liposomal amphotericin B was administered 86 empirically at a dose of 5 mg/kg/dose, once daily within 48 hours of admission. The 87 histopathology showed necrotic tissue containing aseptated, broad fungal hyphae, displaying 88 right angled branching with angio-invasion and thrombosis of the blood vessels, highly 89 suggestive of mucormycosis (Figure 4). The culture of the initial swab confirmed the growth of 90 Rhizopus spp. 91 92 The patient underwent a debridement of the left nasal cavity, an inferior turbinectomy, medial 93 maxillectomy and ethmoidotomy. Unfortunately, she developed skin necrosis in the medial 94 aspect of the left eye two days after the operation. Intraorally, the left palatal region had the 95 appearance of decreased vitality and bone necrosis was suspected. Repeated CT demonstrated 96 that the left orbital phlegmon had extended up to the orbital apex, transformed into an abscess 97 and increased in size to 31 x 10 mm. The optic nerve had thickened. However, there was no 98 intracranial abnormal enhancement and dural sinuses were normal. A left orbital exenteration 99 was discussed, but the parents were reluctant to give consent. She underwent left palatectomy, 100 maxillectomy and debridement on the 10th day after her admission. There was no drainable pus 101 from the orbital abscess site. Despite this, she still had left orbital proptosis and increasing 102 periorbital ecchymosis one week after the second operation. Therefore, magnetic resonance 103 imaging (MRI) with contrast was done to further delineate the anatomy and extension. That 104 showed left ethmoid opacification, abnormal enhancement of the left septal/preseptal area with 105 extension to retro-orbital space and a small abscess formation in the left orbit, measuring 1.9 x 106 0.8 cm with mass effect causing optic nerve deviation and proptosis. It also revealed abnormal 107 enhancement of the cavernous sinus, but no brain parenchyma extension. Lumbar puncture could 108 not be done because she was not stable enough for the procedure. The addition of oral 109 posaconazole was planned but she was not able to tolerate it orally. Instead, caspofungin was 110 added to ambisome on 17th day of admission due to an un-satisfactory response and ceftriaxone 111 was commenced to cover any secondary bacterial central nervous system infection. Furthermore, 112 ethmoid sinus debridement was done and her left orbitotomy did not reveal any pus. 113 114 Only after her third operation did the clinical signs start to gradually improve. She started to see 115 a little from her left eye and was able to count fingers with difficulty. But there was no further 116 improvement as the disease progressed. Trans-orally, her inferior maxillectomy site was healing 117 well with good re-epithelialsation. She was able to take some medicine and food orally after 118 using a resin obturator to cover the post-operative palatal defect. Eventually, the histopathology 119 from the third operation did not show any fungal elements and the culture was negative. Twenty-120 four days after admission, her creatinine started to improve to 104 umol/L after a period of 121 fluctuation. Subsequently, her ambisome dose was gradually increased to 9 mg/kg/day. She was 122 screened for immunodeficiency: she was not lymphopenic, her HIV serology was non-reactive, 123 immunoglobulin levels and lymphocyte subset were normal. An ultrasound of her abdomen did 124 not reveal any abscesses. After 8 weeks of ambisome and 4 weeks of caspofungin, she was 125 discharged home and her therapy was transitioned to oral posaconazole at a dose of 17mg/kg/day 126 in 3 divided doses. That was continued for 3 months whereupon a follow up- MRI showed a 127 complete resolution of the abscesses in the left orbital region and left maxillary sinus. She was 128 followed up regularly in the clinics by a multidisciplinary team. All her clinical signs improved 129 with no relapse of infection to date (Figure 2-B). The mother has given written consent to publish 130 this case and its related images. 131 132 Discussion 133 Mucormycosis is a rare, aggressive, angio-invasive and highly destructive fungal infection with 134 very high morbidity and mortality.1,2,4 It is caused by ubiquitous fungi, predominantly belonging 135 to the order Mucorales.5 The Rhizopus species, the causative agent in our patient, is responsible 136 for about one third of mucormycosis cases overall and accounts for 85% of rhino-cerebral 137 cases.2,6,7 The most important predisposing factors for mucormycosis are malignancies and 138 poorly controlled diabetes mellitus.1-9 Other predisposing factors include chronic kidney disease 139 and malnutrition,1 both of which were present in our patient. Recently, increasing mucormycosis 140 cases were also identified worldwide in people with Coronavirus disease 2019 (COVID-19), 141 particularly more in those with pre-existing diabetes mellitus and corticosteroids use.8 142 143 Rhino-cerebral mucormycosis has been associated with acute and chronic kidney disease with 144 fatal outcome. Altered immune status, leucopenia and metabolic acidosis in those patients may 145 be a plausible mechanism of predisposition.10 As a risk factor, malnourishment in children is 146 mainly associated with gastrointestinal mucormycosis.1 There was no clinical or radiological 147 evidence of abdominal organ involvement in our patient. In addition, her investigations were 148 negative for diabetes mellitus and immunodeficiency. 149 150 The successful management of mucormycosis requires early diagnosis, reversal of underlying 151 predisposing risk factors, prompt administration of active antifungal agents and aggressive 152 surgical debridement.3,4 Due to a lack of awareness of risk factors and nonspecific clinical and 153 radiologic findings, many cases are not diagnosed for many weeks after the time of 154 presentation.3,4 Histopathology and fungal culture are considered the gold standard for the 155 diagnosis.4,7,11 Mucorales are readily recognized morphologically on the basis of non-septate or 156 occasionally pauci-septate, broad, thin walled hyphae with wide angled branching and evidence 157 of angioinvasion.3,9,11 We believe that the early diagnosis achieved within 24 hours of patient’s 158 admission played a very important role in her satisfactory outcome. 159 160 Mucorales are resistant to most antifungals, except amphotericin B(AMB)–deoxycholate 161 (including lipid formulations of AMB, ambisome) and the new triazole posaconazole.5 While 162 liposomal amphotericin B is the recommended first line therapy, posaconazole is mainly used as 163 a stepdown or salvage therapy.3,4,11,12 Chamilos et al showed that delayed amphotericin B therapy 164 (>= 6 days after diagnosis) was associated with a two-fold increase in mortality in patients with 165 hematological malignancy and mucormycosis compared with early treatment (83% vs. 49%).5 166 Ray et al reported a case of rhino-orbital mucormycosis in a child with acute kidney injury. 167 Amphotericin B was started two weeks after admission. Although some clinical response was 168 noticed, the child died of massive gastrointestinal hemorrhage.10 The response rate to liposomal 169 amphotericin B ranges between 23 to 58%.12 The optimal dose is not known, but most experts 170 recommend a daily dose of 5-7.5 mg/kg/day. Although higher doses can lead to nephrotoxicity, 171 doses up to 10 mg/kg/day are recommended for disseminated diseases and are well-tolerated in 172 children.4,6,10,13 173 174 On the contrary, the use of amphotericin B-deoxycholate is limited by its substantial 175 nephrotoxicity, specifically in the doses and treatment duration needed for 176 mucormycosis.9 liposomal amphotericin B was commenced on our patient within 48 hours of 177 admission. She tolerated increasing the dose to 9 mg/kg/dose once daily without worsening her 178 renal parameters. Posaconazole has an overall success rate of 60–70% when used as a salvage 179 agent.14 A dose between 17 and 24 mg/kg/day is suggested in order to achieve target plasma 180 concentration.15 The addition of oral posaconazole as a salvage therapy was postponed in our 181 case till the day of discharge because she was not able to tolerate it after the operation. Despite 182 the late administration, our patient showed a good response to it on follow up. Echinocandins 183 are not recommended because they have a modest effect against Mucorales in vivo and virtually 184 no activity in vitro.10,16 However, some reports suggested its use based on the the theory that 185 Rhizopus oryzae, expresses the target enzyme for echinocandins (1,3-b-glucan synthase). In a 186 small retrospective study, Caitlin et al reported a superior success rate in patients with rhino-187 orbital-cerebral mucormycosis who received polyene-caspofungin therapy compared to patients 188 treated with polyene monotherapy.15 Caspofungin was added to our case because of the 189 progressive disease whilst on liposomal amphotericin B therapy and an inability to tolerate oral 190 posaconazole initially. 191 192 Interestingly, she started to improve after the third operation, which coincided with initiation of 193 caspofungin. Stronger evidence is needed, however, before recommending this agent for the 194 treatment of mucormycosis.9 Our patient received antifungal therapy for approximately 5 195 months. The reported length of treatment ranged between 3-36 months. This should be guided 196 by the clinical and radiological response.6,9 197 198 De-bulking the infection by early aggressive surgical debridement is very important and critical 199 component of therapy. Multiple surgeries may be required in the case of extensive disease.11 200 Pana et al has demonstrated less mortality in those patient given combined antifungals and 201 surgery compared to those given antifungals alone (18.5% versus 60%).17 Our patient required 202 3 sessions of complex operations, without which, it was clear that pharmaceutical interventions 203 were not sufficient to control the infection. 204 205 Conclusions 206 We described the successful management of severe rhino-orbital-cerebral mucormycosis in an 207 Omani child. Despite a very high mortality reported, early diagnosis and prompt medical and 208 surgical interventions were the key factors in achieving a good outcome in this case. Keeping a 209 high index of suspicion and raising the awareness about this aggressive infection and its 210 predisposing factors among all clinicians dealing with immunocompromised paediatric patients, 211 is of paramount importance for early recognition and prompt management. 212 213 Authors’ contribution 214 MAR is the first author who prepared, wrote, and reviewed the manuscript. TAM, AAA and VM 215 contributed to writing and reviewing the manuscript. All authors read and approved the final 216 manuscript. 217 218 References 219 1. Binder U, Maurer E and Lass-Florl C. Mucormycosis – from the pathogens to the disease. 220 Clin Microbiol Infect. 2014;20 (Suppl. 6): 60–66. https://doi.org/10.1111/1469-221 0691.12566. 222 2. Petrikkos G, Skiada A, Drogari-Apiranthitou M. Epidemiology of mucormycosis in 223 Europe. Clin Microbiol Infect. 2014 Jun;20 Suppl 6:67-73. https://doi: 10.1111/1469-224 0691.12563. 225 3. Katragkou A, Walsh TJ, Roilides E. Why is mucormycosis more difficult to cure than 226 more common mycoses? Clin Microbiol Infect. 2014 Jun;20 Suppl 6:74-81. https://doi: 227 10.1111/1469-0691.12466. 228 4. Skiada A, Lass-Floerl C, Klimko N, Ibrahim A, Roilides E, Petrikkos G. Challenges in 229 the diagnosis and treatment of mucormycosis. Med Mycol. 2018 Apr 1;56(suppl_1):93-230 101. https://doi: 10.1093/mmy/myx101. 231 232 5. Chamilos G, Lewis RE, Kontoyiannis DP. Delaying amphotericin B-based frontline 233 therapy significantly increases mortality among patients with hematologic malignancy 234 who have zygomycosis. Clin Infect Dis. 2008 Aug 15;47(4):503-9. https://doi: 235 10.1086/590004. 236 6. Muggeo P, Calore E, Decembrino N, Frenos S, De Leonardis F, Colombini A, et al. 237 Invasive mucormycosis in children with cancer: A retrospective study from the Infection 238 Working Group of Italian Pediatric Hematology Oncology Association. Mycoses. 2019 239 Feb;62(2):165-170. https://doi: 10.1111/myc.12862. 240 7. Jeong W, Keighley C, Wolfe R, Lee WL, Slavin MA, Kong DCM, et al. The 241 epidemiology and clinical manifestations of mucormycosis: a systematic review and 242 meta-analysis of case reports. Clin Microbiol Infect. 2019 Jan;25(1):26-34. https://doi: 243 10.1016/j.cmi.2018.07.011. 244 8. Singh AK, Singh R, Joshi SR, Misra A. Mucormycosis in COVID-19: A systematic 245 review of cases reported worldwide and in India. Diabetes Metab Syndr. 246 2021;15(4):102146. https://doi:10.1016/j.dsx.2021.05.019. 247 9. Cornely OA, Alastruey-Izquierdo A, Arenz D, Chen SCA, Dannaoui E, Hochhegger B, 248 et al; Mucormycosis ECMM MSG Global Guideline Writing Group. Global guideline 249 for the diagnosis and management of mucormycosis: an initiative of the European 250 Confederation of Medical Mycology in cooperation with the Mycoses Study Group 251 Education and Research Consortium. Lancet Infect Dis. 2019 Dec;19(12):e405-e421. 252 https://doi: 10.1016/S1473-3099(19)30312-3. 253 10. Ray MS, Kumar V, Jain D, Dubey NK. Rhino-orbital mucormycosis in acute renal 254 failure. Indian Pediatr. 2002 Apr;39(4):381-5. 255 11. Srinivas R, Jacob TJK, Raj PM, Korula S, Mathew LG. Paediatric mucormycosis: 256 tailoring surgical strategies to compliment antifungal chemotherapy. Different strokes 257 for different folks. Trop Doct. 2020;50(1):87-90. 258 https://doi:10.1177/0049475519874270 259 12. Lanternier F, Dannaoui E, Morizot G, Elie C, Garcia-Hermoso D, Huerre M, et al; French 260 Mycosis Study Group. A global analysis of mucormycosis in France: The RetroZygo 261 https://doi:10.1016/j.dsx.2021.05.019 https://doi.org/10.1177/0049475519874270 Study (2005-2007). Clin Infect Dis. 2012 Feb;54 Suppl 1: S35-43. https://doi: 262 10.1093/cid/cir880. 263 13. Lewis RE., Lortholary O, Spellberg B, Roilides E, Kontoyiannis DP, and Walsh TJ. How 264 Does Antifungal Pharmacology Differ for Mucormycosis Versus Aspergillosis? Clin 265 Infect Dis. 2012;54(S1): S67–72. https://doi: 10.1093/cid/cir884. 266 14. Zaoutis TE, Roilides E, Chiou CC, Buchanan WL, Knudsen TA, Sarkisova TA, 267 Schaufele RL, Sein M, Sein T, Prasad PA, Chu JH, Walsh TJ. Zygomycosis in children: 268 a systematic review and analysis of reported cases. Pediatr Infect Dis J. 2007 269 Aug;26(8):723-7. https://doi: 10.1097/INF.0b013e318062115c. 270 15. Ojeda-Diezbarroso K, Aguilar-Rascón J, Jiménez-Juárez RN, Moreno-Espinosa S, 271 Reséndiz-Sánchez J and Romero-Zamora JL. Successful posaconazole salvage therapy 272 for rhinocerebral mucormycosis in a child with leukemia. Review of the literature. Rev 273 Iberoam Micol. 2019;36(3):160–164. https://doi: 10.1016/j.riam.2018.07.008. 274 16. Reed C, Bryant R, Ibrahim AS, Edwards J Jr, Filler SG, Goldberg R, et al. Combination 275 polyene-caspofungin treatment of rhino-orbital-cerebral mucormycosis. Clin Infect Dis. 276 2008 Aug 1;47(3):364-71. https://doi: 10.1086/589857. 277 17. Pana ZD, Seidel D, Skiada A, Groll AH, Petrikkos G, Cornely OA, et al; Collaborators 278 of Zygomyco.net and/or FungiScope™ Registries*. Invasive mucormycosis in children: 279 an epidemiologic study in European and non-European countries based on two registries. 280 BMC Infect Dis. 2016 Nov 10;16(1):667. https://doi: 10.1186/s12879-016-2005-1. 281 282 Figure 1: An image showing mild proptosis, swelling and redness of the left eye and multiple 283 pustular lesions on the left eyebrow, left side of the forehead and nasal bridge. 284 285 286 Figure 2: (A) An image showing very thick white lesion coating the hard palate with central 287 dark discoloration, measuring 2x2 cm. (B) The oral cavity on follow up showing healthy and 288 clear margin of the lesion. 289 290 A B 291 Figure 3: Axial CT orbit showing left eye proptosis (star), maxillary and ethmoid sinusitis 292 (arrows) with subtle rarefaction of the left lamina paprychea. 293 294 295 Figure 4: Section of nasal biopsy showing blood vessel invasion by PAS positive non-septate, 296 broad, ribbon-like fungal hyphae (arrow), (PAS 200X). 297