Long-term outcomes of transcutaneous retrobulbar amphotericin B in COVID-19-associated mucormycosis.

Purpose: To describe the long-term outcomes of transcutaneous retrobulbar amphotericin B (TRAMB) in COVID-19-associated mucormycosis. Methods: In total, 18 cases of COVID-19-associated mucormycosis were reviewed. In addition to the recommended treatment protocol, all patients were to be given 3.5 mg/ml/day of TRAMB for five days. Results: Of the 18 patients, 2 presented with stage 3a disease, 13 had stage 3c disease, and 3 patients had central nervous system (CNS) involvement (stage 4a and 4c). In addition to planned retrobulbar doses, five patients were given more while two patients received fewer injections (i.e., <5). At the last mean follow-up of 34.67 (±8.88) weeks, 11 patients were in radiological regression and 4 had stable disease while 2 patients had to undergo exenteration; one mortality was observed because of disease progression. Clinical regression in terms of visual and ptosis improvement was seen in seven and nine patients, respectively. Conclusion: Rhino-orbito-cerebral mucormycosis is a serious condition which warrants an aggressive treatment strategy. In unprecedented situations witnessed recently, TRAMB turned out to be an effective and economical alternative. Though large randomized studies are needed to establish its efficacy, TRAMB still manages to halt progression and salvage the globe in significant number of patients, and hence its use should be encouraged on a case-to-case basis especially in developing countries with limited resources.

Corneal manifestations and treatment among patients with COVID-19-associated rhino-orbito-cerebral mucormycosis.

Purpose: TO report the corneal manifestations in patients with COVID-19-associated rhino-orbito-cerebral mucormycosis (ROCM). Methods: This study was a retrospective, observational, and record-based analysis of patients of ROCM with corneal involvement. Results: A total of 220 patients were diagnosed with ROCM over a period of 3 months. Thirty-two patients had developed corneal manifestations. The mean age at diagnosis was 52.84 ± 12.8 years. The associated risk factors were systemic mucormycosis, uncontrolled diabetes, recent COVID-19 infection, and injudicious use of systemic steroids. Twenty-nine patients were known diabetics, 32 had recent COVID-19 infection, and 13 gave a history of injudicious use of steroids. The right eye (RE) was affected in nine patients, the left eye (LE) in 20 patients, and both eyes in three patients. Nine patients had a round-oval corneal ulcer. One patient each had a perforated corneal ulcer with uveal prolapse, sealed perforated corneal ulcer, spontaneously healed limbal perforation, diffuse corneal haze with hyphemia, panophthalmitis, diffuse corneal stromal abscess, limbal ischemia, anterior uveitis with posterior synechiae, inferior corneal facet, and filamentary keratitis. Three patients each had a corneal melt and inferior conjunctival xerosis with chemosis. Orbital exenteration was performed in six patients. Five patients with corneal ulcers healed. Topical eye drops of amphotericin (0.5 mg/ml) cycloplegic, antiglaucoma medications, and lubricant eye drops were started along with systemic antifungals. Conclusion: Central corneal ulcer was the most common manifestation of mucormycosis. A concentration as low as 0.5 mg/ml of amphotericin eye drops was effective in the treatment.

Novel treatment of recurrent orbital venolymphatic malformation with sirolimus and rivaroxaban.

Orbital venolymphatic malformations are rare vascular malformations that typically appear early in life and harbor acute and chronic threats to vision. Historically, there are four categories of management: observation, medication, sclerotherapy, and surgery. Currently, there is neither a gold standard for treatment nor randomized control trials comparing treatments.The authors present a 20-year-old male who presented with spontaneous hemorrhage of an orbital venolymphatic malformation occurring with increased frequency and involving more of the posterior orbit. Surgery and sclerotherapy were not feasible options due to the extensive intraorbital and intracranial involvement of the venolymphatic malformation. Systemic steroids treated symptoms but was not curative. To this end, a combination of sirolimus, an mTOR inhibitor, and rivaroxaban, a factor Xa inhibitor, were used to reduce the size of the lesion and minimize the risk of thromboembolic events. This treatment has successfully kept the patient's symptoms in remission for greater than 2 years.

Hyperglycemia and steroid use increase the risk of rhino-orbito-cerebral mucormycosis regardless of COVID-19 hospitalization: Case-control study, India.

BACKGROUND: In the ongoing COVID-19 pandemic, an increased incidence of ROCM was noted in India among those infected with COVID. We determined risk factors for rhino-orbito-cerebral mucormycosis (ROCM) post Coronavirus disease 2019 (COVID-19) among those never and ever hospitalized for COVID-19 separately through a multicentric, hospital-based, unmatched case-control study across India. METHODS: We defined cases and controls as those with and without post-COVID ROCM, respectively. We compared their socio-demographics, co-morbidities, steroid use, glycaemic status, and practices. We calculated crude and adjusted odds ratio (AOR) with 95% confidence intervals (CI) through logistic regression. The covariates with a p-value for crude OR of less than 0·20 were considered for the regression model. RESULTS: Among hospitalised, we recruited 267 cases and 256 controls and 116 cases and 231 controls among never hospitalised. Risk factors (AOR; 95% CI) for post-COVID ROCM among the hospitalised were age 45-59 years (2·1; 1·4 to 3·1), having diabetes mellitus (4·9; 3·4 to 7·1), elevated plasma glucose (6·4; 2·4 to 17·2), steroid use (3·2; 2 to 5·2) and frequent nasal washing (4·8; 1·4 to 17). Among those never hospitalised, age ≥ 60 years (6·6; 3·3 to 13·3), having diabetes mellitus (6·7; 3·8 to 11·6), elevated plasma glucose (13·7; 2·2 to 84), steroid use (9·8; 5·8 to 16·6), and cloth facemask use (2·6; 1·5 to 4·5) were associated with increased risk of post-COVID ROCM. CONCLUSIONS: Hyperglycemia, irrespective of having diabetes mellitus and steroid use, was associated with an increased risk of ROCM independent of COVID-19 hospitalisation. Rational steroid usage and glucose monitoring may reduce the risk of post-COVID.

Exploring the globe salvaging treatment options in patients of COVID-19-associated mucormycosis with orbital involvement.

Purpose: To explore the various globe salvaging treatment strategies for patients with coronavirus disease 2019-associated mucormycosis (CAM). Methods: This was a prospective: interventional analytical study conducted at a Medical College in rural India. A total of 84 patients of CAM admitted between May 2021 and August 2021 were enrolled for the study. Patients with histologically proven CAM with clinical and/or radiological evidence of orbital involvement were divided into three treatment categories based on the site and extent of the lesion. Re-assessment was performed after 7 days. For patients who worsened with the primary approach, orbital exenteration was considered based on a Sion Hospital Scoring System. A novel approach to intra-orbital anti-fungal therapy, site-centered peri-bulbar injection of amphotericin B (SCPeriAmB), was also explored. All the patients were followed up for at least 3 months. Convenience sampling with descriptive statistics was used. Results: Six patients had to finally undergo exenteration by the end of the study period. The rest of the patients were reported to be stable or improved. No mortalities were reported on delaying the exenteration. No adverse events were noted in patients who were given SCPeriAmB. Conclusion: Globe salvaging treatment options should be advocated as a primary approach in patients with CAM. Site-centered peri-bulbar injections can be considered as an approach for delivering intra-orbital anti-fungal therapy in selected patients.

Uncontrolled diabetes mellitus exacerbated by COVID-19-induced inflammation is the risk factor for COVID-19-associated rhino-orbito-cerebral mucormycosis: A matched pair case-control study.

Purpose: Amidst the ongoing coronavirus disease 2019 (COVID-19) pandemic, India experienced an epidemic of COVID-19-associated rhino-orbito-cerebral mucormycosis (ROCM). This study aimed to describe the epidemiology and elucidate the risk factors for developing COVID-19-associated ROCM, comparing the risk factors among COVID-19 patients with and without ROCM. Methods: This case-control study included all COVID-19-associated ROCM patients treated at our hospital from May 1 to July 30, 2021. Controls included age- and sex-matched COVID-19 patients without ROCM, who were treated during the same time (exact matching, in 1:2 ratio). Matched pair analysis using conditional logistic regression was performed to examine the association of various risk factors with the development of ROCM in COVID-19 patients. Results: The study included 69 patients with COVID-19-associated ROCM and 138 age- and gender-matched controls. Epidemiologically, COVID-19-associated ROCM predominantly affected males (59/69, 85%), in their early 50s (mean 52 years), with 48% (33/69) of patients being from medical resource-constrained settings. On multivariate conditional logistic regression, elevated serum glycated hemoglobin (HbA1c) (odds ratio [OR] = 1.36, 95% confidence interval [CI]: 1.03-1.78), blood glucose (OR = 1.008, 95% CI: 1.003-1.013), and C-reactive protein (CRP) (OR = 1.07, 95% CI: 1.02-1.17) were associated with increased odds of developing COVID-19-associated ROCM. Patients with undetected diabetes mellitus with increasing HbA1c (OR = 3.42, 95% CI: 1.30-9.02) and blood glucose (OR = 1.02, 95% CI: 1.005-1.03) (P = 0.02) had a higher probability of developing COVID-19-associated ROCM than patients with established DM. Conclusion: Uncontrolled DM evidenced by elevated HbA1c and blood glucose levels, exacerbated by COVID-19-induced proinflammatory state indicated by elevated CRP, is the principal independent risk factor for COVID-19-associated ROCM. Middle-aged males with undetected DM, from a resource-constraint setting, are particularly at risk.

Retrobulbar Injection of Amphotericin B in Patients With COVID-19 Associated Orbital Mucormycosis: A Systematic Review.

PURPOSE: Following COVID-19 infection a rising count of rhino-orbito-cerebral mucormycosis is observed, requiring orbital exenteration, a disabling lifetime affecting surgery. One of the potential interventions for globe salvage in these patients is retrobulbar injections of amphotericin B. This study was conducted to review protocols, outcomes, and side effects of retrobulbar injection of amphotericin B in patients with COVID-19 associated rhino-orbito-cerebral mucormycosis (CAM). METHODS: The PubMed, Scopus, Web of Science, and Embase databases were searched using a comprehensive string of relevant keywords. All English studies with the confirmed diagnosis of CAM infection were included. We excluded all studies in which retrobulbar injection of amphotericin B was not implemented in any of the patients or there was a lack of clarified and detailed data about this procedure among participants. RESULTS: A total of 647 cases had a history of retrobulbar injection(s) of amphotericin B in 13 reviewed studies with 3,132 subjects of CAM. The most common protocol was the retrobulbar injection of 1 ml of 3.5 mg/ml liposomal amphotericin B for 3 doses daily or on alternate days. We discerned that the globe salvage rate was 95.0% in eyes with a history of retrobulbar injection(s). The total rate of orbital exenteration was 14.9%, regardless of the history of retrobulbar injection of the drug. Other outcomes of this intervention were vision salvage and reduced major ophthalmic complaints, including pain, swelling, chemosis, ptosis, and ophthalmoplegia. The side effects of this intervention were not serious, and most of them were transient. They included swelling at the injection site, restriction of ocular motilities, exacerbation of orbital inflammation, and even intensification of visual impairment in a few cases. CONCLUSIONS: Retrobulbar injection of amphotericin B should be considered a nearly safe and protective intervention against orbital exenteration in patients with CAM. It may also be effective in saving vision. Since the effectiveness of orbital exenteration in the survival of patients is not ascertained, retrobulbar injections can be considered an alternative intervention.

Local Infiltration Anesthesia for Orbital Exenteration in Patients With Rhino-Orbital Cerebral Mucormycosis: A Case Series.

Orbital exenteration is occasionally required for rhino-orbital cerebral mucormycosis. Multiple associated comorbidities can pose a risk for general anesthesia. There is only 1 report of exenteration being performed under trigeminal nerve block. We describe 5 patients who underwent orbital exenteration under local infiltration anesthesia with sedation. Patients and surgeons reported satisfactory conditions, with stable hemodynamics and successful day care management. Orbital exenteration under local infiltration anesthesia can be a safe and effective alternative for patients with rhino-orbital mucormycosis who are at risk with use of general anesthesia.

Localized surgical debridement for the management of orbital mucormycosis.

PURPOSE: To describe the role of localized debridement and instillation of amphotericin B for the management of orbital mucormycosis post COVID-19 infection with a view to avoid exenteration. METHODS: The records of all patients with orbital mucormycosis post COVID-19 infection in the last 6 months from December 2020 to June 2021 were evaluated, and ten patients were identified who were successfully managed with localized debridement, that is, removing the fungal tissue and necrotic material and amphotericin B gel instillation locally. MRI scan was used to identify the area of fungal infiltration and presence of necrotic material. Early surgery in the form of transconjunctival orbitotomy was performed for disease in the infraorbital fissure area, and superior transcutaneous lid crease approach was employed for disease in the superomedial orbit or medial orbit. Most patients had lid edema, ptosis, and proptosis; this resolved with the medication. Systemic antifungals were given and the follow-up ranged from 1 to 5 months. RESULTS: The ptosis, proptosis, and lid edema subsided in all, except in one patient who had residual ptosis and in one who had residual ophthalmoplegia. Vision deficit did not occur in any patient. All patients were successfully discharged on oral antifungal medication. CONCLUSION: Localized clearance of the fungal tissue and the necrotic material is a good option to avoid exenteration in cases of orbital mucormycosis, avoiding disfigurement and mental trauma to the patient.

Clinical Features and Mortality of COVID-19-Associated Mucormycosis: A Systematic Review and Meta-Analysis.

The recent increase of COVID-19-associated mucormycosis (CAM) has been commanding global attention. However, basic epidemiologic characteristics have not firmly been established. In this systematic review and meta-analysis, we sought to determine the clinical manifestations, potential risk factors, and outcomes of CAM. Observational studies reporting CAM were searched with PubMed and EMBASE databases in January 2022. We collected data on comorbidities and treatment for COVID-19, and performed a one-group meta-analysis on the frequency of orbital exenteration procedure and mortality of CAM using a random-effect model. Fifty-one observational studies, including a total of 2,312 patients with proven CAM, were identified. Among the 51 studies, 37 were conducted in India, 8 in Egypt, and 6 in other countries. The most common comorbidity was diabetes mellitus (82%). While 57% required oxygenation, 77% received systemic corticosteroids. Among CAM, 97% were rhino-orbital-cerebral (ROCM), and 2.7% were pulmonary mucormycosis. Usual presentations were headache (54%), periorbital swelling/pain (53%), facial swelling/pain (43%), ophthalmoplegia (42%), proptosis (41%), and nasal discharge/congestion (36%). Regarding the outcomes, orbital exenteration was performed in 17% (95% CI: 12-21%, I2 = 83%) of the COVID-19-associated ROCM patients. The mortality of CAM was 29% (95% CI; 22-36%, I2 = 92%). In conclusion, this systematic review and meta-analysis indicated that the most prevalent type of CAM was ROCM, and most CAM patients had diabetes mellitus and received systemic glucocorticoids. Clinicians in the endemic areas should have a high index of suspicion for this invasive fungal complication of COVID-19 when a diabetic patient who received high-dose systemic glucocorticoids developed rhino-orbital symptoms.

A clinico-pathological study of COVID-19 associated rhino-orbital-cerebral mucormycosis.

Purpose: Known predisposing factors for mucormycosis are neutropenia and diabetes. Though COVID-19 is associated with hyperinflammatory response, a high surge in rhino-orbital-cerebral mucormycosis (ROCM) cases was observed during the second wave. The histopathological features reflect the background pathogenesis. This study analyzes the histopathological features and clinical presentation of COVID-19-associated ROCM. Methods: In this retrospective observational study, the clinical details of 89 proven ROCM patients treated during May-July 2021 were collected from the case records. Histopathological features were correlated with clinical staging groups and outcomes. The mean neutrophil-to-lymphocyte ratio (NLR) of clinical and outcome groups were compared. Results: The mean age was 54.71 ± 11.03 years, with male patients constituting a majority (78.7%). Uncontrolled diabetes mellitus was noted in 70.8% of patients, and 3.4% had normal range of blood sugar. The mean blood sugar was 298.08 ± 99.51 mg/dL. The mean duration of onset of symptoms of mucormycosis from the diagnosis of COVID-19 was 17.36 ± 7.392 (3-45) days. Poor outcome with disease progression or death occurred in 21.3% of patients. Clinical group II patients (44.9%) with ROCM stages 3c and above had poor outcomes (P = 0.005). Histopathological analysis showed minimal inflammation in 25.8%, neutrophil extracellular trap (NET) in 75.3%, and angio-invasion in 28.1% of patients. Minimal inflammation was associated with clinical group II (P = 0.004) and poor outcome (P = 0.001). Angio-invasion correlated with poor outcome (P = 0.007). Patients with severe clinical group and poor outcome had higher mean NLR with P = 0.017 and P = 0.007, respectively. Conclusion: Vision loss and cerebral involvement had poor outcomes. The histopathologic features such as inflammation and angio-invasion along with NLR aid as prognostic indicators in the management of ROCM. The role of NET in the pathogenesis of COVID-19-associated ROCM needs further studies.

Outcome of transcutaneous retrobulbar injection of liposomal amphotericin B in post-COVID-19 rhino-orbito-cerebral mucormycosis: Our experience.

Purpose: To assess the outcome and response of transcutaneous retrobulbar injection of amphotericin B (TRAMB) in post-coronavirus disease of 2019 (COVID-19) rhino-orbito-cerebral mucormycosis (ROCM) and to establish a scoring system in guiding treatment modalities. Methods: An interventional, prospective study was done on 82 eyes of post-COVID-19 ROCM from May 2021 to July 2021. A comprehensive multi-departmental evaluation along with detailed ophthalmic examination, laboratory investigations, and radiological examination was done. Scoring points were given to each symptom, sign, and radiological features of orbit and the total score was taken. Based on these scores, severity of disease was grouped into A, B, and C corresponding to mild, moderate, and severe orbital ROCM. One milliliter of reconstituted liposomal amphotericin B was given to all patients every alternate day as three doses. Efficacy of these injections was assessed in all groups, even though other treatment modalities like orbital debridement and exenteration were considered for moderate and severe cases. Patients were followed up for a period of 8 weeks. Results: Out of 82 eyes, symptomatic improvement was seen in a major proportion (72%) of patients. A statistically significant improvement in scores was noted in group A (93% improved) with a P value of 0.002, while 68.4% showed improvement in group B (P-value- 0.0001). Group C with severe disease showed minimal improvement in post-injection scores of 41% (P-value 0.086), necessitating surgical intervention. No serious adverse effect of the drug or procedure was noted. Conclusion: Significant improvement in scores of groups A and B highlights TRAMB as an effective and safe treatment modality in mild to moderate ROCM. It is an effective adjunct in severe cases, along with other interventions. Also, the scoring system helps in assessing the severity and guiding in management strategies.

COVID-19-associated rhino-orbital-cerebral mucormycosis: A systematic review, meta-analysis, and meta-regression analysis.

BACKGROUND: Till now, no meta-analysis is available to address the clinical profile, risk factors, different interventions, and outcomes among COVID-19-associated rhino-orbito-cerebral mucormycosis (C-ROCM) cases. MATERIALS AND METHODS: Eight literature databases were screened using appropriate keywords from November 1, 2019, to June 30, 2021. The objectives were to analyze the clinical and microbiological profile, risk factor/comorbidity, intervention, and outcome. "R-metafor package" was used for analysis. RESULTS: A total of 23 studies were included. The mean age of presentation of C-ROCM was 54.6 years. The most common presentation was ptosis (72.7%), lid edema (60.6%), proptosis (60.6%), ophthalmoplegia (57.3%), loss of vision (53.7%), facial edema (34.7%), and nasal-blockage (11.8%). Evidence of intracranial spread was seen in 42.8% of cases. Rhizopus was the most common fungus (57.1%) isolated in fungal culture. Among C-ROCM patients, diabetes was the commonest comorbid condition, and the use of corticosteroids related to COVID-19 treatment was the most common risk factor (85.75%). Compared to controlled diabetics, C-ROCM was significantly higher among uncontrolled diabetics (odds ratio [OR] 0.15, 95% confidence interval [C.I.] 0.041-0.544, P = 0.0010). However, no significant association was seen between C-ROCM and COVID-19 severity (OR 0.930, 95% C.I. 0.212-4.087, P = 0.923). For treatment, amphotericin-B was the most common antifungal drug used which was followed by surgical options. However, mortality was high (prevalence 0.344, 95% C.I. 0.205-0.403) despite treatment. CONCLUSION: Although local rhino-orbito symptoms were the first to appear, rapid intracranial extension was seen in a significant number of C-ROCM cases. Uncontrolled diabetes and excessive use of corticosteroid were the most common risk factors present among the C-ROCM cases. High index clinical suspicion is imperative (specifically among COVID-19 patients with diabetes), and routine screening may be helpful.

Retrobulbar injection of amphotericin B using intravenous cannula for post-COVID-19 rhino-orbital mucormycosis.

Rhino-orbital mucormycosis has seen a huge resurgence in patients post COVID-19 infection. In patients with minimal orbital disease and especially with preserved vision, retrobulbar injections of amphotericin B can be of great help in controlling the disease. Instead of giving daily injections of amphotericin B using needles every time, we used an 18-gauge intravenous (IV) cannula with injection port and suture holes to deliver the amphotericin into the orbital space for a period of 5 days. Patients were more compliant and less distressed with this method compared with being given an injection with a needle daily. We got a good response in terms of orbital disease regression with this method. In our review of the literature, we did not come across any such case of amphotericin B injection using an IV cannula. Injection of amphotericin B into the orbit using an IV cannula is a viable and easy treatment option for cases of rhino-orbital mucormycosis.

Surgical & medical management of ROCM (Rhino-orbito-cerebral mucormycosis) epidemic in COVID-19 era and its outcomes - a tertiary care center experience.

OBJECTIVE: To evaluate the outcome of patients with ROCM (Rhino-orbito-cerebral mucormycosis) following their medical and surgical management. MATERIALS AND METHODS: It is a prognostic study based in a tertiary care center in North-Western India. Patients who developed ROCM post COVID-19 infection from 1st September 2020 to 30th June 2021 were included in this study. Surgical debridement and administration of antifungal therapy was done for the post-COVID-19 ROCM patients. Disease progression and survival was studied up to 5 months of follow-up in the second wave. RESULTS: A total of 145 ROCM patients were included. The mean age at presentation, male: female ratio was 48.2 years and 2:1 respectively. As per our proposed new staging system and treatment strategy, the majority of patients belonged to stage II (31.72%) and stage III (31.03%). On a follow-up period of 5 months, 26 (18%) patients have lost their life and rest of the patients are on strict follow-up. CONCLUSION: ROCM is an extremely aggressive fungal infection which rapidly became an epidemic following the COVID-19 pandemic. The diverse and unique presentation led us to evolve a new strategy to classify and manage these patients.

Risk factors and outcomes of COVID associated mucormycosis in kidney transplant recipients.

BACKGROUND: Invasive mucormycosis (IM) is a life-threatening fungal infection occurring mostly in solid organ transplant (SOT) recipients, patients with hematological malignancies, and diabetes. A sudden spurt of mucormycosis has been reported in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic in India; however, there is little data about coronavirus disease 2019 (COVID-19) associated mucormycosis (CAM) in kidney transplant recipients (KTRs). METHODS: We describe the clinical presentations, risk factors, treatment and outcomes of 11 mucormycosis cases in KTRs post-COVID-19 infection from February 2020 to June 2021 at a single center in India. RESULTS: Mucormycosis was seen in 11/102 (10.7%) KTRs during the pandemic. Six patients had mild disease and rest five had moderate disease. Seven patients had pre-existing diabetes mellitus and four developed new onset hyperglycemia after receiving steroids for COVID-19 infection. All had poorly controlled sugars at the time of presentation. Most common presentation was rhino-orbital-cerebral mucormycosis (ROCM) in 10/11 (89%) patients and one has pulmonary mucormycosis. All patients received combination of amphotericin B and surgical debridement/excision of affected tissue followed by posaconazole prophylaxis. Nine patients recovered, however two patients succumbed to their illness after median of 14 (7-21) days from diagnosis. One patient developed acute T-cell-mediated rejection during the course of recovery. At last follow up, the mean serum creatinine was 2.05 mg/dl as compared to 1.4 mg/dl at presentation. CONCLUSIONS: IM is a common fungal infection in transplant recipients in India after COVID-19. Early diagnosis and prompt treatment with combination of surgical debridement and liposomal amphotericin B are key to better outcomes in CAM. Judicious use of steroids and control of hyperglycemia is key to avoid flaring up of the fungal infection.