Posterior segment findings in post-Covid mucormycosis: A cross-sectional study

Introduction

In December 2019, when the Chinese ophthalmologist Dr. Li Wenliang warned the world about the outbreak of a deadly virus, little did we know that this invisible enemy could take millions of human lives and put the world on standstill. Two years down the lane as the world is still struggling to contain covid-19, the scenario is being further complicated by the surge of mucormycosis.

Mucormycosis is a lethal, angio-invasive fungal disease predisposed by immunosuppressive drugs including corticosteroids, systemic diseases like diabetes mellitus, immunodeficiency disorders, malignancies and iron overload.^[1], ^[2] Black fungus/Mucormycosis refers to infections caused by fungi in the order of Mucorales which includes the genus mucor, rhizomucor, rhizopus and absisdia.

Mucorales are ubiquitous organisms which is combated by immune competent host through the generation of defensins and oxidative metabolites by the mono nuclear and polymorphonuclear phagocytes. Profound lymphopenia in covid-19 owing to the infection per se and steroid use alters the immune response and renders the host susceptible to invasive fungal infections.^[3] On inhalation of the spores, mucor proliferate in the sinus and find its way to the orbit either through direct invasion or nasolacrimal duct.

In this study, we aim to assess the posterior segment findings in cases presenting with post covid mucormycosis. Apart from few case reports, no comprehensive study has been published on this.

Materials and Methods

A cross-sectional observational study was conducted on patients presented to Bowring and Lady Curzon hospital with post covid mucormycosis during the time period from 1/5/2021 to 1/9/2021. Institutional ethical committee clearance was obtained before the initiation of the study. The study was conducted as per declaration of Helsinki. Informed written consent was taken from all the adult study subjects and assents were taken from the parents of paediatric subjects.

All patients with covid recovered status and biopsy proven mucormycosis who were admitted in our wards, and were willing to give valid consent was enrolled in the study. Patients with RT-PCR positive report within the past 14 days, patients who were never reported covid positive previously and eyes with hazy media were excluded from the study.

A detailed clinical history was taken from all the subjects enrolled. Special attention was given to the treatments given during covid-19. Anterior segment examination was done using slit-lamp. Cases were broadly divided into those with or without orbital involvement depending on the clinical features and radiological evidence. Cases with orbital involvement were further divided into involved eye and normal eye. After ruling out narrow angle, all the eyes were dilated with Tropicamide 0.8% & Phenylephrin 5% eye drops. Fundus evaluation of all patients were done with indirect ophthalmoscope and 20 diopter biconvex condensing lens. Findings were photo documented with fundus camera.

Results

In a cohort of 248 patients with post-covid mucormycosis, 183(73.7%) were males and 65(26.2%) were females. The mean age was 50.00 +/-12.33 (range 5-80) years. 3(1.2%) patients belonged to paediatric age group and 30(12.1%) patients belonged to old age group (>65 years). Amongst the study subjects, 210(84.67%)were diabetics, 61(24.6%) patients were hypertensives, 8(3.22%) had cardiac disease, 6(2.41%) had chronic kidney disease, 6(2.41%) were asthmatic, 4(1.61%) had malignancies and 2(0.8%) had previous cerebrovascular accidents. 17(6.85%) had no history of systemic illness. 142(57.25%) patients has undergone in-patient management for covid-19 pneumonitis, 112(45.16%) patient had oxygen therapy, 120(48.38%) patients had systemic steroid therapy. Mean number of days between the declaration of being covid negative or completion of home isolation and onset of symptoms is 18.50 +/- 13.15 days( range:3-90 days).

A total of 480 eyes were evaluated, out of which 151(31.45%) had orbital involvement. 135(54.43%) patients had unilateral involvement, while 8(3.22%) had bilateral involvement. Out of the eyes with orbital involvement, 65 (43.04%) had normal fundus, 26(17.21%) had diabetic retinopathy, 24(15.89%) had CRAO, 12(7.94%) had disc pallor, 10(6.62%) had disc edema, 2(1.32%) eyes had serous retinal detachment, 2(1.32%) had CRVO, 1(0.06%) had cilioretinal artery occlusion and 9(5.96%) eyes had miscellaneous changes. Out of 329 uninvolved eyes, 239(72.64%) had normal fundus, 53(16.10%) had diabetic retinopathy. There was no statistically significant difference between the prevalence of diabetic retinopathy in eyes with orbital involvement and without orbital involvement (p=.39).

Out of the eyes with orbital involvement, 65(43.04%) had normal fundus, 26(17.21%) had diabetic retinopathy, 24(15.89%) had CRAO, 12(7.94%) had disc pallor, 10(6.62%) had disc edema, 2(1.32%) eyes had serous retinal detachment, 2(1.32%) had CRVO, 1(0.06%) had cilioretinal artery occlusion and 9(5.96%) eyes had miscellaneous changes.

Discussion

In the setting of Covid-19 pandemic, ROCM in India and elsewhere is becoming a matter of immediate concern. The use of corticosteroid for preventing immune related lung injury and the need of prolonged hospitalisation for oxygen supplementation and respiratory support are presumed to be the main reasons for this. Covid-19 is also known to cause neutropenia adding to the susceptibility of these patients to mucormycosis. Along with this, comorbidities like diabetes mellitus and immunosuppression further worsens the condition. ^[4] Millette et al ^[5] and Steenblock et al ^[6] has reported the effect of Covid-19 in beta cells of pancreas, and this may add to the deterioration of systemic status, making it all the more easier for the fungi to flourish.

Mucormycosis of the orbit is a vision-threatening and potentially fatal infection resulting in angioinvasion, mycotic thrombosis, and ischemic necrosis of tissues. The factors predisposing to the development of the infection are uncontrolled diabetes mellitus, neutropenia, elevated free iron levels, deferoxamine, haematological malignancies, stem cell transplants, and organ transplant patients on immunosuppressants. ^[1], ^[7], ^[8], ^[9]

The mean age of presentation of covid-19 associated mucormycosis as reported by Hoenigel M et al is 55 years(range 10-86 years).^[10] Various studies has shown that ROCM has male predilection. ^[10], ^[11], ^[12], ^[13], ^[14] Demographic profile in our study was almost consistent with these findings. Mean age of our study sample was 50 years and it ranged between 5 and 80 years. Majority (73.7%) of the subjects were males. Greater outdoor exposure and hence, to fungal spores may be the reason for this sex predilection.

Regarding systemic comorbidities, 84.67% of our study population were diabetics. Diabetes mellites has been identified as an independent risk factor for mucormycosis. ^[12] Multiple literature reviews that has been published seconds this observation. ^[10], ^[11] It is noted that the incidence of mucormycosis is 7.5 times higher among diabetics compared to general population.^[15] Interestingly 17 patients in our study had no systemic comorbidities. Out of this, 7 did not have history of prior hospital admission for covid-19, nor steroid administration. 5 Of them had history of frequent use of nebulisers and steam inhalation, which are also suspected to be associated with the rise in mucormycosis, due to the unsterilized equipment used and poor water quality. ^[16], ^[17], ^[18]

In our study, the mean time period of presentation was around 18 days after recovery from covid-19. Some patients even presented after 2-3 months following covid treatment, which necessitates the need of prolonged follow up following covid recovery.

Out of 480 eyes of 248 patients with rhino-orbito-cerebral mucormycosis evaluated, 151 (31.45%) had orbital involvement. Unlike other anatomical sites, ROCM has visible signs and symptoms leading to early presentation and diagnosis. Most of the patients presented with proptosis, ptosis, loss of vision and facial pain. No predilection in laterality was noted in our study. Cerebral involvement was noted in 37% of the study subjects in previous study, ^[10] whereas in our study it was only 10%.

Apart from isolated case reports, no large study has been published regarding the posterior segment findings in rhino-orbital mucormycosis. Out of 151 eyes with orbital involvement, 65 had normal fundus, 26(17.21%) had diabetic retinopathy, 24 had CRAO, 12 had disc pallor, 10 had disc edema and 14 had miscellaneous changes. As per literature review, incidence of CRAO is 16%-20% in ROCM. ^[19], ^[20], ^[21] It is attributed to the direct invasion of fungi to the internal elastic lamina of the central retinal artery. Optic neuritis in cases with ROCM is a recognised finding and is postulated as a route of perineural spread of the fungi. ^[22], ^[23], ^[24], ^[25], ^[26] In our study, we noted 6 cases with optic neuritis and 4 with papilledema. Exudative retinal detachment in covid-19 associated ROCM has been recorded in the literature ^[27], ^[28], ^[29] and it is proposed that inflammation of the sclera in close contact with necrotic fungi materials may be the cause exudative retinal detachment. We could observe two cases with similar findings in our study. Out of 329 uninvolved eyes, 239 had normal fundus, 53(16.10%) had diabetic retinopathy. We could not find statistically significant difference between the prevalence of diabetic retinopathy in eyes with orbital involvement and without orbital involvement (p=.39).

Conclusion

Around one-third of the patients with post-covid mucormycosis had posterior segment findings. These are related to direct disease manifestation as well as underlying co-morbidities.

Declaration of Patient Consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Acknowledgment

None.

Source of Funding

None.

Conflict of Interest

None.