Corona virus disease-19 (COVID-19), first reported in Wuhan in China in December 2019 1 The COVID‑19 manifestations can range from asymptomatic presentation to severe respiratory distress in severe cases. It affects all parts of the body including the eye. Ocular manifestations include involvement from lid to optic nerve. Different ocular manifestations occur during different phases of the disease.2 Ocular manifestations may result from systemic COVID 19 infection, adverse reactions to treatment and various opportunistic infections. Sen M et al have reported mucormycosis in high risk COVID -19 patients who are recovering from COVID- 19 infection.3 Here we are reporting two cases of post COVID- 19 fungal infection in type II diabetes mellitus presenting in the form of unilateral endogenous endophthalmitis with clinical course and confocal microscopy features for the first time in published medical literature. Changes in corneal nerves were analysed using CCmetric analysis software
Case 1
A 54 year Asian Indian male, a known case of type 2 diabetes mellitus who was on oral hypoglycemic agents developed severe COVID 19 infection. At the local hospital nasopharyngeal swab for Reverse Transcription Polymerase Chain Reaction (RT PCR) for severe acute respiratory syndrome corona virus-2 (SARS CoV-2) confirmed the diagnosis of COVID 19 infection for which he was treated with (Inj. Remdesivir(100mg BD), T. Dexamethasone(6 mg), Inj Tocilizumab 400mg and oral tab. Cefixime 200 mg bd) 4 months back, and recovered well. Subsequently he presented with the complaints of mild pain, redness and blurring of vision of the left eye (LE) two months duration. He was diagnosed elsewhere with left eye (LE) intermediate uveitis and investigations revealed reactive lymphocytosis with eosinophilia, increased erythrocyte sedimentation rate (ESR), Toxoplasma IgG, IgM antibodies, Venereal disease research laboratory test (VDRL) and Mantoux test were negative. (Table 1) He was started on oral antibiotics with weekly tapering dose of oral steroids and oral albendazole. His clinical condition did not improve with above medications and he was referred to us for second opinion.
On examination, Best corrected visual acuity (BCVA) in RE 20/20 and in LE 20/32. Intraocular pressure (IOP) was normal in both eyes. Examination of the right eye was normal. Slit lamp biomicroscopic examination of the LE revealed grade 1 nasal pterygium, spheroidal degeneration on the nasal interpalpebral cornea, diffuse pigmented keratic precipitates on the corneal endothelium (Figure 1a) with prominent corneal nerves, grade 1 flare and cells in the anterior chamber, pupil was round, regular and reactive to light and pigments over the anterior lens capsule was noted. Posterior segment examination of the left eye revealed grade 2 vitritis and vitreous haze2+, vitreous membranes, mild hyperaemia of the disc and multiple snow ball opacities, and rest of the fundus details were hazily seen (Figure 1b). Corneal sensation was decreased and it was measured by Cochet-Bonnet esthesiometer with the value of 0.5 in the left eye. Spectral Domain Optical coherence tomorgraphy (SD-OCT) revealed hyperreflectivity of the inner retinal layer in the midperiphery of the retina (Figure 1d). Fasting blood sugar (FBS), Post prandial blood sugar (PPBS), Glycated hemoglobin (HbA1c) levels were increased ( Table 1) with his abnormal CT scan of the chest findings. ( Table 2) Confocal microscopy was done to scan the cornea using by the HRT II Rostock Cornea Module (Heidelberg Engineering GmbH, Heidelberg, Germany). In vivo confocal microscopy (IVCM) revealed significant decrease in the sub basal corneal nerve plexus, activated keratocytes in the stroma with highly reflective ovoid shaped cells were present in the in the corneal endothelium suggestive of candida yeast like structure (Figure 1c). Patient underwent anterior chamber paracentesis in the LE and the aqueous humor was analysed for gram stain, Potassium hydroxide (KOH) mount and PCR for panfungal genome, eubacterial genome and SARS CoV-2. Patient received intravitreal 3 voriconazole (100 μg/0.1 ml) injections. Oral steroids were rapidly tapered and stopped. Patient was started on topical and systemic itraconazole therapy. All the investigations came negative and patient did not respond to the medical management. Patient underwent left eye pars plana vitrectomy along with intravitreal voriconazole injection under local anaesthesia. PCR for panfungal genome from vitreous humor sample was positive ( Figure 1e) and vitreous humour culture revealed Candida Tropicalis confirming the diagnosis of left eye Candida Tropicalis endogenous endophthlamitis with post COVID-19 infection. Patient received two more doses of intravitreal voriconazole (50 μg/0.1 ml)
On follow up, after 6 weeks patient visual acuity had improved to 20/25 in the LE. Corneal sensation was normal with the aesthesiometer reading of 1.0. Anterior segment examination revealed flare +, pigments on the anterior lens capsule (Figure 2a) and posterior segment examination was normal following antifungal therapy and pars plana vitrectomy (Figure 2b). Confocal microscopy revealed the presence of dendritic cells with normal nerve fibres (Figure 5c) with normal endothelial cells (Figure 2c). corneal nerve fibre density (CNFD) number of main nerve fibre in mm/mm2, Corneal nerve branch density (CTBD)the total number of branch points per mm2, corneal nerve fiber area (CNFA): the total nerve fiber area per mm2 values are increased in the post treatment compared to pretreatment scans.( Figure 6)Spectral domain optical coherence tomography (SD-OCT) of the left eye revealed disappearance of the retinal exudates with hyper-reflectivity corresponding to the area of retinal vessel with after shadowing (Figure 2d).
Case 2
A 37 year Asian Indian male, with a recent history of severe COVID-19 infection two months ago, RT PCR for SARS- COV- 2 was positive from the nasopharyngeal swab for which he was admitted for 1 week and he was treated with oral steroids 40mg in tapering doses, T.Favipiravir 1800mg BD first day followed by 800mg BD for next 13 days and T. Ivermectin12 mg OD for 10 days. Ten days later after being diagnosed with COVID-19, he presented with pain, redness and diminution of vision in the LE for which he consulted multiple hospitals and was diagnosed elsewhere with LE panuveitis with hypopyon and investigations done are shown in Table 3. LE anterior chamber paracentesis done elsewhere showed eosinophilic fibrinous material and an occasional lymphocyte. Gram stain smear, potassium hydroxide (KOH) mount and culture for bacteria and fungi were negative. He was started on Dexamethasone + Moxifloxacin eye drops 6 times per day, Homatropine eye drops BD, Nepafenac eye drops BD in the left eye, T. Prednisolone 10 mg OD, T. Itraconazole 100 mg BD, T. Cefixime 200 mg BD, and T. Aceclofenac 100 mg + T. Paracetamol 325 mg BD His clinical condition did not improve with above medications and he was referred to us for second opinion. He was a known case of type II diabetes mellitus on oral hypoglycemic agents (T. Metformin 500mg + T. Glimepiride 2mg). On examination, Best corrected visual acuity (BCVA) in right eye (RE) is 20/20 and in LE is hand motion present. IOP was normal in both eyes. Examination of the RE was normal. Slit lamp biomicroscopy of the left eye revealed hazy cornea with endothelial exudates, grade 3 flare and cells with 1mm hypopyon in the anterior chamber, exudates and membranes covering the pupil, fluffy white clumps on iris was seen (Figure 3a), lens and posterior segment could not be visualized. LE ultrasound B scan revealed increased vitreous echoes of medium reflectivity and retina was attached (Figure 3b). Patient underwent anterior chamber paracentesis in the LE for PCR for panfungal genome which was positive. He also underwent LE diagnostic pars plana vitrectomy with vitreous tap for Grams stain, KOH and culture sensitivity along with intravitreal antibiotics. Vitreous humor analysis revealed no bacterial or fungal growth. Confocal microscopy LE showed multiple hyperreflective ovoid shaped yeast like structures (red arrow)with hyper reflective lines suggestive of hypae /fungal filament(yellow arrow) and well defined cyst (blue arrow), (Figure 3 c). He was started on Prednisolone acetate eye drops 6 times per day, Homatropine eye drops BD, Gatifloxacin eye drops 6 times per day, Itraconazole eye ointment BD in the left eye, T. Ciprofloxacin 500 mg BD and T. Itraconazole 100 mg BD. Since there was increased anterior chamber exudates (ten days after diagnostic vitrectomy), He then underwent LE lensectomy, membranectomy, surgical peripheral iridectomy, core vitrectomy, silicone oil injection with half dose intravitreal injection vancomycin, ceftazidime with voriconazole. Anterior chamber exudative membrane by histopathological examination revealed fungal hyphae within the fibrinous membrane in the anterior chamber of the left eye ( Figure 3d) and Grocott methenamine silver (GMS) stain showing a narrow aseptate non-branching hyphae from the anterior chamber exudate in the left eye confirming the diagnosis of fungal endophthalmitis ( Figure 3e & Table 3) Post operatively, his clinical condition improved. On his final visit 3 months later, BCVA in left eye improved to 20/100. Slit lamp biomicroscopy of the LE anterior segment revealed clear cornea with few pigments on the endothelium, grade 1 flare, traces of cells and patent surgical peripheral iridectomy with aphakia (Figure 4a). LE posterior segment showed status post vitrectomy with silicone oil filled eye, disc hyperaemia, flame shaped haemorrhages with attached retina ( Figure 4b), with B- scan showed silicone filled eye with attached retina (Figure 4c). Confocal microscopy LE showed multiple hyperreflective resolving ovoid shaped lesions with normal endothelial cells (Figure 4d) Confocal microscopy revealed dentritic cells in the sub basal epithelial area with significant decrease in sub basal corneal nerve plexus (Figure 5a& 5e) along with clusters of highly reflective, irregular shaped cells in the corneal stroma with activated keratocytes ( Figure 5 b & 5f) at the time of presentation in both the cases . Follow up scan after 6 weeks in first case and 8 weeks in second case showed increase in immature dentritic cells with improvement in the sub basal corneal nerve plexus (Figure 5c & 5g) with decrease in the numbers of highly reflective irregular shaped cells with the presence of activated keratocytes( Figure 5d & 5h) in the affected eyes . However the cc metric analysis of the nerve fibers revealed decreased corneal nerve fiber length (CNFL): the total length of nerve per mm2 and Corneal nerve branch density (CTBD): the total number of branch points per mm2. ( Figure 6)