key: cord-0883035-8n12fxtw
authors: Nayak, Sameera; Das, Taraprasad; Parameswarappa, Deepika; Sharma, Savitri; Jakati, Saumya; Jalali, Subhadra; Narayanan, Raja; Basu, Soumyava; Tyagi, Mudit; Dave, Vivek Pravin; Pappuru, Rajeev Reddy; Pathengay, Avinash; Kaza, Hrishikesh; Rani, Padmaja Kumari; Behera, Shashwat; Sahoo, Niroj Kumar; Kapoor, Aditya; Agrawal, Hitesh; Agarwal, Komal; Takkar, Brijesh; Raval, Vishal Ramesh
title: Sight-threatening intraocular infection in patients with COVID-19 in India
date: 2021-11-26
journal: Indian J Ophthalmol
DOI: 10.4103/ijo.ijo_1474_21
sha: 3a9049c0698975c5a53ce910667a432ec736df98
doc_id: 883035
cord_uid: 8n12fxtw

PURPOSE: Intraocular infection in patients with COVID-19 could be different in the presence of treatment with systemic corticosteroid and immunosuppressive agents. We describe the epidemiology and microbiological profile of intraocular infection in COVID-19 patients after their release from the hospital. METHODS: We analyzed the clinical and microbiological data of laboratory-confirmed COVID-19 patients from April 2020 to January 2021 presenting with features of endogenous endophthalmitis within 12 weeks of their discharge from the hospital in two neighboring states in South India. The data included demography, systemic comorbidities, COVID-19 treatment details, time interval to visual symptoms, the microbiology of systemic and ocular findings, ophthalmic management, and outcomes. RESULTS: The mean age of 24 patients (33 eyes) was 53.6 ± 13.5 (range: 5–72) years; 17 (70.83%) patients were male. Twenty-two (91.6%) patients had systemic comorbidities, and the median period of hospitalization for COVID-19 treatment was 14.5 ± 0.7 (range: 7–63) days. Infection was bilateral in nine patients. COVID-19 treatment included broad-spectrum systemic antibiotics (all), antiviral drugs (22, 91.66% of patients), systemic corticosteroid (21, 87.5% of patients), supplemental oxygen (18, 75% of patients), low molecular weight heparin (17, 70.8% of patients), admission in intensive care units (16, 66.6% of patients), and interleukin-6 inhibitor (tocilizumab) (14, 58.3% of patients). Five (20.8%) patients died of COVID-19-related complications during treatment for endophthalmitis; one eye progressed to pan ophthalmitis and orbital cellulitis; eight eyes regained vision >20/400. Fourteen of 19 (73.7%) vitreous biopsies were microbiologically positive (culture, PCR, and microscopy), and the majority (11 patients, 78.5%) were fungi. CONCLUSION: Intraocular infection in COVID-19 patients is predominantly caused by fungi. We suggest a routine eye examination be included as a standard of care of COVID-19.

We analyzed the patients reporting to our out-patient service after being treated for COVID-19 in designated hospitals and discharged after such treatment. We collected the data from the electronic medical record of consecutive patients with a clinical diagnosis of endogenous endophthalmitis/ panophthalmitis from April 2020 to January 2021. All of them were laboratory (reverse transcriptase-real time polymerase chain reaction, RT-PCR)-confirmed SARS-CoV-2 infection and had reported within 12 weeks of discharge from the hospital treated for viral infection. Appropriate consent and institutional review board (IRB) approval were obtained (LEC-BHR-P-09-20-512), and all patients were treated as per the declaration of tenets of Helsinki. The collected data included age, gender, associated co-morbidities, time to onset of COVID-19 symptoms, time to onset of ocular symptoms, history of admission to hospital/ICU, systemic medications including administration of intravenous fluid, blood chemistry including the inflammatory markers, the occurrence of sepsis, ventilator use, culture report of blood/urine/tissue biopsy, and oxygen therapy. Patients were classified into mild, moderate, and severe COVID-19 as per the oxygen requirement. [19] In brief, it was mild COVID-19 (uncomplicated upper respiratory tract infection without evidence of breathlessness or hypoxia), moderate COVID-19 (pneumonia with dyspnoea, hypoxia, fever and cough, respiratory rate >24/min, and blood oxygen saturation between 90% and 94% on room air ), severe COVID-19 (respiratory rate >30/min and blood oxygen saturation <90% on room air, severe pneumonia, acute respiratory distress syndrome, sepsis, and septic shock).

Each patient received a comprehensive eye examination. This included presenting visual acuity (PVA), slit-lamp, and fundus examination (indirect ophthalmoscopy). Essential ophthalmic investigations included ocular ultrasonogram and fundus photography when possible. Endophthalmitis was suspected clinically based on the cluster of symptoms (pain, redness, and reduced vision) and signs (hypopyon, exudates in the anterior chamber, and vitreous opacities). These patients were managed as per the endophthalmitis treatment protocol of the institute, which essentially included a vitrectomy and intravitreal antibiotic injections, microbiology of vitreous sample, repeat vitreous surgery, and/or repeat culture-susceptibility adjusted intravitreal antibiotic/antifungal agents. [20, 21] Undiluted vitreous (0.5-1.0 mL) was collected from eyes at the time of vitrectomy and sent for a detailed microbiological study. Grams staining and calcofluor white (CFW) mount were done for the undiluted vitreous for direct microscopy. The sample was inoculated onto solid (5% sheep blood agar, chocolate agar, Sabouraud dextrose agar, potato dextrose agar) and liquid (brain heart infusion, thioglycolate broth, anaerobic bacteria broth) media to detect any growth of bacteria/fungi. All media were incubated aerobically at 37°C except Sabouraud dextrose agar and potato dextrose agar, which were incubated at 27°C for 2 weeks. Chocolate agar was incubated in 5% CO 2 at 37°C. Species identification (bacteria and yeast) was done whenever possible using the Vitek 2 compact system (bioMérieux, France). PCR for eubacteria (16S rDNA), panfungus (ITS), and herpes virus type I and II (Glycoprotein D gene) detection was performed where possible. A small volume of vitreous sample was set aside for RT-PCR under the appropriate cold chain for SARS-CoV-2 detection wherever possible.

We documented the PVA and best-corrected visual acuity (BCVA), ocular findings, and response to treatment in the subsequent examinations. Systemic antibiotic/antifungal agents and topical antibiotics/steroids were considered as and when appropriate to manage the eye conditions. The vitreous biopsy and vitrectomy, along with single or multiple antibiotics/antifungals, were performed when the systemic condition of the patient allowed; the remaining patients were treated with systemic antibiotics/antifungals only with/without intravitreal antibiotics. Vitrectomy and silicone oil tamponade (1000 centistoke) was considered for eyes with necrotic retina and half-dose intravitreal antibiotics/antifungals. Evisceration was considered whenever the globe was not salvageable. Persistent exudates in the vitreous cavity after primary vitrectomy needed vitreous lavage with intravitreal antibiotic/antifungal agents.

This analysis included 24 consecutive subjects examined between April 2020 and January 2021 in two adjoining states in South India, Andhra Pradesh (AP) and Telangana state (TS) [ Fig. 1 ].

Cases of endogenous endophthalmitis (EE) coincided with the peak of COVID-19 in both states. Severe, moderate, and mild cases of COVID-19 were present in 14 (58.3%), seven (29.2%), and two subjects, respectively, and one subject was asymptomatic. All patients were RT-PCR SARS-CoV-2 infection positive (nasopharyngeal swab) and were hospitalized for COVID-19 treatment within 12 weeks of presentation. The mean interval of COVID-19 systemic symptoms to ophthalmic symptoms was 14.9 ± 8.9 (range: 6-72) days in 23 symptomatic patients. The mean age of the patients was 53.6 ± 13.5 (range: 5-72) years, and 17 (70.8%) patients were male. Over 90% (22, 91.6%) patients had multiple pre-COVID-19 systemic comorbidities, and 16 (66.6%) patients were admitted to the intensive care unit (ICU) [ Table 1 ]. Most patients (n = 15; 62.5%) had anemia, neutrophilia, lymphopenia, thrombocytopenia, and raised inflammatory blood markers (C-reactive protein, lactate dehydrogenase, serum ferritin, D-dimer, and IL-6 level) [ Table 2 ]. One patient was asymptomatic who did not receive blood investigation, and eight patients did not possess a detailed laboratory result.

Systemic medications during hospitalization for COVID-19 treatment are listed in Table 2 . The mean duration of corticosteroid treatment was 22.1 (range: 5-62) days. Regular microbiological assays such as blood culture, urine culture, samples from the central line, bronco alveolar lavage fluid, and sputum culture were not done in all patients.

In this cohort, we diagnosed endophthalmitis in 33 eyes (including one panophthalmitis) of 24 patients, and both eyes were involved in 9 (37.5%) patients. The ocular features included exudates in the vitreous body and retina (9/33, 27.3%) to complete vitreous abscess (23/33, 69.7%), the involvement of ocular coats, periocular tissue, and orbit (1/33). Figs. 2-5 document description of four representative patients.

The mean presenting visual acuity was 0.0415 ± 0.1445 (range: 0.0013-0.8). All patients complained of pain, redness, and blurring of vision at presentation. Vitreous biopsy could not be obtained in five patients (eight eyes); three of them were critically ill with fluctuating blood oxygen saturation, unfit for any surgical procedure, and expired due to COVID-19-related complications during the course of systemic treatment; and two patients refused any surgical interventions. Fourteen of 19 vitreous biopsies (73.68%) were microbiologically positive: 11 (78.6%) fungi, 2 bacteria, and 1 virus [ Table 1 ]. The systemic focus of infection was identified in 11 of 21 subjects (tests were not performed in three subjects); five had candidemia, three had bacteremia (two Streptococcus pneumoniae, one Escherichia coli), two Aspergillus spp. (one renal biopsy and one paranasal sinus biopsy), one Mucormycosis (Mucor in paranasal sinuses). RT-PCR for COVID-19 did not detect any virus in the vitreous sample in any of these patients.

At a median follow-up of 90 ± 19.8 (range: 2-164) days, 19 patients recovered, and five patients expired due to COVID-19-related complications [ Fig. 6 ]. Table 1 lists the treatment for the eye ailment, and the summary is shown in Fig. 7 . Brief descriptions of few cases Case 2, Table 1 : A 58-year-old man presented with pain, redness, and reduction of vision in the right eye (BCVA 20/320). The eye Fig. 4f] ) on SDA. His renal biopsy had also grown Aspergillus spp. He received vitrectomy and intravitreal amphotericin-B (2 times). At 90 days, his eyes were quiet, but the vision did not improve beyond light perception in either eye.

Case 13, Table 1 : A 69-year-old man presented with periocular swelling, discharging fistula, and exudates externally [ Fig. 5a ] with light perception vision in the right eye. USG showed disorganized eyeball [ Fig. 5b ], computer tomography (CT) scan revealed protrusion of the right eye with elongated axial length [ Fig. 5c ]. His eviscerated material and tissue from paranasal sinuses were suggestive of mucormycosis. He received intravenous amphotericin-B and posaconazole. Eyeball was not salvageable; evisceration was done. The histopathology of the eviscerated contents showed broad aseptate fungal filaments with right-angle branching suggestive of mucormycosis [hematoxylin and 

Endogenous endophthalmitis results from the hematogenous spread of septic embolus from the bloodstream. [22] Untreated or inadequately treated, endophthalmitis initially confined to the vitreous cavity spreads to the ocular coats, resulting in panophthalmitis and orbital cellulitis. [23] Endogenous endophthalmitis has been reported in patients with systemic comorbidities such as diabetes mellitus, hepato-biliary disease, prolonged hospitalization, ICU admission, intravenous medication, indwelling urinary catheter, and use of corticosteroid/immunosuppressive agents. [24] In our cohort, all patients were hospitalized and had received intravenous medications; 91.6% (n = 22) patients had systemic illness (diabetes mellitus, chronic kidney disease, and hypertension); 66.6% (n = 16) patients were treated in the ICU, and 8.3% (n = 2) needed a ventilator. In our cohort, prolonged administration of three classes of drugs might have predisposed to endogenous endophthalmitis. These drugs are systemic corticosteroids, IL-6 inhibitors (tocilizumab), and broad-spectrum antibiotics.

Corticosteroid is known to cause immunosuppression and increases the risk of bacterial/fungal infection. [25] The RECOVERY trial recommended dexamethasone 6 mg daily for up to 10 days in hospitalized COVID-19 patients who require oxygen supplementation. [26] The other corticosteroids used in COVID-19 are methylprednisolone, prednisolone, and hydrocortisone. [27] In our cohort, the majority (21/24, 87.5%) of the patients were treated with corticosteroid, 71.42% (15/24) with intravenous methylprednisolone, and the mean duration of such treatment was 22.12 days.

Broad-spectrum antibiotics kill the bacteria and commensals that keep the yeast at bay and allow yeast multiplication. [28] Their use has been associated with systemic fungal infection. [29] In our cohort, all patients were treated with systemic antibiotics (Invariably azithromycin/doxycycline, or meropenem/Imipenem) during hospital admission for COVID-19, and the median treatment duration was 21 ± 4.9 (range: 5-35) days. IL-6 inhibitors impair the function of neutrophils, macrophages, and T cells and increase the risk of fungal infection. [30] Tocilizumab is an IL-6 receptor monoclonal blocking agent used for rheumatoid arthritis for several years. [31] In COVID-19 patients, tocilizumab is administered in patients with severe pneumonia with cytokine storm, increased demand for oxygen, raised inflammatory markers, and worsened CT chest. [32] Bacterial infection associated with tocilizumab has been reported earlier. [31] Recently, candidemia in hospitalized COVID-19 patients has been reported after tocilizumab use, [33] An experimental study has shown severe impairment of macrophage, neutrophil, helper T-cell functioning leading to candidemia in IL-6 deficient mice. [30] In our cohort, 58.3% (14/24) had received tocilizumab. [4, 6, 34] Like the systemic infection, the spectrum of fungal infection in our patients was wide: Candida, Aspergillus, Fusarium, and Mucor.

In our group, there was fewer bacterial endophthalmitis: only three patients (two Streptococcus pneumoniae and one Escherichia coli in blood culture). It is probable that bacterial endophthalmitis, if any, did not manifest due to the systemic antibiotics used in these patients for COVID-19 treatment. All three antibioticsazithromycin, doxycycline, meropenem/Imipenem-are known to cross the blood-retinal barrier. [35, 36] However, the use of these drugs and prolonged systemic steroid use could have resulted in endogenous fungal endophthalmitis. Viral coinfection in hospitalized COVID-19 patients is 3%, including respiratory syncytial virus (RSV) and Influenza. [4] In our cohort, one patient was positive for HSV-1 in viral PCR analysis of the ocular sample. The negative RT-PCR of the vitreous samples for SARS-CoV-2 precluded intraocular inflammation directly caused by the virus.

We compared the current endogenous endophthalmitis data in COVID-19 treated patients with other recently published series from other parts of the world [37] [38] [39] [40] [ Table 3 ]. In the current cohort, the mean patient age (53.66 years vs. culture (29.16% vs. 6.35%) were higher than our earlier report of endogenous endophthalmitis without COVID-19 infection; [37] this trend was similar to reports from other parts of the world. [38, 40] In the current series, there was higher fungal infection (58.33% vs. 15%) and lesser gram-negative infection (4.1% vs. 7%). [37] Bilgic et al. [16] reported three consecutive cases of endogenous endophthalmitis, all bacterial origin in the COVID-19 recovery stage. The better visual outcome after vitreous biopsy, vitrectomy, and intraocular antibiotic in their series could be related to bacterial endogenous endophthalmitis. In our series, the majority belonged to fungal endogenous endophthalmitis, which could have led to poor anatomical and functional outcomes. We did not see any SARS-Cov-2 virus in the vitreous samples in eight patients where vitreous biopsy material was subjected to RT-PCR for SARS-Cov-2 whereas Bilgic et al. had found one vitreous biopsy sample positive for the same virus. [16] Limitations of this study The tertiary care referral nature of our practice could have skewed some of the clinical presentations. The lack of the denominator of total hospitalized COVID-19 patients and their systemic comorbidities and interventions limits the conclusions drawn in our study.

Endophthalmitis is a rare but not uncommon occurrence in patients even after hospitalized care for COVID-19. This is associated with high mortality and blindness. Ocular infection is correlated with associated comorbidities, hospitalization, ICU admission, systemic therapy with a broad-spectrum antibiotic, corticosteroid, IL-6 inhibitor, raised inflammatory markers, and indwelling catheter. Candida spp. are the most common infecting organism. The treating physician should keep these facts in mind while treating patients with COVID-19. We recommend the inclusion of a routine eye examination (external eye and fundus) and estimation of vision as a part of the standard of care for hospitalized patients with COVID-19 who develop eye symptoms like blurring of vision and or redness.

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Dr Jay Kumar Chhablani, MD; University of Pittsburg, Pennsylvania.

Hyderabad Eye Research Foundation, Hyderabad, India.

There are no conflicts of interest.

We congratulate Nayak et al. for their excellent article. [1] Besides infective etiology, ocular inflammation and hypercoagulability status may be possible causes leading to loss of vision post COVID-19. [2] [3] [4] Previously, we had reported sight-threatening cases of multifocal retinitis with vascular occlusions [3] and a case of panuveitis with optic neuritis. [4] The authors can illustrate more about COVID-19-related systemic complication in their case series. Our series from a similar cohort of patients (unpublished data, submitted for publication), with final visual outcomes ranging from no perception of light to 20/36, again predominantly males, showed that D-dimer and serum ferritin were disproportionately raised during their ocular manifestations in patients with endophthalmitis/ panophthalmitis post COVID-19 and were statistically significant compared to the patients with milder and non-vision-threatening manifestations. Lactate dehydrogenase levels, erythrocyte sedimentation rate, and C-reactive protein were also raised but were not statistically significant. Diabetes and hypertension were also the systemic risk factors in our series. We were not able to isolate the SARS-CoV-2 virus on ocular sampling, but we had polymerase chain reaction positive for eubacteria and panfungal genome.The level (primary, secondary, or tertiary care) and details of COVID-19 care received by individual patients, including duration of hospital admission, intravenous fluid administration, oxygen supplementation, and assisted ventilation details, will provide additional information to study the risk factors that may also have affected the final outcomes. The fact that the patients reported belong to a specific geographic location (South India) could attribute to the COVID-19 treatment protocol in that region, which could contribute to the spike in the cases.A detailed description of the clinical presentation of the pediatric case who had a secondary viral infection (HSV-1 infection) with additional information regarding management with antiviral therapy can give additional insight into this clinical entity. Following vitrectomy, intravitreal antiviral agent injection would have helped faster resolution of retinal lesions secondary to HSV-1 infection. There have been reports of acute retinal necrosis in patients following COVID-19 [5, 6] where the authors have hypothesized that SARS-Cov-2 may have decreased the peripheral CD3+ and CD8+ T lymphocytes, consequently inhibiting both the regulatory and protective mechanisms against latent HSV.The authors have mentioned the duration of corticosteroids during COVID-19 as one of the risk factors, which has been similar in our cohort too. Additional information regarding systemic status such as preexisting diabetic status and de novo diabetes during COVID-19 will add additional information, especially because there was a greater percentage of fungal endophthalmitis in the study group. Shroff et al. [7] also reported a series of fungal endophthalmitis in patients who received intensive corticosteroid therapy, with Candida sp. being the most common fungal organism isolated from ocular samples. Additional information of systemic disease status in patients