DOI: https://doi.org/10.21203/rs.3.rs-1551747/v1
Purpose: To describe a case of bilateral Aspergillosis endogenous endophthalmitis in post COVID-19 recovered patient.
Case presentation: 54-year-old man presented with bilateral decreased vision three weeks after post-Covid hospitalization discharge. Initially, he was diagnosed as noninfectious uveitis and by mistake treated with systemic prednisolone. Subsequently, after positive vitreous sample PCR result for Aspergillus fumigatus, he was properly treated with systemic voriconazole.
Conclusion: According to the possibility of Aspergillosis EE in post-COVID-19 patients, this article highlights the need for an in-depth examination of the fundus of patients who have ocular symptoms after COVID-19 and takes fungal pathogens into account.
The coronavirus has recently challenged the medical system. Various ocular manifestations of coronavirus infection have been reported. [1, 2] One of the disastrous ocular manifestations detected in these patients is endophthalmitis. There have been previous case series of patients with Covid-19 pneumonia having endogenous bacterial endophthalmitis (EE) originating from the throat, kidneys, and teeth as a source of infection, and even the covid virus had been isolated from the vitreous sample.[3] Regarding fungal EE, Candida species are reported as the most common pathogen, although there are two reports with a specific diagnosis of Aspergillus. [4, 5] Emergency admission for respiratory assistance, intensive care and intravenous corticosteroids. predisposed recovered patients to the occurrence of Aspergillus EE with the presentation of subretinal abscess and retinal necrosis formation. [4, 6] The present case report on bilateral Aspergillosis EE is novel in this respect.
A 54yearold man presented with both eyes blurred vision two days before visiting an ophthalmologist. He had a history of COVID-19 related pneumonia with approximately 40% lung involvement, confirmed by polymerase chain reaction (PCR), which led to eight-day hospitalization. In addition to other respiratory supportive care, he also received intravenous dexamethasone (8 mg/day) during admission. The patient had a history of first dose Covid-vaccination with COVIran Barekat (Barkat Pharmaceutical Group) vaccine three weeks before infection. He did not have any other systemic disease before.
His ocular symptoms developed three weeks after post-Covid hospitalization discharge. At presentation, the best corrected visual acuity (BCVA) of the right and left eyes was 20/200 and finger counts (FC) 4 m, respectively. He was diagnosed as noninfectious uveitis by his primary ophthalmologists and received systemic prednisolone (25mgr /day) with topical steroid and cycloplegic drops. Due to lack of recovery, he was referred to our clinic after two weeks. On examination, the BCVA of right and left eyes were CF 6m and CF 1 m, respectively. Anterior segment was remarkable, vitreous cell (+ 2 in both eyes) was detected. Funduscopy in the right eye showed extensive confluent yellowish intraretinal and subretinal collections in the inferior arcade involving the foveal area. In the left eye, the same lesion with surrounding sub-retinal turbid fluid was seen in the temporal area of the macula, which reached to the fovea. (Fig. 1A-B) Macular optical coherence tomography (OCT) of both eyes revealed intraretinal and subretinal hyper-reflective materials with mild intraretinal and subretinal fluid (SRF), which disrupted macular structure. (Fig. 2A-B) Fundus fluorescein angiography displayed early hyper fluorescence due to vascular leakage around the lesions. (Fig. 3)
Clinically suspected of EE, the patient received systemic antibiotic (ciprofloxacin 500mgr/bid), and concurrent systematic workups were performed, including obtaining blood and urine culture, vasculitis laboratory tests, purified protein derivative (PPD) skin test, trans-esophageal echocardiography, and repeating spiral chest CT, no systemic source of infection was detected. Unfortunately, lesions appeared to expand in size and his vision was declining, highly suspected of fungal chorioretinitis, the patient was admitted, and oral voriconazole (200 mg/bid) was started, and vitreous sampling for smear, culture and PCR for herpes viruses, Mycobacterium, Candida, and Aspergillus species was done. Although the culture from vitreous aspirate failed to yield any organism, Real-time PCR analysis detected the Aspergillus Fumigatus while negative for Candida, HSV-1, HSV-2, CMV, VZV, and Mycobacterium genome. By diagnosis of confirmed Aspergillus EE, oral voriconazole was continued. After three weeks, vitreous inflammation and the size of the subretinal lesions and SRF reduced significantly. The patient's vision gradually enhanced in both eyes. After eight weeks, in the last follow up, BCVA was 7/10 in the right, and 5/10 in the left eye. Fundus photography and OCT showed improved lesions. (Fig. 1C-Fig. 2C)
Coronavirus creates circumstances that place the patient at risk for opportunistic infections. Conditions such as hospitalization or intensive care unit admission, having a urinary catheter or intravenous cannula and receiving various immunosuppressive drugs, besides high doses of corticosteroids, may result in opportunistic infections (OIs) for instance, fungal endophthalmitis.[7, 8] Corticosteroids may reduce the mortality risk in Covid-19 patients. However, they can place the patient at the chance of opportunistic infection by altering the immune system function. [9] This potential effect can be synchronized with the direct consequence of the coronavirus on the immune system, like a noticeable increase in the production of free radicals, release of IL-4, IL-10, IL-1β, monocyte chemoattractant protein 1(MCP-1), IP-10, and interferon-gamma (IFN-γ). [10]
Aspergillus EE is a rare intraocular infection, which is usually diagnosed clinically according to fundus lesions by experienced specialists. Most of these patients are initially misdiagnosed as noninfectious uveitis by their primary ophthalmologists and treated with Inadvertent local or systemic steroids or immunomodulators. This scenario was happening for our patient and cases who have recently been reported. [4, 5] Also, all recent reports regarding post Covid recovery Fungal EE indicate no systemic focus of infection and negative blood and urine culture in these patients; therefore, misdiagnosis of noninfectious uveitis is expected if it is evaluated only on this basis, such as happened in our case. [3–5, 9]Modjtahedi et al. Reported 69% of positive culture vitrectomies in all fungal spices EE in a situation of initial negative tap and given that the positive vitreous sample in filamentous fungi is uncommon than yeast because of vitreous involvement with molds is rare, also the concomitant prophylactic use of antibiotics for a long time during the Covid-19 pneumonia care may influence the result of cultures; therefore, it seems that the diagnosis of Aspergillus EE according to vitreous tap culture is not reliable.[11] Sowmya p et al. showed that the PCR reported for fungal genomes verified a 100% microbial detection rate and can be regarded as a gold standard.[12]
According to the contents, we believe that in these critical covid situations, it is necessary to consider the following triad of early diagnosis; positive history for corticosteroid use through Covid-19 pneumonia, existence of posterior pole necrotizing chorioretinal lesion, and confirmatory PCR of vitreous sample for Aspergillus.
We present a chart review of five patients of confirmed Aspergillus associated fungal EE in Covid-19 related pneumonia recovered case recently reported. (Table 1) As it was seen in our patient, all cases had already been hospitalized for COVID-19-related pneumonia with an average of 9.6 ± 5.4 days of hospitalization and had received systemic corticosteroid therapy. Characteristic retinal signs include; necrotizing subretinal exudate or abscess formation in the posterior pole extending to macula with overlying vitreous opacity were seen in all recently reported cases. Once comparing clinical details and characteristics of the present case, there are some crucial differences; our patient only received systemic voriconazole and did not require a pars plana vitrectomy or intravitreal antifungal injection, although baseline BCVA in our case was better than other cases and the poor presenting vision was related to poor visual outcome, [13] the visual outcome and healing process were significantly restored in comparison to other previous fungal EE cases. [4, 5]Early diagnosis and prompt treatment might be the main causes of this variance. However, by reviewing patients' clinical details, other factors that can justify this distinction is injection of the COVID-19 vaccine before Covid-19 related pneumonia and using the antiviral drug (Remdesivir) during hospitalization that may have influenced the immune system recovery and response to opportunistic infections. Injection of the COVID-19 vaccine, despite potential side effects such as the possibility of various forms of ocular inflammation, may be effective in relieving symptoms and improving response to antifungal treatment. [8, 14]The preventive vaccine might have reduced the symptoms and accelerated recovery in our case, compared to the previous ones.
| Case 1[5] | Case 2 [4] | Case 3[4] | Case 4[4] | Case 5[4] | Case 6 | |
|---|---|---|---|---|---|---|
| Age (in years) | 47 | 51 | 46 | 62 | 54 | 54 |
| Gender | Male | male | Male | Male | Male | Male |
| Systemic illness | HTN | None | None | None | DM | None |
| Duration of hospitalization | 8 days | 9 days | 10 days | 8 days | 15 days | 8 days |
| ICU admission | Yes | Yes | No | No | Yes | No |
| THE INTERVAL between discharge and onset of symptoms | 4 weeks | 1 day | 4 days | 31 days | 9 days | 21 days |
| Treatment for COVID (CORTICOSTEROID) | Dexamethasone IV and oral Dexamethasone (18 days) | Methylprednisolone IV *7 days, oral prednisolone in tapering doses | Dexamethasone IV *10 days, oral prednisolone*9 days | Dexamethasone IV *8 days, oral Prednisolone *15 days | Methylprednisolone IV *14 days, oral prednisolone in tapering doses | Dexamethasone IV *8 days, oral Prednisolone *14 days |
| Other COVID treatment | NM | Immunoglobulins *15 doses | None | None | Tocilizumab | Remdesivir |
| Vaccination status | NM | Not received | Not received | Not received | Not received | First dose (COVIran Barekat) |
| Systemic work-up | Negative | Presumed lung Aspergillosis. | Negative | Negative | Negative | Negative |
| Eye | OS | OD | OS | OD | OS | OU |
| Presenting Visual Aquity | CFCF | HM | CFCF | LP | HM | OD: CF 6 m OS: CF 1 m |
| Posterior segment finding | Vitreous exudates, granuloma nasally and at posterior pole. Total RD. | Condensed vitreous exudates, yellowish subretinal infiltrate with interspersed hemorrhage involving the entire posterior pole | Condensed vitreous exudates, Pseudo hypopyon retinal infiltrates with interspersed temporal hemorrhage at posterior pole extending beyond inferior arcade | Condensed vitreous exudates, retinal abscess of about 1 DD no involving fovea | Condensed vitreous exudates, t yellowish subretinal infiltration and hemorrhage spreading from nasal peripapillary to entire posterior pole | OD: subretinal exudate the inferior and temporal to the fovea, and a bulky subretinal abscess beneath the fovea covering with area suspected of retinal necrosis and localized vitritis in front of the lesion. OS: retinal abscess in the same area as the previous eye but with a smaller size. Localized vitritis |
| Treatment | Re-Vitrectomy +Lensectomy +SOI + IVV | IVV + PPV + SOI | PPV + SOI | IVV + PPV + SOI | IVV + PPV + SOI | Oral Voriconazole 200mg BD |
| Organism | Aspergillus sp. | Aspergillus niger | Aspergillus niger | Aspergillus fumigatus | Aspergillus fumigatus | Aspergillus fumigatus |
| Visual Outcome | 20/1200 | HM | 20/400 | CFCF | HM | OD: 7/10 OS: 5/10 |
| HTN-hypertension, DM-Diabetes Mellitus, OD-Right eye, OS-Left eye, HM-hand motion, CFCF-counting finger close to face, PL- Perception of light, NM-Not mentioned, IV- intravenous injection, DD-disc diameter, PPV-pars plana vitrectomy, SOI-silicone oil injection, IVV-intravitreal Voriconazole | ||||||
The presented case is the first bilateral confirmed Aspergillus EE in a Covid-19-recovered patient. In 2002, Riddle et al. reported 27% eventual bilateral involvement in their review article about Aspergillus EE. [15] As a gradual progression of ocular symptoms in fungal infections, vision reduced slowly and patients cannot understand the early sign of contralateral eye infection; consequently, emphasis placed on the importance of accurate examination of the fundus of both eyes in cases presented with unilateral symptoms. There is a various treatment protocols for Aspergillus EE. Systemic voriconazole is the critical drug. [16] It is suggested to begin systemic voriconazole in clinically presumed cases until the results of PCR or vitreous aspiration culture reveal the definitive diagnosis. Surgical procedures such as multiple intravitreous injections of antifungal drugs, and pars plana vitrectomy with or without silicone injection have been reported as valuable ways for the management of fungal EE. [3, 4, 15]
The purpose of presenting this case is to draw attention to considering fungal pathogens as the cause of EE in patients following COVID. In addition to demonstrating differences in the course of illness, progression, and even treatment compared to previously reported cases.
According to the possibility of Aspergillosis EE in post-COVID-19 patients, this article highlights the need for an in-depth examination of the fundus of patients who have ocular symptoms after COVID-19 and takes fungal pathogens into account.
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The consent was received from the patient to publish his data and pictures without mentioning his name.
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Authors' contributions
The patient was introduced by Dr. Mohammadkarim Johari
All authors participated in all stages of the article
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The authors declare no conflict of interest.