|CASE BASED REVIEW
|Ahead of print publication
Post corona virus Disease-19 (COVID-19): Hyper inflammatory syndrome-associated bilateral anterior uveitis and multifocal serous retinopathy secondary to steroids
Srinivasan Sanjay1, Vijay K R. Rao2, Deepashri Mutalik1, Padmamalini Mahendradas1, Ankush Kawali1, Rohit Shetty3
1 Department of Uveitis and Ocular immunology, Narayana Nethralaya, Bengaluru, Karnataka, India
2 Divisha Arthritis and Medical Center, Manipal Hospitals, Bengaluru, Karnataka, India
3 Department of Neuro-Ophthalmology, Cornea and Refractive Surgery, Narayana Nethralaya, Bengaluru, Karnataka, India
|Date of Submission||05-Dec-2020|
|Date of Acceptance||08-Jul-2021|
|Date of Web Publication||28-Oct-2021|
Department of Uveitis and Ocular immunology, Narayana Nethralaya, Bengaluru, Karnataka
Source of Support: None, Conflict of Interest: None
Coronavirus disease 2019 (COVID-19) pandemic can cause ocular manifestations which include conjunctivitis to retinal manifestations. A 41-year-old Asian Indian male presented with unilateral blurring, glare, and pain in the left eye (LE), 22 days after COVID-19 infection. He had been administered intravenous steroids followed by oral steroids. Eye evaluation showed corrected distance visual acuity of 20/20 in both the eyes (BEs). Anterior chamber showed inflammation in the LE, a day later in the right eye. Fundus examination of the BE showed retinal pigment epithelial changes with serous elevation suggestive of multifocal serous chorioretinopathy. A month later, he had improvement in his symptoms with no cells in BE with topical steroids with resolution of serous retinopathy. Bilateral anterior uveitis possibly represents an immune-mediated trigger of his clinically quiescent psoriasis causing first-ever uveitis episode, possibly due to COVID-19. Serous chorioretinopathy could be secondary to steroids following treatment of COVID-19-related sequelae.
Keywords: Anterior uveitis, central serous chorioretinopathy, COVID-19, ophthalmic manifestations, spectral-domain optical coherence tomography
|How to cite this URL:|
Sanjay S, R. Rao VK, Mutalik D, Mahendradas P, Kawali A, Shetty R. Post corona virus Disease-19 (COVID-19): Hyper inflammatory syndrome-associated bilateral anterior uveitis and multifocal serous retinopathy secondary to steroids. Indian J Rheumatol [Epub ahead of print] [cited 2021 Dec 9]. Available from: https://www.indianjrheumatol.com/preprintarticle.asp?id=329490
| Introduction|| |
Ophthalmic manifestations can occur after recovery from coronavirus disease 2019 (COVID-19). Conjunctivitis, anterior uveitis, episcleritis, cotton wool spots, retinal hemorrhages, dilated and tortuous veins, retinitis, retinal artery and vein occlusions, ophthalmic artery occlusion, papillophlebitis, multifocal chorioretinitis, central serous retinopathy, and Adie's syndrome.,,,,,,,,
We would like to describe a unique case of bilateral anterior uveitis and multifocal serous chorioretinopathy in a patient who had just recovered from COVID-19 and was on systemic steroids.
The study was approved by the hospital ethics committee, vide Ethics Committee approval number: C/2020/09/09 and adhered to the declarations of Helsinki.
| Case Report|| |
A 41-year-old Asian Indian male presented to us with unilateral blurring of vision in the left eye (LE), 22 days after being treated for COVID-19 disease.
Prior to admission, he had fever, body ache, and cough of 4 days. His investigations during the stay at the hospital showed normal ferritin 82.8 ng/ml (30–490), liver function, renal function, complete blood count, C-reactive protein (CRP), increased D-dimer 0.52 (0.0–0.5), plasma interleukin 6 (IL-6) 14.6 (0.3–5.0), erythrocyte sedimentation rate (ESR) 16 (<10), reduced troponin-I 0.03 (0.029–0.039), and negative procalcitonin (<0.05). Upper respiratory swab for COVID-19 using real-time PCR was positive and B-beta coronavirus (CoV)-specific target gene and severe acute respiratory syndrome-CoV2 (SARS-CoV2)-specific target gene were detected.
COVID-19 pneumonitis with a computerized tomography chest score of 5 showing round mild nonsegmental bilateral ground-glass 5–6 opacities noted bilaterally in the lung in all lobes with subpleural distribution was seen. He was administered intravenous dexamethasone, ceftriaxone, remdesivir 200 mg 1st day followed by 100 mg for next 4 days, and subcutaneous low-molecular-weight heparin 40 mg for prophylaxis and oral azithromycin 500 mg/oseltamivir 75 mg orally twice a day for 5 days and was discharged after a week with oral steroids 20 mg and apixaban 2.5 mg twice daily.
Three days after the discharge from the hospital, the patient developed gradual onset of fever, associated with chills, and headache without breathlessness. His investigations showed increased white blood count 13400 (4400–11000 cell/cu mm) and absolute neutrophils 80.8% (40%–75%), ESR-37 (0-10mm/hr), CRP 18.60 (1–10mg/L), lactate dehydrogenase 299 (100-250 IU/L),IL-6 8.93 (0.3-5 pg/ml) normal values of SGOT/SGPT/D-dimer/serum Ferritin and procalcitonin were negative.
Intravenous methylprednisolone was administered for a delayed cytokine storm in the second admission followed by oral tapering dose of 20 mg steroids and insulin for diabetes at discharge. Steroids were gradually tapered over next 4 weeks. He was a recently detected diabetic and was on 50 mg oral sitagliptin for the last 6 months and mild cutaneous psoriasis and not on any treatment for the past 5 years.
On ophthalmic examination, his corrected distance visual acuity was 20/20 in both the eyes (BEs). Intraocular pressure was 18 mmHg in BE. Examination of the anterior segment showed an anterior uveitis LE – Flare 1+ cells 1+, and a day later in RE-Flare 1+, cells 1+. Anterior vitreous was clear in BE. RE showed a serous chorioretinopathy temporal to the optic disc. The LE also showed serous chorioretinopathy near superior/inferior arcade. There were retinal pigment alterations in macula of BE possibly due to resolved serous retinopathy.
A diagnosis of LE anterior uveitis with bilateral multifocal serous chorioretinopathy was made. A day later, he developed anterior uveitis in the RE.
A spectral-domain optical coherence tomography scan on the Spectralis™ (Heidelberg Engineering, Heidelberg, Germany) of the RE showed serous detachment temporal to the disc and in the LE showed posterior vitreous cells and serous detachment near the superior/inferior arcade [Figure 1]a (RE), [Figure 2]a (LE). An optical coherence tomography angiography done on the Optovue AngioVue ™(Optovue, Inc., Fremont, CA) did not show any pathological changes in retinal or choroid circulation. [Figure 3] shows presence of ground glass opacities in his chest computed tomography of the lungs.
|Figure 1: (a) (Top row) Multicolor imaging of the right eye showing yellow arrow adjacent to the optic disc showing the location of serous retinopathy indicated by a slight bulge with other white arrows retinal pigment epithelial defects indicating a resolved serous retinopathy. (b) (Bottom row) Yellow arrow adjacent to the optic disc showing complete reduction of the bulge a month later. (c) (Top row) Optical coherence tomography images showing (R) retina and (C) choroid and subretinal fluid yellow arrow indicating location of serous detachment. Above the retina is the vitreous showing hyperreflective white dots which are posterior vitreous cells which may be of inflammatory origin. (d) (Bottom row) Complete resolution of serous detachment (yellow arrow)|
Click here to view
|Figure 2: (a) (Top row) Multicolor imaging of the left eye showing yellow arrows adjacent to the inferior arcade and near the superior arcade showing the location of serous retinopathy indicated by a slight bulge with other white arrows retinal pigment epithelial defects indicating a resolved serous retinopathy. (b) (Bottom row) Yellow arrow adjacent to the optic disc showing reduction of the bulge a week later. (c) (Top row) Optical coherence tomography images showing (R) retina and (C) choroid and subretinal fluid yellow arrow indicating location of serous detachment. Above the retina is the vitreous showing hyperreflective white dots. (d) (Bottom row) Resolution of serous detachment. Posterior vitreous cells have reduced|
Click here to view
|Figure 3: Axial computed tomography of the lungs showing 5–6 ground-glass opacities bilaterally|
Click here to view
Based on the clinical and imaging findings, a diagnosis of bilateral anterior uveitis and multifocal central serous chorioretinopathy (CSCR) was made. The patient was started on topical prednisolone acetate 1% 3 hourly with homatropine 2% twice daily in BE. The patient was also suggested to stop oral steroids.
At 1-week follow-up, the patient was symptomatically better in BE and the serous detachment also had reduced. A month later, there was complete resolution of bilateral anterior uveitis and CSCR. [Figure 1]a shows pseudocolour image of right eye with a greenish area adjacent to the disc which corresponds to a serous detachment on SD-OCT, [Figure 1]b shows SD-OCT showing a serous detachment. [Figure 1]c shows pseudocolour image reduction of greenish area adjacent to the disc a month later. [Figure 1]d shows SD-OCT of resolved serous detachment. [Figure 2]a shows a pseudocolour image of the left eye in the posterior pole of the retina showing blister like lesions. [Figure 2]b shows SD-OCT of the left eye depicting serous detachment. [Figure 2]c shows pseudocolour image reduction of blister like lesions a month later.[Figure 2]d shows SD-OCT of resolved serous detachment.
| Discussion|| |
Studies suggest that SARS-CoV-2 binds to the host cells via the angiotensin-converting enzyme (ACE) 2 receptor. ACE 2 receptors are present in all major organs with higher density in the lungs, heart, veins, and arteries. ACE2 receptors' expression within endothelial cells makes them vulnerable to SARS-CoV-2 binding and systemic endothelial dysfunction. Endothelial alterations and endotheliitis tilt the vascular balance toward vasoconstriction, ischemia, tissue edema, and a procoagulant state. The exact pathophysiology of ocular transmission of the virus remains incompletely understood, although there is preliminary evidence of SARS-CoV-2 being detected in ocular secretions. The ocular tropism of the virus and its potential to cause localized ocular disease are worth considering.
Simultaneously, an exacerbated proinflammatory cytokine response has been observed in COVID-19 patients, which was seen in our patient 4 days after discharge from the hospital. The SARS-CoV-2 cytokine storm precipitates the onset of a systemic inflammatory response syndrome, resulting in the activation of the coagulation cascade and a hypercoagulable state. However, whether the coagulation cascade is directly activated by the virus or secondary to local or systemic inflammation is not clear. Elevation in fibrinogen and D-dimer levels observed in patients hospitalized with COVID-19 correlates with a parallel rise in inflammatory markers. The cytokine storm needs to be managed by immunosuppression including steroids.
CSCR occurs or is aggravated by administration of corticosteroids irrespective of the route of administration, namely topical for skin conditions, intra-articular, intravenous, intramuscular, oral, epidural, intranasal, and inhalation. CSCR secondary to corticosteroids can occur few days as seen in our patient to several years after the initiation of exogenous corticosteroids, and the doses of prednisone may be as low as 10 mg/day. CSCR can occur due to disruption of blood retinal barrier induced by the damage of retinal pigment epithelial pump and hyperpermeability of choriocapillaris.
Central serous retinopathy has no causal relationship with COVID-19. It occurred in our patient due to administration of glucocorticoids during COVID-19 management.
The possible explanations for the observed increased risk of uveitis among psoriasis patients could be due to the ocular inflammation triggered by the increased systematic inflammatory burden. Furthermore, several cytokines involved in the pathogenesis of psoriasis, such as tumor necrosis factor-alpha, IL-2, IL-6, and IL-17, are also found to be at an increased concentration in the aqueous humor of patients with uveitis., Psoriasis and uveitis may share some genetic predisposition such as HLA-B27 which has an antigen presenting role in the autoimmunity process involving BE and the skin. Our patient was HLA-B27 negative. The role of quiescent psoriasis in our patient in anterior uveitis is a matter of debate. We propose the role of COVID-19 infection in the inflammatory reaction seen in this patient.
Autoimmune diseases can flare up after viral infections especially in genetically susceptible individuals. Parvovirus B19, Epstein–Barr virus, cytomegalovirus, herpes virus-6, HTLV-1, hepatitis A and C virus, and rubella virus are some of the known viruses. The postulated mechanisms include activation of IL-6-dependent pathways, leading to cytokine storm and macrophage activation syndromes., It can also alter interferon signaling and affect antigen presentation.
The formation of neutrophilic extracellular traps in COVID-19 can provide a fertile ground for autoantibody formation, especially against intranuclear components (antinuclear antibody).
Viruses break down the self-tolerance by “molecular mimicry” and “bystander activation.” Viruses carry structurally similar antigens to self-antigens that activate B and T cells and lead to a cross-reactive response against both self-and nonself-antigens, and this mechanism is known as “molecular mimicry.” Nonspecific and an overreactive antiviral immune response creates a localized pro-inflammatory environment, leading to the release of self-antigens from the damaged tissue. These self-antigens are subsequently taken up and presented by antigen presenting cells to stimulate the autoreactive T cells in the vicinity triggering autoimmunity called “bystander activation”.
The SARS-CoV-2 virus can disturb self-tolerance of host antigens at least in part through molecular mimicry. Development of autoantibodies and sometimes organ-specific Guillain–Barre syndrome or systemic (e.g. systemic lupus erythematosus-like disease) autoimmunity has been observed in COVID-19 and also novel autoimmune features may be seen.,
In a recent correspondence, the authors have suggested that a paucity of data on patients with rheumatic diseases in COVID-19 has led to “the COVID-19 global rheumatology alliance,” which may ultimately provide answers. There is a paucity of data on patients with rheumatic diseases in COVID-19. This has led to “the COVID-19 global rheumatology alliance,” which may ultimately provide answers, till then the speculation of the role of COVID-19 and autoimmune diseases and may continue.
We hereby describe a post-COVID-19 infection patient with bilateral anterior uveitis and serous chorioretinopathy while being treated with steroids. Our patient recovered completely after a course of topical steroids and cessation of oral steroids during the course of his ocular management. Patients with COVID-19 should be warned about possible ophthalmic sequelae even after recovery. Physicians/rheumatologists treating COVID-19 should be aware of these important sequelae and refer the patient to an ophthalmologist for timely intervention.
| Patient consent|| |
Written informed sign consent was obtained from the patient.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given their consent for the images and other clinical information to be reported in the journal. The patient understands that their name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Wu P, Duan F, Luo C, Liu Q, Qu X, Liang L, et al.
Characteristics of ocular findings of patients with coronavirus disease 2019 (COVID-19) in Hubei Province, China. JAMA Ophthalmol 2020;138:575-8.
Acharya S, Diamond M, Anwar S, Glaser A, Tyagi P. Unique case of central retinal artery occlusion secondary to COVID-19 disease. IDCases 2020;21:e00867.
Insausti-García A, Reche-Sainz JA, Ruiz-Arranz C, López Vázquez Á, Ferro-Osuna M. Papillophlebitis in a COVID-19 patient: Inflammation and hypercoagulable state. Eur J Ophthalmol. 2020 Jul 30:1120672120947591. doi: 10.1177/1120672120947591. Epub ahead of print.
Dumitrascu OM, Volod O, Bose S, Wang Y, Biousse V, Lyden PD. Acute ophthalmic artery occlusion in a COVID-19 patient on apixaban. J Stroke Cerebrovasc Dis 2020;29:104982.
Ortiz-Seller A, Martínez Costa L, Hernández-Pons A, Valls Pascual E, Solves Alemany A, Albert-Fort M, et al.
Ophthalmic and Neuro-ophthalmic Manifestations of Coronavirus Disease 2019 (COVID-19). Ocul Immunol Inflamm 2020;28:1285-9.
Sanjay S, Mutalik D, Gowda S, Mahendradas P, Kawali A, Shetty R. “Post Coronavirus Disease (COVID-19) Reactivation of a Quiescent Unilateral Anterior Uveitis”. SN Compr Clin Med. 2021:1-5. doi: 10.1007/s42399-021-00985-2. Epub ahead of print.
Sanjay S, Srinivasan P, Jayadev C, Mahendradas P, Gupta A, Kawali A, et al
. Post COVID-19 Ophthalmic Manifestations in an Asian Indian Male. Ocul Immunol Inflamm. 2021;29:656-61. doi: 10.1080/09273948.2020.1870147. Epub 2021 Mar 18.
Sanjay S, Gowda PB, Rao B, Mutalik D, Mahendradas P, Kawali A, et al.
“Old wine in a new bottle”-post COVID-19 infection, central serous chorioretinopathy and the steroids. J Ophthalmic Inflamm Infect 2021;11:14.
Mahendradas P, Hande P, Patil A, Kawali A, Sanjay S, Ahmed SA, et al.
Bilateral post fever retinitis with retinal vascular occlusions following severe acute respiratory syndrome corona virus (SARS-CoV2) infection. Ocul Immunol Inflamm. 2021:1-6. doi: 10.1080/09273948.2021.1936564.
To KF, Lo AW. Exploring the pathogenesis of severe acute respiratory syndrome (SARS): the tissue distribution of the coronavirus (SARS-CoV) and its putative receptor, angiotensin-converting enzyme 2 (ACE2). J Pathol 2004;203:740-3.
Ho D, Low R, Tong L, Gupta V, Veeraraghavan A, Agrawal R. COVID-19 and the ocular surface: A review of transmission and manifestations. Ocul Immunol Inflamm 2020;28:726-34.
Klok FA, Kruip MJ, van der Meer NJ, Arbous MS, Gommers DA, Kant KM, et al.
Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res 2020;191:145-7.
Becker RC. COVID-19 update: Covid-19-associated coagulopathy. J Thromb Thrombolysis 2020;50:54-67.
Tittl MK, Spaide RF, Wong D, Pilotto E, Yannuzzi LA, Fisher YL, et al.
Systemic findings associated with central serous chorioretinopathy. Am J Ophthalmol 1999;128:63-8.
Kao LY. Bilateral serous retinal detachment resembling central serous chorioretinopathy following epidural steroid injection. Retina 1998;18:479-81.
El-Asrar AM, Struyf S, Kangave D, Al-Obeidan SS, Opdenakker G, Geboes K, et al.
Cytokine profiles in aqueous humor of patients with different clinical entities of endogenous uveitis. Clin Immunol 2011;139:177-84.
Queiro R, Morante I, Cabezas I, Acasuso B. HLA-B27 and psoriatic disease: A modern view of an old relationship. Rheumatology (Oxford) 2016;55:221-9.
Ehrenfeld M, Tincani A, Andreoli L, Cattalini M, Greenbaum A, Kanduc D, et al.
Covid-19 and autoimmunity. Autoimmun Rev 2020;19:102597.
Soy M, Keser G, Atagündüz P, Tabak F, Atagündüz I, Kayhan S. Cytokine storm in COVID-19: Pathogenesis and overview of anti-inflammatory agents used in treatment. Clin Rheumatol 2020;39:2085-94.
Merad M, Martin JC. Pathological inflammation in patients with COVID-19: A key role for monocytes and macrophages. Nat Rev Immunol 2020;20:355-62.
Hadjadj J, Yatim N, Barnabei L, Corneau A, Boussier J, Smith N, et al.
Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science 2020;369:718-24.
Barnes BJ, Adrover JM, Baxter-Stoltzfus A, Borczuk A, Cools-Lartigue J, Crawford JM, et al.
Targeting potential drivers of COVID-19: Neutrophil extracellular traps. J Exp Med 2020;217:e20200652.
Gupta S, Kaplan MJ. The role of neutrophils and NETosis in autoimmune and renal diseases. Nat Rev Nephrol 2016;12:402-13.
Smatti MK, Cyprian FS, Nasrallah GK, Al Thani AA, Almishal RO, Yassine HM. Viruses and autoimmunity: A review on the potential interaction and molecular mechanisms. Viruses 2019;11:762.
Liu Y, Sawalha AH, Lu Q. COVID-19 and autoimmune diseases. Curr Opin Rheumatol 2021;33:155-62.
Ahmed S, Zimba O, Gasparyan AY. COVID-19 and the clinical course of rheumatic manifestations. Clin Rheumatol 2021;40:2611-9.
Liew JW, Graef ER. Rheumatic disease and COVID-19 Ann Rheum Dis 2021;80:e43.
[Figure 1], [Figure 2], [Figure 3]