Ocular Manifestations of COVID-19 (SARS-CoV-2): A Critical Review of Current Literature.

The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in China in the city of Wuhan in December of 2019 and since then more than 5,000,000 people have been infected, with approximately 338,000 deaths worldwide. The virus causes the coronavirus disease 2019 (COVID-19), which is characterized by fever, myalgia and cough, with severe acute respiratory syndrome being the most fearsome complication. Nevertheless, the vast majority of cases present mild symptoms or none. Central nervous system and cardiovascular manifestations have been reported. The range of ocular manifestations, either as a result of the infection or as a result of the treatment, has not yet been discussed. In this study, a systematic review of current literature relevant to COVID-19 was performed with focus on modes of transmission, ocular manifestations related to infection and medications, as well as the control of infection in ophthalmic practice.

Reasons for visits to an emergency center and hemostatic alterations in patients with recurrent spontaneous subconjunctival hemorrhage.

PURPOSE: To evaluate causes of visits to the Eye Emergency Department, determine the prevalence of subconjunctival hemorrhage (SCH), and assess the role of hemostatic abnormalities among patients with spontaneous recurrent SCH (SRSCH). METHODS: In a prospective study conducted over 2 years, hemostatic function was studied in a subgroup of 105 consecutive patients (39 male) with SRSCH free of systemic risk factors and in 53 age- and sex-matched healthy controls (HC) (24 male). RESULTS: A total of 10,090 patients (mean age 57.2 ± 16.7 years, range 0-94, median 58.4) were evaluated. A total of 39.3% had ocular trauma, 34.9% inflammatory ocular surface disorder, 5.7% floaters, 3.3% visual symptoms of neurologic origin, 1.6% uveitis, 1.5% ocular hypertension, 0.8% retinal tear or detachment, 0.7% retinal vascular disease, and 0.5% other causes. A total of 1.6% of the patients were hospitalized. A total of 11.7% of patients had SCH: in 86.7% it was spontaneous, in 13.3% consequent to trauma or to ocular surface disorders. A total of 105 patients had SRSCH, and the prevalence of hemostatic abnormalities among them was not different from HC. Type I von Willebrand disease was diagnosed in 1 patient with SCH and in none of the HC (χ² = 0.13, p = 0.72). CONCLUSIONS: Most patients had ocular infection or trauma and were treated on an outpatient basis; SCH was the third cause of access. The large majority of SCH were unprovoked, and the prevalence of hemostatic alterations in patients with SRSCH and no systemic causes was not different from the general population. Hemostatic screening or second level blood clotting tests were of no use in these patients.

Correlation between conjunctival and corneal calcification and cardiovascular calcification in patients undergoing maintenance hemodialysis.

The purpose of this study was to investigate the correlation of conjunctival and corneal calcification (CCC) with cardiovascular calcification in patients undergoing maintenance hemodialysis (MHD). A total of 122 patients undergoing MHD in our hospital were included in this study. Conjunctival and corneal calcification was examined by slit lamp and graded. Abdominal aortic calcification (AAC), aortic valve calcification (AVC), and mitral valve calcification (MVC) were determined by X-ray or ultrasound. The correlation of CCC with AAC, AVC, and MVC was analyzed. Biochemical, hematological, and cardiovascular data were compared between patients with different severity of CCC or AAC. Mitral valve calcification was significantly associated with AAC in our patients. Conjunctival and corneal calcification positively correlated with AAC. We also found that patients with severe CCC exhibited significantly higher levels of serum calcium, phosphate, product of calcium and phosphate, serum copper, cystatin, intact parathyroid hormone, and vitamin D than patients with mild CCC. In addition to significantly increased levels of serum calcium, product of calcium and phosphate, serum copper, and cystatin, patients with severe AAC also had higher high-sensitivity C-reactive protein level and greater left ventricular posterior wall thickness and left ventricular end-diastolic interventricular septum thickness than patients with mild AAC. Our results suggest that patients undergoing MHD with severe CCC or AAC have high degree of mineral metabolism disorder, inflammation, and cardiovascular function disorder. The strong correlation between CCC and AAC indicates that CCC score might be used as an indirect indicator to predict cardiovascular risks in patients undergoing MHD.

Significance of acellular smears in conjunctival impression cytology.

OBJECTIVES: Conjunctival xerosis is a marker for vitamin A deficiency. Conjunctival impression cytology (CIC) is a widely used technique to detect xerosis in field studies. Inadequate and acellular samples are generally considered technical failures and are treated as uninterpretable. The purpose of this study is to determine the significance of acellular smears in the detection of vitamin A deficiency. STUDY DESIGN: CIC with transfer (CICT) and blood samples were collected from freshly diagnosed cancer patients and healthy controls. CICT smears were classified as cellular or acellular. Serum vitamin A levels were tested by high-performance liquid chromatography. CICT results were compared with vitamin A levels. RESULTS: CICT was collected from 1,694 subjects. There were 118 (7%) acellular smears, i.e. 99 in patients and 19 in controls. Serum vitamin A levels were available in 112 of these subjects. Levels <20 µg/dl were seen in 82.1% of the subjects with acellular smears and in 18.9% of the subjects with cellular smears (p < 0.001). Of the gastrointestinal and hepatobiliary and hematologic cancers, 15.6% and 10.5% showed acellular smears, respectively. CONCLUSIONS: Acellular smears in conjunctival imprint cytology may indicate hypovitaminosis A, provided technical failure to obtain cellularity is ruled out.

Ocular adnexal IgG4-related lymphoplasmacytic infiltrative disorder.

OBJECTIVE: To determine the clinicopathological characteristics of patients with infiltration of IgG4-positive plasma cells into the ocular adnexa. METHODS: We designed a prospective study to evaluate 24 patients with ocular adnexal lymphoplasmacytic infiltrative lesions, including sclerosing inflammation and reactive lymphoid hyperplasia. We analyzed peripheral blood and biopsy specimens from all patients. The classification criteria for placement in the IgG4-related group included having both an elevated serum level of IgG4 of 135 mg/dL or greater and an IgG4:IgG ratio of infiltrating plasma cells of 30% or greater. RESULTS: Ten patients met the classification criteria (IgG4-related group), 9 patients did not meet the criteria (IgG4-unrelated group), and 5 patients met 1 but not both criteria (indeterminate group). Patients in the IgG4-related group had significantly higher bilateral involvement (P = .02), a higher number of allergic diseases (P = .01), and elevated IgE serum levels (P = .01). Of the 10 patients in the IgG4-related group, 3 also had polyclonal hypergammaglobulinemia, 6 had systemic lymphadenopathy or salivary gland enlargement, and 1 developed autoimmune pancreatitis. Patients in the IgG4-unrelated group did not have these serum and/or systemic abnormalities. CONCLUSION: The IgG4-related and IgG4-unrelated groups have different patterns of tissue involvement and systemic disease associations and possibly different prognoses.

T-helper 17 lymphocytes in ocular cicatricial pemphigoid.

PURPOSE: T-helper 17 lymphocytes (Th17) were identified in the healthy conjunctiva and in patients with ocular cicatricial pemphigoid (OCP), a disease characterized by chronic ocular surface inflammation. METHODS: Conjunctival biopsies and blood samples were obtained from 10 patients with OCP (4 males, 6 females; 57-90 years of age) and 6 age/sex matched healthy subjects. Conjunctival samples were immunostained with anti-human IL17/CD4 antibodies and stained cells were then counted by confocal microscopy in three 60X field images per each sample. Mononuclear cells were isolated from both OCP and healthy blood samples and evaluated for IL17 and CD4 by FACS. IL17, TGF-beta, IL4, and IFN-gamma levels were determined in plasma of OCP and healthy patients by ELISA. RESULTS: The presence of Th17 lymphocytes in conjunctival biopsies was significantly (p<0.05) increased in patients with OCP (14.9+/-12.8 cells per microscopic field) compared to healthy subjects (0.5+/-0.8 cells per microscopic field). Th17 lymphocytes comprised 72% of CD4(+) cells in four stage-III OCP conjunctival samples. No significant difference was observed for IL17 in peripheral blood of OCP versus healthy subjects. CONCLUSIONS: In this study, we report an increased localization of Th17 lymphocytes in OCP conjunctiva, not accompanied by similar findings in peripheral blood. This finding suggests an increased recruitment of Th17 lymphocytes in conjunctiva and/or a dysfunctional local immune response in the chronically inflamed conjunctiva of OCP. Our findings are in line with previously reported evidence demonstrating that Th17 cells play a critical pathogenic role in mucosal autoimmunity.

The use of autologous serum in the development of corneal and oral epithelial equivalents in patients with Stevens-Johnson syndrome.

PURPOSE: To evaluate the use of autologous serum (AS) from patients with severe ocular surface disease (OSD) in the development of transplantable corneal and oral epithelial tissue equivalents and to compare it with the use of conventional culture methods by using fetal bovine serum (FBS). METHODS: AS was obtained from patients with severe OSD secondary to Stevens-Johnson syndrome. Corneal and oral epithelial cells were cultivated in medium supplemented with either AS or FBS. Corneal and oral epithelial equivalents were constructed on denuded amniotic membranes. The bromodeoxyuridine (BrdU) ELISA cell proliferation assay and colony-forming efficiency (CFE) of cells cultivated in AS- or FBS-supplemented media were compared. The morphologic characteristics and the basement membrane assembly of cultivated epithelial equivalents were analyzed by light and electron microscopy, as well as by immunohistochemistry. RESULTS: BrdU proliferation assay and CFE analysis showed that human corneal and oral epithelial cells cultivated in AS-supplemented media had comparable proliferative capacities compared with FBS-supplemented media. The corneal and oral epithelial equivalents cultivated in AS- and FBS-supplemented media were morphologically similar and demonstrated the normal expression of tissue-specific keratins and basement membrane assembly. The presence of a well-formed stratified epithelium, a basement membrane, and hemidesmosomal attachments was confirmed by electron microscopy. CONCLUSIONS: AS-supplemented cultures were effective in supporting the proliferation of human corneal and oral epithelial cells, as well as the development of transplantable epithelial equivalents. The use of AS is of clinical importance in the development of autologous xenobiotic-free bioengineered ocular surface equivalents for clinical transplantation.

Blood group related antigens in ocular cicatricial pemphigoid.

AIM: To study the MUC5AC and the blood group related antigen expression in ocular cicatricial pemphigoid (OCP) according to the distribution of Lewis and secretor phenotypes in OCP patients compared to normal subjects. METHODS: Immunostaining was performed on conjunctival biopsy specimens from 22 consecutive patients suffering from OCP, using monoclonal antibodies (Mabs) directed against the peptidic core MUC5AC mucin (anti-M1/MUC5AC Mabs) and against the saccharide moieties (anti-blood group related antigens). These latter included anti-Le(a), anti-Le(b), anti-sialyl Le(a), and H type 2 Mabs, which immunoreact with Lewis positive and non-secretor (Le(a)), Lewis positive and secretor (Le(b)), Lewis positive (sialyl Le(a)), and secretor (H type 2) phenotypes respectively. Serological tests were also performed to confirm the phenotype of each patient. The immunohistopathological patterns and the distribution of Lewis and secretor phenotypes were compared with the results of a previous study in normal individuals. RESULTS: (1) In OCP patients compared to the normal population, anti-M1 immunoreactivity of goblet cells was unchanged, whereas anti-Le(a), anti-Le(b), and anti-sialyl Le(a) immunoreactivities of epithelial and/or goblet cells were markedly decreased. (2) 41% of OCP patients had a non-secretor phenotype, which is statistically significantly more than the estimated incidence of the same phenotype in the French population (20%) (p approximately 0.04). CONCLUSIONS: Mucins in OCP patients showed a decreased expression of blood group related antigens whereas the MUC5AC peptidic core detected by anti-M1 Mab remained unchanged. These results also seem to indicate that OCP may be associated with a non-secretor phenotype.

Effects of IL-4 on conjunctival fibroblasts: possible role in ocular cicatricial pemphigoid.

PURPOSE: Increased stromal accumulation of macrophages and submucosal fibrosis due to excessive accumulation of collagens are central histologic features in ocular cicatricial pemphigoid (OCP). Interleukin (IL)-4 plays an important role in both the inflammatory and fibrotic events in several human and experimental diseases. In the present study, the possible role of IL-4 in the pathogenesis of OCP was investigated. METHODS: Biopsy specimens from the conjunctivae of 10 patients with OCP and 5 normal subjects were studied for the expression of IL-4 by immunohistochemistry. The expression level of IL-4 was also examined in conjunctival fibroblasts of normal control subjects and patients with OCP. The effects of IL-4 in the induction of inflammatory and fibrogenic molecules was studied in IL-4-treated conjunctival fibroblasts, and the expression levels of macrophage colony-stimulating factor (m-CSF), heat shock protein (HSP)-47 and type I collagen was determined by quantitative real-time PCR. The level of IL-4 was also measured by enzyme-linked immunosorbent assay (ELISA) in serum samples obtained from patients with OCP during active stage and remission and were compared with the levels in control sera. RESULTS: Compared with the weak expression of IL-4 in the normal conjunctival sections, an increased expression of IL-4 was noted in conjunctival sections of patients with OCP. A similar increase in the expression of IL-4 was also detected in fibroblasts isolated from conjunctiva of patients with OCP, compared with control fibroblasts. Real-time PCR and ELISA detected a significantly increased level of m-CSF, at both the mRNA and protein levels in IL-4-stimulated cells. Similarly, IL-4 treatment resulted in the induction of type I collagen and collagen-binding HSP47 by conjunctival fibroblasts, as detected by real-time PCR. However, no apparent changes in the levels of IL-4 were detected by ELISA in serum samples of patients with OCP and control subjects. CONCLUSIONS: Increased conjunctival expression of IL-4 may play an important role in the regulation of local accumulation of macrophages (by inducing m-CSF), and matrix accumulation (by inducing HSP47 and collagen) during conjunctival scarring in patients with OCP. IL-4, therefore, may augment or enhance both conjunctival inflammatory and subsequent fibrotic responses in patients with OCP.

Biology of interleukin-5 in ocular cicatricial pemphigoid.

BACKGROUND: Ocular cicatricial pemphigoid (OCP) is an autoimmune disease characterized by the presence of autoantibodies, T-cell dysregulation, and abnormal serum levels of cytokines such as interleukin-6, interleukin-1, and tumor necrosis factor-alpha. The purpose of the present study was to investigate levels of interleukin-5 (IL-5) in the sera, eosinophil counts in the peripheral blood, and eosinophil and mast cell counts in the inflamed conjunctivae of patients with active OCP. METHODS: Seven patients diagnosed in the active phase of OCP presenting with chronic cicatrizing conjunctivitis were studied. The serum levels of IL-5 were compared to a group of seven age-, race-, and sex-matched normal human subjects. Eosinophil and mast cell counts in the patients' conjunctivae were compared to those in normal conjunctivae harvested during cataract surgery from seven normal individuals. In addition, eosinophil counts in peripheral blood of patients with active OCP were compared to those in normal individuals. RESULTS: The mean serum level of IL-5 in patients with active OCP was higher (67.23 pg/ml, range 46.33-98.26 pg/ml) than that in normal individuals (12.18 pg/ml, range 7.66-18.86). The difference was statistically significant ( P<0.001). On light microscopy the biopsied conjunctivae stained with hematoxylin and eosin revealed statistically significant differences ( P<0.001) in the mean numbers of eosinophils in the substantia propria between the patients with active OCP (6.8 cells/cm(2), range 4.8-8.2 cells/cm(2)) and normal controls (0.91 cells/cm(2), range 0.4-1.8 cells/cm(2)). The average number of mast cells found in the substantia propria of the biopsied conjunctivae was statistically significantly higher in patients with OCP (13.79 cells/cm(2), range 6.6-19.4) than in normal individuals (4.34 cells/cm(2), range 3.2-7.8; P<0.01). The average number of eosinophils in the peripheral blood of patients with active OCP (6.6x10(7)/l, range 2.9 - 9.3x10(7)/l) was statistically significantly higher ( P<0.01) than in normal controls (2.09x10(7)/l, range 0 - 4.5x10(7)/l). CONCLUSIONS: The results suggest that IL-5 may play an important role in the pathogenesis of OCP.

[Morphometric parameters of the bulbar conjunctiva vessels in patients with gout]. / Morphometricheskie pokazateli sosudov bulbarnoi koniunktivy u bolnykh podagroi.

Morphometry of the bulbar conjunctiva vessels in 50 patients with gout was carried out by television capillaroscopy with videorecording. The findings indicate that microcirculatory disorders start with dilatation of the venules, after which arterioles and capillaries are involved. This results in alteration of the arteriovenular coefficient and of the bloodflow velocity in the capillaries. Hence, the metabolic form of gout may be regarded as the initial stage of disease.

Ocular tumoral calcinosis. A clinicopathologic study.

Tumoral calcinosis is a rare systemic disorder characterized by para-articular ectopic soft-tissue calcification. This case report describes the ophthalmic features (palpebral conjunctival calcific nodules, the white limbal girdle of Vogt, disc drusen, and angioid streaks) in a 38-year-old Asian woman who had tumoral calcinosis associated with hyperphosphatemia. A morphologic study of the calcified nodules on the palpebral conjunctiva disclosed deposition of hydroxyapatite crystals in an extracellular matrix (deposit) containing alcianophilic mucopolysaccharides. Excision of the eyelid nodules was not followed by recurrence.

A local challenger of ocular calciphylaxis in patients with chronic renal failure: a hypothesis.

BACKGROUND: It is generally accepted that the elevated calcium phosphate product in dialysis patients is associated with the development of extraskeletal calcification. There is, however, no clear association between the raised levels of calcium and phosphate ions and the degree of limboconjunctival calcification. This article focuses on the role of tissue devitalisation in the development of ocular calcification. METHODS: Local injury of the outer eye can be visualised by the Lissamine green staining test. We measured the pre- and postdialysis staining score in 38 dialysis patients. The differences between pre- and postdialysis tear fluid secretion and tearfilm stability were also assessed, as was the degree of limboconjunctival calcification. Serum calcium and phosphate levels were measured in all patients. RESULTS: In 14 of the 38 patients, demonstrable tissue injury was present as a result of a recurrent decrease of tear secretion after each dialysis session. There was a statistically significant association between the degree of limboconjunctival calcification and both the difference between the pre- and postdialysis Lissamine green staining score and the total number of haemodialysis sessions. CONCLUSION: Local factors, such as minor tissue injury of the limboconjunctival epithelium, referred to as "local challenger", are more likely to determine the degree of ocular calcification in dialysis patients than are systemic factors. Tissue injury of the outer eye in these patients is the result of a chronic decrease of tear fluid that occurs after each hemodialysis session.

Human immunodeficiency virus-related microvasculopathy and Kaposi's sarcoma: a case-control study.

Ocular microangiopathic syndrome including retinal and conjunctival abnormalities is frequently found in patients with human immunodeficiency virus type 1 (HIV-1) disease. Kaposi's sarcoma (KS) is the most frequent neoplasia found in patients with HIV-1 disease. We have recently reported a significant association between conjunctival microvasculopathy and KS in 117 patients with HIV-1 disease. The objective of the present study was to determine whether this association is existent when matched patients with and without KS are compared. A total of 22 matched pairs were obtained under consideration of the absolute CD4+ lymphocyte count, Walter Reed (WR) classification, gender, and serum levels of beta-2-microglobulin and neopterin. Conjunctival microangiopathy was determined for each eye by a standardized rating scale ranging from 0 to 5, allowing a reliable and valid quantification of conjunctival blood-flow sludging. The mean value obtained for conjunctival sludge was 1.8 (SEM, 0.4) for patients without KS and 3.2 (SEM, 0.3) for patients with KS, demonstrating a clinically and statistically significant difference between the two groups (Student's t = 3.0; P = 0.003). This difference was higher when patients with a CD4+ lymphocyte count exceeding 200/microliters were regarded. Similar factors or mechanisms may contribute to HIV-related conjunctival microvasculopathy and KS.

The role of serum calcium in the development of the acute red eye in chronic renal failure.

In patients with chronic renal failure treated by long-term dialysis, inflammatory reactions occasionally develop in the bulbar conjunctiva; the episcleral tissue is only rarely involved. Diffuse congestion of both the conjunctiva and episclera was present in 5.3% of our patients and was associated with a sudden, marked rise in serum calcium. Histopathological examination suggests that this form of hyperemia, clinically preceded by a marked shedding of calcific precipitates, is the result of a neurogenic-driven inflammatory reaction in which mast cell degranulation is mediated by the axon reflex. Focal hyperemia associated with elastosis ("pingueculitis") was present in 6.7% of the patients. This type of hyperemia was observed after an extended period of increasing levels of BUN and seemed independent of both serum calcium and phosphorus. Diffuse hyperemia of the conjunctiva, being clinically distinctly different from the combined diffuse conjunctival and episcleral hyperemia, was also observed in 6.7%. Diffuse conjunctival hyperemia seemed to be associated with low BUN. Here, again, there was no association with serum calcium and phosphorus levels.

Conjunctival and corneal changes in chronic renal failure patients treated with maintenance hemodialysis.

Conjunctival and corneal depositions of calcium salts are common complications in hemodialysis (HD) patients. We examined 14 HD patients; in 11 (79%), typical conjunctival and corneal calcifications were found. Patients with calcifications were older than those without. Patients treated longer with HD were found to have a higher grade of calcifications. We did not find the highest grade of calcifications in our patients. Serum calcium, phosphate, product of calcium and phosphate and parathyroid hormone concentration did not differ in patients with or without calcifications.