Rhino-orbital-cerebral-mucormycosis in COVID-19: A systematic review.

Since the onset of COVID-19 pandemic, parallel opportunistic infections have also been emerging as another disease spectrum. Among all these opportunistic infection, mucormycosis has become a matter of concern with its rapid increase of cases with rapid spread as compared to pre-COVID-19 era. Cases have been reported in post-COVID-19-related immune suppression along with the presence of comorbidity which adds on the deadly outcome. There is no systematic review addressing the issue of COVID-19-associated mucormycosis. This is the first systematic review of published studies of mucormycosis associated with COVID-19. The aim was to analyze the real scenario of the disease statement including all the published studies from first November 2019 to 30th June to analyze the contemporary epidemiology, clinical manifestations, risk factor, prognosis, and treatment outcome of COVID-19 associated rhino-orbito-cerebral-mucormycosis. A comprehensive literature search was done in following databases, namely, PubMed, Google Scholar, Scopus, and EMBASE using keywords mucormycosis, rhino orbital cerebral mucormycosis, COVID-19, and SARS-CoV-2 (from November 01, 2019 to June 30, 2021). Our study shows that, while corticosteroids have proved to be lifesaving in severe to critical COVID-19 patients, its indiscriminate use has come with its price of rhino-orbito-cerebral mucormycosis epidemic, especially in India especially in patients with preexisting diabetes mellitus with higher mortality. Corticosteroid use should be monitored and all COVID-19 patients should be closely evaluated/monitored for sequelae of immunosuppression following treatment.

Increased Dysfunctional and Plastic Regulatory T Cells in Idiopathic Orbital Inflammation.

Background: Idiopathic orbital inflammation (IOI) is a disfiguring and vision-threatening fibroinflammatory disorder. The pathogenesis of IOI has not been elucidated. We sought to clarify the regulatory T cell (Treg) distribution and function in patients with IOI. Methods: The frequency, phenotype and function of Tregs were identified by multicolor flow cytometry and in vitro cell functional assays. Plasma and tissue samples were obtained to investigate cytokines, chemokines and their receptors of interest by relative real-time polymerase chain reaction (PCR) and Luminex assays. Results: Compared with healthy subjects, patients with IOI exhibited obvious increases of Tregs in peripheral blood and affected orbital tissues. Circulating Tregs from patients with IOI were significantly more polarized to a Th17-like phenotype with defective regulatory function, whereas orbit-derived Tregs were polarized to a Th2-like phenotype. Furthermore, ST2 expression levels in circulating Tregs and interleukin (IL)-33 mRNA levels in orbital tissues were decreased in IOI. IL-33 restored the suppressive function of Tregs, reduced interferon (IFN)-γ production by Tregs and decreased the activation of orbital fibroblasts (OFs) cocultured with Tregs in IOI. Conclusion: Increased Tregs with proinflammatory and profibrotic polarization were first identified in IOI, suggesting that Treg plasticity and heterogeneity plays an essential role in IOI pathogenesis. Additionally, our study identified a regulatory effect of IL-33 on inflammation and fibrosis in IOI. Reversing the plastic Tregs via IL-33 might be a potential option for IOI patients.

Pseudotumor orbitario relacionado con IgG4 / IgG4-related orbital pseudotumor

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IgG4-positive Cell Quantification Distinguishes Between Inflammatory and Noninflammatory Diseases of the Orbit.

IgG4-related ophthalmic disease (IgG4-ROD) is a rare inflammatory disorder often refractory to corticosteroids and prone to recurrence. IgG4-ROD may frequently lack the characteristic histopathological features seen in other organs. Thus, the criteria for diagnosis of IgG4-ROD relies on elevated IgG4 cells seen on biopsied tissue. Proposed threshold levels of IgG4 to diagnose IgG4-ROD are currently based on a limited understanding of this cell type's presence in the orbit. This study seeks to describe the population of IgG4 in inflammatory and noninflammatory orbital tissues. A tertiary care center's pathology database was searched with keywords "orbit" or "orbital" from 1995 to 2013. Specimens meeting the selection criteria were evaluated, and regions of highest inflammation were identified and immunostained with IgG4 and CD138 antibodies. Immunohistochemical quantification proceeded as previously established by the international consensus criteria. Eighteen cases without a history of orbital inflammation were included as controls and were evaluated as above. Specimens from 68 inflammatory and 18 noninflammatory orbits met the selection criteria. Pathologist interreader correlation coefficient on quantification was >0.70 (P<0.001). The mean IgG4+/high powered field (HPF) and IgG4+/CD138 was 10.3 and 0.1 in inflammatory tissues and 0.5 and 0.01 in noninflammatory tissues, respectively. The spearman rho correlation coefficient between IgG4/HPF and IgG4+/CD138+ was >0.95 (P<0.0001). The mean IgG4/HPF in our study reached previously proposed threshold values for diagnosis of IgG4-ROD, illustrating the need for further discussion regarding diagnostic criteria of IgG4-ROD.

TIMP-1 Mediates Inflammatory and Immune Response to IL-6 in Adult Orbital Xanthogranulomatous Disease.

Purpose: To explore the pathogenesis that TIMP-1 mediated in adult orbital xanthogranulomatous disease (AOXGD), a rare type of non-Langerhans histiocytosis that damages the appearance and quality of life of patientsMethods: We reviewed 22 patients diagnosed with AOXGD based on clinical manifestations and histological analysis, and then investigated the expression of TIMP-1 and IL-6 with q-PCR and IHC in AOXGD tissues and the possible mechanism involved in the induction of TIMP-1 by IL-6.Results: IL-6 and TIMP-1 were significantly increased in AOXGD tissues. IL-6 promoted TIMP-1 production by M1 macrophages by stimulating the phosphorylation of JAK2 and STAT3. Moreover, IL-17 and IFN-γ, the classical markers of Th1 and Th17 cells, were increased in AOXGD.Conclusion: These data implied that the IL6~JAK2/STAT3-TIMP-1 signalling pathway is activated in AOXGD and that adaptive Th1 and Th17 responses are involved in the development of AOXGD.

A pan-inflammatory microRNA-cluster is associated with orbital non-Hodgkin lymphoma and idiopathic orbital inflammation.

Non-Hodgkin orbital lymphoma (NHOL) and idiopathic orbital inflammation (IOI) are common orbital conditions with largely unknown pathophysiology that can be difficult to diagnose. In this study we aim to identify serum miRNAs associated with NHOL and IOI. We performed OpenArray® miRNA profiling in 33 patients and controls. Differentially expressed miRNAs were technically validated across technology platforms and replicated in an additional cohort of 32 patients and controls. We identified and independently validated a serum miRNA profile of NHOL that was remarkably similar to IOI and characterized by an increased expression of a cluster of eight miRNAs. Pathway enrichment analysis indicated that the miRNA-cluster is associated with immune-mediated pathways, which we supported by demonstrating the elevated expression of this cluster in serum of patients with other inflammatory conditions. The cluster contained miR-148a, a key driver of B-cell tolerance, and miR-365 that correlated with serum IgG and IgM concentrations. In addition, miR-29a and miR-223 were associated with blood lymphocyte and neutrophil populations, respectively. NHOL and IOI are characterized by an abnormal serum miRNA-cluster associated with immune pathway activation and linked to B cell and neutrophil dysfunction.

The treatment outcomes in IgG4-related orbital disease: a systematic review of the literature.

IgG4-related disease (IgG4-RD) is an immune-mediated systemic fibro inflammatory disease. Treatment of IgG4-related orbital disease (IgG4-ROD) is often indicated to relieve the symptoms and to prevent complications. For IgG4-ROD, no international formal treatment guidelines are available and the optimal treatment strategy is uncertain. In this systematic review, we describe the efficacy of conventional and biologic disease-modifying antirheumatic drugs (DMARDs) in IgG4-ROD. A systematic search of Embase, Medline, Web-of-Science, PubMed publisher, Cochrane and Google Scholar was performed for treatment outcomes in IgG4-ROD. Relevant articles on treatment of IgG4-ROD were retrieved to last date of inclusion 3 January 2018. The following inclusion criteria were used: articles in English or English translation, studies evaluating the use of DMARDs (conventional and biologic) in the treatment of IgG4-ROD. Meta-analysis and review articles were excluded. A final selection after full-text evaluation was made by independent reviewers, based on treatment of IgG4-ROD with DMARDs and the availability of treatment outcomes. With this systematic review, we identified 35 studies and case reports/series on IgG4-ROD, describing 95 patients, treated with conventional and/or biologic DMARDs. The success of conventional DMARDs varies between 36% and 75% in patients with IgG4-ROD, while rituximab is successful in the majority (93%) of the patients. Based on this systematic review, rituximab is the most effective DMARD in IgG4-ROD, while the efficacy of conventional DMARDs is limited. We propose early initiation of rituximab in case of refractory and organ- or life-threatening disease.

IGG4-RELATED OPHTHALMIC DISEASE PRESENTING AS CHOROIDAL AND ORBITAL LESIONS.

PURPOSE: To report a case of IgG4-related ophthalmic disease (IgG4-ROD) which presented as choroidal and orbital lesions. METHODS: Case report. RESULTS: A 64-year-old man presented with left eye photopsias and a history of IgG4-related perirenal fibrosis. Fundoscopic examination showed multiple bilateral yellow choroidal lesions, and optical coherence tomography showed multiple choroidal lesions. Magnetic resonance imaging of the orbits showed an enhancing lesion present circumferential to the optic nerve, but greater medially, abutting the posterior surface of the left globe. Workup for infectious, autoimmune, and malignant etiologies was negative, and the patient has responded well to treatment with rituximab. CONCLUSION: IgG4-related disease is a systemic fibroinflammatory disease, which often presents in another location, as in our patient. In cases of uncertain choroidal and orbital lesions, a thorough workup for other etiologies is indicated, and lymphoma must be ruled out. Steroids are the mainstay of treatment for IgG4-ROD, however, small case series and our patient responded well to rituximab. To our knowledge, this is the first reported case of choroidal and orbital lesions secondary to IgG4-ROD.

[Clinical analysis of patients with orbital nonspecific inflammatory response diseases whose CT or MR images show enlargement of the infraorbital nerves].

Objective: To discuss the clinical features, imaging features, pathological patterns, treatment principles and prognosis of the orbital nonspecific inflammatory response diseases patients whose CT or MR images show enlargement of the infraorbital nerves. Methods: A retrospective case series study. Seven orbital disease patients who were treated at Tianjin Medical University Eye Hospital between March 2013 and May 2017 were included. All patients, imaging pictures showed enlargement of the infraorbital nerve. The medical histories, clinical featuers, imaging features, pathologies, serological examinations, therapeutic processes and prognosis were collected and analyzed. Results: The 7 patients included 4 males and 3 females aged from 55 to 68 years (the average age was 60). Bilateral involvement was present in 5 of 7 patients. The main clinical manifestations include proptosis, increasing of orbital pressure, impairment of visual functions, reduction in ocular motility, facial sensation, periocular ache, involvement of lymph node and salivary gland, etc. CT results showed enlargement of infraorbital nerve, accompanied with or without the destruction of bone. The inflammatory response may involve with extraocular muscles and lacrimal glands, or were shown as lesions with irregular shape and blurred borders. The MR images generally showed equal T(1) and equal T(2) signal, accompanied with evident enlargement of the infraorbital nerve. Of all the 7 patients, 6 underwent operation, and the pathology confirmed that 2 of the 6 were involved with inflammatory pseudotumors and the rest 4 were involved with IgG4-related ophthalmic disease (IgG4-ROD). The level of IgG4 in the serum were detected for 4 patients, the results of 3 were high and the other was normal. Of all the 7 patients,1 patient underwent conservative treatment, but disease recurred for several times, and the serum IgG4 level for the patient was higher than normal;1 inflammatory pseudotumor patient was cured completely only by surgery, and has a favourable prognosis; 1 IgG4-ROD patient accepted glucocorticoid, surgery, radiotherapy and chemotherapy, but disease recurred several times; The rest of the patients accepted glucocorticoid and operation, 2 were sensitive to glucocorticoid, 2 were not sensitive, and 1 involved with recurrence. Conclusions: If orbital nonspecific inflammation response was accompanied with enlargement of infraorbital nerve, it is suggested that patient is more likely to be involved with IgG4-ROD;Pathology and serological tests can be used for the diagnosis of IgG4-ROD, however treatment effect appears to be poor for most patients, and patients prone to relapse. (Chin J Ophthalmol, 2018, 54: 515-519).

IgG4-related orbital disease. / Enfermedad orbitaria relacionada con Ig-G4.

CASE REPORT: The case is presented of a 64-year-old woman with bilateral palpebral swelling and dacryoadenitis, exophthalmos, and a history of chronic rhinitis and asthma. An increase in serum IgG4 was observed, and an incisional biopsy of lacrimal glands was performed, which showed fibrosis and a lymphoplasmacytic infiltrate with IgG4 producing cells. DISCUSSION: Orbital involvement in IgG4-related disease is frequent. Bilateral dacryoadenitis is the most common manifestation. Histopathology is essential for the diagnosis and to exclude malignancy.

Ocular presentation of myasthenia gravis: A natural history cohort.

INTRODUCTION: There are limited data on the natural history of untreated myasthenia gravis (MG) with ocular presentation. METHODS: We analyzed 93 patients from symptom onset who presented to the Birmingham Midlands Eye Centre (BMEC) between January 2004 and July 2015. We used multiple stepwise logistic regression to identify predictive factors of generalization and Kaplan-Meier analysis on time to generalization. RESULTS: Forty-six percent of patients developed generalized symptoms during the study period. Median time to generalization was 7 months. Time to generalization was earlier in patients seropositive for acetylcholine receptor (AChR) antibody (median 5 months vs. 21 months, P < 0.0001) and bilateral ptosis at onset (P = 0.015). Multivariate analysis identified AChR seropositivity [hazard ratio (HR) 5.03; 95% confidence interval (CI) 1.48-17.14; P = 0.001] and disease onset < 50 years (HR 3.58; 95% CI 1.18-10.90; P = 0.035) as risk factors for generalization. DISCUSSION: As patients were steroid-naive before generalization, our cohort approximated the natural history of the condition. Muscle Nerve 57: 622-627, 2018.

IgG4-related orbital disease masquerading as thyroid eye disease, vice versa, or both?

A 40 year-old male presented after one year of unilateral, progressive, steroid-responsive, orbital inflammatory disease causing proptosis, extraocular muscle (EOM) restriction, and compressive optic neuropathy. The development of anti-thyroidal antibodies prompted the diagnosis of thyroid eye disease (TED); however, the prolonged active phase, remarkable reversibility of ophthalmic features with high-dose corticosteroids, unilaterally of disease, uncharacteristic EOM involvement (including both obliques), and the absence of autoimmune thyroid disease provoked consideration of alternative diagnoses. Inferior oblique biopsy stained positive for IgG4 with histologic features atypical of TED. The patient received rituximab for presumed IgG4-related orbital disease (IgG4-ROD) with subsequent reversal of compressive optic neuropathy, near complete resolution of EOM restriction, and improved proptosis, the latter two of which are not routinely anticipated in advanced TED. The possible role for B-cell depletion in both TED and IgG4-ROD suggests a degree of overlap in the underlying immune-related pathophysiology that is yet to be defined.

Treatment of Pediatric IgG4-Related Orbital Disease With TNF-α Inhibitor.

The authors describe a 9-year-old female who presented with swelling, proptosis, and tenderness of the right upper eyelid and MRI imaging demonstrating right lacrimal gland enlargement. After failing treatment with corticosteroids, the patient underwent a biopsy that was consistent with IgG4-related orbital disease. She was subsequently successfully treated with adalimumab (TNF-α inhibitor). This is the first case report of the successful use of a TNF-α inhibitor for the treatment of IgG4-related orbital disease in a child.

Usefulness of Flow Cytometry in Diagnosis of IgG4-Related Ophthalmic Disease and Extranodal Marginal Zone B-Cell Lymphoma of the Ocular Adnexa.

BACKGROUND/AIM: Although flow cytometry (FCM) is used to evaluate cell surface markers of various leucocyte populations quantitatively, little is known about the usefulness of FCM in lymphoproliferative disorders of the ocular adnexa. The aim of this study was to disclose results of FCM, which were compared among IgG4-related ophthalmic disease (IgG4-ROD), idiopathic orbital inflammation (IOI), and extranodal marginal zone B-cell lymphoma (EMZL). MATERIALS AND METHODS: This is a retrospective observational study. Sixty-nine tumors comprising of 16 IgG4-ROD, 24 IOI, and 29 EMZL were enrolled in the study. All tumors, surgically excised, were diagnosed based on histopathology, immunoglobulin (Ig) heavy chain gene rearrangement, and FCM. In FCM, the percentage of T-cell markers (CD2, CD3, CD4, CD5, CD7, CD8), B-cell markers (CD10, CD19, CD20, CD23), NK cell marker (CD56) and cell surface kappa/lambda was searched based on medical records. Ig light chain restriction was evaluated from results in kappa/lambda deviation by FCM. RESULTS: The percentage of CD2, CD3, CD4, CD7, and CD10 was significantly higher in IgG4-ROD/IOI than EMZL (p<0.05 in every factor). In contrast, CD19 and CD20 percentages were significantly greater in EMZL than IgG4-ROD/IOI (p<0.01). There was no significant difference in any marker between IgG4-ROD and IOI. Kappa-positive cells were significantly greater in EMZL than IgG4-ROD/IOI (p<0.05). In kappa/lambda deviation, false-positive was noted in 3 (7.5%) benign IgG4-ROD/IOI and false-negative was observed in 10 (34.5%) EMZL cases. Sensitivity and specificity of Ig light chain restriction were 65.5 and 92.5%, respectively. CONCLUSION: Analyses of cell surface markers using FCM were useful in differentiating EMZL from IgG4-ROD/IOI. Sensitivity of Ig light chain restriction was relatively low in diagnosis of EMZL using FCM.

Clinical characteristics of inflammatory ocular disease in anti-neutrophil cytoplasmic antibody associated vasculitis: a retrospective cohort study.

Objective: To characterize the clinical correlates and outcome of inflammatory ocular disease (IOD) among patients with ANCA-associated vasculitides (AAV). Methods: Medical records of potential cases of AAV seen at Mayo Clinic from 2003 to 2013, inclusive, were reviewed to identify confirmed cases meeting the diagnosis of AAV using the Chapel Hill Consensus Conference 2012 descriptors. Records of confirmed cases of AAV were then further reviewed for IOD, and clinical characteristics, treatment and outcomes abstracted. Results: A total of 1171 confirmed cases of AAV were identified of which 183 patients (mean age 49.0 years; 51% female; 95% Caucasian) had IOD. The most common manifestation of IOD was injection of the eye (57%) followed by eye pain (46%) and visual acuity loss (18%). Scleritis was the most common type of IOD (22%) followed by episcleritis (21%), orbital inflammation (18%), lacrimal duct stenosis (10%) and uveitis (9%). Oral glucocorticoids were used to treat IOD in the majority of patients (96%). CYC and rituximab were the most frequently used immunosuppressive agents (54 and 36%, respectively). Of those with orbital inflammation, 52% underwent therapeutic surgical intervention. Clinical remission of IOD was achieved in 91% of patients but relapses were seen in 23%. Significant visual acuity loss was observed in only six patients. Conclusion: IOD is a common manifestation of AAV and seen in about 16% of patients with AAV. Scleritis, episcleritis and orbital inflammation are the most common subtypes. Most patients respond well to glucocorticoids and immunosuppression, but relapse of IOD is common.