Sudden Vision Loss Heralding Covid-19-Associated Aspergillosis. Report of 2 Cases

Purpose To describe clinical, radiographic, laboratory and cytopathologic findings in 2 patients who developed vision loss due to endogenous aspergillus endophthalmitis during hospitalization for COVID-19 pneumonia. Observations Two unvaccinated sexagenarian male smokers lost vision within one month of contracting COVID-19 pneumonia. Initially, both received high dose steroids, nasal cannula oxygen and remdesivir. Immunomodulators tocilizumab or baricitinib were added during week 2 in case 1 and 2 respectively. Upon presentation after discharge from a post-COVID rehabilitation unit, visual acuities were light perception and hand motion. In both cases, inpatient blood and ocular fluid cultures were negative, serum 1,3-beta-D-glucan was positive, and vitreous cytopathology revealed filamentous fungi and PCR was positive for Aspergillus fumigatus. Large solitary intravitreal fungus balls were debulked in patient 1 and excised in patient 2. Final visual acuities were no light perception and 20/200 respectively. MRI revealed previously unsuspected brain and lung lesions consistent with disseminated aspergillosis in patient 2. Conclusions Vision loss due to fungal endophthalmitis may be the first or only sign of systemic aspergillosis associated with COVID-19 pneumonia. Aspergillosis should be suspected in patients who develop vision loss. Diagnosis limited by negative fungal cultures may be confirmed by vitreous cytopathology and PCR. Systemic imaging for disseminated aspergillosis is indicated. Ultimate visual acuity may depend upon surgical approach

Epistatic Gene-Based Interaction Analyses for Glaucoma in eMERGE and NEIGHBOR Consortium

Primary open angle glaucoma (POAG) is a complex disease and is one of the major leading causes of blindness worldwide. Genome-wide association studies have successfully identified several common variants associated with glaucoma; however, most of these variants only explain a small proportion of the genetic risk. Apart from the standard approach to identify main effects of variants across the genome, it is believed that gene-gene interactions can help elucidate part of the missing heritability by allowing for the test of interactions between genetic variants to mimic the complex nature of biology. To explain the etiology of glaucoma, we first performed a genome-wide association study (GWAS) on glaucoma case-control samples obtained from electronic medical records (EMR) to establish the utility of EMR data in detecting non-spurious and relevant associations; this analysis was aimed at confirming already known associations with glaucoma and validating the EMR derived glaucoma phenotype. Our findings from GWAS suggest consistent evidence of several known associations in POAG. We then performed an interaction analysis for variants found to be marginally associated with glaucoma (SNPs with main effect p-value <0.01) and observed interesting findings in the electronic MEdical Records and GEnomics Network (eMERGE) network dataset. Genes from the top epistatic interactions from eMERGE data (Likelihood Ratio Test i.e. LRT p-value <1e-05) were then tested for replication in the NEIGHBOR consortium dataset. To replicate our findings, we performed a gene-based SNP-SNP interaction analysis in NEIGHBOR and observed significant gene-gene interactions (p-value <0.001) among the top 17 gene-gene models identified in the discovery phase. Variants from gene-gene interaction analysis that we found to be associated with POAG explain 3.5% of additional genetic variance in eMERGE dataset above what is explained by the SNPs in genes that are replicated from previous GWAS studies (which was only 2.1% variance explained in eMERGE dataset); in the NEIGHBOR dataset, adding replicated SNPs from gene-gene interaction analysis explain 3.4% of total variance whereas GWAS SNPs alone explain only 2.8% of variance. Exploring gene-gene interactions may provide additional insights into many complex traits when explored in properly designed and powered association studies

Flow chart explaining all the steps for gene based interaction analysis in discovery (eMERGE) and replication dataset (NEIGHBOR).

<p>Flow chart explaining all the steps for gene based interaction analysis in discovery (eMERGE) and replication dataset (NEIGHBOR).</p

Principal component analysis (PCA) of 5090 samples (glaucoma cases and controls) from eMERGE network.

<p>Eigenvector 1 is on x-axis and eigenvector 2 is on y-axis. Each point is a sample and they are color coded by case and control status.</p

POAG GWAS Results in eMERGE dataset.

<p><b>(A)</b> Manhattan plot shows chromosome and base pair positions on x-axis and -log10 of p-value on y-axis. Each point here represents a SNP. Red line is the genome-wide significance line at 5e-08. Highlighted points indicate annotation of SNPs with previously reported GWAS associated genes. <b>(B)</b> Shows a QQ-plot from GWAS analysis.</p

Heat map representing expression of the unique genes found in the ocular tissue database from GXG interaction results.

<p>Here, the x-axis lists all genes and y-axis lists the names of 10 tissues from the eye. Scale and color intensity represent PLIER values as reported in the ocular tissue database.</p

Synthesis view plot representing unique gene-gene interaction models and their p-values in discovery and replication dataset.

<p>Synthesis view plot representing unique gene-gene interaction models and their p-values in discovery and replication dataset.</p

All replicating gene-gene interactions at LRT p-value <1e-04 for replication dataset.

<p>All replicating gene-gene interactions at LRT p-value <1e-04 for replication dataset.</p

Results from GWAS analysis, showing previously reported gene regions that are known to be associated with glaucoma; the lowest p-value of the gene region in eMERGE GWAS analysis for glaucoma is reported.

<p>Results from GWAS analysis, showing previously reported gene regions that are known to be associated with glaucoma; the lowest p-value of the gene region in eMERGE GWAS analysis for glaucoma is reported.</p

Circular plot representing only unique gene-gene interactions.

<p>Genes are colored as red if they are expressed in eye and as grey if not expressed in the eye. All genes are ordered by chromosome. Links between the genes represent gene-gene interactions that are replicated.</p