Characterization of Retinopathy Among Patients With Yellow Fever During 2 Outbreaks in Southeastern Brazil

Abstract

IMPORTANCE Yellow fever still threatens people in endemic areas, and besides conjunctival icterus, little is known about the ocular changes that occur in these patients. OBJECTIVE To characterize retinal changes in patients with confirmed yellow fever during 2 recent outbreaks of the disease in Minas Gerais, Southeastern Brazil. DESIGN, SETTING, AND PARTICIPANTS This cross-sectional, observational study conducted at a single referral center for infectious diseases in Southeastern Brazil collected data between January 2017 and February 2018 from 94 consecutive patients with suspicion of yellow fever who were eligible for the study. MAIN OUTCOMES AND MEASURES Patients underwent ophthalmic examination. Clinical findings, laboratory results, and occurrence of retinopathy and death during hospitalization were reported, including age, sex, comorbidities, disease severity, serum aspartate aminotransferase level, total bilirubin level, serum creatinine level, arterial lactate level, international normalized ratio, and platelet count at hospital admission. RESULTS In total, 64 patients were included who had received a confirmed diagnosis of yellow fever, with a median (interquartile range) age of 47 (38-56) years, and 12 patients (19%) were women. Twenty eyes (16%) of 13 patients (20%) had retinopathy at the same time as yellow fever. The most common fundus changes among the 20 eyes were retinal nerve fiber layer infarcts (11 [55%]), superficial hemorrhages (7 [35%]) and grayish deep lesions (6 [30%]), possibly at the level of the outer retina or choroid. Aspartate aminotransferase levels higher than 3000 U/L (odds ratio [OR], 14.2; 95% CI, 3.5-77.8; P < .001), total bilirubin levels higher than 2.3 mg/dL (OR, 20.0; 95% CI, 4.4-159.7; P < .001), serum creatinine levels higher than 2.0 mg/dL (OR, 8.2; 95% CI, 2.1-36.0; P = .003), arterial lactate levels higher than 17.1/mg/dL (OR, 4.6; 95% CI, 1.1-19.0; P = .03), platelet count lower than 94 × 10 3 /μL (OR, 7.8; 95% CI, 1.8-59.9; P = .004), and classification of disease as severe (OR, 11.7; 95% CI, 2.0-301.0; P = .003) were associated with retinopathy. Arterial hypertension, diabetes, international normalized ratio, and death were not associated with retinopathy. CONCLUSIONS AND RELEVANCE Retinopathy was present in 20% of patients with yellow fever and appeared to be associated with more severe systemic disease. Retinal nerve fiber layer infarcts and superficial hemorrhages, but not the grayish deep lesions, resembled those associated with other flavivirus (eg, dengue virus) infections. The clinical relevance of these findings may warrant further investigation.

Thrombocytopenia in Virus Infections

“…Despite this, only mild thrombocytopenia was present, with a median platelet count of 74 × 10 9 /L, indicating platelet consumption as a result of hemorrhage, rather than thrombocytopenia-induced bleeding [ 100 ]. This is supported by the presence of ischemic and hemorrhagic microvascular pathology upon fundoscopic examination of hospitalized yellow fever patients, which correlate with the degree of thrombocytopenia present, disease severity and markers for renal and hepatic disease [ 101 ].…”

Seeking clarity on retinal findings in patients with COVID-19

“… 3 Some of these retinal changes might even serve as non-invasive biomarkers of systemic disease, similar to what has been shown for yellow fever. 4 …”

“…Careful interpretation of novel imaging observations is essential in this context. In addition to microangiopathic changes (indicated by retinal cotton wool spots and microhaemorrhages), which are also seen in other viral conditions, 3 , 4 Marinho and colleagues 1 report hyper-reflective lesions on optical coherence tomography at the level of the retinal ganglion cell and inner plexiform layers. After carefully analysing these images, we argue that these changes represent oblique sections and cross-sections of perifoveal retinal blood vessels.…”

SARS‐CoV‐2 and COVID‐19 for the ophthalmologist

“…As an example, the combined effect of the cytokine storm, vascular endothelial dysfunction and hypercoagulability in COVID‐19 105, 106 may be associated not only with retinal microangiopathic changes, but also occlusion of the central retinal vessels and/or their branches, and even involvement of the choriocapillaris or of the microvasculature of the optic nerve head 107 . Retinal microangiopathy, including cotton‐wool spots and microhaemorrhages have been reported in patients with COVID‐19, 108‐110 more frequently in those hospitalized with more severe disease, 111 as observed with other viral infections 112 . Increased venular tortuosity and dilation has also been observed 110 .…”

“…On the other hand, despite anecdotal reports of the detection of SARS‐CoV‐2 in intraocular tissue, whether the virus can directly induce intraocular inflammation remains an important issue to be determined 107 . Retinal changes in individuals with COVID‐19, including cotton wool spots, microhaemorrhages and even occlusion of larger retinal vessels and of the choriocapillaris are likely the consequence of microvascular damage and increased thrombogenesis, in the context of a systemic hyperinflammatory response, as also observed in other bodily organs, and in other viral infections, including dengue, chikungunya and even yellow fever 112,130,131 . Further prospective and controlled studies on the ocular manifestations of COVID‐19, possibly examining ocular samples and performing multimodal ophthalmic imaging, may shed light on many of the yet unanswered questions surrounding the impact of COVID‐19 on the eye.…”