We herein present a case of bilateral asymmetric choroidal, RPE- and outer retinal alterations, accompanied by conjunctivitis and vitritis, preceded by a mild SARS-CoV-2-positive respiratory infection two months after uncomplicated ISBCS in a non-diabetic, kidney transplant recipient. This constellation of findings was followed, at a later stage, by clinical signs of inner retinal ischemia without persistent visual decline.
Despite being a primarily respiratory disease, COVID − 19 has been associated with a systemic inflammatory syndrome as well as a hypercoagulable state, predisposing to thromboembolic complications such as pulmonary embolism, deep vein thrombosis, acute coronary syndrome, ischemic and hemorrhagic strokes, transient ischemic attacks and cerebral venous thrombosis [29]. Regarding blood supply of the eye there is evidence suggesting a higher likelihood of retinal microvasculopathy in the setting of COVID-19 [11]. Although the mechanism of microvasculopathy remains poorly understood, angiotensin-converting enzyme 2 (ACE-2) receptors found in the retina and choroid, are believed to bind SARS-CoV-2 spike protein and facilitate transmission and cell entry of the virus [30].
The term thrombo-inflammation is used to best describe the cytokine- and complement-mediated endothelial cell injury [31–33] (dysfunction, apoptosis [34] or direct viral invasion [35])and platelet activation [36] with subsequent local thrombus formation, which in turn, together with increases vascular permeability, has been reported as early hallmark of organ damage in COVID-19 [37]. The role of complement-activation and the induced inflammatory cascade driven by a so-called “cytokine storm” may be complementary to the direct impact of the viral infection and replication to the target organs. However, in our case, the impact of a primarily inflammatory process calls for further investigation in view of our patient’s triple immunosuppressive regime. Unfortunately, one may only assume that the effect of direct coronavirus invasion in the ocular tissues is to be blamed for the abovementioned clinical and imaging findings.
We cannot overlook the fact that a mild respiratory illness was followed by of number of diverse ocular clinical signs. As a matter of interest, microvascular perfusion deficits have been described in individuals, without significant comorbidities, who have recovered mild or even asymptomatic COVID-19 infections [7,16,17]. In a cohort of young patients, 11,6% had retinal microvascular signs [38]. However, preexisting medical conditions such as hypertension and renal dysfunction, in patients with COVID-19 are considered to further increase the risk of microvascular impairment. Without any doubt, neither obesity nor underlying sleep apnea, are insignificant risk factors for vascular disease, further increasing the likelihood of microvascular abnormalities.
Kidney transplant recipients (KTRs) are considered to be at increased risk of adverse COVID-19 outcomes and need for hospitalization due to underlying comorbidities and immunosuppressed status. Even mortality rates appear to be higher compared to age-matched population [18]. According to a recent study among approximately 4000 hospitalized, non-KTRs, COVID-19 patients in the USA, less than one-third had full recovery of kidney function by the time of discharge[21]. Extrapolating these data to KTR-population raises concern about renal graft function and survival both in the acute stage and into the long-term. A prospective, single-center cohort study that evaluated the outcomes of 104 KTRs following acute COVID-19 reported that only 11.53% were symptom-free and without any laboratory abnormalities during the first 2 months [20], suggesting that post-COVID-19, temporary, renal allograft abnormalities are not uncommon, although kidney function did return to baseline in most patients. It is noteworthy that only 2 patients (1.9%) remained dialysis dependent. Having said that, we need to highlight that dialysis and in a similar manner transplant recovery, may have a direct impact on ocular parameters such as choroidal thickness [39], by restoring fluid retention, decreasing body fluid volume and optimizing its composition, namely colloid and interstitial osmotic pressures [40]. Moreover, lower blood pressure is to be anticipated. Ishibazawa et al. have previously described that hemodialysis decreases choroidal thickness as measured with spectral domain (SD)-OCT [22]. In addition, Hwang et al. concluded that both central subfield thickness and subfoveal choroidal thickness significantly decreased in patients undergoing dialysis for the first time [23]. A number of studies have shown similar results [41,42] supporting that altered ocular fluid dynamics and subsequent choroidal congestion may be directly linked to temporary renal dysfunction. Similarly, we find it highly likely that our patient experienced, to some extent, a transient renal impairment, despite the normal findings during late nephrology consultation, that may explain, or at least contribute to the appearance of a congested choroid.
The main feature of the so-called “Pachychoroid Disease Spectrum” (PDS), is the prominence of congested outer choroidal layers, underlying an area of reduced or absent choriocapillaris. In addition to inner choroidal attenuation, outer nuclear layer (ONL) thinning has been observed [43]. Choroidal venous dilation and hyperpermeability are angiographic key features of PDS, best seen in indocyanine green (ICG) studies. Moreover, dilated vessels in Haller’s layer may be seen with Enhanced Depth Imaging (EDI) in spectral-domain (SD) OCT and Swept-Source OCT, allowing for more detailed imaging of outer choroid. Unfortunately, in our case, only standard SD-OCT images were available, thus accurate measurements of choroidal thickness cannot be obtained. Nevertheless, we can safely demonstrate the presence of increased outer choroidal vascular caliber.
Phenotypes associated with PDS can be divided in exudative, neovascular and atrophic disease. Our patient presented features compatible with Pachychoroid Pigment Epitheliopathy (PPE), often considered a precursor or forme fruste of Central Serous Chorioretinopathy (CSC) is characterized primarily by choroidal thickening and RPE changes such as focal hyperplasia, small pigment epithelial detachment (PED), subretinal drusenoid deposits (pachydrusen), RPE irregularity and atrophy. Uncomplicated PPE is typically asymptomatic. The presence of SRF signifies decompensation of the RPE barrier and a clinical diagnosis of CSC as seen in the temporal macular of our patient’s right eye.
The presence of pachyvessels associated with choroidal hyperpermeability, without apparent inflammation, can be observed or exacerbated in the context of COVID-19 [25]. A cross- sectional observational case-control study of patients recovered from COVID-19 reported that dilated choroidal vessels and retinal pigment epitheliopathy were evident in 68% and 6.6% respectively [44]. The role of the renin-angiotensin-aldosterone system (RAAS) on PDS has been previously described [45,46]. As mentioned above, SARS-CoV-2 binds ACE-2 receptors, thus a relationship between these diseases can be speculated and COVID-19 may be proposed as a new etiology for PDPS. This fact can be of paramount importance in a patient with underlying renal disease, where RAAS imbalance is not only more likely to happen, but to a greater extent and with a greater impact as well. However it remains unclear whether the choroid, one of the most highly vascularized tissues in the body, is involved directly in the process of SARS-CoV-2 infection or during the cytokine storm thereafter.
A striking feature of the OCT images of our patient was the irregular, hyper-reflective lesions located in the OPL, as well as between the PRE and the EZ. Marinho et al. first described hyper-reflective lesions in all retinal layers [26]. However Vavvas et al. [47] soon thereafter, argued that these bands, most likely, correspond to abnormal and prominent vessels, indicating vascular involvement (i.e. microthrombosis and vasodilation) associated with SARS-CoV-2 infection. This hypothesis seems less likely to explain outer retinal hyper-reflectivity. Such bands in outer retinal layers have been noted in the setting of COVID-19 [44], suggesting an inflammatory or ischemic process originating from retinal deep capillary plexus (DCP) or the choriocapillaris. When it comes to the latter we have already referred to inner choroidal attenuation with subsequent ischemia, seen as early hypofluorescence in ICG angiography, as a result of choroidal congestion in PDS. On the other hand, DCP ischemia is considered to, at least partly, explain the clinical entity of Acute Macular Neuroretinopathy (AMN), with prominent hyperreflective lesions at the level of outer plexiform and outer nuclear layer (OPL-ONL), corresponding EZ disruption and residual ONL thinning [48,49]. AMN is a primarily ischemic manifestation that can be preceded by both viral infection and vaccination [50,51]. An imbalance of the renin-angiotensin-aldosterone system (RAAS) leading to vasoconstriction has been postulated [52–54] which can be in accordance with one of the proposed mechanisms of PDS in COVID-19 patients as mentioned above. AMN typicaly presents with acute-onset central or paracentral scotoma. In the absence of such symptoms, we may assume that vitritis solely accounted for blurry vision in our case.
Cotton wool spots have been reported in the context COVID-19-associated microvasculopathy [11,26] and their presence has been proposed as an indicator of inner retinal ischemia, with normal visual acuity and no evidence of intraocular inflammation. Interestingly, CWS in our case became apparent only at after all other signs of microangiopathy had already started to subside.
Acute conjunctivitis is the most common [55] and not infrequently the first [56,57] ocular manifestation among individuals infected with SARS-CoV-2. On the other hand, there is lack of reports and existing literature on vitritis, mostly comprised of case reports [58]. It is unclear whether having undergone uncomplicated ISBCS two months ago could have triggered, to some extent, this uncommon, inflammatory reaction.
There are some limitations in our study. First, we are lacking fluorescein angiography images that were done elsewhere and reported without leakage or signs of inflammation. A careful review of the images could have revealed varying degrees of hyper- and hypo-fluorescence that can be compatible with PDS and PPE. Moreover, choroidal hyperpermeability and venous dilation associated with PDS are best seen with ICGA imaging, thus rendering it the gold standard imaging modality when such a suspicion arises. In addition, a detailed study of DCP- and choriocapillaris scan segments in OCTA, would be expected to show perfusion deficits and reduced vessel density. Unfortunately, none of the above mentioned imaging techniques was available at the time of this report.
Another limitation of this report is the lack of baseline structural OCT at the time of first presentation, that would most likely confirm the absence of pachyvessels and RPE irregularities. Should they have been present before SARS-CoV-2 infection, then an exacerbation during or shortly his viral illness would have been anticipated.
Finally, it remains unclear whether topical treatment with dexamethasone 0.1% drops had some additional effect on top of the pre-existing immunosuppression regimen or the clinical improvement can be solely attributed to COVID-19 natural course.
In conclusion, the concurrent appearance of numerous, seemingly unrelated, phenotypes could possibly fit in the expanding spectrum of clinical manifestations of COVID-19. Although the exact aetiology remains unclear, various pathogenic mechanisms such as inflammation, microangiopathy, endothelial injury, renal dysfunction, RAAS imbalance, choroidal congestion, DCP- and choriocapillaris ischemia seem to play role. Previous renal transplant as an underlying systemic comorbidity in our patient can both increase the risk of vascular complications and add to the significance of this case report in the current literature.