Case report: A case of Acute Macular Neuroretinopathy secondary to Influenza A virus during Long COVID

Ocular abnormalities have been reported in association with viral infections, including Long COVID, a debilitating illness caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). This report presents a case of a female patient diagnosed with Acute Macular Neuroretinopathy (AMN) following an Influenza A virus infection during Long COVID who experienced severe inflammation symptoms and ocular complications. We hypothesize that the rare occurrence of AMN in this patient could be associated with the immune storm secondary to the viral infection during Long COVID.


Introduction
Acute Macular Neuroretinopathy (AMN) is a rare condition that was first described by Bos and Deutman, and it is characterized (1) by subacute paracentral scotoma and damage to the outer retinal layers.It is widely agreed among scholars that AMN has been associated with various vascular factors (2), viral infections (3), and the use of oral contraceptives (1).With the outbreak of Coronavirus Disease 2019 (COVID- 19), an increasing number of patients have experienced diverse symptoms (4) as adverse outcomes following Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection (5).Interestingly, the incidence (6) of AMN has significantly risen following the COVID-19 outbreak.Although the precise mechanism of retinal diseases caused by SARS-CoV-2 remains unknown, several scholars have proposed hypotheses for infection pathogenesis.These hypotheses suggest that SARS-CoV-2 targets cells, enhances binding to the Angiotensin-Converting Enzyme 2 (ACE2) receptor, triggers the release of proinflammatory factors, causes vascular endothelial dysfunction (7), and eventually leads to a systemic cellular immune storm (8)(9)(10).Notably, ACE2 receptors are expressed in retinal structures (6).Influenza virus infection is a common cause of respiratory tract diseases in humans.Moreover, severe Influenza A Viruses (IAVs) infection can lead to the production of a large number of chemokines and inflammatory factors, resulting in a severe immune storm (11).Additionally, unusual cases of secondary infections with violent immune inflammation caused by influenza viruses post SARS-CoV-2 infection warrant further attention.

Case description
A 49-year-old Chinese woman was admitted to our hospital, presenting with a 3-day history of paracentral scotoma in both eyes.
An Influenza A virus infection was confirmed through antibody detection from a nasopharyngeal swab.She reported experiencing a viral prodrome 1 week prior to the onset of visual symptoms, which included hyperpyrexia.Laboratory examinations revealed elevated levels of white blood cells, neutrophil percentage, hypersensitive Creactive protein, and procalcitonin, indicating severe systemic inflammation.The patient had completed a full course of the COVID-19 vaccine and had not received the influenza vaccine.She had been suffering from fatigue and memory loss since she contracted SARS-CoV-2 3 months prior.Before seeking medical attention, she had taken oral oseltamivir for 5 days.The bestcorrected visual acuities in both eyes were 20/50, with slit-lamp examinations revealing no abnormalities.China CDC has reported that all the random gene samples collected in China between December 2022 and January 2023 were identified as Omicron strains.Optical coherence tomography (OCT) conducted at a local hospital revealed macular edema (ME) in both eyes (Figure 1A).Classic wedge-like lesions were detected in infrared reflectance (IR) and fundus photography at our hospital (Figures 2A, B), but weak reflex lesions were unremarkable in Autofluorescence (AF) (Figure 2D).Spectral-domain optical coherence tomography (SD-OCT) indicated hyperreflectivity at the retinal outer layer (Figure 1B), which is consistent with paracentral acute middle maculopathy (PAMM) (Figure 2C).Further examinations using fundus fluorescein angiography (FFA) and optical coherence tomography angiography (OCTA) were conducted.FFA results showed preretinal arteriolar obstruction in both eyes, with perivascular fluorescence shielded in the early angiography, and perivascular fluorescence leakage and mild telangiectasia in the later stage, corresponding to the lesions in the IR image (Figures 2E, F).OCTA revealed an incomplete macular arch ring structure and hypoperfusion in both the superficial capillary plexus (SCP) and the deep capillary plexus (DCP) (Figure 2G).The patient was diagnosed with AMN  secondary to Influenza A. Following treatments of oral Oseltamivir, glucocorticoid anti-inflammatories, and traditional Chinese medicine, the patient reported a slight persistent scotoma.A 1month follow-up showed the presence of a microcapsule cavity in the retina of both eyes (Figure 1C) and significant repair of the retinal structure (Figure 1D).

Discussion
Numerous studies have demonstrated that female patients (12)(13)(14) are more susceptible to complications associated with Long COVID (LC).This susceptibility could potentially be attributed to factors such as active centromeric features (15), variations in sex hormone levels (16), persistent deficiencies in dendritic cells, and dysbiosis (12).However, further investigation is required to ascertain the significance of these differences.Recent research has further uncovered that residual SARS-CoV-2 can persist in various organ systems (17)(18)(19)(20), thereby increasing oxidative stress response (21) and cytotoxic effects (7), which may contribute to LC development.The prevalence of LC is estimated to exceed 10% (22,23), with some reports suggesting that it could impact 50-70% (24, 25) of hospitalized patients.Neurological manifestations (26) of LC encompass fatigue (27,28) and memory (29) impairment.Studies have also disclosed long-term alterations in the rigidity of blood cells and vessels (30), potentially affecting oxygen transport and reducing blood flow density in LC patients during follow-up appointments (26).Additionally, as COVID-19 prevention and control measures are relaxed (31), the incidence of influenza infection has rebounded to pre-pandemic levels (32).Influenza virus infection may cause a delayed innate immune response (33).This, in turn, may disrupt the biphasic immune response, triggering virus-independent mechanisms (34,35) following immune escape.These mechanisms, including immune dysregulation and vascular inflammation, could potentially exacerbate LC symptoms.Intriguingly, research has indicated that both SARS-CoV-2 and all three subtypes (36) of IAVs can activate the Retinoic Acid-Inducible Gene I (RIG-I) pathway (37,38), leading to the formation of Neutrophil Extracellular Traps (NETs) (39).This suggests a potential similarity between the two viruses.RIG-I receptors, found in various cells such as dendritic cells (40), retinal Müller cells (41), and endothelial cells (42), play a pivotal role in retinal inflammation and the production of Type I Interferon (IFN) immune responses by retinal pigment epithelium (RPE) (43).Notably, several studies have identified a potential link between IAVs and eye disorders (44)(45)(46).Moreover, IAVs have been found to replicate in RPE cells (45,46).Furthermore, it has been observed that LC can potentially impair the function and structure of dendritic cells (47), leading to adaptive immune response disorders that exacerbate immune disorders and microcirculatory vascular dysfunction (48).Some researchers propose that SARS-CoV-2 infection can disrupt the peripheral immune system, leading to the release of cytokines and resulting in long-term chronic low-grade inflammation (14), oxidative stress (49), and tissue damage (39).Studies on primary care patients (50) with COVID-19 have found that neutrophil levels, which are chronically affected by LC, participate in the cytokine storm through activated inflammatory vesicles (51).The persistence of NETs in LC suggests a potential risk of long-term imbalance of the innate immune response and low levels of the prothrombotic state (39, 52).The activation of neutrophils indicates their involvement in immune thrombosis, while NETs play a crucial role in the mechanism of thrombosis (53).
In the context of the innate immune response, the RIG-I receptor, a Pattern Recognition Receptor (PRR), plays a crucial role in recognizing viral infections (54).RIG-I is responsible for the recognition of viral RNA through the ubiquitination (55) of long non-coding RNAs (lncRNAs), aerobic glycolysis, and phosphorylation.This recognition triggers a cascade reaction between RIG-I/Melanoma Differentiation-Associated Protein 5 (MDA5) and Mitochondrial Antiviral Signaling Protein (MAVS), promoting the production of IFN and coordinating the antiviral immune response (56-58).Additionally, RIG-I is responsible for the secretion of inflammatory factors and cytokines such as Interleukin-6 (IL-6), Interleukin-8 (IL-8), and Vascular Endothelial Growth Factor (VEGF) (59).However, the regulation of the immune response by RIG-I is not stable, necessitating further studies to clarify the mechanisms involved.
The RIG-I pathway of the innate immune system primarily initiates the signaling cascade during the early stage of viral infection (60).However, severe infections and hyperthermia can cause a rapid depletion of retinol and a reduction in retinoic acid levels (61, 62).Consequently, the RIG-I pathway becomes blunted and eventually collapses due to this depletion (63).This disruption (62) in the production of Type I IFN results in the immune defense mechanism transitioning into adaptive immunity, leading to the activation of a large number of centrocytes.This activation triggers the generation of cytokine storms through the over-discharge pathway of the nuclear factor kappa B (NF-k B) (64), causing a condition known as "Retinoic Acid Depletion Syndrome" (RADS) (64).RADS leads to vascular dysfunction, tissue damage, and the generation of reactive oxygen species (ROS) (65).Therefore, we hypothesize that the low-grade inflammatory state induced by LC, coupled with the hyperthermia caused by acute IAV infection, led to RADS and the activation of NETs.This activation, in turn, stimulated the release of proinflammatory factors, leading to retinal vascular endothelial dysfunction.This ultimately resulted in hyperreflectivity and severe ME in the outer structures of the retina.However, further studies are needed to confirm the link between the relevant pathological mechanisms and the severe AMN and ME in this patient.
Given the limited research on AMN, our study may be the first to report a case of AMN secondary to IAV during LC.Notably, our research differs from previous reports (44,(66)(67)(68) as we observed early signs of binocular macular edema and disorganization of the retinal layer following the resolution of ME.The etiology of AMN is complex and remains to be fully established.Turbeville et al. (3) have postulated that vascular factors may unify infection, inflammation, and ischemia in the pathogenesis of this condition.Our reported case may be associated with the microvascular mechanism of AMN.A study (69) conducted by Marc et al. revealed that infections can trigger innate immune responses, which in turn can cause cytotoxicity, dysfunctional angiogenesis, and ME.Furthermore, research (70) on ME secondary to other retinal diseases has indicated that swelling of Müller cells and activated neuroglia can lead to a decrease in Platelet-Derived Growth Factor (PGDF) and the release of pro-inflammatory cytokines such as VEGF through leukocyte-mediated processes.This occurs when the human body is in a state of ischemia or inflammation, and can induce impaired blood-retinal barrier, increased vascular permeability, dysfunctional angiogenesis, accumulation of subretinal fluid, and formation of retinal edema.In fact, similar to Gomel et al. (71), we strongly believe that the possible mechanisms for the ME of the patient may include systemic immune storm such as hyperpyrexia and an increasing index of inflammation.In our case, the patient who had a history of SARS-CoV-2 infection accompanied by long-term fatigue and memory loss.Combined with the positive influenza A test, we suspect that the patient's AMN with PAMM was likely secondary to IAV infection during LC.
PAMM refers to banded hyperreflective lesions (72) in the inner layer of the retina that manifest clinically.Several reports have suggested that PAMM may occur earlier than lesions such as in the Foveal Avascular Zone (FAZ) (73), and it could be an early manifestation of retinal vascular diseases.Multiple studies have revealed that the occurrence of PAMM indicates ischemia (72) of the deep retinal capillaries and impairment of the deep capillary complex, which is likely the main site of progression of retinal ischemia.Influenza virus can cause disturbances in redox and impairments such as anoxia (74, 75), which may explain why the patient experienced retinal inner layer injury, PAMM, and decreased density of SCP and DCP.Additionally, the occurrence of retinal ischemia and PAMM may have prompted the retinal inner layer to develop tiny gaps, which could have been caused by increased levels of extracellular glutamate and inflammation in the retina due to swelling Müller cells (76).Finally, the tiny gaps subsided as the inflammation disappeared and the patient's systemic symptoms improved.
In conclusion, the occurrence of AMN in a patient who had taken oral oseltamivir during the early stages of an Influenza A infection could potentially be attributed to the excessive viral load in the body and the ensuing severe inflammatory reaction.Following a short-term oral corticosteroid treatment, the patient's symptoms were alleviated and the retinal structure restored.However, due to the absence of follow-up in the later stages of this patient's treatment, there is a relative lack of observation of the disease's prognosis.Furthermore, the sample size of this study is small, indicating the need for more data to analyze the clinical impact and mechanism of AMN caused by influenza virus infection during LC.

1 (
FIGURE 1 (A) OCT image of the patient with the paracentral scotoma with oral 3-day oseltamivir, showing the macular edema (red arrowhead) and the hyperreflectivity at the retinal outer layer (yellow arrowhead).(B) the AMN lesions in the outer retinal layer can be found easily (yellow arrowhead) with 1 week of oral oseltamivir.(C) some repair of the microcapsule cavity (red arrowhead) in the retina and the structure of the outer retinal layer 2 weeks of treatment (yellow arrowhead).(D) the retinal structure was obviously repaired at the 1-month follow-up appointment (yellow arrowhead).
FIGURE 2 (A) the wedge-like AMN lesion is classic (yellow arrowhead) and some perivascular cotton plaques (blue arrowhead) in the fundus photograph.(B) IR image showing a wedge-like AMN lesion (yellow arrowhead) and radial weak reflex lesions (blue arrowhead).(C) the SD-OCT image shows the hyperreflectivity at the retinal outer layer (yellow arrowhead) with PAMM lesion in inner retinal layers (orange arrowhead).(D) the AMN lesion is an unremarkable weak reflex lesion (yellow arrowhead), and there is a perivascular weak reflex lesion not detectable (blue arrowhead) in the AF image.(E, F) FFA showed the unremarkable weak reflex lesions (yellow arrowhead) and the perivascular occluded fluorescence (blue arrowhead) at the early stage, then the weak reflex lesion in macula (yellow arrowhead), and the strong perivascular fluorescence at the later stage (blue arrowhead).(G) the OCTA image showed the decreased density of SCP and DCP.