COVID-19 ocular ndings in paediatric population

Purpose To investigate and describe ocular ndings in COVID-19 paediatric patients. Methods A total of 17 COVID-19 patients aged between 0 and 17 years old were recruited at the Paediatric Hospital of La Paz University Hospital (Madrid, Spain). A complete ophthalmological examination was performed in all patients. Results Of 17 patients, 50% had a known COVID-19 previous exposure. PCR from nasopharyngeal swabs was positive in 35.29%, whereas IgM and/or IgG serology tests were positive in 81%. Clinical manifestations were: 6 COVID-19associated Paediatric Inammatory Multisystem Syndrome (PIMS), 7 pneumonias and 2 cutaneous purpura and/or chilblains. Ocular ndings were ocular hyperaemia (5 patients), as bilateral acute conjunctivitis (3 patients) or unilateral episcleritis (2 patients). Mean best corrected visual acuity was 1/1 in all tested cases. Only one patient, presenting unilateral optic neuritis, had visual symptoms as unilateral inferior temporal quadrantanopsy. Retinal involvement was found in one patient, where ocular fundus exam showed unilateral retinal vasculitis. Conclusion SARS-CoV-2 infection could produce ocular pathology in children, frequently presented weeks after the acute phase of the disease. We should take into account COVID-19 when performing differential diagnosis of children presenting with conjunctivitis, episcleritis, retinal vasculitis and/or optic neuritis, meanwhile this world-wide pandemic lasts.


Introduction
Since December 2019 we are immersed in a declared public health emergency of international concern, caused by the Severe Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2). Children have Since most of them presented with mild forms of acute respiratory infections, the focus was on children with underlying/comorbid disease who concentrated the rare fatalities ( She et al. 2020;Climent et al. 2020).
In children with active COVID-19, the most common clinical manifestations were fever and cough, sometimes accompanied by fatigue, myalgia, rhinorrhoea, sneezing, sore throat, headache, dizziness, diarrhoea, vomiting, and abdominal pain ( She et  The most common ocular manifestation described is conjunctival congestion, although it is rarely mentioned in non-ophthalmology-speci c studies (Li et al. 2020). However, it was present in 1 to 5% of adults consistent with mild follicular conjunctivitis without pseudomembrane formation (Hu et al. 2020 Scarce literature has been published so far regarding ocular ndings in COVID-19 paediatric population. A cross-sectional study performed in Wuhan (China) showed conjunctival discharge and conjunctival congestion as the most common manifestation, and a higher risk of developing ocular symptoms when systemic clinic was present (referencia 35). Therefore, we aim to share our experience with ocular involvement possibly related to COVID-19 paediatric infection in our media.

Materials And Methods
This is a prospective observational, study performed at the Paediatric Ophthalmology Department of La Paz University Hospital (Madrid, Spain) between the 1 st of April and the 1 st of June 2020. Informed consent was obtained from all parents and/or legal tutors of patients involved. Demographic, epidemiological and clinical data were collected from patient's electronic medical records.
All patients underwent a complete ophthalmological examination and detailed anamnesis, that included: best corrected visual acuity (Pigassou or Wecker eye chart based on patient's cooperation), slit lamp examination (Haag-Streit Diagnostics® or handle Keeler® model), ocular fundus exam and, in some cases, optical coherence tomography (OCT; Heidelberg Engineering SPECTRALIS®). When PCR was positive, appropriate safety equipment was used: ltering facepiece mask 2 (FFP2), protective goggles and personal protective equipment. In all cases, the examination room and the devices were disinfected every time a patient was examined, and monodose eye drops were used.

Results
A total of 17 patients aged between 4 and 17 years old were recruited, Table 1 shows demographic data. The mean age was 9.23 years, and the proportion of female patients was 18%. None of them had any relevant systemic or ocular disease previous to the pandemic. Half of patients had a positive epidemiological history for COVID-19, being parents the most frequent known contact. PCR from nasopharyngeal swabs was positive in 6 patients (35%), whereas 14 patients had positive IgG (82%), and 19% had both IgM and IgG positive serology tests. Systemic manifestations were the following: 35% had PIMS, 41% were diagnosed with pneumonia, 12% had chilblains and cutaneous purpura and 12% of them only had red eye. There was only one patient referring visual symptoms, as unilateral inferior temporal quadrantanopsy, who was later diagnosed with unilateral optic neuritis (Case 2).
Mean best corrected visual acuity was 1/1 in all patients. 29% of patients presented red eye and they were diagnosed by slit lamp examination of: mild acute bilateral conjunctivitis (3 patients) and unilateral episcleritis (2 patients) ( Figure.1). Ocular fundus exam was normal in all patients, but in one of them, with unilateral retinal vasculitis, perivascular in ltrates and retinal exudates (Case 1) (12). OCT exam showed preserved macular and optic nerve head architecture in all patients, without any in ammatory signs.
Case 1 was the rst child we explored. He was an 11-year-old patient who arrived at the Paediatric Emergency Department with a 2-weeks history of asymptomatic plaques on his toes, and he was diagnosed of chilblains with SARS-CoV-2 positive IgG antibodies. At that time, concern had raised about potential thromboembolic complications related to COVID-19, and the patient was referred to the Ophthalmology Department, despite being visually asymptomatic and not reporting any ocular complaint. Ocular fundus exam showed retinal vasculitis with perivascular in ltrate and retinal exudates on retinal equator of his left eye.(12) OCT did not show in ammation on macular area. A close follow-up was held, and after two weeks retinal exudates disappeared with no residual signs of atrophy. The patient did not receive any speci c treatment for COVID-19.
Case 2 was a 13-year-old boy, with no previous medical records, who consulted rst for red eye; he was diagnosed with unilateral episcleritis and treated with corticosteroid drops with good response. He returned to the Paediatric Emergency Department 10 days after, due to blurry vision on his right eye. Two members of his family referred possible COVID-19 infection during the previous 3 weeks, but he had remained asymptomatic up to that date. Visual acuity was 1/1 on both eyes and Ishihara test was 21/21 on both eyes. A relative afferent pupillary defect was found on his right eye. Slit lamp exam was normal, as well as ocular fundus and OCT exam ( Figure.2). A computerized perimetry was performed, showing defects on the inferior temporal quadrant with a Visual Field Index (VFI) of 75% and a Mean Defect (MD) of -9.64 Db ( Figure.2). The magnetic resonance image of brain and orbits showed no optic nerve Gadolinium enhancement. A complete laboratory and serology test for bacterial and viral infections was performed (Mycoplasma pneumoniae , Brucella spp., Toxoplasma gondii, Rubella, Cytomegalovirus, Epstein-Barr Vi, SARS-CoV-2V2). They all turned out to be negative, but SARS-CoV-2 IgG which was positive. PCR from nasopharyngeal swabs was negative. Considering the epidemiological situation and the serology test results, the patient was diagnosed with a post-infectious right optic neuritis most likely caused by SARS-CoV-2. An extended oral Prednisone treatment was started. Visual symptoms disappeared within 3 weeks since the debut, with no recurrence thus far.

Discussion
Conjunctivitis was the most frequent nding, especially in patients with PIMS versus those with acute pneumonia. This is a common feature with KD, however and unlike it, no cases of anterior uveitis were diagnosed. Ocular ndings were mainly detected in the convalescence phase of the disease, two children with episcleritis, one with chilblains and retinal vasculitis, and a teenager presenting with optic neuritis. Conjunctival congestion was the main ocular manifestation described in up to 5% of adults during active COVID-19 infection. SARS-CoV-2 has been associated with increased conjunctival secretion, ocular pain, photophobia, dry eye or tearing during a mean time of 6 days (Liu et al. 2018; Chen et al. 2020). Ocular exam ndings were consistent with mild follicular conjunctivitis without pseudomembrane formation (8). We explored seven children admitted with pneumonia. Nor parents or children refer any ocular symptom or sign, and we did not nd any case of red eye among them. Conjunctivitis in adults seemed to be more common in hospitalized patient with severe disease (Wu et al. 2020;Loffredo et al. 2020). This nding suggests that conjunctivitis during the acute phase is rare in children.
In April 2020, alarms were triggered among paediatricians since COVID-19 was linked with a KD-like disease (Deza et al. 2020). KD is a medium vessel vasculitis with predilection for coronary arteries of unknown aetiology that occurs mainly in infants and young children less than 5 years old (Singh et al.  (Shulman 2020). PIMS began to appear approximately 1 month after COVID-19's incidence peak, rather than contemporaneously, in the heavily impacted areas (Shulman 2020). This delay and the frequent SARS-CoV-2 PCR negativity suggest that COVID-19 infection would serve as a delayed trigger for PIMS, following a post-infectious in ammatory process (Shulman 2020). Bilateral conjunctival injection, without exudate and limbus sparing, is one of the main KD diagnostic criteria, together with persistent fever (Singh et al. 2018). It may be seen in up to 89% of patients. The second most common KD ocular manifestation is anterior uveitis, it is usually bilateral, mild and can present keratic precipitates; most frequently appears 1 week after fever onset and recovers within 2-8 weeks without any sequelae ( Ohno et al. 1982). Therefore, ophthalmic examination is usually demanded in children with persistent fever and suspected KD. In this context of PIMS rst cases emerging in Spain, we explored 6 children with the disease between 4 and 13 years of age. 3 of them showed bilateral non-purulent conjunctival injection, but no signs of anterior uveitis or posterior pole involvement were detected in any case. A Korean research group studied the incidence of anterior uveitis in KD, and found that it appeared in 37% of cases. An interesting nding, was that coronary artery dilatation was signi cantly higher in patients with uveitis (27%) compared to patients without it (1.4%) (Choi et al. 2015;). Authors even suggested, that detection of anterior uveitis could lead to earlier diagnosis and treatment of KD before coronary artery lesions were developed. None of our cases showed coronary artery dilatation.
Episcleritis is an uncommon in ammatory condition that is localized to the super cial layers of Tenon's capsule. Diagnosis is based on clinic, as a selective dilation of the super cial episcleral venous plexus in absence scleral involvement, without exudation and conjunctival in ammation. It is a benign, self-limited in ammatory process that usually responds to topical anti-in ammatory agents (Jabs et  Optic neuritis is an in ammatory condition of the optic nerve, that causes visual impairment and is associated to demyelinating in ammatory diseases in most non-idiopathic cases (Lock et al. 2019). Initial visual acuity of optic neuritis, varies from normal to no light perception, although it is usually poor in children. Bilateral involvement and optic disc oedema are more common in children, whereas pain and dyschromatopsia are more likely to be found in adults (Vieira et al. 2017;Good et al. 1992). Viral infections precede optic neuritis in up to two thirds of paediatric patients, even in the context of demyelinating diseases (Morales et al. 2000). This latter setting is designated as parainfectious optic neuritis. It seems to develop more often in prepubescent, teenagers and young adults (Rappoport et al. 2014). Interval from febrile illness to symptom onset ranges from days, in the youngest patients, to weeks in adults; what reinforce the theory that parainfectious optic neuritis is due to an immunologicin ammatory reaction when doesn't happen simultaneously. Visual prognosis tends to be excellent and recurrences are rare ( Rappoport et al. 2014).
In case 2, the most inconsistent nding was the absence of Gadolinium enhancement on the orbit MRI . The visual scotoma appeared a few days after an unilateral episcleritis, and weeks after his family had presented a mild form of COVID-19 infection, which made us suspect we were facing a case of parainfectious optic neuritis. Coronaviruses can cause severe ocular disease in animals, including anterior uveitis, retinitis, vasculitis, and optic neuritis in feline and murine species. However, so far, ocular manifestations described in humans were mild and rare (Seah et al. 2020;Amesty et al. 2020).
Retinal vasculitis may occur as an isolated idiopathic condition, associated with a systemic in ammatory disease or as a complication of neoplastic disorders or infections. Diagnosis is made by ocular fundus exam, characterized by exudates around retinal vessels and sheathing or cu ng of the affected vessels. Leakage from the in amed vessels, results in retinal swelling and exudation. Leakage of dye and staining of the blood vessels seen in fundus uorescein angiography con rms the diagnosis (Abu et al. 2009). We decided not to perform the procedure in our patient, due to age, special pandemic circumstances and the absence of immediate visual threat. On the other hand, the patient was followed closely. The most frequent causes of viral retinal vasculitis or retinitis, come from the herpes virus family and usually affect immunosuppressed patients. Nevertheless, some viruses such as Dengue and Chikungunya are known to cause retinal vasculitis, usually after acute infection, as shown in our patient (Lee et al. 2017). Retinal vasculitis has also been reported in KD (12), but our patient didn´t develop any other manifestation of PIMS, as none of the patients with PIMS in our study had retinal vasculitis.
Six out of 17 patients presented ocular manifestations, as conjunctivitis in children with PIMS, episcleritis and isolated cases of retinal vasculitis and retrobulbar optic neuritis. COVID-19 PCR was negative in all of them, while SARS-CoV-2 IgG antibodies were positive. Therefore, ophthalmic complications seem to occur in a convalescent and non-infectious phase of the disease. Wider studies are needed to con rm this hypothesis, but meanwhile ophthalmologists must keep in mind these potential clinical presentations of COVID-19 infection. To date, the pathogenic origin of these lesions remains unknown. SARS-CoV-2 enters the cells via the angiotensin-converting enzyme II (ACE-2) which is only present in the retina and aqueous humour (Lock et al. 2019). This warned us about the possibility of anterior uveitis or posterior pole in involvement. So far, no other cases have been reported. Other hypothesis, mentions an autoimmune mechanism as a type I interferons response to coronavirus or the increased levels of serum interleukin 6. More exhaustive studies should now be designed to our better understanding of the disease. Attention should be devoted to children, mainly in the convalescence phase of the infection. SARS-CoV-2 tests should be included in the differential diagnosis of ocular pathology in children who present episcleritis or retinal vasculitis, as well as neuro-ophthalmological manifestations such as optic neuritis or cranial nerve paresis, which may be triggered by viral infections. Further studies are needed to delve into the current state of knowledge.

Declarations
Funding Not applicable.

Con ict of interest
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Availability of data and material
All data and material concerning the patients included in this case series are accessible if required under the data protection statements.
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Funding
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Ethics approval
The presented study has been approved by the Ethics Committee of Hospital Universitario La Paz.

Consent to participate
All patients that were included gave their consent to participate in the present study.

Consent to participate
All patients that were included gave their consent to participate in the present study.