Conjunctivitis was the most frequent finding, 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 findings 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 findings 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 find 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 finding 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. 2018; Choi et al. 2015; Fernandez-Cooke et al. 2019). PIMS is the termed used to denominate the initial KD-like disease (Deza et al. 2020). This entity involved systemic hyperinflammation, multiorgan involvement, abdominal pain, gastrointestinal symptoms, and very prominent cardiogenic shock with myocardial dysfunction (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 inflammatory 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 (Choi et al. 2015; Ohno et al. 1982). Less common ocular findings in KD have been: superficial punctate keratitis, vitreous opacity, papilledema and subconjunctival haemorrhage ( Choi et al. 2015; Ohno et al. 1982). Therefore, ophthalmic examination is usually demanded in children with persistent fever and suspected KD. In this context of PIMS first 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 finding, was that coronary artery dilatation was significantly 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 inflammatory condition that is localized to the superficial layers of Tenon’s capsule. Diagnosis is based on clinic, as a selective dilation of the superficial episcleral venous plexus in absence scleral involvement, without exudation and conjunctival inflammation. It is a benign, self-limited inflammatory process that usually responds to topical anti-inflammatory agents (Jabs et al. 2000; Read et al. 1999). In Jabs D. et al review, episcleritis was associated to systemic rheumatic disease in 30% of cases, such as rheumatoid arthritis, and in 5% to infections like Herpes Zoster ophthalmicus or Lyme disease (Jabs et al. 2000). Read R. et all, published the largest series of episcleritis in 12 children, 50% had a bilateral disease and 92% had simple episcleritis. 3 out of those 12 cases, were possibly related to a viral infection: one patient had a history of a previous febrile episode with skin rash, and two patients have had upper respiratory tract infections (Read et al. 1999). Ali Shah SA et all studied 6 children with recurrent episcleritis, 4 of them had a history of upper respiratory tract infection in the recent past (Syed et al. 2006). Ocular episcleritis is a rare disease in childhood, but 4 cases were diagnosed in our Emergency Department in a month (2 of them with negative serology test, despite positive COVID-19 family members).
Optic neuritis is an inflammatory condition of the optic nerve, that causes visual impairment and is associated to demyelinating inflammatory 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 immunologic–inflammatory 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 finding 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 inflammatory 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 cuffing of the affected vessels. Leakage from the inflamed vessels, results in retinal swelling and exudation. Leakage of dye and staining of the blood vessels seen in fundus fluorescein angiography confirms 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 confirm 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.