Abstract
The coronavirus disease–19 (COVID-19) infection may remain asymptomatic or may have several different presentations. Although this disease primarily affects the respiratory system, systemic manifestations affecting the gastrointestinal, cardiovascular, neurological, otorhinolaryngologic, and ophthalmic systems have been reported. Ophthalmic signs may be the first and only sign of COVID-19 infection in children. In the current narrative review, we report the ophthalmic manifestations of COVID-19 in the pediatric age cohort. We performed a comprehensive literature search for the publications on ophthalmic manifestations of COVID-19 in children between 1 March 2020 and 1 January 2022 and compiled the ophthalmic manifestations of this entity among the pediatric population. Conjunctivitis is the most common ophthalmic manifestation in children and can develop at any stage of the disease. Ophthalmic manifestations are seen more commonly in children with severe systemic disease. Long-term and indirect consequence of the COVID-19 disease is the rise of myopia among children. Ophthalmic signs may be the first and only sign of COVID-19 infection in children. Pediatricians, as well as ophthalmologists, must keep observing all children with COVID-19 closely for ophthalmic signs.
Introduction
The severe acute respiratory syndrome coronavirus (SARS-CoV-2) or coronavirus disease–19 (COVID-19) was declared a global pandemic by the World Health Organisation (WHO) on 10 March 2020, and since then, the numbers have increased exponentially. 1 While the virus primarily causes significant pulmonary disease, including pneumonia and acute respiratory distress syndrome (ARDS), the extensive evidence in the literature indicates many extrapulmonary manifestations, including ocular disorders due to inflammation induced by it. In the literature, pediatric COVID-19 cases account for ~1% of the total number of cases, primarily presenting with mild symptoms such as fever, cough, myalgia, rhinorrhea, sneezing, and sore throat.2–4 The different strains of SARS-CoV-2 presented with varied clinical presentations and degrees of severity. The alpha variant (B.1.1.7) was the predominant strain during the first wave, and the delta variant (B.1.617.2) was the dominant strain during the second wave of the pandemic. 5
The ocular manifestations in pediatric cases are highly variable, and various studies have reported it to be between 0.7% and 31.6%.6–10 A recent meta-analysis of 30 studies reported conjunctival hyperemia (7.6%), conjunctival discharge (4.8%), epiphora (6.9%), and foreign body sensation (6.9%) to be the most common ophthalmic symptoms in patients infected with SARS-CoV-2. 11 The ophthalmic disorders associated with COVID-19 have been primarily reported in adults, with very few cases reported from the pediatric age group. This literature review evaluates the cases and case series of ophthalmic manifestations reported in pediatric patients (from birth up to 18 years of age) (Table 1).
Common ocular manifestations of COVID-19 and their possible pathophysiological mechanisms.
Conjunctival and corneal disorders
Conjunctival hyperemia and discharge are the most commonly reported ocular manifestations of COVID-19. 9 Early reports of pediatric cases from Wuhan, China, reported conjunctival discharge and congestion in 55.1% and 10.2% of the patients, respectively. A meta-analysis of the reports by Zhong et al. 11 found conjunctival hyperemia (7.6%) and discharge (4.8%) were the most common ocular presentations in pediatric patients. The beta variant (B.1.351) of the virus has a high affinity for the angiotensin-converting enzyme 2 (ACE-2) receptors in the conjunctiva. 12 Interestingly, ACE2 gene expression is higher in older children and young adults than in younger children. Therefore, it is speculated to be one of the causes of lower rates of SARS-CoV-2 transmission in younger children through tears. 9 The omicron strain (B.1.1.529) newer symptoms are being reported. Two further subsets of the omicron strain have been recognized; the B.2 strain is predominantly associated with ‘itchy eyes’ rather than conjunctival hyperemia, persisting for several months even after the infection subsides. 13
The acute febrile multisystem vasculitis, known as the Kawasaki disease (KD), has a similar presentation in pediatric patients due to SARS-CoV-2 infection. This atypical presentation of KD is known as a multisystem inflammatory syndrome in children (MIS-C) or pediatric inflammatory multisystem syndrome (PIMS) and has various systemic manifestations, including conjunctivitis. 14 As observed in KD, infection with SARS-CoV-2 also causes a cytokine storm and severe systemic inflammation. 15 The pathogenic mechanism of conjunctivitis due to respiratory viruses is not entirely understood. It is primarily attributed to the viral particles or, in some cases, vasculitis post-infection. 16 An Italian study documents a nearly 30-fold increase in the incidence of KD-like condition in children strongly associated with COVID-19. 8 In cases of conjunctivitis, the treatment primarily directed toward suppression of systemic inflammation using corticosteroids, intravenous immunoglobulin (IVIG), and aspirin have been used in the cases reported. 17
Chiotos et al. 18 reported six cases of MIS-C in which two patients were diagnosed with conjunctivitis post-SARS-CoV-2 infection. While one child had conjunctivitis at presentation, the other developed it on the fifth day of inpatient admission. Similarly, Rauf et al. reported a case of a 5-year-old child with atypical KD post-SARS-CoV-2 who presented with multi-organ dysfunction and non-purulent bulbar conjunctivitis. The inflammatory markers (erythrocyte sedimentation rate and C-reactive protein) were significantly elevated, and the child also presented with myocarditis, hypoalbuminemia, and sterile pyuria. 15 Two were reported with conjunctivitis in a case series of four children (ages 6–12 years) infected with SARS-CoV-2. 19 An even higher proportion of children (5 out of 8, 62.5%) with conjunctivitis in COVID-19 children between ages 4 and 14 were reported by Riphagen et al. 20 In a cross-section study conducted in New York, 11 out of 17 children with MIS-C post-SARS-CoV-2 infection had conjunctivitis at presentation. 21 Conjunctivitis is a common presentation in children who are a few weeks old to adolescents. Limbus sparing conjunctivitis was also reported in a SARS-CoV-2 infected 6-month-old infant. 22 Godfred-Cato et al. reported that 48.4% of cases of MIS-C post-SARS-CoV-2 infection had conjunctivitis in a retrospective study of a large cohort of 570 children between the ages of 2 weeks to 20 years. The children were treated with aspirin, i.v. immunoglobulins, and steroids. 23
Mechel et al.24 reported a case of a 4-day-old infant who presented with acute-onset mucopurulent discharge, subconjunctival hemorrhage, and palpebral injection unilaterally. As no bacterial (for Chlamydia trachomatis, Neisseria gonorrhea) or viral (herpes simplex virus) etiology could be established through standardized laboratory diagnostic techniques, the diagnosis of ophthalmia neonatrum was associated with SARS-CoV-2 infection established by a positive polymerase chain reaction (PCR) test. The infant did not present with any other systemic signs and symptoms.
In a case series including 15 new born children, Perez-Chimal et al. observed periorbital edema and hyaline section in all of them, hemorrhagic conjunctivitis and chemosis (73.3%), and ciliary injection (53.3%). They also reported that corneal edema was observed in 40% of the newborns, and only one child had had rubeosis and posterior synechiae. 25
Adnexal disorders
Orbital inflammatory disorders have been rarely reported in pediatric patients infected with SARS-CoV-2. Turbin et al. reported two cases (12 and 15 years old) with mild systemic manifestations of COVID-19, who presented with unilateral orbital cellulitis, sinusitis, and intracranial abnormalities. The authors attributed the clinical presentation to poor mucociliary clearance and congested upper respiratory tract, resulting in bacterial infection, which spread to the orbital and intracranial areas. 26 The patients presented with severe lid edema with erythema, non-hemorrhagic conjunctival chemosis, proptosis, and limited supraduction. In another case report, Eleiwa et al. 27 reported lateral rectus myositis in a 10-year-old male patient without any other typical systemic COVID-19 symptoms. In addition, the patient also presented with lacrimal gland enlargement and orbital inflammation. The patient’s clinical symptoms improved significantly on treatment with oral prednisolone over 2 weeks. In a case series from India, 8.3% of the patients with COVID-19-associated multisystemic inflammatory syndrome presented with eyelid swelling. 10
Diwakar et al. reported two cases of rhino-orbito-cerebral mucormycosis (ROCM) in two pediatric patients with type 1 diabetes mellitus. The patients had asymptomatic SARS-CoV-2 infection and developed ROCM during the diabetic ketoacidosis treatment and did not have any prior treatment with systemic steroids. 28 In a case series including 12 pediatric patients with COVID-19-associated mucormycosis, 4 patients had orbital manifestations. 29 Among these patients, two received high-dose steroids for managing COVID-19-associated inflammation; one had a history of uncontrolled type 1 diabetes, and one had no co-morbidity. ROCM is common in immunocompromised patients due to diabetes or prolonged exposure to systemic corticosteroids, specifically in the rural communities where there is high exposure to spores of fungi belonging to mucormycetes.
Neuro-ophthalmological manifestions
Neurological and neuro-ophthalmological symptoms related to COVID-19 infections in the pediatric population are sparsely reported and may occur either as a complication of the MIS-C or may occur as a post-infectious complication. Knoflach et al. reported a case of a 2-year-old male child with unilateral sixth nerve palsy likely as a post-infectious complication of COVID-19. Although the child tested negative for COVID-19 on real-time reverse-transcriptase polymerase chain reaction (RT-PCR) of the oropharyngeal swab, serology and cerebrospinal fluid (CSF) testing did show elevated IgG antibody levels of SARS-CoV-2 antibodies. Hence, the presumed etiology of the sixth nerve palsy was COVID-19 infection. 30 Olivera et al. reported a case of a 2-year-old girl presenting with an oculomotor nerve palsy, pupillary sparing. On serological testing, she tested positive for IgM antibodies for SARS-CoV-2. 31 A case of a 23-month-old female child with facial nerve palsy has been reported by Zain et al. The child presented with inability to close the left eye and drooping of the mouth to the right indicative of a left facial nerve palsy. The child tested positive for COVID-19 on RT-PCR, and the other inflammatory tests came out to be negative. 32 All the reported nerve palsies were isolated, radiologically confirmed, and resolved spontaneously or by conservative management.
The possible mechanism for these nerve palsies is the neuro-inflammatory process due to the neuroinvasive nature of the virus that infects the host cells via membrane bound ACE-2 receptors interaction, which is also expressed in various organ systems including the neurological system.30–32
Retina
Over the past few years, several reports have highlighted the pathological changes in the retina due to inflammatory processes associated with SARS-CoV-2 infection, such as cotton-wool spots, microhemorrhages, and vein dilation that have been identified through fundoscopic examination and optical coherence tomography (OCT).17,30 However, these cases have been primarily reported from the adult population, and very few studies have reported retinal changes in pediatric patients.
Perez-Chimal et al. 25 reported abnormal fundoscopy findings in 8 of the 15 full-term infants with suspected SARS-CoV-2 infections. The infants were diagnosed with retinopathy of prematurity (ROP) (13%), oxygen-induced retinopathy (13%), cotton-wool spots (20%), and vitreous hemorrhage (7%).
In the same study, fluorescein angiography showed pathological changes associated with ROP (20%), oxygen-induced retinopathy (13%), patchy choroidal filling (20%), and peripapillary hyperfluorescence (20%), and delayed retinal filling, venous laminar flow, and boxcarring was observed in the remaining 13% newborn infants with suspected SARS-CoV-2. Comba et al.33,34 performed an ophthalmic assessment and objective analysis of the changes in two retinal vascular networks using OCT in pediatric patients with SARS-CoV-2 infection. The authors found that the vascular density in the superficial layer of the fovea was significantly lower in the eyes of SARS-CoV-2 infected patients compared with normal eyes. They also reported that except in parafoveal, parafoveal inferior-hemi, and parafoveal inferior areas, the vascular density was significantly lower in all the deep layers. The vascular density of the deep capillary plexus was also reduced in parafoveal quadrants in the eyes of SARS-CoV-2 patients compared with normal eyes. The authors attributed the lower vascular density in deeper layers to arterial and venule vasoconstriction due to coagulopathy and hyperoxia, leading to microvascular obstruction. The authors also associated these changes with inflammation-mediated endothelial dysfunction and apoptosis.33–38
Fernandez et al. evaluated the eyes of 17 children between 4 and 17 years. They found that in addition to conjunctivitis, several other inflammatory changes such as episcleritis, retinal vasculitis, optic neuritis, or cranial nerve paresis were triggered on infection with SARS-CoV-2. 39 Recently, Soni et al. 40 reported a case of acute retinal necrosis in a 5-year-old boy a month after recovering from a SARS-CoV-2 infection. The authors attributed these pathological changes to the reactivation of the herpes virus secondary to immune deregulation as a consequence of the SARS-CoV-2 infection. Walinjkar et al. 41 reported a case of a 17-year-old female infected with SARS-CoV-2 who presented with central retinal vein obstruction.
Conclusion and future directions
The rapidly evolving understanding of the pathological mechanisms and associated clinical changes pose a global challenge to clinicians. Over the past 2 years, several studies have reported an array of ocular manifestations of SARS-CoV-2 infection, primarily in adults. The data have shown that significantly fewer children present with severe or symptomatic disease post-SARS-CoV-2 infection compared with adults. 42 The annual COVID-19-associated hospitalization rate among children < 18 years old in the United States is 48.2 per 100,000, compared with 105.3 per 100,000 in adults (>18 years).43–45 The ocular signs in most cases are mild and limited to conjunctival hyperemia or chemosis. However, the patients infected with SARS-CoV-2 who present with severe ophthalmic disorders indicate high viral load and severe pathological changes systemically.
The development of vaccines for SARS-CoV-2 has been shown to be efficacious in reducing the morbidity and mortality associated with viral infection.46,47 Several countries, including the United States and China, have expanded the vaccine coverage to include children. Until the vaccine coverage for children expands adequately, the ophthalmologists and pediatricians must be cautious and maintain a high clinical suspicion for ophthalmic manifestations due to the inflammatory changes induced by the virus. As the pandemic evolves, it has led to the detection of several variants of concern of SARS-CoV-2; therefore, it is likely that newer systemic manifestations, including ophthalmic manifestations associated with this virus, will be diagnosed and reported. Here, we have attempted to briefly outline the known ocular manifestations of the SARS-CoV-2 virus from the published scientific evidence limited to case reports, case series, and a few retrospective/cross-sectional studies.
