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Ophthalmology
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection has become a worldwide threat resulting in a pandemic in 2020. SARS-CoV-2 infection manifests itself as coronavirus disease 2019 (COVID-19) that is evidenced in a vast number of either specific or nonspecific symptoms. Except for typical (but nonspecific) symptoms such as fever, dry cough, or muscle weakness, the infected patients might also present atypical symptoms including neurological, dermatological, or ophthalmic manifestations.
- ophthalmic manifestations
- SARS-CoV-2
- atypical symptom
1. Introduction
Severe acute respiratory syndrome, coronavirus 2 (SARS-CoV-2), which can cause coronavirus disease 2019 (COVID-19), was first observed in the city of Wuhan, China in late 2019 [1]. The infection induced by the virus can spread rapidly and may lead to serious systemic complications, especially those associated with the respiratory system [1,2]. The disease was announced as a pandemic in March 2020 with an infection rate of about 291,000,000 between December 2019 and January 2022, causing nearly 5,500,000 deaths [2,3]. SARS-CoV-2 is a single, positive-stranded RNA beta coronavirus that has transmitted and spread all over the world since January 2020 [2,4]. The transmission (mainly by aerosol and droplets) is related to the angiotensin-converting enzyme 2 (ACE2) receptor located in the membrane of the lungs, heart, kidneys, or ocular cells to which the coronavirus attaches [4]. COVID-19 manifests itself as flu-like condition but can expose many other symptoms, frequently of an unusual nature [4].
SARS-CoV-2 impacts different systems of the human body. Some patients exhibit nonspecific symptoms, such as headache, nausea, vomiting, dizziness, and confusion, while some present with more specific ones such as: seizures and cerebrovascular disorders [5,6]. COVID-19 can also lead to some serious cardiovascular complications [7]. Furthermore, the frequency of acute kidney injury (AKI) in patients with COVID-19 is quite common; besides that, SARS-CoV-2 presented a tropism in female and male reproductive organs [8,9]. What is more, some cutaneous manifestations of COVID-19, which include maculopapular, chilblain-like, urticarial, vesicular, livedoid, and petechial lesions, are observed (Table 1).
Table 1. Comparison of typical and atypical COVID-19 infection symptoms.
| Typical Manifestations | Atypical Manifestations |
|---|---|
| Fever | Kawasaki-like disease |
| Cough | Cerebrovascular disorders |
| Fatigue | Cutaneous manifestations |
| Headache | AKI |
| Loss of smell and taste | Conjunctival congestions |
| Dyspnea | Seizure |
Pediatric patients with SARS-CoV-2 usually have a higher rate of mild infection than adults and present fewer complications. Over one-third of pediatric patients present normal chest computed tomography (CT) scans. The most common radiological findings regardless of patients’ age include ground glass opacities and the presence of consolidations or pneumonic infiltrates.
Most infected patients prove to have a higher rate of the following biomarkers—C-reactive protein, serum amyloid A, interleukin-6, lactate dehydrogenase, neutrophil-to-lymphocyte ratio, D-dimer, cardiac troponin, renal biomarkers, lymphocytes, and platelet Mount [10]. Concerning the accuracy of SARS-CoV-2 diagnostic tests, RT-PCR remains the gold standard for COVID-19 diagnosis. The combination of IgM and IgG antibodies also demonstrated promising results as for sensitivity and specificity [11].
2. Pathophysiology and Transmission of SARS-CoV-2 Infection
SARS-CoV-2 is a 45726 single-stranded positive-sense RNA virus classified as betacoronaviridae. It can spread in many ways in the form of aerosols, droplets, or conjunctival transmission [1,12]. Following the entry, mainly due to the ACE-2 receptor, the virion binds to the host cells and enters the cells through endocytosis or membrane fusion [11]. ACE-2 receptors are found in almost every organ, such as the lungs, heart, kidneys, or gastrointestinal system. This could partially explain some atypical symptoms and dangerous complications of SARS-CoV-2 infection [1,13]. As presented earlier, following entry, the virus releases its RNA in the epithelial cells (ECs) [1]. In infected Ecs, inflammation; abnormal cytokine release (VEGF, MCP-1, and IL-8); and tissue damage are consecutively observed [1]. All these disorders might eventually lead to multiorgan failure or acute respiratory distress syndrome (ARDS) [1].
Transmission is possible owing to droplets and other body fluids, air, and fomite. There is also a possibility of conjunctival transmission; aerosols < 5 μm in diameter can cause airborne transmission [14]. Infected tears or respiratory droplets may come into contact with the conjunctiva and lead to SARS-CoV-2 infection [15].
3. SARS-CoV-2 Infection Effect in Eyes
3.1. Episcleritis
A study from Turkey found a 2.2% prevalence of episcleritis in COVID-19 patients [72]. It was also shown that episcleritis was associated with higher D-dimer levels. In another case, episcleritis developed after the main COVID-19 respiratory symptoms were resolved, and the patient reported to the ophthalmologic clinic with red eyes, foreign body sensations, epiphora, and photophobia. Nodular episcleritis was diagnosed [73]. A case of episcleritis in a 29-year-old male who was diagnosed 3 days before the onset of full-blown COVID-19 has also been reported [74]. About one-third of cases can be associated with viral infections, such as Ebola, hepatitis B virus (HBV), hepatitis C virus (HCV), and herpes zoster virus (HZV), and also, the immune-vascular factors and thrombotic complications of COVID-19 have evoked suspicion in the role of COVID-19 in developing episcleritis [75].
3.2. Kawasaki Disease
Children suffer from COVID-19 more mildly, mainly because of more effective immune responses [76]. The prevalence of conjunctivitis in infected children is estimated to be low (1–5%) [77]. However, an increase in morbidity of Kawasaki disease has been noticed, presenting as vasculitis of small and medium vessels that also results in fever, lymphadenopathy, cutaneous and palmar–plantar erythema, conjunctivitis, limb edema, and less frequently, coronary aneurysms [78]. The ocular manifestations are mostly: iridocyclitis, punctate keratitis, vitreous opacities, papilledema, subconjunctival hemorrhage, and conjunctival injection [79]. The majority of patients present with better clinical outcomes in a few days, but some children (0.5–5%) might present toxic shock [78]. A case of a 6-month-old baby with generalized erythema and conjunctivitis has also been described in the literature; the child completely recovered after a treatment with intravenous immunoglobulins (IG) over 48 h [80].
Verdoni et al., conducted a comparative study of two groups—(1) 19 children with a ‘Kawasaki-like’ disease before the start of the SARS-CoV-2 outbreak in Lombardia and (2) 10 children with the disease after the start of the pandemic there [81]. The second group was observed to have had a higher mean age (7.5 years vs. 3 years); the majority had AC antibodies against the virus (8 out of 10) and suffered from a more severe form of the disease: greater cardiac involvement (6 out of 10 vs. 2 out of 19), toxic shock syndrome (5 of 10 vs. 0 of 19), and macrophage activation syndrome (5 of 10 vs. 0 of 19). Thus, SARS-CoV-2 could have been a strong stimulus in the host capable of triggering a disproportionate immune response. The predictors of this response are still unknown.
3.3. Opthalmoparesis Consistent with Abducens Nerve Palsies
Two cases of patients with a diagnosis of COVID-19 after presenting with diplopia and ophthalmoparesis were described [82]. The combination of ophthalmoparesis with bilateral abducens nerve palsies, leg paresthesia, and areflexia in the first case could suggest acute demyelinating inflammatory polyneuropathy secondary to a virus-mediated immune response. In the second case, although the radiological evidence of abducens nerve involvement was missing, the presence of painless diplopia and abduction palsy of the right eye might reflect viral leptomeningeal invasion. The event of cranial neuropathies ought to provoke the consideration of SARS-CoV-2 infection in patients with even gentle symptoms and signs of SARS-CoV-2 infection.
3.4. Oculomotor Nerve Palsy
The clinical presentation of oculomotor nerve palsy includes ptosis and the restriction of adduction, elevation, and depression movements of the eyeball. The case of a 55-year-old male with confirmed SARS-CoV-2 infection and diagnosed with third cranial nerve palsy was described. The patient was treated supportively for his infection and remained stable on room air during his hospitalization. No connective factors other than COVID-19 were identified as a cause for his cranial third nerve palsy, which resolved spontaneously during outpatient follow-up. The pathogenesis and prognosis of cranial nerve palsy in SARS-CoV-2 infection are still unclear [83]. Another reported case of acquired non-pupil-sparing oculomotor nerve palsy in a previously asymptomatic child indicated a possible link to SARS-CoV-2 infection. The patient, in contrast to oculomotor nerve palsies caused by presumed inflammation, presented no findings in the MRI. Regarding the patient’s spontaneous improvement, researchers hypothesized that the damage to the oculomotor nerve caused by SARS-CoV-2 was not permanent and that oculomotor nerve palsy could resolve spontaneously within a short time [84].
3.5. Cerebrovascular Accident (CVA) with Vision Loss
Vision loss can be the most disabling residual effect after cerebral infarction; temporary vision problems can equally be an indication of stroke, and a prompt evaluation after recognition of the visual signs can prevent future vascular injury [85]. In the COVID-19 era, vigilance for cerebrovascular complications of the aforementioned illness is needed. Scientists presented a case of bilateral occipitotemporal infarction observed as a sudden cortical loss of vision with hemorrhagic transformation after intravenous thrombolysis in a patient with diabetes infected by SARS-CoV-2 [86]. It is currently known that SARS-CoV-2 can penetrate the brain, leading to neuronal defects. Moreover, it is suggested that SARS-CoV-2 could, due to its cerebrovascular system effects, possibly provoke neuronal complications. Early data show that stroke can be one of the leading neurological complications in COVID-19 patients [87].
3.6. Acute Angle Closure Glaucoma and Horner’s Syndrome as Complications of ICU Treatment
Nerlikar et al., reported the case of a 53-year-old male with ocular discomfort and blurred vision in both eyes that was caused by prone positioning during ventilation for COVID-19 pneumonia. The patient was under sedation and was placed for 8 h in a prone position every day for 2 weeks. Additionally, he could not manifest his symptoms, so the detection and treatment were shifted over time. Moreover, it was also suggested that the medication that was given to the patient, such as Glycopyrrolate, Noradrenaline, and Salbutamol, could cause acute angle closure. Another possible reason for elevated intraocular pressure could be steroids [88].
A similar study described a patient admitted to the ICU due to COVID-19 who developed acute closure glaucoma after the use of ipratropium bromide and salbutamol, darkroom conditions, and prone positioning for 3 weeks. Despite treatment with eye drops and cataract surgery, the patient lost vision in her right eye [89]. Other studies have also indicated that some anticholinergics, sympathomimetics, and other drugs may induce AACG [90,91].
Other researchers strive to explain the main mechanisms of acute angle closure glaucoma caused by drugs. The first hypothesis assumes pupillary block and iridocorneal angle closure, and the second one blames the mass effect, which causes anterior displacement of the lens–iris diaphragm [92]. According to some studies, SARS-CoV-2 infection is not directly related to acute angle-closure glaucoma; however, it possibly contributes to AACG due to a prolonged prone position and some medications used in the treatment of COVID-19-related pneumonia.
Horner’s syndrome is characterized by ptosis, miosis, enophthalmos, and, rarely, a lack of sweating on the affected side of the face [93]. So far, the data on COVID-19-related Horner’s syndrome are still limited, but some reports have confirmed a correlation. The first report presented a 65-year-old female who tested positive for SARS-CoV-2 and was admitted to the hospital due to hypoxemia. The next day, she developed ptosis and miosis and was diagnosed with Horner’s syndrome. Despite the lack of an unequivocal mechanism and significant examination explaining the appearance of Horner’s syndrome, in this case, the influence of the SARS-CoV-2 infection could be associated with the development of ptosis and miosis 2 days after the COVID-19 diagnosis [67].
Other researchers described a 38-year-old patient with left ptosis, fever, general weakness, mild headache, slight left pupil construction, and left enophthalmos. Horner’s syndrome was diagnosed based on a neurological examination. Further, the chest CT and RT-PCR test detected SARS-CoV-2 infection. The mechanism of this syndrome, in this case, is debatable. It was suggested that it could be related to the inflammation of the upper lobe of the lungs or a reactive enlargement of the cervical lymph nodes. Another reason might be the direct impact of the virus on the nervous system [94].
3.7. Miller Fisher Syndrome
There have been several cases describing post-COVID-19 Miller Fisher syndrome, and they all presented similar symptoms and evolution [95,96,97,98,99,100,101]. Neurological symptoms were usually observed 5–20 days after the COVID-19 diagnosis [95,96,97,98,99,100,101]. The most common symptoms related to MFS included paresthesia, ophthalmoplegia, blurred vision, ataxia, areflexia, and others. It remains uncertain whether post-COVID-19 MFS is induced by viral neurotropism or the disturbed immune response. The presence of a GQ1b antibody, increased proinflammatory cytokines in the plasma, and the absence of SARS-CoV-2 in the cerebrospinal fluid suggest immune-mediated injury. However, when the testing for anti-GQ1b is negative, the pathogenesis could be explained by the neuroinvasive capacity of SARS-CoV-2 [95,102]. Generally, most cases of MFS show positive anti-GQ1b, but it is not an obligatory sign of a MFS diagnosis. Moreover, the presence of GQ1b antibodies indicates a faster recovery. According to the studies, most patients have responded well to intravenous immunoglobulin [95]. Of note, post-COVID-19 MFS was also reported in a 7-year-old child [98].
3.8. Xerophtalmia
A vitamin A deficiency might lead to various ocular symptoms, including conjunctival and corneal xerosis, Bitot’s spots, keratomalacia, nyctalopia, and retinopathy, which refer to xerophthalmia. So far, the data on xerophthalmia as a COVID-19 complication are still limited [103,104,105]. The research paper about ocular manifestations and clinical characteristics of 535 cases of COVID-19 in Wuhan, China, reported that some patients with COVID-19 had chronic ocular diseases, such as xerophthalmia (24 patients, 4.5%). However, this conclusion was found additionally and was not the subject of the study. The association between COVID-19 and xerophthalmia still remains unclear [21]. Other researchers referenced this study showing that, so far, no other study has been performed on this matter, and the knowledge about xerophthalmia as a complication of SARS-CoV-2 infection is still insufficient [106,107].
3.9. Mucormycosis
SARS-CoV-2 infection might induce opportunistic fungal infections, such as pulmonary aspergillosis, pneumocystis pneumonia, oral candidiasis, or, rarely, mucormycosis [108]. Despite that, the amount of the literature reporting COVID-19-related mucormycosis is continually increasing. A major risk factor is the use of corticosteroids while managing a severe course of COVID-19. Additionally, it was reported that diabetic patients are more predisposed toward acquiring mucormycosis [109,110,111,112]. Other risk factors include neutropenia and hematologic cancers, stem cell transplant patients, and immunity-reduced patients [113]. The most common predilections were nasal, rhino-orbital, and rhino-orbital–cerebral mucormycosis [110,114,115].
A recent review by Singh et al., showed that SARS-CoV-2-infected males (78,9%) were more prone to mucormycosis than females. Furthermore, 80% of the patients had diabetes and 14.9% presented diabetic ketoacidosis. Corticosteroids were used in 76.3% of the cases. The most common was mucormycosis of the nose and sinuses, and the second was rhino-orbital. Fatalities were reported in 30% of the cases [114].
3.10. Endogenous Endophthalmitis
Endogenous endophthalmitis is usually reported in patients with numerous coexisting comorbidities, as well as those with prolonged hospitalization, intravenous mediations, or corticosteroid/immunosuppression therapy. Nayak et al. (2021), in their cohort study, presented that SARS-CoV-2 infection might be associated with an onset of endogenous endophthalmitis. The researchers observed that the prolonged administration of three drugs—namely, systemic corticosteroids, broad-spectrum antibiotics, and IL-6 inhibitors (tocilizumab)—predisposed the patients toward the onset of endogenous endophthalmitis [116]. Additionally, Bilgic et al. (2021) reported three cases of endogenous bacterial endophthalmitis in patients during their COVID-19 recovery stage [117].
This entry is adapted from the peer-reviewed paper 10.3390/jcm11123379
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