Why COVID-19 Long Haulers Should Have an Eye Exam

The global pandemic of coronavirus disease 2019 (COVID-19), caused by the viral pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), has been the deadliest pandemic in living memory. COVID-19 is a multi-organ disease and has a broad spectrum of manifestations, including ocular manifestations. The infection can range from asymptomatic or mild to life-threatening multi-system sequelae.

As the pandemic draws on, more long-term effects are being elucidated leading to recognition of post-acute sequelae of SARS-CoV-2 infection or PASC (persistent symptoms or long-term complications beyond four weeks from onset of symptoms)—colloquially known as “long haulers.”¹ As of March 2021, more than 28 million Americans have been diagnosed with COVID-19, and an estimated 10-30% (possibly as many as 8.4 million people) fall into this category of “long haulers.”²

In this article, the pathophysiology of COVID-19 will be explored and a comprehensive review of the ocular manifestations, acute and post-acute, will be discussed. An evaluation and treatment protocol will be recommended with an emphasis towards interdisciplinary management.

Pathophysiology

The pathophysiology of SARS-CoV2 begins with the binding of the viral spike protein to the angiotensin-converting enzyme 2 (ACE-2) receptor on the human host cell. ACE-2 is mainly expressed on respiratory mucosal and alveolar epithelial cells, thus causing the significant respiratory manifestations commonly associated with COVID-19. ACE-2 is also expressed on the gastrointestinal tract, kidney tissue, vascular endothelial cells, immune cells, and neurons.³ The pathophysiologic mechanisms of acute COVID-19 can be broken down into the following:

Direct viral toxicity
Endothelial damage and microvascular injury
Immune system dysregulation, cytokine storm, and stimulation of hyperinflammatory state
Hypercoagulability resulting in thrombosis¹

SARS-CoV2 and the eye

Ocular surface cells are susceptible to infection by SARS-CoV2 and could serve as a portal of entry as well as a reservoir for person-to-person transmission. Ciliary body, choroid, retina and RPE cells all express significant levels of ACE receptors through immunohistochemical analysis.⁴ The ocular manifestations will be broken down into anterior segment, posterior segment, neurologic, and orbital. Ophthalmic sequelae in intensive care unit (ICU) patients and ocular side effects from COVID-19 treatments will also be explored.

Anterior Segment

Conjunctivitis

Conjunctivitis is the most common ocular side effect documented in COVID-19 patients, with incidence reports ranging from 0.8% to 31.6% ^5,6,7. Though Chen et al suggested that ocular manifestations are more common in the middle phase of the disease (around the 13th day of illness),⁸ Nakay et al reported a delayed onset of follicular conjunctivitis in a 65-year-old male four weeks after severe COVID-19 infection. The authors concluded that viral shedding in the conjunctiva may persist even after the nasopharyngeal swab is negative for SARS-CoV-2.⁹

Keratoconjunctivitis may be the initial presenting symptom of a COVID-19 patient and should always be on the list of differentials for red eye patients. There may be two stages of viral keratoconjunctivitis:

The initial viral invasion and inflammation of the ocular surface
A relapse due to an autoimmune regulated response causing a cytokine surge.^10,11

Episcleritis

A case of episcleritis in a 29-year-old male as the initial presenting symptom of COVID-19 was reported by Otaif et al.¹² A third of episcleritis cases are associated with viral infections, including ebola, HSV, hepatitis C, and now, SARS-CoV-2.¹³

Dry eye and other inflammatory conditions

Given the uniquely strong immune response and cytokine storm associated with COVID-19, Dr. Laura Periman, dry eye expert, expects to see an uptick in eye diseases that involve immune dysregulation and inflammation, such as dry eye, episcleritis, uveitis, and corneal neuropathy.¹⁴

Posterior Segment

Due to the vascular changes from endothelial cell damage, the procoagulant state and hyperinflammatory response, many posterior segment manifestations can be possible.¹⁵

These may include:

Central retinal vein occlusion (CRVO)
Central retinal artery occlusion (CRAO)
Acute macular neuroretinopathy (AMN)
Paracentral middle maculopathy (PAMM)
Vitritis and outer retinal abnormalities
Acute retinal necrosis (ARN)
Serpiginous choroiditis reactivation¹⁶
Retinal changes, including retinal hemorrhages, macular hyperpigmentation, retinal sectoral pallor, peripapillary flame-shaped hemorrhages, hard exudates, and cotton wool spots¹⁷
OCT findings: hyperreflective lesions at the ganglion cell and inner plexiform layer, more prominent at the papillomacular bundle¹⁸
Ocular MRI: hyperintense nodules by FLAIR imaging, mostly presenting in the macular region¹⁹

Neurologic

Neuro-ophthalmic manifestations are not common, but isolated case reports have established a list of rare occurrences that eyecare providers should know.¹⁵

Papillophlebitis
Optic neuritis
Adie’s tonic pupil
Miller Fisher Syndrome (with acute onset ataxia, loss of tendon reflexes, and ophthalmoplegia)
- 6th nerve followed by oculomotor nerve were most common
- Facial nerve palsy is also possible
Neurogenic ptosis
Cerebrovascular accident (CVA) with vision loss

Orbital

Orbital manifestations of COVID-19 are rare, but some manifestations can lead to mortality, so prompt and correct diagnosis is of utmost importance.¹⁵

Dacryoadenitis
Retro-orbital pain
Orbital cellulitis and sinusitis
Mucormycosis
- A life-threatening, opportunistic infection, in patients with moderate to severe COVID-19, associated with comorbidities, such as diabetes mellitus
- Mortality rate is as high as 50% even with treatment^{20, 21}
- Symptoms typically presented 30-42 days after diagnosis of COVID-19^{22, 23}
Orbital histiocytic lesion

Opthalmic sequelae in intensive care unit (ICU) patients

The incidence of eye-related complications in ICU patients varies from 3 to 60%. Ocular surface disorders have been reported in up to 60% of critically ill patients and can range from mild conjunctival irritation to severe infectious keratitis.²⁴ Some of the risk factors for ICU patients are due to the treatments, while others are due to the ICU environment itself. In mechanically ventilated patients, common in severe COVID-19 cases, the ocular surface defenses are impaired, and muscle relaxants and sedating agents lead to lagopthalmos. Exposure keratopathy affects up to 42% of ICU patients and 60% of those sedated longer than 48 hours.²⁵

Rare ophthalmic complications in ICU patients include:

Acute ischemic optic neuropathy
- Prone positioning can cause a rise in IOP to 40 mmHg after 320 minutes
- Prone position can also increase venous pressure
Valsalva retinopathy
Horner’s syndrome
Acute angle-closure glaucoma can be triggered by prone positioning as well as local and systemic drugs, such as anticholinergics, sympathomimetics^27,28

COVID-19 treatments and their ocular side effects

While some of these therapeutic options have been proven ineffective in treating COVID-19, all potential treatment options (past and present) are listed along with their ocular side effects. Given the uncertainty and experimental nature of the initial medical community's response to treating COVID-19, it is not out of the question that an early COVID-19 patient may have been exposed to one of the listed medications.²⁹

Chloroquine and hydroxychloroquine
- Retinal toxicity
Remdesivir
- No adverse ocular effects
Lipinavir/ritonavir
- Resurgence of autoimmune conditions such as Grave’s orbitopathy
Ribavirin
- Retinopathy, retinal vein occlusion, serous retinal detachment, non-arteritic anterior ischemic optic neuropathy (NAION), Vogt-Koyanagi-Harada disease (particularly in heptaitis C-positive patients)
Interferons
- Interferon-associated retinopathy, Vogt-Koyanagi-Harada, blurred vision, ocular pain, conjunctivitis, uveitis, optic neuropathy and corneal disorders, including ulcers, epithelial defects, and Sjogren’s Syndrome
Tocilizumab
- Bilateral retinopathy with multifocal cotton-wool spots and retinal hemorrhages (in patients with rheumatoid arthritis)
Oseltamivir
- Bilateral acute angle closure glaucoma
- Transient myopia
Umifenovir
- No ocular side-effects
Nitazoxanide
- Eye discoloration
Favipiravir
- Teratogenic and should be avoided in pregnant women
- No ocular side effects reported
Camostat mesylate
- Conjunctival discoloration due to liver dysfunction (jaundice)
Corticosteroids
- Cataracts, glaucoma, central serous chorioretinopathy (CSR)
Immunoglobulin therapy
- Thromboembolic events (CVA, myocardial infarction, deep vein thrombosis)
- Iatrogenic bilateral central retinal vein occlusion

Ophthalmic exam and recommended auxiliary testing

Pupils
- Check for APDs, Adie’s Tonic pupil and Horner’s
Extraocular motility
- Rule out nerve palsies (particularly 3rd and 6th), pain on eye movement, diplopia
Color vision
- Rule out optic neuropathy
Contrast sensitivity
- Rule out optic neuritis
Sinus tenderness
- Rule out mucormycosis
Anterior segment slit lamp evaluation
- Check for conjunctivitis, inflammatory signs, ocular surface disease (particularly in ICU patients)
IOP
- Monitor for angle-closure glaucoma in ICU patients
- Check patients on long-term steroid treatment
Dilated fundus evaluation
- Evaluate for retinopathy and/or serous detachments
- Rule out optic nerve edema
OCT retina and optic nerve
- Look for hyperreflective lesions in ganglion and outer retinal layers
Visual field testing
- Rule out CVA or central scotomas associated with maculopathy

Post-acute COVID-19 syndrome

The post-acute COVID-19 US study found that 32.6% of the 488 surveyed reported persistent symptoms, including 18.9% with new or worsened symptoms. The most common symptom was dyspnea (difficulty or labored breathing) while walking up the stairs at 22.9%. Other common symptoms included cough (15.4%) and persistent loss of taste and/or smell (13.1%).³⁰

The chronic symptoms or long-term complications that are persistent after 12 weeks from symptom onset can be broken down into several groups: musculoskeletal, pulmonary, neuropsychiatric, cardiovascular, hematologic, renal, endocrine, and dermatologic.¹

Musculoskeletal
- Fatigue
- Decline in quality of life
- Muscular weakness
- Joint pain
Pulmonary
- Dyspnea
- Cough
- Persistent oxygen requirement
Neuropsychiatric
- Anxiety/Depression
- Sleep disturbances
- PTSD
- Cognitive disturbances (brain fog)
- Headaches
Cardiovascular
- Palpitations
- Chest pain
Hematologic
- Thromboembolism
Renal
- Chronic kidney disease
Endocrine
- New or worsening control of existing diabetes mellitus, subacute thyroiditis, and bone demineralization
Dermatologic
- Hair loss

Multidisciplinary management

COVID-19 is a multi-system disease, and it necessitates a multi-disciplined approach to management care. As an eyecare provider, the first step is to evaluate and treat any ocular manifestation, including, most commonly, conjunctivitis and ocular surface disease. Other ophthalmic COVID-19 sequelae, such as retinopathy or acute-angle-closure glaucoma, may necessitate referral to ocular specialists, such as retina or glaucoma. Case history is of utmost importance to rule out stroke symptoms or neuro-ophthalmic complications. Consider referral for MRI testing or neurology evaluation if warranted.

Due to the post-acute effect of COVID-19 on the endocrine system, all diabetics should be evaluated and monitored closely in tandem with their endocrinologist. Given the cardiovascular and pulmonary chronic complications of COVID-19, it would also be prudent to ask patients about any lingering symptoms, such as dyspnea or chest pain and refer appropriately to their primary care, cardiologist, or pulmonologist. The list for neuropsychiatric chronic complications of COVID-19 is extensive and it may also be appropriate to have a psychiatric evaluation for such symptoms as anxiety and depression.

As of March 2021, NBC News had identified more than 80 “post-COVID” clinics nationwide that have seen at least 10,000 patients.² These clinics are actively engaging with COVID-19 patients who continue to have symptoms months after their acute infection cleared. Because COVID-19 is a new disease, the recovery and long-term implications are unknown and many of these practitioners must draw from experience of treating other long-term illnesses.

The rehabilitation process can range from recommendations of a healthy lifestyle (including sleep, diet, and exercise); speech therapy for patients with brain fog; botox, massage or acupuncture for recalcitrant headaches; inhaled or oral allergy drugs for shortness of breath; and eating oranges to clear congestion.² In addition to sharing care of these complicated patients with their other health providers, it may be beneficial to refer them to a specialized post-COVID clinic to manage their long-term COVID-19 complications.

COVID-19 is a complex disease with a broad array of manifestations and sequelae, both acute and chronic. As of the time of this article’s publication in July 2021, there have been 33.6 million cases of COVID-19 in the United States.³¹ The eyecare field will inevitably see more patients present with either acute COVID-19 manifestations, such as conjunctivitis, or post-acute COVID-19 complications, such as immune mediated inflammatory conditions (i.e., ocular surface disease, episcleritis, uveitis).

Post-acute sequelae from SARS-CoV-2 infection may also affect other organ systems and lead to presentations in the exam room chair, such as progressed diabetic retinopathy, headaches or nerve palsies. A well-informed and prepared eyecare provider will know what to look for and how to manage these patients with a consideration towards a multidisciplinary management approach.

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