COVID conjunctivitis

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Disease Entity

COVID conjunctivitis is an ocular manifestation of a new disease entity called Corona Virus Disease-19 (COVID-19)

Disease

COVID-19 started in December 2019 in Wuhan city of China and within no time evolved into the deadliest Pandemic of the present times. Earlier diseases related to Coronavirus were severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). No cases of conjunctivitis or any other ocular sign or symptoms were reported with either MERS-CoV or SARS-CoV.[1] [2] [3] However, there are reports of conjunctivitis associated with COVID-19. 

Etiology

It is not yet confirmed whether the disease started from bats or not. However, the current wild spread is due to human-to-human transmission through droplets and direct contact with the mucous membranes including eyes, nose, or mouth.  

The causative organism is a beta coronavirus, which belongs to Coronaviridae family. It is an enveloped single-stranded RNA virus, which is closely related to the severe acute respiratory syndrome coronavirus.[4] It has been named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Phylogenetic analysis showed that there are more than 100 strains of SARS-CoV-2 with two different types; type L and type S. The receptor-binding region of SARS-CoV-2 is also similar to SARS-CoV. For entry into the cell, the virus uses angiotensin-converting enzyme 2 receptor (ACE2).[5]ACE2 receptors were found in conjunctiva and cornea, although the receptor density in ocular tissues was lower.[6] 

Risk Factors

Old age, living in a congested area, chronic lung diseases, comorbidities including immuno-compromised states, diabetes, obesity, chronic renal, and liver diseases are the risk factors for severe systemic disease. In addition to this, health care workers are at increased risk of acquiring the infection. The risk factor for COVID conjunctivitis is direct contact with a person having COVID. Li Wenliang, the whistleblower of the disease, contracted this virus from an asymptomatic glaucoma patient. This suggested that transmission of the virus may occur through the eyes.[7]

General Pathology

The incubation period of COVID-19 is within 14 days with maximum numbers occurring within 4 to 5 days of exposure. Virus spread may occur through droplets, contact with infected surfaces, mucous membranes of infected persons, and also via the oro-fecal route. The median time of virus shedding is 20 days with a maximum recorded time period of 37 days.[8][8] According to another study, the mean incubation period for SARS-CoV-2 was 5 to 7 days, and patients were typically infectious for several days prior to symptom onset. Approximately 97% of patients develop symptoms within 11.5 days of exposure. This supported the 14-day quarantine recommendations.[9][9]

Recently, viral RNA was detected in the samples collected from the rooms of COVID-19 patients admitted in the hospital, which further confirmed spread through direct contact with the surfaces contaminated with virus particles.[10]Conjunctival infection can be due to direct inoculation of the ocular tissues from droplets of an infected patient, from nasopharynx by nasolacrimal duct or from the lacrimal glands. [reference needed]

Pathophysiology

The pathophysiology of SARS-CoV2 related conjunctivitis is not completely understood. However, if we consider SARS-CoV model, the disease occurs in three stages; viral replication followed by immune hyperactivity and then tissue destruction.[11] Similar to lung tissue, cells in conjunctiva die either by viral-mediated lysis or by immune reactions. Cell death results in the release of the virus into tears.  

Primary prevention

Preventive measures, which must be adopted by practicing ophthalmologists, to avoid the spread of infection include;

  • Pre-appointment screening of the patient. Patients with respiratory symptoms, patients with a history of travel, or contact with a traveler should not be given an appointment unless it is an emergency.
  • Wearing of masks all the time by the patients, attendants, and the health care personnel.
  • Regular hand wash and use of sanitizer.
  • Disinfection of instruments and surfaces having potential patient contact, before and after the examination. For surface disinfection, 0.1% of sodium hypochlorite or 70% ethanol for 1 minute is recommended.
  • Avoiding air puff tonometer as it poses a danger of aerosol spread. It is preferable to use disposable devices. Tonometer should be sterilized using a 10% diluted sodium hypochlorite solution.
  • Minimum examination protocol that can help in diagnosis and management and avoiding additional clinical tests and investigations unless necessary.
  • Use of proper slit lamp shields and their regular disinfection after every patient.
  •  Use of PPE with eye protection when it is necessary to examine a patient with respiratory symptoms
  • Implementation of telemedicine wherever possible. 

Diagnosis

Any patient coming to the clinic with a red-eye should be suspected of COVID conjunctivitis until proved otherwise.

History

Patients with red-eye must be inquired about recent traveling, cough, flu-like symptoms, fever, and history of similar symptoms in close contacts or recent contact with COVID-19 suspected or diagnosed cases. 

Physical examination

Positive clinical findings on physical examination of the patients with COVID-19 include; fever, cough, shortness of breath, myalgias, sore throat, headache, rhinorrhea, new-onset loss of taste or smell and chest pain. Gastrointestinal symptoms including diarrhea, nausea, and vomiting have also been reported. Although fever is a common symptom there are reports of afebrile COVID patients as well.[12]

Signs

Conjunctivitis and keratitis are the only reported ocular signs of COVID-19 to date. No case of uveitis is yet reported. Lack of retinal findings may be attributed to failure to perform the retinal examination in the COVID-19 patients. However, very mild retinal microvascular abnormality involving the ganglion cell and inner plexiform layers of the retina is described by Marinho et al.[13]

COVID-19 conjunctivitis starts as unilateral redness of eye with follicular reaction (inferior palpebral) like any other viral conjunctivitis.[14]It may resolve by itself or progress to involve coarse epithelial keratitis, pseudomembranous conjunctivitis and bilateral hemorrhagic, pseudomembranous conjunctivitis or pseudodendritic keratitis.[15] [16]It may also be associated with tender lymphadenopathy. Animal studies have shown anterior uveitis, retinitis, vasculitis, and optic neuritis, as well.[17]

Symptoms

Patients with COVID-19 can have symptoms of watering, foreign body sensation, and red-eye, or they may be asymptomatic. There are reports in which conjunctivitis was the only sign of COVID-19. Other reports showed that the patients of COVID-19 developed conjunctivitis later in their course of disease after hospitalization.

Clinical diagnosis

Clinical diagnosis is through a high level of suspicion

Diagnostic procedures

The tear sample collection varies from the use of Schirmer strips to conjunctival swabs. False-negative results are common because of the timing of sampling. Use of topical anesthesia may also alter the results.[18]

For systemic investigations, nasopharyngeal, throat, upper respiratory, and saliva swabs are taken for RT-PCR. Imaging of COVID patients shows pneumonia, multiple mottling, and ground-glass lung opacity and pneumothorax. 

Laboratory test

Serology and RT-PCR are the most common laboratory tests being performed. Reverse-transcription polymerase chain reaction (RT-PCR) is a specific but less sensitive test in the diagnosis of COVID conjunctivitis. Different RNA gene targets are employed by different manufacturers.[19] It is recommended that two consecutive negative RT-PCR tests results are required before a patient can be considered safe.[20]

Early after acquiring infection, antibodies to SARS-CoV-2 are detected in serum. If a patient is IgM positive and IgG negative, the patient is actively infected. If IgM and IgG are both positive, infection is recent and may or may not be active. If IgM is negative and IgG positive, the infection is old. However, a positive IgG test alone does not mean the patient is no longer contagious or is immune.

Lymphopenia, elevated aminotransaminase levels, elevated lactate dehydrogenase levels and elevated inflammatory markers (eg, ferritin, C-reactive protein, and erythrocyte sedimentation rate) have been reported in hospitalized patients with COVID-19.

Differential diagnosis

Differential diagnosis of COVID conjunctivitis includes all causes of red-eye as there are cases of COVID conjunctivitis, which were otherwise systemically asymptomatic. However, important causes from a never-ending list of red-eye include; Adenoviral, Bacterial, Allergic conjunctivitis, Herpes simplex virus keratitis, Anterior uveitis, Foreign body, Corneal abrasion, Dry eye syndrome, Exposure keratopathy, and Chemosis.  

Management

General treatment

Currently, data to propose or oppose a therapy is insufficient. There was initial data regarding the use of hydroxychloroquine, which later proved ineffective for COVID. Remedisivir is currently approved by the FDA for the treatment of suspected or laboratory-confirmed COVID-19 in adults and children hospitalized with severe disease. Another recent study showed that patients with COVID-19 who were treated with a combination of lopinavir, ritonavir, ribavirin, and interferon-beta-1b became PCR negative more quickly than those treated with lopinavir and ritonavir (control group).[21] Both these studies suggest the positive role of antiviral therapy if given early in infection. Plasma from recovered patients is also in the trial. Anticoagulant use to prevent thromboembolism caused by COVID is also suggested. Several vaccines are in progress as well.

Medical therapy

COVID conjunctivitis like any other viral conjunctivitis is self-limiting and can be managed with lubricants and cold compresses unless cornea is involved. Topical antibiotics can be given to prevent secondary bacterial infection.

Medical follow up

Once the diagnosis is made, the patient should be quarantined and closely followed for the development of complications.

Surgery

There is no role of surgical management in COVID conjunctivitis.

Surgical follow up

None

Complications

COVID conjunctivitis is self-limiting and so far no ocular complications have been reported. However, the following complications may occur; punctate keratitis with subepithelial infiltrates, bacterial superinfection, conjunctival scarring and symblepharon, severe dry eye, irregular astigmatism, corneal ulceration, and corneal scarring.

Systemic complications include; acute respiratory distress syndrome, pneumonia, stroke, acute cardiac injury, cardiomyopathy, renal failure, and encephalopathy. In children, SARS-CoV-2 infection resulted in a severe multi-system inflammatory syndrome similar to Kawasaki disease and toxic shock syndrome.

Prognosis

COVID conjunctivitis resolves by itself without any morbidity if systemic complications do not occur.

Additional Resource

References

  1. Belser JA, Rota PA, Tumpey TM. Ocular tropism of respiratory viruses. Microbiol Mol Biol Rev 2013;77:144–56.doi:10.1128/MMBR.00058-12
  2. Arabi YM, Balkhy HH, Hayden FG, et al. Middle East respiratory syndrome. N Engl J Med 2017;376:584–94.doi:10.1056/NEJMsr1408795
  3. Yuen KSC, Chan W-M, Fan DSP, et al. Ocular screening in severe acute respiratory syndrome. Am J Ophthalmol 2004;137:773–4.
  4. Lu R, Zhao X, Li J, et al. Genomic characterization and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet 2020;395:565-574.
  5. Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020; 579:270.
  6. Sungnak W, Huang N, Bécavin C. et al. SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nat Med 2020;26:681–687. doi.10.1038/s41591-020-0868-6
  7. Hui KPY, et al. Tropism, replication competence, and innate immune responses of the coronavirus SARS-CoV-2 in human respiratory tract and conjunctiva: an analysis in ex-vivo and in-vitro cultures. Lancet Respiratory Med, published on line May 7, 2020. https://doi.org/10.1016/S2213-2600(20)30193-4.Accessed May 8, 2020
  8. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020;395(10229): 1054-1062. 
  9.  Lauer SA, Grantz KH, Bi Q, Jones FK, Zheng Q, Meredith HR, et al. The Incubation Period of Coronavirus Disease 2019 (COVID-19) From Publicly Reported Confirmed Cases: Estimation and Application. Ann Intern Med 2020;172(9):577-582
  10. Santarpia JL, Rivera DN, Herrera V, Morwitzer MJ, Creager H, Santarpia GW, et al. Transmission Potential of SARS-CoV-2 in Viral Shedding Observed at the University of Nebraska Medical Center. medRxiv 2020;20039446. doi:10.1101/2020.03.23.20039446
  11. Tsui PT, Kwok ML, Yuen H, Lai ST. Severe acute respiratory syndrome: clinical outcome and prognostic correlates. Emerg. Infect. Dis.2003;9:1064-1069.
  12. Guan W, Ni Z, Hu Y, Liang W, Ou C, He J, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med 2020; 382:1708-1720. Doi:10.1056/NEJMoa2002032
  13. Marinho PM, Marcos AAA, Romano AC, Nascimento H, Belfort R. Jr. Retinal findings in patients with COVID-19. The Lancet. 2020;395(10237):1610. doi: 10.1016/S0140-6736(20)31014-X.
  14. Xia J et al. J Med Virol. 2020. doi: 10.1002/jmv.25725.
  15. Cheema M, Aghazadeh H, Nazarali S, et al. Keratoconjunctivitis as the initial medical presentation of the novel coronavirus disease 2019 (COVID-19). [published online ahead of print, 2020 Apr 2]. Can J Ophthalmol. 2020;S0008-4182(20)30305-7. doi:10.1016/j.jcjo.2020.03.003
  16. Navel V, Chiambaretta F, Dutheil F. Haemorrhagic conjunctivitis with pseudomembranous related to SARS-CoV-2. Am J Ophthalmol 2020;19:100735. Doi: 10.1016/j.ajoc.2020.100735.
  17. Seah I, Agrawal R. Can the Coronavirus Disease 2019 (COVID-19) Affect the Eyes? A Review of Coronaviruses and Ocular Implications in Humans and Animals. Ocul Immunol Inflamm. 2020;28(3):391‐395. doi:10.1080/09273948.2020.1738501
  18. Turgut B. Adv Ophthalmol Vis Syst. 2020;10(2):31-34.
  19. Nalla  AK, Casto  AM, Huang  MW,  et al. Comparative performance of SARS-CoV-2 detection assays using seven different primer/probe sets and one assay kit.   J Clin Microbiol. 2020 May;58(6) . doi:10.1128/jcm.00557-20. PMID: 32269100.
  20. Wölfel  R, Corman  VM, Guggemos  W,  et al.  Virological assessment of hospitalized patients with COVID-2019.  Nature. 2020; 581:465–469.Doi:10.1038/s41586-020-2196-x
  21. Hung IF, Lung K, Tso EY, Liu R, Chung TW, Chu M, et al. Triple combination of interferon beta-1b, lopinavir–ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. Lancet 2020; 395(10238):1695-1704.