Emerging Pathogens and Ophthalmic Disease

Emerging Pathogens and Ophthalmic Disease: Comparison

Please note this is a comparison between Version 1 by Tolulope Fashina and Version 2 by Peter Tang.

Ophthalmologists are essential health care workers who provide urgent and emergent vision care services during outbreaks and address the ocular consequences of epidemic and pandemic infectious diseases. In 2017, the World Health Organization (WHO) identified high priority pathogens likely to cause a future epidemic with the goal of guiding research and development to improve diagnostic tests, vaccines, and medicines.

emerging infectious disease
ophthalmic manifestations
ophthalmic sequalae
retinitis
uveitis
viral persistence
ebola virus disease
ebola survivor
marburg virus disease
anterior uveitis
posterior uveitis
tear film transmission
COVID-19

1. Introduction

In response to the West African Ebola Virus Disease (EVD) epidemic in 2014–2016, experts convened by the World Health Organization (WHO) identified a list of eight emerging infectious diseases with the potential to evolve into a public health emergency in the future, and for which there were few countermeasures for a sufficient preventive or curative response ^[1][2][1,2]. These WHO efforts aimed to better identify country-specific constraints in response capabilities, generate accelerated research and development, and enhance the WHO’s capacity to facilitate access to diagnostic, preventive, and therapeutic products in public health emergencies. The diseases included: Crimean-Congo hemorrhagic fever, Filovirus diseases (Marburg hemorrhagic fever and EVD), human Coronaviruses, Lassa Fever, Nipah virus infection, Zika, Rift Valley fever, and Disease X [2].

New infectious agents are often underestimated, and rapid public health recognition and interventions are necessary to reduce further infection. Ophthalmologists remain essential to the efforts of global health and addressing infectious disease threats, exhibited prominently by the trachoma epidemic caused by Chlamydia trachomatis ^[3][4][3,4], Zika virus, Yellow Fever, and EVD outbreaks ^[5][6][7][5,6,7]. The significant ophthalmic complications of the EVD epidemic further highlighted the key role that ophthalmologists may play in outbreak responses, particularly when ocular sequelae have been incompletely studied [8]. Given the potential for vision-compromising ophthalmic complications either during the acute phase of infectious illness disease or as long-term sequelae, as well as viral transmission to and from ocular surface mucosal surfaces, there is an urgent need to recognize and understand infectious eye diseases in the global health context.

This entry summarizes the key ophthalmic consequences of WHO High Priority pathogens, viral disease pathogenesis, disease findings, and areas of unmet research need (Table 1).

Table 1. Summary of World Health Organization High Priority diseases with systemic and ophthalmic findings of clinical significance.

Disease	Virus Family		Geographic Region(s) and Countries Affected		Systemic Findings			Ophthalmic Disease Findings			Other Vision Health Implications
Crimean-Congo Hemorrhagic fever	Nairovirus	(Bunyavirus)		Eastern Europe, Asia, Middle East, Central Africa, West Africa, South Africa, Madagascar. [9]			Headache, fever, back pain, joint pain, and vomiting. Illness progression to severe bruising, nosebleeds, and uncontrolled bleeding. [10]			Multiple subconjunctival hemorrhages, retinal hemorrhage. [10]
Marburg-Virus Disease	Marburg Virus	(Filovirus)		Central Africa—Democratic Republic of Congo, Angola; East Africa- Uganda, Kenya; South Africa, Germany, Netherlands, Serbia, United States, Yugoslavia. [9]			Fever, headache, malaise, diarrhea, vomiting. Extreme lethargy, and multiple organ failure as disease progresses without treatment. [11] Orchitis in severe cases. [12]			Acute MVD: Conjunctivitis, iritis, retinitis. [13]		Convalescence: iritis, increased intraocular pressure, active unilateral hypertensive uveitis. ^[13]^[14]	[ 13,14]		Marburg viral persistence in aqueous tap during convalescence reported. ^[13]^[14]	[13,14]
Ebola Virus Disease	Ebola virus (Filovirus)		Democratic Republic of the Congo, West Africa—Sierra Leone, Liberia, Guinea, Nigeria, Senegal, Mali; United States, United Kingdom, Italy, Spain. [9]		Fever, vomiting, diarrhea, hypovolemic shock, and multi-organ failure without treatment. ^[15]^[16]	[15,16]		Acute EVD: Conjunctivitis, subconjunctival hemorrhage		Convalescence: Anterior uveitis, Intermediate uveitis, panuveitis with heterochromia; uveitis complications if not treated; optic neuropathy. ^[16]^[17]	[ 16,17]		Risk of viral persistence in aqueous humor reported during convalescence. ^[16]^[17]	[16,17]
Human Coronavirus	Coronaviridae		SARS-CoV: Southeast Asia, Europe, South Africa.	MERS-CoV: Middle East—Saudi Arabia, Lebanon, Iran, United Arab Emirates, Oman, Jordan; Europe- Greece, Germany, Italy; Asia; Philippines, Malaysia, China, Thailand; United States, United Kingdom.	[ 9]	SARS-CoV-2: 191 countries affected globally to date.	[ 18 ]		SARS-CoV: Fever, cough, headache, malaise, shortness of breath. ^[18]^[19]	[18,19]	MERS-CoV: fever, cough, shortness of breath, diarrhea, vomiting ^[20]^[21]	[ 20,21]	SARS-CoV-2: Fever, cough, fatigue, headache, shortness of breath, sore throat, loss of taste or smell. ^[ ^18]^[22]	[ 18 ,22]		SARS-CoV: SARS-CoV RNA seen in tear film during early phase of SARS infection. ^[23]^[24]	[23,24]	MERS-CoV: No reports of ophthalmic findings to-date	SARS-CoV-2: Chemosis and Conjunctivitis reported in COVID-19 infection, SARS-CoV-2 RNA seen in conjunctival swab and Schirmer’s strip. ^[ ^25]^[26]	[ 25 ,26]	Retinal manifestations including hyperreflective lesions reported on OCT, cotton wool spots and microhemorrhages seen. ^[ ²⁷ ^]^[28]	[ 27 , 28]
Lassa fever	Mammarenavirus	(Arenavirus)		West Africa- Sierra Leone, Guinea, Liberia, and Nigeria. [9]			Fever, sore throat, vomiting, malaise. Neurological complications including hearing loss in severe cases. ^[29]^[30]	[29,30]		Acute Lassa fever: Conjunctivitis		Convalescence: cataract, chorioretinal scarring, retinal fibrosis, and vitreous opacity noticed.		Anterior uveitis, iritis. ^[ ^31]^[32]	[ 31 ,32]		Visual acuity worsened in LHF survivors with ophthalmic manifestations. [32]
Nipah Virus	Henipavirus	(Paramyxoviridae)		Malaysia, Bangladesh, India, Singapore, Cambodia, Ghana, Indonesia, Madagascar, the Philippines, and Thailand. [9]			Fever, headache, vomiting. Respiratory and neurologic complications including seizures recorded as illness progresses. ^[33]^[34]	[33,34]		Neurological associated dysfunctions including pupillary abnormalities, oculomotor palsies, abnormal oculocephalic reflexes, nystagmus, persistent diplopia from cranial nerve VI palsy, and retinal artery occlusion. ^[35]^[36]	[35,36]		Ptosis, miosis, and anhidrosis associated with Horner syndrome noticed as late manifestations. [37]
Rift Valley fever	Phlebovirus	(Bunyaviridae)		Sub-Saharan Africa-Egypt, the Gambia, Kenya, Madagascar, Mauritania, Mozambique, Namibia, Saudi Arabia, Senegal, South Africa, South Sudan, Sudan, Tanzania, Yemen, Zambia, Zimbabwe. [25]			Fever, malaise, back pain, and dizziness. Neurological complications including seizures as disease progresses. [38]			Non-granulomatous anterior uveitis, Macular and paramacular retinitis, retinal hemorrhage, optic disc edema, vasculitis. ^[39]^[40]	[39,40]
Mosquito transmitted diseases	Chikungunya: Alphavirus (Togavirus)	Zika and Dengue: Flavivirus		Chikungunya: Sub-Saharan Africa- Tanzania, Kenya; India, Indonesia, Thailand, Brazil, Colombia. [9]		Zika: South America, Central America, North America, and the Caribbean.	[ 9]	Dengue: Caribbean- Guyana, Grenada, Haiti, Jamaica, Panama; Asia- Bangladesh, Cambodia, Malaysia, Thailand; Africa- Ethiopia, Burkina Faso, Eritrea, Somalia.	[ 41 ]		Chikungunya: fever, headache, joint pain, joint swelling. [25]		Zika: Asymptomatic in most cases. Mild symptoms including fever, rash, headache, and joint pain seen in some cases	[ 42].	Dengue: asymptomatic in most cases. Mucousal bleeding, nausea and vomiting in some cases. Multiple organ failure and shock seen as complications if left untreated.	[ 43 ]		Chikungunya: photophobia, conjunctival injection, retroocular pain, and floaters. Anterior uveitis, optic neuritis, and retinitis. [25]	Zika: Conjunctivitis, Uveitis, unilateral acute maculopathy noticed in adults during acute phase.		Macular scarring, retinal mottling, chorioretinal atrophy, optic nerve hypoplasia noticed as complications in congenital syndrome.	[ 42 ]	Dengue: Uveitis, Sub-conjunctival hemorrhage, maculopathy.	[ 25 ]

2. Pathophysiology of Ocular Manifestations of Viral Illness

The pathogenesis of ocular manifestations vary between viruses given different cell targets and disease-specific immunologic response. Respiratory viruses may often cause ocular symptoms and signs given the anatomic continuity between the ocular and respiratory systems via the nasolacrimal duct system. In addition, hand-eye contact increases the risk of contaminating the conjunctival epithelium from droplets and body fluids.

Delayed onset of some ocular symptoms may indicate a delayed immune response due to antigenic mimicry, delayed hypersensitivity reactions, or stimulation of a pathogenic lymphocyte reaction. Viral persistence in the eye for pathogens that may establish residence in the immune privileged eye may also contribute to inflammatory activation. In EVD survivors, for example, viral persistence has been detected and is associated with severe panuveitis, optic neuropathy, and iris heterochromia. Understanding this interplay between viral infection and severe inflammation is a key component in determination of an appropriate medical countermeasure, which may include antiviral and anti-inflammatory medications [8]. Besides direct lytic viral effects, inflammatory mechanisms and coagulation abnormalities can lead to endothelial damage which may lead to damage to the retinal circulation and resultant retinopathy ^[11][25][11,25]. Known pathophysiologic mechanisms specific for ocular disease are described in the subheadings for each viral pathogen.

3. Conclusions

As recent outbreaks including Zika and Ebola have highlighted the impact of epidemic and pandemic threats on vision health, there remains an imperative to advance diagnostic and therapeutic tools for ophthalmic care and research, as part of the public health responses during infectious disease outbreaks ^{[15][16][17][42]}[15,16,17,42]. While ophthalmic findings have been observed in a minority of cases of COVID-19 (e.g., conjunctivitis, retinopathy), assessment of SARS-CoV-2 within the ocular surface has demonstrated the presence of SARS-CoV-2 viral RNA within tear film ^{[11][27][28][44]}[11,27,28,50]. The protocols employed to understand the clinical phenotypes of these WHO high priority viral pathogens, as well as methods for ocular fluid sampling (i.e., tear film, aqueous humor), are key learnings that will inform research related to ophthalmic disease in other emerging infectious disease threats.

The ophthalmic sequelae and vision health consequences described in association with WHO High Priority Pathogens range in the degree of visual morbidity (i.e., high morbidity with Rift Valley Fever retinopathy ^[38][39][38,39] and potential for vision-threatening uveitis with EVD [8] versus infrequent conjunctivitis observed with COVID-19 [11]). However, there also remain public health implications given the unique ability for virus to persist within the eye (e.g., Marburg, Ebola virus) and potential for viral presence in tear film during acute infection (e.g., SARS-CoV-1 and SARS-CoV-2).

Understanding the disease phenotypes on this WHO high priority roadmap will provide not only useful information to for patients during epidemic and outbreak threats from known agents, but also will allow emergency responders to develop health systems needed to protect vision as outbreaks emerge and evolve in the future.