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Invited Commentary
March 5, 2020

Further Considerations About the Ophthalmic Sequelae of Ebola

Author Affiliations
  • 1Center for Global and Immigrant Health, Department of Epidemiology, UCLA Jonathan and Karin Fielding School of Public Health, University of California, Los Angeles, Los Angeles
  • 2The University of California, Los Angeles–Democratic Republic of Congo Health Research and Training Program, Kinshasa, Democratic Republic of Congo
  • 3Ocular Inflammatory Disease Center, UCLA Stein Eye Institute, David Geffen School of Medicine at UCLA, Los Angeles, California
  • 4Department of Ophthalmology, David Geffen School of Medicine at UCLA, Los Angeles, California
JAMA Ophthalmol. Published online March 5, 2020. doi:10.1001/jamaophthalmol.2020.0185

In this issue of JAMA Ophthalmology, Steptoe and associates present another in their series of articles dealing with ocular lesions found in survivors of the 2013-2016 outbreak of Ebola virus disease (EVD) in West Africa.1 They describe fundus changes that had occurred over a 1-year period among a cohort of 57 survivors of EVD whose median posthospitalization interval was slightly more than 2 years. This article expands on their June 2018 article2 about selected individuals from their primary cohort of 82 survivors of EVD; we also provided commentary about that article.3 Ebola virus disease has continued to be a major public health problem since those articles were published.

Three recent outbreaks of EVD have occurred in the Democratic Republic of the Congo (DRC), 1 in 2017 and 2 sequential outbreaks in 2018; one is still ongoing at the time of this writing. Occurrence of EVD in the northeast region of DRC was declared a “public health emergency of international concern”4 by the World Health Organization on July 17, 2019, after cases spread to the city of Goma, bordering the Republic of Rwanda. As of December 8, 2019, 3324 EVD cases had been reported; among the affected individuals, 2209 (66.5%) had died. In view of the high mortality associated with EVD, why study its ophthalmic manifestations? Also, what are the obstacles to doing so?

Ocular involvement adds substantially to EVD-associated morbidity among survivors of EVD; visual acuity loss limits activities of daily living, the ability to work, and the capacity to care for oneself and family members. An understanding of EVD-associated eye disease is increasingly important as the number of survivors increases. Not only are there current survivors of past EVD outbreaks, but the proportion of people with EVD who will survive current and future outbreaks is likely to increase because of new treatments in development. Candidate therapies have been studied through the Pamoja Tulinde Maisha (PALM; “Together Save Lives” in the Kiswahili language) trial in DRC,5 which was stopped early when 2 of 4 active treatments were found to be significantly better than control treatments. As noted by Steptoe and associates,1,2 the study of eye disease may provide insight into disease mechanisms, but there are more immediate, practical reasons for monitoring the eyes of people with EVD. As we have learned, the eye can be a reservoir of residual virus after treatment.3 We know from other infections that intraocular drug delivery may be poor, emphasizing the importance of monitoring eyes with EVD-associated lesions for a complete response to treatment. If progression of ocular lesions occurs, there may be late visual acuity loss. All of these examples highlight the need for a thorough understanding of the nature of EVD-associated ophthalmic lesions.

There are, however, substantial obstacles to achieving that understanding. Many individuals infected with Ebola virus are not in areas where they can be easily evaluated and followed up, especially with the sophisticated equipment and techniques used by Steptoe and associates.1,2 Many factors will hamper evaluation and follow-up: lack of trained personnel; poor infrastructure, including means of transportation; and political instability. Cataract and corneal diseases, which are common in Central and West Africa, may alter the ability to visualize the fundus.

Confounders must be also considered; they include other causes of retinal infection, which are common in Africa. Not only must their clinical presentations be differentiated from lesions caused by Ebola virus, but there might be interactions between pathogens that alter the host response to Ebola virus. Treatment and vaccination are other potential confounders.

Vaccination has become an important tool for controlling Ebola virus in the 2019 outbreaks and may alter the picture of EVD. A ring vaccination strategy with the recombinant vesicular stomatitis virus–Zaire Ebola virus-glycoprotein (rVSV-ZEBOV-GP) Ebola vaccine (Merck Sharp & Dohme) began 7 days after declaration of the outbreak by the DRC Ministry of Health6; by November 3, 2019, a reported 246 824 individuals at risk had been vaccinated.7 Among 217 172 individuals vaccinated as of September 8, 2019, 54 159 (24.9%) were contacts of someone with EVD and 149 837 (69.0%) were secondary contacts of people who had direct contact with individuals with EVD. Ebola virus disease has been documented after vaccination; it is unclear whether cases represent vaccine failures or disease that was already incubating at the time of vaccination. Vaccine efficacy is estimated to be 88.1% based on diagnosis of EVD any time after vaccination. A second vaccine (the Johnson & Johnson vaccine; Janssen Pharmaceutica) was introduced in DRC on December 8, 2019. Health care workers are being vaccinated with both vaccines in several neighboring countries considered to be at high risk for EVD outbreaks. Studies are needed to determine how vaccines and therapeutic interventions modulate the immune system response to Ebola virus and affect the short-term and long-term sequelae of EVD, including inflammatory eye disease.

The current article by Steptoe and associates1 adds to a growing body of information about the ophthalmic sequelae of EVD in the West Africa outbreak,8,9 yet illustrates some of the challenges of studying this disease. Their cohort was highly selected, and loss to follow-up (15 of 72 individuals [20.8%]) was substantial. Although longitudinal, their study interval was quite short compared with survival of up to 40 years among individuals infected in some past outbreaks.3 Discovery of new toxoplasmic retinochoroidal scars in 2 patients highlights the problem of concurrent infections. Without knowledge of the incidence of ocular involvement among individuals infected with Toxoplasma gondii in West Africa, the association between EVD and toxoplasmosis, if any, remains uncertain.

The authors make a distinction between so-called Ebola lesions and areas of dark without pressure (DWP), both of which are seen in survivors of EVD. As they state, a previous case-control study showed that Ebola lesions are specific to EVD, while DWP lesions have been seen in other conditions. Nevertheless, DWP may be associated with Ebola virus infection in this setting, and the evolution of these lesions may signal ongoing disease processes. Encouraging is the fact that no visual acuity was lost during their study period, but the continued evolution of DWP lesions is concerning.

In summary, it is now clear that the eye is a common target organ for Ebola virus, and there is a growing pool of survivors who need ophthalmologic evaluation and care. We are encouraged by the current attention being paid to the ophthalmic manifestations of EVD and efforts to develop procedures and facilities for examination of survivors of EVD.9 While there have been past descriptions of ophthalmic disease in very long-term survivors, sometimes by nonophthalmologists, these descriptions have been inadequate for a complete understanding of lesion characteristics, their course, and their association with other aspects of the disease.10 The current article by Steptoe and associates1 advances our knowledge incrementally, but additional work must be done in population-based studies. Critical is the need to identify lesions specifically caused by Ebola virus. It will also be important to refine techniques for quantifying lesions and inflammatory reactions precisely, which will allow cross-study comparisons and measurement of change during longitudinal studies. Investigations must be in the context of a better understanding of eye disease among African populations in general. We look forward to additional progress in all of these areas.

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Article Information

Corresponding Author: Gary N. Holland MD, Ocular Inflammatory Disease Center, UCLA Stein Eye Institute, David Geffen School of Medicine at UCLA, 100 Stein Plaza, Los Angeles, CA 90095-7000 (uveitis@jsei.ucla.edu).

Published Online: March 5, 2020. doi:10.1001/jamaophthalmol.2020.0185

Conflict of Interest Disclosures: Dr Rimoin reports receiving funds from the Faucett Catalyst Fund. Dr Holland reports receiving funds from the Skirball Foundation and an unrestricted grant to the UCLA Stein Eye Institute from Research to Prevent Blindness Inc. No other disclosures were reported.

References
1.
Steptoe  PJ, Momorie  F, Fornah  AD,  et al.  Evolving longitudinal retinal observations in a cohort of survivors of Ebola virus disease  [published online March 5, 2020].  JAMA Ophthalmol. doi:10.1001/jamaophthalmol.2020.0173Google Scholar
2.
Steptoe  PJ, Momorie  F, Fornah  AD,  et al.  Multimodal imaging and spatial analysis of Ebola retinal lesions in 14 survivors of Ebola virus disease.  JAMA Ophthalmol. 2018;136(6):689-693. doi:10.1001/jamaophthalmol.2018.1248PubMedGoogle ScholarCrossref
3.
Holland  GN, Rimoin  AW.  The ophthalmic sequelae of Ebola.  JAMA Ophthalmol. 2018;136(6):693-694. doi:10.1001/jamaophthalmol.2018.1237PubMedGoogle ScholarCrossref
4.
World Health Organization. Ebola outbreak in the Democratic Republic of the Congo declared a public health emergency of international concern. https://www.who.int/news-room/detail/17-07-2019-ebola-outbreak-in-the-democratic-republic-of-the-congo-declared-a-public-health-emergency-of-international-concern. Published July 17, 2019. Accessed December 17, 2019.
5.
Mulangu  S, Dodd  LE, Davey  RT  Jr,  et al; PALM Writing Group; PALM Consortium Study Team.  A randomized, controlled trial of Ebola virus disease therapeutics.  N Engl J Med. 2019;381(24):2293-2303. doi:10.1056/NEJMoa1910993PubMedGoogle ScholarCrossref
6.
World Health Organization. Preliminary results on the efficacy of rVSV-ZEBOV-GP Ebola vaccine using the ring vaccination strategy in the control of an Ebola outbreak in the Democratic Republic of the Congo: an example of integration of research into epidemic response. https://www.who.int/csr/resources/publications/ebola/ebola-ring-vaccination-results-12-april-2019.pdf. Published April 12, 2019. Accessed December 17, 2019.
7.
World Health Organization. Ebola virus disease Democratic Republic of Congo: external situation report 66 / 2019. https://www.who.int/publications-detail/ebola-virus-disease-democratic-republic-of-congo-external-situation-report-66-2019. Published November 5, 2019. Accessed December 17, 2019.
8.
Hereth-Hebert  E, Bah  MO, Etard  JF,  et al; Postebogui Study Group.  Ocular complications in survivors of the Ebola outbreak in Guinea.  Am J Ophthalmol. 2017;175:114-121. doi:10.1016/j.ajo.2016.12.005PubMedGoogle ScholarCrossref
9.
Shantha  JG, Hayek  BR, Crozier  I,  et al.  Development of a screening eye clinic for Ebola virus disease survivors: lessons learned and rapid implementation at ELWA Hospital in Monrovia, Liberia 2015.  PLoS Negl Trop Dis. 2019;13(3):e0007209. doi:10.1371/journal.pntd.0007209PubMedGoogle Scholar
10.
Kibadi  K, Mupapa  K, Kuvula  K,  et al.  Late ophthalmologic manifestations in survivors of the 1995 Ebola virus epidemic in Kikwit, Democratic Republic of the Congo.  J Infect Dis. 1999;179(suppl 1):S13-S14. doi:10.1086/514288PubMedGoogle ScholarCrossref
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