Ebola virus poses threat of ocular complications during convalescence

As the 2014 Ebola epidemic in West Africa wanes, the largest number of survivors of an Ebola outbreak in history are left in its wake, with ocular complications persisting through convalescence and forcing a demand for better understanding of the lingering effects of the virus.

Chronic pain, headaches and eye problems such as eye pain, eye redness and blurred vision are some of the “post-Ebola syndrome” symptoms seen among survivors in West Africa.

“It seems that eye problems are very common in Ebola survivors. Uveitis, or inflammation of the interior of the eye, seems to be particularly common and can be particularly severe, even leading to blindness,” Daniel G. Bausch, MD, MPH&TM, senior consultant for the WHO’s Pandemic and Epidemic Diseases clinical team, said. “These are not minor complications. These are things that can have a major impact on the lives of Ebola survivors.”

Although there are up to 16,000 survivors of Ebola virus infection in West Africa, few systematic studies have been conducted since the epidemic peaked, and it is unclear how common, severe or persistent these late complications are.

A case report, published in The New England Journal of Medicine, discussed the clinical course of Ian Crozier, MD, who developed severe, acute, unilateral panuveitis, which is a combination of anterior, intermediate and posterior uveitis, as a direct cytopathic effect of the Ebola virus just 9 weeks after the clearance of viremia.

Images: Yeh S and colleagues

Case report

After working in an Ebola treatment unit in Sierra Leone, Crozier, an infectious disease specialist previously mentoring in HIV management in Uganda, was diagnosed with Ebola virus disease (EVD) on Sept. 6, 2014, and evacuated to Emory Hospital in Atlanta. He underwent treatment with TKM-100802 (Tekmira Pharmaceuticals), an experimental small interfering RNA antiviral agent, as well as convalescent plasma and aggressive supportive care, the report said. While Crozier was critically ill and hospitalized for 40 days and nights, he recovered and was discharged after his blood and urine tested negative for the Ebola virus.

After discharge, 10 weeks after the onset of initial symptoms, new symptoms developed, including occasional bilateral foreign body sensation and photophobia, as well as a need for an adjusted prescription for his reading glasses. The initial ophthalmic evaluation revealed multiple peripheral chorioretinal scars with hypopigmented halos in both eyes and a small intraretinal hemorrhage adjacent to one scar in the left eye, leading to a diagnosis of posterior uveitis. The plan of action was close clinical follow-up.

One month after discharge and 14 weeks after the EVD diagnosis, Crozier presented with an acute onset of redness, blurred vision with halos, pain and photophobia in his left eye, as well as a highly elevated IOP of 44 mm Hg. Slit lamp examination showed conjunctival injection, mild corneal edema, rare nongranulomatous keratic precipitates, and grade 1+ leucocytes and protein flare in the anterior chamber. He was diagnosed with hypertensive anterior uveitis in the left eye.

Treatment challenges

Steven Yeh, MD, director of uveitis and vasculitis at Emory Eye Center, and Jessica Shantha, MD, a third-year Emory ophthalmology resident at the time, were careful in determining which treatment plan to follow because no antiviral drug has been proven to work against the Ebola virus. Additionally, the use of corticosteroids could have potentially made the infection worse.

Image: Emory Eye Center

“We knew that because he had viral persistence, it was always a balance of being able to treat the inflammatory process and knowing that the live virus inside the eye actually might take a different course depending on what treatments he was exposed to,” Yeh said. “We knew that he had severe inflammation that was ongoing, and we also knew that we wanted to treat that inflammation with corticosteroids. This was tempered by the fact that we also know that corticosteroids can sometimes cause infectious processes to worsen.”

Crozier was treated with 1% prednisolone acetate eye drops four times daily in combination with 500 mg of oral acetazolamide twice daily, as well as eye drops containing 0.2% brimonidine, 2% dorzolamide and 0.5% timolol twice daily. Therapy was increased after inflammation escalated.

With the continued escalation of inflammation, paracentesis of the anterior chamber was performed, and the aqueous humor that was extracted tested positive for the Ebola virus RNA. With a conjunctival swab and peripheral blood specimen both testing negative, Crozier posed no known risk of Ebola transmission to others.

Five days after the onset of symptoms, visual acuity in Crozier’s left eye decreased to 20/60 with evidence of scleritis, anterior uveitis and intermediate uveitis. Oral prednisone was then added to the therapy regimen.

In the subsequent 72 hours, the scleritis improved but the anterior uveitis worsened, and visual acuity decreased to 20/400. Ten days after his symptoms started, Crozier’s left eye changed color from blue to a green coloration.

With continued decline in visual acuity despite symptomatic improvement, Yeh, Shantha and infectious disease colleagues initiated topical difluprednate (Alcon Laboratories), a 21-day course of oral favipiravir (MediVector), a periocular injection of triamcinolone and a 10-week tapering course of oral prednisone.

Three months after presentation, the uveitis in Crozier’s left eye was resolving and his visual acuity recovered to 20/15. He continues to undergo ophthalmic evaluation.

Ocular manifestations of Ebola

The 2014 Ebola outbreak has been the largest to date. Past outbreaks consisted of no more than a few hundred cases, with fatality rates of 50% to 80%.

In 1995, an Ebola epidemic occurred in the Democratic Republic of the Congo with a cumulative total of 318 cases, with only 71 survivors. Twenty survivors were enrolled in a retrospective study, in which three patients presented with uveitis between 42 days and 72 days after onset of the virus. Patients were treated with 1% atropine and steroids.

Image: Beth Fankhauser

“This study was important in that it told us that patients can develop an intermediate uveitis as in Dr. Crozier’s case, but also that all of their patients actually resolved with topical corticosteroid treatment,” Shantha said. “That helped us feel a little bit more comfortable treating with corticosteroids, knowing that their patients all got better.”

Because so few studies have been performed, the incidence and clinical manifestations of ocular persistence from the Ebola virus are uncertain and of particular concern among health care providers.

“It is concerning that the virus can persist in immune-privileged areas such as the eye and cause problems for the patient, as well as be potential sources of contagion for others,” Gargi Khare Vora, MD, assistant professor in the department of ophthalmology at Duke University, said.

Early ocular manifestations of the Ebola virus include conjunctival hyperemia, as well as reports of lacrimation and conjunctival hemorrhage, which can most likely be attributed to thrombocytopenia, she said.

Late ocular manifestations include various forms of uveitis, wherein patients can present with blurred vision, eye pain, decreased visual acuity, retinal hemorrhages and photophobia from ocular inflammation. Approximately 40% of survivors have blind spots in their visual fields.

“Most data are not controlled, so it’s hard to sort out whether someone’s visual acuity is actually due to Ebola or existed before infection,” Bausch said. “Pain in the eye is certainly a concern, one that we see frequently, with concern that it is indicative of uveitis that can even lead to blindness if not treated.”

Prevention and protocols

In Crozier’s case, all examinations and procedures were vetted with the Infectious Disease Division, in particular physicians with the Serious Communicable Disease Unit at Emory University Hospital, Shantha said. The team of physicians and technicians also followed protocol set by the CDC.

“Since the Ebola virus is transmitted by contact with bodily fluids, health care workers would need to wear personal protective equipment covering all skin, mask and eye protection. In accordance with CDC recommendation, a trained observer should be present to ensure all protocol is correctly followed,” Vora said. “The Ebola virus is killed with hospital-grade disinfectants, and thus all equipment in contact with the patient needs to be sterilized or disposed of appropriately.”

Although general ophthalmic examination can be safe, the active virus still persists in the aqueous humor, and any providers in contact with this fluid potentially could be at risk of exposure to the virus, Yeh said.

“Thus, if patients have penetrating trauma or require ocular surgery including cataract surgery, ophthalmologists and surgical staff could potentially be exposed to the virus,” he said. “No studies or reports that I have seen have discussed this scenario, but it could potentially be a concern with future Ebola survivors.”

When screening survivors, health care workers should take precautionary measures, such as wearing protective goggles, face masks, gowns and gloves, and look for any signs of the Ebola virus in the eye, including visual acuity assessment, anterior segment examination, measurement of IOP and fully dilated fundus examination, Naz Jehangir, MD, and Majid Moshirfar, MD, FACS, from the University of California San Francisco’s department of ophthalmology, said.

“Regular follow-up depending on the baseline evaluation should be encouraged,” they said. “More ophthalmic health care services are needed in these areas to screen and evaluate patients for ophthalmic manifestations.”

Continuing efforts in West Africa

With such a large number of survivors to screen and treat, challenges in West Africa include resource and personnel limitations, as well as issues of access from rural settings.

“Thousands of survivors are at risk of developing ocular complications with the virus viable in the ocular fluid months after the initial infection,” Jehangir and Moshirfar said. “Lack of ophthalmologists in the affected areas and high infectivity of the virus make screening for detection of ocular signs difficult.”

In order to address this issue, groups from Emory University and the National Eye Institute recently met in Freetown, Sierra Leone, to discuss screening and treatment protocols using expert advice from those who have worked with Ebola victims and survivors, particularly those with problems in the eye, Bausch said.

Funded by the Serving in Mission group and Eternal Love Winning Africa (ELWA) Hospital in Monrovia, Liberia, Yeh and Shantha, along with Crozier and Brent Hayek, MD,of the Emory Eye Center, joined ELWA Medical Director John Fankhauser, MD, to help with treatments and supplies to assess approximately 100 survivors with ophthalmic symptoms following recovery from EVD.

“Dr. Fankhauser contacted Dr. Yeh and had noticed that many of his survivors in his survivor clinics were developing ocular symptoms, and so he wanted a team to come and set up a mobile clinic in his outpatient clinic to train some of his staff as well as evaluate EVD survivors,” Shantha said. “That was really our goal, to help educate their staff as well as other ophthalmic providers and to screen survivors.”

During these overseas efforts, called “Quiet Eye West Africa,” Yeh, Shantha, Hayek and Crozier himself used their experiences in Crozier’s clinical course in their assessment of Ebola survivors. The Quiet Eye West Africa project team set up an ophthalmology clinic, assisted with patient flow, worked with local providers and screened survivors for eye disease; the survivors were referred to local eye care providers for ongoing care.

“The goals were to assess the situation, to exchange information with the ophthalmologists and eye care providers on the ground, including the Ministry of Health in Liberia, and to provide clinical care,” Yeh said. “It led to an initial assessment of what the eye disease involves so we could inform other groups in West Africa about eye disease in Ebola survivors and try to figure out the spectrum and severity of disease. I think we were able to accomplish the initial phase of this during our visit to Liberia. There are many groups, including the National Institutes of Health, that are continuing to assess Ebola survivors longitudinally in Liberia.”

With ongoing work and additional trips, the Quiet Eye West Africa team has continued to collaborate with the WHO, Partners in Health, Médecins Sans Frontières, Helen Keller International, local ophthalmologists and many other partners in Sierra Leone to broadly assess the on-the-ground situation within West Africa.

Image: Yeh S

Moving forward

Ebola survivors have mental and social problems in addition to medical problems, according to Bausch.

Going forward, eye care will be an important aspect of Ebola survivors’ ongoing care, in addition to addressing their psychosocial issues and other conditions that emerge in the context of the post-Ebola syndrome, Yeh said.

“The Ebola outbreak is fading, at least from public media discussion, and there are fewer and fewer cases, fortunately. But survivors need long-term, ongoing care, particularly since we are continuing to assess the incidence and prevalence of the eye disease,” he said.

The precise role of the various corticosteroid interventions used in Crozier’s case, the role of antiviral treatments, the natural history of the disease and the different severities of the disease all still need to be studied.

Analysis of tears, conjunctival samples and aqueous fluid will help in determining how long the virus is viable in ocular fluid, and screening for ocular signs should be done for early detection and to prevent visual loss, Jehangir and Moshirfar said.

“Not much is known about ocular transmission of the virus during cases of ocular complication secondary to Ebola virus, which means that thousands of Ebola survivors and health care workers in their home countries will need to be monitored for eye disease in the post-Ebola period,” Jehangir and Moshirfar said.

“Education and proper dissemination of vaccinations are recommended to help prevent spread of the disease and future outbreaks,” Vora said. “However, a few antiviral treatment therapies are under investigation to assist in eliminating Ebola.”

Yeh and Shantha believe that Crozier’s case may help prevent blindness in Ebola survivors by raising awareness of the severity of uveitis. From a public health standpoint, the potential threat of viral persistence in ocular fluids to eye care providers and other health care workers in West Africa is also important to recognize.

“It is important to be really vigilant about screening and treating, and also monitoring the patients while on therapy because of the complexities and nuances of uveitis,” Yeh said. “Moving forward, we also need to think about survivors more broadly to encompass their eye and systemic disease.”

With the worst of the 2014 Ebola outbreak in the past, Bausch said he considers late complications such as ocular persistence during convalescence to be an “emergency within an emergency.”

“We need to act rapidly,” he said. “And resources are a problem, particularly technical and financial. So donations are key at this point in order to face those problems when treating Ebola survivors.” – by Kristie L. Kahl

Editor’s note: Donations for funding eye care services for Ebola survivors can be made through Emory’s Development office by specifying Quiet Eye West Africa under the Global Ophthalmology designation at: https://securelb.imodules.com/s/1705/giving/index.aspx?sid=1705&gid=3&pgid=600&cid=1358&dids=2698&bledit=1&appealcode=W6GOE

• References:
• Ebola (Ebola virus disease). CDC website. http://www.cdc.gov/vhf/ebola/healthcare-us/evaluating-patients/think-ebola.html. Accessed Sept. 4, 2015.
• Grady D. After nearly claiming his life, Ebola lurked in a doctor’s eye. The New York Times. http://www.nytimes.com/2015/05/08/health/weeks-after-his-recovery-ebola-lurked-in-a-doctors-eye.html?_r=0. Published May 7, 2015. Accessed Sept. 4, 2015.
• Kibadi K, et al. J Infect Dis. 1999;doi:10.1086/514288.
• Moshirfar M, et al. Clin Ophthalmol. 2014;doi:10.2147/OPTH.S73583.
• Mott M. On the ground in Liberia: Two YOs tackle the Ebola epidemic in West Africa. American Academy of Ophthalmology website. http://www.aao.org/young-ophthalmologists/yo-info/article/on-ground-in-liberia-two-yos-tackle-ebola-epidemic. Published May 19, 2015. Accessed Sept. 4, 2015.
• Shieh C, et al. JAMA Ophthalmol. 2015;doi:10.1001./jamaophthalmol.2015.0703.
• Varkey JB, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1500306.

• For more information:
• Daniel G. Bausch, MD, MPH&TM, can be reached at Department of Pandemic and Epidemic Diseases, World Health Organization, Avenue Appia 20, 1211 Geneva 27, Switzerland; email: bauschd@who.int.
• Naz Jehangir, MD, can be reached at UCSF Department of Ophthalmology, 10 Koret Way, K101, San Francisco, CA 94143, USA; email: njehangir@hotmail.com.
• Majid Moshirfar, MD, FACS, can be reached at UCSF Department of Ophthalmology, 10 Koret Way, K101, San Francisco, CA 94143; email: majid.moshirfar@ucsf.edu.
• Jessica Shantha, MD, can be reached at Emory Clinic Building B, 1365B Clifton Road, NE, Atlanta, GA 30322.
• Gargi Khare Vora, MD, can be reached at Department of Ophthalmology, Duke University, 2351 Erwin Road #3802, Durham, NC 27705; email: gargi.vora@dm.duke.edu.
• Steven Yeh, MD, can be reached at Emory Clinic Building B, 1365B Clifton Road, NE, Atlanta, GA 30322.

Disclosures: The sources in this article report no relevant financial disclosures.

At what point in the management of infectious uveitis do you consider weighing the risks and benefits of corticosteroids?

Controlling the infection first

In considering corticosteroids, we apply similar principles in treating challenging cases of infectious uveitis. Uveitis may be caused by different etiologies: infectious, non-infectious, or masquerade syndromes – for example, malignancy that manifested as uveitis. Once we have gathered sufficient evidence(s) to suggest that the underlying etiology is infectious, then our first and foremost step is to treat the infection broadly and rapidly. For example, if the patient has uveitis that is secondary to syphilis or tuberculosis, our initial approach is to treat the infection acutely with medical therapy that can eradicate the infectious agents.
However, we also recognize that there are two stages in the course of the disease: the early infectious stage and the subsequent inflammatory response stage. Therefore, we would like to treat patients initially very aggressively with anti-infectious agents and shortly afterward, to begin anti-inflammatory therapy to control the full cascade of disease. Thus, in a case like Ebola-associated uveitis, we are in complete agreement that initially, the patient should be treated with the most efficacious algorithm to control the viral infection. Soon afterwards, however, the patient should begin anti-inflammatory therapy, with either prednisone or its equivalence.

I believe that, in employing such therapeutic principles, we very much follow the guidelines that have been established to manage infectious uveitis. Therefore, in this case, initiating prednisone is appropriate. I usually allow 72 to 96 hours after the initiation of anti-infectious treatment before beginning anti-inflammatory agents. For example, when I treat syphilitic uveitis, I begin intravenous penicillin for 2 to 3 days and then I start systemic steroids. The stepladder is the best way to control the overall process in managing the infection and the subsequent inflammation.

Quan Dong Nguyen, MD, MSc, is the chairman and director of the Stanley M. Truhlsen Eye Institute. Disclosure: Nguyen reports no relevant financial disclosures.

Editor’s note: This article has been updated to reflect the corrected version of Dr. Nguyen’s response.

Risk relates to reactivation of infection

Corticosteroids, being such powerful therapeutic agents, are commonly associated with a wide range of side effects, both ocular and systemic. When dealing with uveitis secondary to a primary infective condition, attention should be paid to the optimal timing for initiation of steroidal therapy. The main risk of a wrong choice relates to worsening or reactivation of the infection due to corticosteroids’ immunosuppressive properties. It is not unusual that viable pathogens can be found in vitreous and aqueous specimens even when the primary condition appears to be well controlled with systemic medical therapy. An extreme case of this is represented by Ebola virus disease: It has been reported that viable viruses can unexpectedly be detected in aqueous humor even 2 months after the clearance of viremia. Thus, a conscious approach consists of recognizing the primary condition and immediately starting the specific anti-infective drugs associated with topical/local anti-inflammatory/steroidal therapy. Systemic steroidal therapy should then be initiated only when the primary disease is well-controlled. There is no fixed term for this because it depends on the pathogen itself and on the time required by the anti-infective drug to reach the minimum inhibitory concentration in the infection site and to achieve anti-infectious efficacy. In general terms, we learned that in the majority of cases the most appropriate time for starting systemic steroids varies between 1 and 3 days after initiation of the anti-infective treatment. It must now be noted that the most critical time frame is during the first 1 to 2 days after initiation of systemic steroids. Worsening of the clinical picture can be seen even within 2 to 3 hours after a premature immunosuppressive therapy. Thus, patients should be frequently examined during this period.

Additionally, the immunocompetent status of the patient should be carefully evaluated before starting therapy. For example, corticosteroids and immunomodulatory therapies have been found to enhance immune suppression and to facilitate opportunistic infections in HIV-infected patients. On the other side, they can be very helpful as an adjunctive therapy in the treatment of the primary opportunistic infection both when the infection affects the ocular tissues and when it is located in other districts (eg, Pneumocystis carinii pneumonia).

In conclusion, in noninfectious uveitis, corticosteroids are the mainstay of treatment and should be used promptly, aggressively and with confidence; in case of infectious uveitis, the primary condition should be controlled with specific anti-infective agents before considering reducing inflammation with corticosteroids.

Daniele Veritti, MD, is from the Department of Medical and Biological Sciences – Ophthalmology, University of Udine, Italy. Disclosure: Veritti reports no relevant financial disclosures.