Opinion
VIEWPOINT
Christine Shieh, MD Department of Ophthalmology, Duke University, Durham, North Carolina. Gargi Vora, MD Department of Ophthalmology, Duke University, Durham, North Carolina. Terry Kim, MD Department of Ophthalmology, Duke University, Durham, North Carolina.
Corresponding Author: Terry Kim, MD, Department of Ophthalmology, Duke University, 2351 Erwin Rd, DUMC 3802, Durham, NC 27705 ([email protected] .edu).
jamaophthalmology.com
Eyes on Ebola Virus Disease The current Ebola epidemic has been deemed the largest in history, with the World Health Organization declaring it a “public health emergency of international concern.”1 Ebola virus disease has a high fatality rate, and the Ebola virus belongs to the family Filoviridae, a family of viruses that causes hemorrhagic fever in humans and nonhuman primates.2 Bats are suspected to be the reservoir hosts.2 Many hospitals and practices have protocols to screen patients for Ebola. For example, at Duke University Medical Center in Durham, North Carolina, our eye clinics have posted signs asking patients, even if they are asymptomatic, to alert our staff if they have recently traveled to West Africa, specifically Guinea, Liberia, Mali, Nigeria, or Sierra Leone. Even asymptomatic patients should be of high interest if they have traveled to this region because it takes 2 to 21 days from the time of Ebola virus infection to the commencement of symptoms.3 Per the American Academy of Ophthalmology and the Centers for Disease Control and Prevention (CDC), suspected patients should be isolated from other patients, and the local or state health officials should be immediately alerted to determine whether testing is needed. In turn, the US health department reports to the CDC’s Emergency Operations Center. Patients are not considered infected until they have developed symptoms.3 Early symptoms include sudden onset of fever, severe headache, and constitutional symptoms such as joint/ muscle aches, chills, and fatigue.1,3 Late symptoms include vomiting, diarrhea, rash, and internal and external bleeding, usually from the eyes.1,3 As ophthalmologists and physicians, it is important for us to be aware of other ocular symptoms and signs of Ebola virus disease. A retrospective case series of 103 patients in the 1995 outbreak of Ebola virus documented bilateral conjunctival hyperemia as an early sign of the virus in patients; this was not positively or negatively correlated with survival.4 Another study of the same outbreak followed up 21 patients with Ebola virus disease who survived and noted that 4 of these survivors developed uveitis during convalescence.5 These patients were successfully treated with topical atropine, 1%, and corticosteroid drops, and the pathogenesis of the disease was attributed to a delayed hypersensitivity reaction to viral antigens.5 It is critical for health care personnel to be mindful of protecting themselves and of preventing the further spread of the virus. The virus is transmitted through direct contact (through fissures in the skin or in the mucous membranes of the eyes, nose, or mouth) or via the blood/body fluids of infected patients.3 The bodies of deceased patients with Ebola virus disease still present a risk because the virus can survive for several days at room temperature in the blood and in
body fluids.3 Airborne human-to-human transmission has not definitely been demonstrated, although it has been hypothesized. Other, less common means of transmission that have been implicated include skin-to-skin contact with an infected patient and indirect exposure to blood and body fluids (via fomites) due to the dried virus surviving on doorknobs and countertops for several hours.3 Fortunately, the Ebola virus is killed with hospitalgrade disinfectants, such as household bleach, so all equipment used with any possibly infected patients should be appropriately cleaned and sterilized, although ideally disposable equipment would be used.3 In addition, owing to the various means of human-tohuman transmission, health care workers are recommended to wear personal protective equipment (PPE) covering all skin.3 According to PPE policy, in addition to gowns and gloves, it is important for health care workers to wear masks and eye protection. The CDC’s PPE policy also recommends that there is a trained observer to monitor all health care workers to ensure they properly put on and remove their PEE. A more detailed PPE protocol is available at the CDC website (http://www.cdc.gov/vhf/ebola/hcp/procedures-for-ppe .html). Virus transmission has been studied in the laboratory as well. Kondratowicz et al6 have proposed that TIM-1 (T-cell immunoglobulin and mucin domain 1) is a likely receptor for Ebola virus. In their study,6 they found that TIM-1 is expressed on a number of mucosal surfaces and on the tissues thought to be involved in the transmission of Ebola virus: the cornea, conjunctiva, and trachea. As such, there is concern that Ebola virus could be transmitted by ocular tissue. In response to the current Ebola crisis, the Eye Bank Association of America, the American Association of Tissue Banks, and the Association of Organ Procurement Organizations have developed a policy. The Eye Bank Association of America recommends that no tissue be accepted from any potential donor who has lived in or traveled to a country (including Guinea, Liberia, or Sierra Leone) with widespread Ebola virus transmission or who had contact with an individual with confirmed Ebola virus disease within the past 60 days (Jennifer DeMatteo, MCM, Director of Regulation and Standards, Eye Bank Association of America, email communication, March 2015). Similarly, the Eye Bank Association of America defers any acceptance of tissue from a patient who was told by a health care professional that she or he was either infected with Ebola virus or exposed to Ebola virus within the past 60 days. This policy is in effect for all potential donors until the Ebola virus is no longer considered an active threat or until the virus is considered a long-term threat needing a different solution.
(Reprinted) JAMA Ophthalmology July 2015 Volume 133, Number 7
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archopht.jamanetwork.com/ by a University of Pittsburgh User on 05/07/2016
743
Opinion Viewpoint
-statement/ebola-virus-disease-what -ophthalmologists-need-to. Published November 2014. Accessed March 11, 2015.
ARTICLE INFORMATION Published Online: April 16, 2015. doi:10.1001/jamaophthalmol.2015.0703. Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
2. Ansari AA. Clinical features and pathobiology of Ebolavirus infection. J Autoimmun. 2014;55:1-9.
REFERENCES
4. Bwaka MA, Bonnet MJ, Calain P, et al. Ebola hemorrhagic fever in Kikwit, Democratic Republic of the Congo: clinical observations in 103 patients. J Infect Dis. 1999;179(suppl 1):S1-S7.
1. Ebola virus disease: what ophthalmologists need to know—2014. American Academy of Ophthalmology website. http://one.aao.org/clinical
VIEWPOINT
Farzin Forooghian, MD, MSc, FRCSC Department of Ophthalmology, University of British Columbia, Vancouver, British Columbia, Canada; and Department of Ophthalmology, St Paul’s Hospital, Vancouver, British Columbia, Canada.
Corresponding Author: Farzin Forooghian, MD, MSc, FRCSC, Department of Ophthalmology, St Paul's Hospital, 1081 Burrard St, Vancouver, BC V6Z 1Y6, Canada (farzin.forooghian @gmail.com). 744
3. Ebola (Ebola virus disease). Centers for Disease Control and Prevention website. http://www.cdc.gov /vhf/ebola/index.html. Accessed March 11, 2015.
5. 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. 6. Kondratowicz AS, Lennemann NJ, Sinn PL, et al. T-cell immunoglobulin and mucin domain 1 (TIM-1) is a receptor for Zaire Ebolavirus and Lake Victoria Marburgvirus. Proc Natl Acad Sci U S A. 2011;108 (20):8426-8431.
The Uncertainty Regarding Antiretinal Antibodies Autoimmune retinopathy is a term that encompasses cancer-associated retinopathy, melanoma-associated retinopathy, and nonparaneoplastic retinopathy. The diagnosis of autoimmune retinopathy remains challenging, partly due to lack of consensus regarding diagnostic criteria. Basic science experiments have revealed autoimmune retinopathy to be an antibody-mediated disease. The general requirement for diagnosing autoimmune retinopathy is clinical evidence of retinal degeneration in the presence of serum antiretinal antibodies (ARAs). Some laboratories are now offering ARA testing to outside institutions, and in some cases, this is offered as a commercial service.1,2 Antiretinal antibody testing is commonly performed using 1 or more techniques: Western blot, immunohistochemistry, and enzyme-linked immunosorbent assay. Antiretinal antibody testing could potentially have an important role in the diagnosis of autoimmune retinopathy. However, several hurdles and uncertainties should be overcome before this testing can truly become clinically reliable. Antiretinal antibody testing currently lacks standardization, which can lead to false-positive and falsenegative test results.3 The most common method for ARA detection is the Western blot. Because there is no standardization, the laboratories that perform this testing tend to use different methods. Some laboratories performing ARA testing have Clinical Laboratory Improvement Amendments (CLIA) certification.4 It is important to note that CLIA approval simply refers to the practice of good laboratory techniques and does not mean that the laboratory test being offered is standardized (or validated). A comparative study of the concordance between reported Western blot bands from 2 different laboratories accepting samples from outside their own institutions reported an ARA-specific concordance rate of only 36% for a single band on Western blot.5 Even when there was one common ARA band detected, 80% of patients had additional ARAs detected by one laboratory but not the other.5 The poor agreement and high discordance between laboratories have
led to the recommendation by several authors that samples for ARA testing should be sent to at least 2 different laboratories for confirmation.1,5 Sending samples to numerous laboratories is costly and not very practical for patients because they often pay for these tests. Proper standardization of ARA testing among the different laboratories that offer ARA testing could decrease the cost burden to patients and provide clinicians with information that is potentially more clinically meaningful. In addition to lacking proper standardization, ARA testing is currently not clinically validated. Western blots of patients with suspected autoimmune retinopathy often reveal several bands.2 Furthermore, it has been shown that normal healthy serum also shows several bands when tested for ARA and that ARA can be detected in patients with a wide variety of infectious, inflammatory, vascular, and degenerative ocular conditions.2,6 The question is: which bands, or combination of bands, help support the diagnosis of autoimmune retinopathy? Unfortunately, the answer to this question is not known. Clinical validation of Western blot bands for ARA is needed. Such validation could be similar to that which exists for Lyme disease—where certain bands are needed to establish its diagnosis. To enable clinicians to fully understand and interpret the results of any test, parameters such as specificity, sensitivity, positive predictive value, and negative predictive value are needed. These test parameters have never been reported for ARA testing. Clinical validation of ARA testing is needed. The final uncertainty with ARA testing is the lack of evidence for pathogenicity of most ARAs. Numerous reports suggest that various ARAs are associated with autoimmune retinopathy, and several putative ARAs have been reported based on their presence in the serum of patients with suspected autoimmune retinopathy.1-3 The mere presence of an autoantibody in a patient with suspected autoimmune retinopathy does not mean that the autoantibody is the causative agent of the retinal de-
JAMA Ophthalmology July 2015 Volume 133, Number 7 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archopht.jamanetwork.com/ by a University of Pittsburgh User on 05/07/2016
jamaophthalmology.com
VIEWPOINT
Christine Shieh, MD Department of Ophthalmology, Duke University, Durham, North Carolina. Gargi Vora, MD Department of Ophthalmology, Duke University, Durham, North Carolina. Terry Kim, MD Department of Ophthalmology, Duke University, Durham, North Carolina.
Corresponding Author: Terry Kim, MD, Department of Ophthalmology, Duke University, 2351 Erwin Rd, DUMC 3802, Durham, NC 27705 ([email protected] .edu).
jamaophthalmology.com
Eyes on Ebola Virus Disease The current Ebola epidemic has been deemed the largest in history, with the World Health Organization declaring it a “public health emergency of international concern.”1 Ebola virus disease has a high fatality rate, and the Ebola virus belongs to the family Filoviridae, a family of viruses that causes hemorrhagic fever in humans and nonhuman primates.2 Bats are suspected to be the reservoir hosts.2 Many hospitals and practices have protocols to screen patients for Ebola. For example, at Duke University Medical Center in Durham, North Carolina, our eye clinics have posted signs asking patients, even if they are asymptomatic, to alert our staff if they have recently traveled to West Africa, specifically Guinea, Liberia, Mali, Nigeria, or Sierra Leone. Even asymptomatic patients should be of high interest if they have traveled to this region because it takes 2 to 21 days from the time of Ebola virus infection to the commencement of symptoms.3 Per the American Academy of Ophthalmology and the Centers for Disease Control and Prevention (CDC), suspected patients should be isolated from other patients, and the local or state health officials should be immediately alerted to determine whether testing is needed. In turn, the US health department reports to the CDC’s Emergency Operations Center. Patients are not considered infected until they have developed symptoms.3 Early symptoms include sudden onset of fever, severe headache, and constitutional symptoms such as joint/ muscle aches, chills, and fatigue.1,3 Late symptoms include vomiting, diarrhea, rash, and internal and external bleeding, usually from the eyes.1,3 As ophthalmologists and physicians, it is important for us to be aware of other ocular symptoms and signs of Ebola virus disease. A retrospective case series of 103 patients in the 1995 outbreak of Ebola virus documented bilateral conjunctival hyperemia as an early sign of the virus in patients; this was not positively or negatively correlated with survival.4 Another study of the same outbreak followed up 21 patients with Ebola virus disease who survived and noted that 4 of these survivors developed uveitis during convalescence.5 These patients were successfully treated with topical atropine, 1%, and corticosteroid drops, and the pathogenesis of the disease was attributed to a delayed hypersensitivity reaction to viral antigens.5 It is critical for health care personnel to be mindful of protecting themselves and of preventing the further spread of the virus. The virus is transmitted through direct contact (through fissures in the skin or in the mucous membranes of the eyes, nose, or mouth) or via the blood/body fluids of infected patients.3 The bodies of deceased patients with Ebola virus disease still present a risk because the virus can survive for several days at room temperature in the blood and in
body fluids.3 Airborne human-to-human transmission has not definitely been demonstrated, although it has been hypothesized. Other, less common means of transmission that have been implicated include skin-to-skin contact with an infected patient and indirect exposure to blood and body fluids (via fomites) due to the dried virus surviving on doorknobs and countertops for several hours.3 Fortunately, the Ebola virus is killed with hospitalgrade disinfectants, such as household bleach, so all equipment used with any possibly infected patients should be appropriately cleaned and sterilized, although ideally disposable equipment would be used.3 In addition, owing to the various means of human-tohuman transmission, health care workers are recommended to wear personal protective equipment (PPE) covering all skin.3 According to PPE policy, in addition to gowns and gloves, it is important for health care workers to wear masks and eye protection. The CDC’s PPE policy also recommends that there is a trained observer to monitor all health care workers to ensure they properly put on and remove their PEE. A more detailed PPE protocol is available at the CDC website (http://www.cdc.gov/vhf/ebola/hcp/procedures-for-ppe .html). Virus transmission has been studied in the laboratory as well. Kondratowicz et al6 have proposed that TIM-1 (T-cell immunoglobulin and mucin domain 1) is a likely receptor for Ebola virus. In their study,6 they found that TIM-1 is expressed on a number of mucosal surfaces and on the tissues thought to be involved in the transmission of Ebola virus: the cornea, conjunctiva, and trachea. As such, there is concern that Ebola virus could be transmitted by ocular tissue. In response to the current Ebola crisis, the Eye Bank Association of America, the American Association of Tissue Banks, and the Association of Organ Procurement Organizations have developed a policy. The Eye Bank Association of America recommends that no tissue be accepted from any potential donor who has lived in or traveled to a country (including Guinea, Liberia, or Sierra Leone) with widespread Ebola virus transmission or who had contact with an individual with confirmed Ebola virus disease within the past 60 days (Jennifer DeMatteo, MCM, Director of Regulation and Standards, Eye Bank Association of America, email communication, March 2015). Similarly, the Eye Bank Association of America defers any acceptance of tissue from a patient who was told by a health care professional that she or he was either infected with Ebola virus or exposed to Ebola virus within the past 60 days. This policy is in effect for all potential donors until the Ebola virus is no longer considered an active threat or until the virus is considered a long-term threat needing a different solution.
(Reprinted) JAMA Ophthalmology July 2015 Volume 133, Number 7
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archopht.jamanetwork.com/ by a University of Pittsburgh User on 05/07/2016
743
Opinion Viewpoint
-statement/ebola-virus-disease-what -ophthalmologists-need-to. Published November 2014. Accessed March 11, 2015.
ARTICLE INFORMATION Published Online: April 16, 2015. doi:10.1001/jamaophthalmol.2015.0703. Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
2. Ansari AA. Clinical features and pathobiology of Ebolavirus infection. J Autoimmun. 2014;55:1-9.
REFERENCES
4. Bwaka MA, Bonnet MJ, Calain P, et al. Ebola hemorrhagic fever in Kikwit, Democratic Republic of the Congo: clinical observations in 103 patients. J Infect Dis. 1999;179(suppl 1):S1-S7.
1. Ebola virus disease: what ophthalmologists need to know—2014. American Academy of Ophthalmology website. http://one.aao.org/clinical
VIEWPOINT
Farzin Forooghian, MD, MSc, FRCSC Department of Ophthalmology, University of British Columbia, Vancouver, British Columbia, Canada; and Department of Ophthalmology, St Paul’s Hospital, Vancouver, British Columbia, Canada.
Corresponding Author: Farzin Forooghian, MD, MSc, FRCSC, Department of Ophthalmology, St Paul's Hospital, 1081 Burrard St, Vancouver, BC V6Z 1Y6, Canada (farzin.forooghian @gmail.com). 744
3. Ebola (Ebola virus disease). Centers for Disease Control and Prevention website. http://www.cdc.gov /vhf/ebola/index.html. Accessed March 11, 2015.
5. 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. 6. Kondratowicz AS, Lennemann NJ, Sinn PL, et al. T-cell immunoglobulin and mucin domain 1 (TIM-1) is a receptor for Zaire Ebolavirus and Lake Victoria Marburgvirus. Proc Natl Acad Sci U S A. 2011;108 (20):8426-8431.
The Uncertainty Regarding Antiretinal Antibodies Autoimmune retinopathy is a term that encompasses cancer-associated retinopathy, melanoma-associated retinopathy, and nonparaneoplastic retinopathy. The diagnosis of autoimmune retinopathy remains challenging, partly due to lack of consensus regarding diagnostic criteria. Basic science experiments have revealed autoimmune retinopathy to be an antibody-mediated disease. The general requirement for diagnosing autoimmune retinopathy is clinical evidence of retinal degeneration in the presence of serum antiretinal antibodies (ARAs). Some laboratories are now offering ARA testing to outside institutions, and in some cases, this is offered as a commercial service.1,2 Antiretinal antibody testing is commonly performed using 1 or more techniques: Western blot, immunohistochemistry, and enzyme-linked immunosorbent assay. Antiretinal antibody testing could potentially have an important role in the diagnosis of autoimmune retinopathy. However, several hurdles and uncertainties should be overcome before this testing can truly become clinically reliable. Antiretinal antibody testing currently lacks standardization, which can lead to false-positive and falsenegative test results.3 The most common method for ARA detection is the Western blot. Because there is no standardization, the laboratories that perform this testing tend to use different methods. Some laboratories performing ARA testing have Clinical Laboratory Improvement Amendments (CLIA) certification.4 It is important to note that CLIA approval simply refers to the practice of good laboratory techniques and does not mean that the laboratory test being offered is standardized (or validated). A comparative study of the concordance between reported Western blot bands from 2 different laboratories accepting samples from outside their own institutions reported an ARA-specific concordance rate of only 36% for a single band on Western blot.5 Even when there was one common ARA band detected, 80% of patients had additional ARAs detected by one laboratory but not the other.5 The poor agreement and high discordance between laboratories have
led to the recommendation by several authors that samples for ARA testing should be sent to at least 2 different laboratories for confirmation.1,5 Sending samples to numerous laboratories is costly and not very practical for patients because they often pay for these tests. Proper standardization of ARA testing among the different laboratories that offer ARA testing could decrease the cost burden to patients and provide clinicians with information that is potentially more clinically meaningful. In addition to lacking proper standardization, ARA testing is currently not clinically validated. Western blots of patients with suspected autoimmune retinopathy often reveal several bands.2 Furthermore, it has been shown that normal healthy serum also shows several bands when tested for ARA and that ARA can be detected in patients with a wide variety of infectious, inflammatory, vascular, and degenerative ocular conditions.2,6 The question is: which bands, or combination of bands, help support the diagnosis of autoimmune retinopathy? Unfortunately, the answer to this question is not known. Clinical validation of Western blot bands for ARA is needed. Such validation could be similar to that which exists for Lyme disease—where certain bands are needed to establish its diagnosis. To enable clinicians to fully understand and interpret the results of any test, parameters such as specificity, sensitivity, positive predictive value, and negative predictive value are needed. These test parameters have never been reported for ARA testing. Clinical validation of ARA testing is needed. The final uncertainty with ARA testing is the lack of evidence for pathogenicity of most ARAs. Numerous reports suggest that various ARAs are associated with autoimmune retinopathy, and several putative ARAs have been reported based on their presence in the serum of patients with suspected autoimmune retinopathy.1-3 The mere presence of an autoantibody in a patient with suspected autoimmune retinopathy does not mean that the autoantibody is the causative agent of the retinal de-
JAMA Ophthalmology July 2015 Volume 133, Number 7 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archopht.jamanetwork.com/ by a University of Pittsburgh User on 05/07/2016
jamaophthalmology.com
