- Email: [email protected]
The prevalence of adenoviral conjunctivitis at the Wills Eye Hospital Emergency Room
Optometry (2007) 78, 236-239
The prevalence of adenoviral conjunctivitis at the Wills Eye Hospital Emergency Room Robert P. Sambursky, M.D.,a Nicole Fram, M.D.,b and Elisabeth J. Cohen, M.D.b a
Manatee-Sarasota Eye Clinic, Bradenton, Florida, and bWills Eye Hospital, Philadelphia, Pennsylvania. KEYWORDS Adenoviral conjunctivitis; Acute conjunctivitis
Abstract OBJECTIVE: The aim of this study was to evaluate the prevalence of adenoviral conjunctivitis by analyzing data from a prospective clinical study of 50 consecutive patients presenting to the Wills Eye Hospital Emergency Room (WEH ER) with a clinical diagnosis of infectious conjunctivitis from July 2003 to October 2003. METHODS: The polymerase chain reaction (PCR) was used to evaluate all cases of clinically diagnosed infectious conjunctivitis. Based on the laboratory findings, the prevalence of adenovirus was determined. RESULTS: Of the 50 consecutive patients with acute infectious conjunctivitis, 31 patients were PCR positive for adenovirus. CONCLUSIONS: The prevalence of adenoviral conjunctivitis was found by PCR to represent 62% of all patients presenting with a clinical diagnosis of infectious conjunctivitis from July 2003 to October 2003. Optometry 2007;78:236-239
Human adenoviruses are classified into 6 subgenera and 51 serotypes.1,2 Approximately one third of the human adenovirus serotypes have been associated with common forms of adenoviral-related eye infections,3 but the most common causes of acute conjunctivitis are related to serotypes 3, 4, 8, 11, 19, and 37.4 The serotypes have the following associations: serotypes 8, 19, and 37 are most responsible for epidemic keratoconjunctivitis,5-7 serotypes 3, 4, 5, and 7 tend to cause pharyngeal-conjunctival fever (which usually affects children),5 and serotypes 1 through 11 and 19 are the primary cause of nonspecific follicular conjunctivitis.5 However, the other serotypes can also produce clinically indistinguishable episodes of acute follicular conjunctivitis.6,8
Corresponding author: Robert P. Sambursky, M.D., 13946 Wood Duck Circle, Bradenton, Florida 34202. E-mail: [email protected]
Despite not always being easy to differentiate viral conjunctivitis from allergic or bacterial disease, most patients are not routinely sent for additional laboratory studies because they can take days to weeks to produce a result.9-10 Although usually a clinical diagnosis, laboratory diagnosis of adenoviral infections is currently based on virus isolation in cell culture, antibody studies, antigen detection, and the polymerase chain reaction (PCR).11 The conventional technique for diagnosing viral conjunctivitis includes conjunctiva cytologic investigation in which inoculation of susceptible cell lines are followed with observation for a cytopathic effect.12 It is costly and time consuming but remains the “gold standard” because isolation of an infectious agent is definitive and allows for further characterization.10 After the first week of most viral illnesses, positive viral cultures are difficult to obtain.13 Since its introduction as a laboratory test for eye disease in 1990,14 PCR is now being used widely in clinical ophthalmology15,16 and may replace cell culture as the new gold
1529-1839/07/$ -see front matter © 2007 American Optometric Association. All rights reserved. doi:10.1016/j.optm.2006.11.012
Sambursky et al
Clinical Research
standard. The technique has been shown to be more sensitive, accurate, and rapid than culture for detecting and typing adenovirus in cases of conjunctivitis.2,17,19-20 Sensitivity of PCR is largely independent of adenovirus subgenus or serotype.21 Newer multiplex PCR for the detection of adenovirus has been shown to be nearly 100% sensitive and specific. Elnifro et al.18 and Cooper et al.19 found that 92.7% to 98% of clinical specimens were positive for adenovirus by the multiplex PCR compared with 53% to 72.7% by adenovirus isolation. Other studies suggest that PCR was 37.9% more sensitive in detecting adenovirus than other virologic methods.20 However, PCR still requires sending out a sample that may take 1 to 2 days to process, technical equipment, and expertise in running and interpreting samples and can cost up to 6 times as much as a viral culture. Recently, the U.S. Food and Drug Administration cleared a point-of-care diagnostic test for detecting adenoviral conjunctivitis, the RPS Adeno Detector. A multicenter clinical trial found a sensitivity of 89% and specificity of 94% for the RPS Adeno Detector when compared with PCR, whereas cell culture showed 91% sensitivity and 100% specificity.22 The American Academy of Ophthalmology revised its Preferred Practice Patterns for the management of conjunctivitis and referenced the RPS Adeno Detector as a useful in-office diagnostic test for clinically unclear cases.23 Such testing allows for a laboratory-quality diagnosis at the office visit.
Methods Investigational review board approval was obtained from the Wills Eye Hospital. A prospective nonrandomized clinical study evaluated 50 consecutive patients presenting to the Wills Eye Emergency room from July 2003 through October 2003 within 1 week of developing signs and symptoms consistent with acute infectious conjunctivitis and when an IRB-approved ophthalmologist was available for specimen collection. Those patients who were found clinically by an ophthalmologist to have infectious conjunctivitis and who met the enrollment criteria were included in the study. Informed consent was obtained by a co-investigator. A form that compiled patient demographic information was first completed. The patients were then clinically evaluated and specimens collected before the administration of any topical anesthetic or fluorescein dye. Using a Dacron sterile swab (Copan, Italy) a tear specimen was obtained. After gently retracting the lower eyelid, the inferior palpebral fornix was exposed and, using a gentle swirling motion, tears were allowed to accumulate on the Dacron swab until it was saturated with fluid. The sample was collected as described above and was placed in a 15-mL polystyrene conical tube (Falcon, Blue Max, Jr.; Becton, Dickinson and Co., Franklin Lakes, New Jersey) with 1 mL of nonbuffered, thimersol-free, basic salt
237 solution. This specimen was kept refrigerated below 50o F until it was sent directly to ViraCor (St. Louis, Missouri) laboratory for real-time PCR. All PCR samples were processed within 96 hours of sampling. If adenovirus was detected, no further testing was performed and the result was deemed positive. If the PCR was negative, the sample was considered negative for the presence of adenovirus.
Inclusion and exclusion criteria The following inclusion and exclusion criteria used in this study were identical to the criteria used by Sambursky et al.22 in their multicenter clinical trial evaluating the efficacy of the RPS Adeno Detector. Patients who were older than 1 month of age, were seen within 7 days of developing a red eye consistent with acute conjunctivitis, and who demonstrated at least 1 criteria from 2 out of the 3 categories (1-3) below were included: I. History: 1) Spread from one eye to the other several days later, 2) recent or concurrent upper respiratory symptoms within the preceding 2 weeks, or 3) an exposure to someone with “pink eye” within the preceding 3 weeks; II. Symptoms: 1) tearing, 2) mucoid, or purulent discharge, 3) eye lash matting, 4) burning, 5) itching, or 6) foreign body sensation; III. Signs: 1) an inferior palpebral conjunctival reaction with 1⫹ or more papillary or follicular reactions, or 2) presence of a preauricular node. Patients with associated skin vesicles, corneal dendrites, traumatic corneal abrasion, concurrent corneal ulcers, foreign bodies, ocular pemphigoid, trauma, history of chemical/thermal injury to eyes or eyelids (in the past 90 days), or more than trace intraocular inflammation were excluded from the study. Additionally, patients with an allergy to corn starch, talcum powder, and Dacron also were excluded.22
Results Of the 50 consecutive patients with acute conjunctivitis, 31 patients were PCR positive for adenovirus. In 19 patients, the PCR was negative for adenovirus. No bacterial cultures were performed. All positive real-time results were available within 2 to 3 days from sampling, and this increased to 4 to 5 days if the initial real-time PCR was inconclusive and required additional PCR testing.
Discussion Although conjunctivitis typically is caused by a virus, bacteria, or allergy, adenovirus is the most common cause of both viral and infectious conjunctivitis. Japanese studies have found that adenovirus comprised 90% of all viral cases of conjunctivitis,24 whereas worldwide, adenovirus repre-
238 sents 15% to 70% of all cases of infectious conjunctivitis.24-33 Other viruses, such as the herpes simplex virus, may present as an indistinguishable acute conjunctivitis without associated lid ulcers or keratitis in 2.3% to 4.3% of all ocular herpes simplex infections.24,27-30,32,34,35 It is often difficult to clinically distinguish adenoviral disease from other etiologies of conjunctivitis, and studies have found that the clinical diagnostic accuracy compared with laboratory studies of acute conjunctivitis ranges between 40% and 75%.25-27 The use of in-office testing, such as the RPS Adeno Detector, may aid the eye doctor in making a more accurate diagnosis. Correctly identifying patients with adenoviral conjunctivitis may reduce the spread of disease and limit the toxicity, allergy, and antibiotic resistance associated with unnecessary empiric treatments. Our study found a prevalence of adenoviral conjunctivitis of 62% (31 of 50) of all patients presenting with a clinical diagnosis of infectious conjunctivitis to the WEH ER from July 2003 to October 2003. Because adenoviral demonstrates seasonal variability, it often is higher during the summer months and is thought to be related to the increased risk of transfer seen with summer-related activities such as swimming and day camps.36 Additionally, the urban population and the increased likelihood of poor hygiene and overcrowding may explain the high prevalence of adenoviral conjunctivitis. With the advent of new laboratory techniques such as PCR the ability to analyze tear samples from the inferior palpebral fornix has improved dramatically. PCR can identify more pathogens than routine virus isolation. Most likely, the previous assessments of both viral conjunctivitis and, in particular, adenoviral conjunctivitis, represent underestimates of their true prevalence. Many of the older studies show 18% to 45%25-31 of acute conjunctivitis that had no identifiable etiology. Based on the relatively increased sensitivity of PCR over viral isolation, it seems likely that PCR analysis during the aforementioned studies may have resulted in more substantiated cases of viral conjunctivitis.
Conclusion There is a current and ongoing need for the rapid, accurate diagnosis of ocular infection. Although PCR provides significant improvements in both sensitivity and specificity of tear sampling, it is still expensive, requires technical equipment not readily available as well as expertise, is relatively time consuming, and does not allow for a point-of-care diagnosis. Missing the diagnosis of viral conjunctivitis also is important because of the high risk of the contagion. Also, adenoviral conjunctivitis is associated with significant complications such as subepithelial infiltrates,37-40 lacrimal drainage abnormalities,41 and symblepharon formation.42 Adenovirus is the most frequent cause of conjunctivitis. For the busy clinician, an ideal rapid diagnostic test to determine ocular pathogens would be an inexpensive test,
Optometry, Vol 78, No 5, May 2007 the result of which is available before the patient leaves the provider’s office so that treatment can be appropriately instituted. Improved in-office immunoassays, such as the RPS Adeno Detector,22 may provide for highly sensitive and specific diagnostic capabilities for detecting ocular pathogens at the point of care. The rapid, accurate diagnosis of adenoviral ocular infections would not only limit the transmission of virus within the community but also would avoid expensive, unnecessary, and ineffective antibiotic therapy.
Acknowledgments The authors thank Rapid Pathogen Screening, Inc. for providing funding for the polymerase chain reaction studies. Robert P. Sambursky, M.D., serves as the chief medical officer for Rapid Pathogen Screening, Inc. Nicole Fram, M.D., and Elisabeth J. Cohen, M.D., have no financial interest.
References 1. Baum J. Infections of the eye. Clin Infect Dis 1995;21:479-86. 2. Pring-Åkerblom P, Adrian T. Type- and group-specific polymerase chain reaction for adenovirus detection. Res Virol 1994;145:25-35. 3. Kinchington PR, Turse SE, Kowalski RP, et al. Use of polymerase chain amplification reaction for the detection of adenoviruses in ocular swab specimens. Invest Ophthalmol Vis Sci 1994;35:4126-34. 4. Schnurr D, Dondero ME. Two new candidate adenovirus serotypes. Intervirol 1993;36:79-83. 5. Wood SR, Sharp IR, Caul EO, et al. Rapid detection and serotyping of adenovirus by direct immunofluorescence. J Med Virol 1997;51: 198-201. 6. Takeuchi S, Itoh N, Uchio E, et al. Serotyping of adenoviruses on conjunctival scrapings by PCR and sequence analysis. J Clin Microbiol 1999;37:1839-45. 7. Saitoh-Inagawa W, Oshima A, Aoki K, et al. Rapid diagnosis of adenoviral polymerase chain reaction assay for rapid diagnosis of conjunctivitis. Invest Ophthalmol Vis Sci 1999;40:90-5. 8. Roba LA, Kowalski RP, Gordon AT, et al. Adenoviral ocular isolates demonstrate serotype-dependent differences in in-vitro infectivity titers and clinical course. Cornea 1995;14:388-93. 9. Chien L, Llaues-Rodas R. Application of immunofluorescent staining technique to the study of pathogenesis and rapid diagnosis of viral infections. Am J Clin Pathol 1972;57:829-34. 10. Van Rij G, Klepper L, Perkamp E, et al. Immune electron microscopy and a cultural test in the diagnosis of adenovirus ocular infection. Br J Ophthalmol 1982;66:317-9. 11. Wadell G, Allard A, Hierholzer JC. Adenoviruses. In: Murray PR, Baron EJ, Pfaller MA, et al (eds). Manual of clinical microbiology, ed 7. Washington, DC: American Society for Microbiology, 1999; 970-82. 12. Elnifro EM, Cooper RJ, Klapper PE, et al. Diagnosis of viral and chlamydial keratoconjunctivitis: which laboratory test? Br J Ophthalmol 1999;83:622-7. 13. Knopf HL, Hierholzer JC. Clinical and immunologic responses in patients with viral keratoconjunctivitis. Am J Ophthalmol 1975;80: 661-72.
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Clinical Research
14. Pflugfelder SC, Crouse C, Atherton S. Detection of Epstein Barr virus genomes in normal human lacrimal glands. J Clin Microbiol 1990;28: 1026-32. 15. Adleberg JM, Wittwer C. Use of the polymerase chain reaction in the diagnosis of ocular disease. Curr Opin Ophthalmol 1995;6:80-5. 16. Della GN. Molecular biology in ophthalmology: a review of principles and recent advances. Arch Ophthalmol 1996;114:457-63. 17. Saitoh-Inagawa W, Oshima A, Aoki K, et al. Rapid diagnosis of adenoviral conjunctivitis by PCR and restriction fragment length polymorphism analysis. J Clin Microbiol 1996;34:2113-6. 18. Elnifro EM, Cooper RJ, Klapper PE, et al. Multiplex polymerase chain reaction for diagnosis of viral and chlamydial keratoconjunctivitis. Invest Ophthalmol Vis Sci 2000;41:1818-22. 19. Cooper RJ, Yeo AC, Bailey AS, et al. Adenovirus polymerase chain reaction assay for rapid diagnosis of conjunctivitis. Invest Ophthalmol Vis Sci 1999;40:90-5. 20. Madhavan HN. Laboratory investigations on viral and Chlamydia trachomatis infections of the eye: Sankara Nethralaya experiences. Indian J Ophthalmol 1999;47:241-6. 21. Morris DJ, Bailey AS, Cooper RJ, et al. Polymerase chain reaction for rapid detection of ocular adenovirus infection. J Med Virol 1995;46: 126-32. 22. Sambursky R, Tauber S, Schirra F, et al. The RPS Adeno detector for diagnosing adenoviral conjunctivitis. Ophthalmology 2006;113(10): 1758-64. 23. American Academy of Ophthalmology. Conjunctivitis, preferred practice patterns. San Francisco: American Academy of Ophthalmology, 2003. 24. Infectious Agents Surveillance Center of Japan. Viruses isolated from the eye, Japan, 1990-1994. Infectious Agents Surveillance Report 1995;16:97-8. 25. Mahajan VM. Acute bacterial infections of the eye: their etiology and treatment. Br J Ophthalmol 1983;67:191-4. 26. Stenson S, Newman R, Fedukowicz H. Laboratory studies in acute conjunctivitis. Arch Ophthalmol 1982;100:1275-7. 27. Fitch CP, Rapoza PA, Owens S, et al. Epidemiology and diagnosis of acute conjunctivitis at an inner-city hospital. Ophthalmology 1989;96: 1215-20.
239 28. Gigliotti F, Williams WT, Hayden FG, et al. Etiology of acute conjunctivitis in children. J Pediatr 1981;98:531-6. 29. Woodland RM, Darougar S, Thaker U, et al. Causes of conjunctivitis and keratoconjunctivitis in Karachi, Pakistan. Trans R Soc Trop Med Hyg 1992;86:317-20. 30. Ishii K, Nakazono N, Fujinaga K, et al. Comparative studies on aetiology and epidemiology of viral conjunctivitis in three countries of East Asia—Japan, Taiwan and South Korea. Int J Epidemiol 1987;16: 98-103. 31. Torres Rojas G, Goyenechea A, Savon C, et al. The incidence of adenoviruses in viral conjunctivitis. Rev Cubana Med Trop 1998;50: 182-5. 32. Weiss AH, Brinser JH, Nazar-Stewart V. Acute conjunctivitis in childhood. J Pediatr 1993;122:10-4. 33. Harding SP, Mallinson H, Smith JL, et al. Adult follicular conjunctivitis and neonatal ophthalmia in a Liverpool eye hospital, 1980-1984. Eye 1987;1:512-21. 34. Isenberg SJ, Apt L, Valenton M, et al. A controlled trial of povidoneiodine to treat infectious conjunctivitis in children. Am J Ophthalmol 2002;134:681-8. 35. Adleberg JM, Wittwer C. Use of the polymerase chain reaction in the diagnosis of ocular disease. Curr Opin Ophthalmol 1995;6:80-5. 36. Gordon JS, Aoki K, Kinchington PR. Adenovirus keratoconjunctivitis. In: Pepose JS, Holland GN, Wilhelmus KR, (eds). Ocular infection & immunity. St. Louis: Mosby, 1996;877-94. 37. Butt AL, Chodosh J. Adenoviral keratoconjunctivitis in a tertiary care eye clinic. Cornea 2006;25:199-202. 38. Weiss A. Acute conjunctivitis in childhood. Curr Probl Pediatr 1994;24:4-11. 39. Weber CM, Eichenbaum JW. Acute red eye: differentiating viral conjunctivitis from other, less common causes. Postgrad Med J 1997; 101:185-96. 40. Syed NA, Hyundiuk RA. Infectious conjunctivitis. Infect Dis Clin North Am 1992;6:789-805. 41. Hyde KJ, Berger ST. Epidemic keratoconjunctivitis and lacrimal excretory system obstruction. Ophthalmology 1988;95:1447-9. 42. Hammer LH, Perry HD, Donnenfeld ED, et al. Symblepharon formation in epidemic keratoconjunctivitis. Cornea 1990;9:338-40.
The prevalence of adenoviral conjunctivitis at the Wills Eye Hospital Emergency Room Robert P. Sambursky, M.D.,a Nicole Fram, M.D.,b and Elisabeth J. Cohen, M.D.b a
Manatee-Sarasota Eye Clinic, Bradenton, Florida, and bWills Eye Hospital, Philadelphia, Pennsylvania. KEYWORDS Adenoviral conjunctivitis; Acute conjunctivitis
Abstract OBJECTIVE: The aim of this study was to evaluate the prevalence of adenoviral conjunctivitis by analyzing data from a prospective clinical study of 50 consecutive patients presenting to the Wills Eye Hospital Emergency Room (WEH ER) with a clinical diagnosis of infectious conjunctivitis from July 2003 to October 2003. METHODS: The polymerase chain reaction (PCR) was used to evaluate all cases of clinically diagnosed infectious conjunctivitis. Based on the laboratory findings, the prevalence of adenovirus was determined. RESULTS: Of the 50 consecutive patients with acute infectious conjunctivitis, 31 patients were PCR positive for adenovirus. CONCLUSIONS: The prevalence of adenoviral conjunctivitis was found by PCR to represent 62% of all patients presenting with a clinical diagnosis of infectious conjunctivitis from July 2003 to October 2003. Optometry 2007;78:236-239
Human adenoviruses are classified into 6 subgenera and 51 serotypes.1,2 Approximately one third of the human adenovirus serotypes have been associated with common forms of adenoviral-related eye infections,3 but the most common causes of acute conjunctivitis are related to serotypes 3, 4, 8, 11, 19, and 37.4 The serotypes have the following associations: serotypes 8, 19, and 37 are most responsible for epidemic keratoconjunctivitis,5-7 serotypes 3, 4, 5, and 7 tend to cause pharyngeal-conjunctival fever (which usually affects children),5 and serotypes 1 through 11 and 19 are the primary cause of nonspecific follicular conjunctivitis.5 However, the other serotypes can also produce clinically indistinguishable episodes of acute follicular conjunctivitis.6,8
Corresponding author: Robert P. Sambursky, M.D., 13946 Wood Duck Circle, Bradenton, Florida 34202. E-mail: [email protected]
Despite not always being easy to differentiate viral conjunctivitis from allergic or bacterial disease, most patients are not routinely sent for additional laboratory studies because they can take days to weeks to produce a result.9-10 Although usually a clinical diagnosis, laboratory diagnosis of adenoviral infections is currently based on virus isolation in cell culture, antibody studies, antigen detection, and the polymerase chain reaction (PCR).11 The conventional technique for diagnosing viral conjunctivitis includes conjunctiva cytologic investigation in which inoculation of susceptible cell lines are followed with observation for a cytopathic effect.12 It is costly and time consuming but remains the “gold standard” because isolation of an infectious agent is definitive and allows for further characterization.10 After the first week of most viral illnesses, positive viral cultures are difficult to obtain.13 Since its introduction as a laboratory test for eye disease in 1990,14 PCR is now being used widely in clinical ophthalmology15,16 and may replace cell culture as the new gold
1529-1839/07/$ -see front matter © 2007 American Optometric Association. All rights reserved. doi:10.1016/j.optm.2006.11.012
Sambursky et al
Clinical Research
standard. The technique has been shown to be more sensitive, accurate, and rapid than culture for detecting and typing adenovirus in cases of conjunctivitis.2,17,19-20 Sensitivity of PCR is largely independent of adenovirus subgenus or serotype.21 Newer multiplex PCR for the detection of adenovirus has been shown to be nearly 100% sensitive and specific. Elnifro et al.18 and Cooper et al.19 found that 92.7% to 98% of clinical specimens were positive for adenovirus by the multiplex PCR compared with 53% to 72.7% by adenovirus isolation. Other studies suggest that PCR was 37.9% more sensitive in detecting adenovirus than other virologic methods.20 However, PCR still requires sending out a sample that may take 1 to 2 days to process, technical equipment, and expertise in running and interpreting samples and can cost up to 6 times as much as a viral culture. Recently, the U.S. Food and Drug Administration cleared a point-of-care diagnostic test for detecting adenoviral conjunctivitis, the RPS Adeno Detector. A multicenter clinical trial found a sensitivity of 89% and specificity of 94% for the RPS Adeno Detector when compared with PCR, whereas cell culture showed 91% sensitivity and 100% specificity.22 The American Academy of Ophthalmology revised its Preferred Practice Patterns for the management of conjunctivitis and referenced the RPS Adeno Detector as a useful in-office diagnostic test for clinically unclear cases.23 Such testing allows for a laboratory-quality diagnosis at the office visit.
Methods Investigational review board approval was obtained from the Wills Eye Hospital. A prospective nonrandomized clinical study evaluated 50 consecutive patients presenting to the Wills Eye Emergency room from July 2003 through October 2003 within 1 week of developing signs and symptoms consistent with acute infectious conjunctivitis and when an IRB-approved ophthalmologist was available for specimen collection. Those patients who were found clinically by an ophthalmologist to have infectious conjunctivitis and who met the enrollment criteria were included in the study. Informed consent was obtained by a co-investigator. A form that compiled patient demographic information was first completed. The patients were then clinically evaluated and specimens collected before the administration of any topical anesthetic or fluorescein dye. Using a Dacron sterile swab (Copan, Italy) a tear specimen was obtained. After gently retracting the lower eyelid, the inferior palpebral fornix was exposed and, using a gentle swirling motion, tears were allowed to accumulate on the Dacron swab until it was saturated with fluid. The sample was collected as described above and was placed in a 15-mL polystyrene conical tube (Falcon, Blue Max, Jr.; Becton, Dickinson and Co., Franklin Lakes, New Jersey) with 1 mL of nonbuffered, thimersol-free, basic salt
237 solution. This specimen was kept refrigerated below 50o F until it was sent directly to ViraCor (St. Louis, Missouri) laboratory for real-time PCR. All PCR samples were processed within 96 hours of sampling. If adenovirus was detected, no further testing was performed and the result was deemed positive. If the PCR was negative, the sample was considered negative for the presence of adenovirus.
Inclusion and exclusion criteria The following inclusion and exclusion criteria used in this study were identical to the criteria used by Sambursky et al.22 in their multicenter clinical trial evaluating the efficacy of the RPS Adeno Detector. Patients who were older than 1 month of age, were seen within 7 days of developing a red eye consistent with acute conjunctivitis, and who demonstrated at least 1 criteria from 2 out of the 3 categories (1-3) below were included: I. History: 1) Spread from one eye to the other several days later, 2) recent or concurrent upper respiratory symptoms within the preceding 2 weeks, or 3) an exposure to someone with “pink eye” within the preceding 3 weeks; II. Symptoms: 1) tearing, 2) mucoid, or purulent discharge, 3) eye lash matting, 4) burning, 5) itching, or 6) foreign body sensation; III. Signs: 1) an inferior palpebral conjunctival reaction with 1⫹ or more papillary or follicular reactions, or 2) presence of a preauricular node. Patients with associated skin vesicles, corneal dendrites, traumatic corneal abrasion, concurrent corneal ulcers, foreign bodies, ocular pemphigoid, trauma, history of chemical/thermal injury to eyes or eyelids (in the past 90 days), or more than trace intraocular inflammation were excluded from the study. Additionally, patients with an allergy to corn starch, talcum powder, and Dacron also were excluded.22
Results Of the 50 consecutive patients with acute conjunctivitis, 31 patients were PCR positive for adenovirus. In 19 patients, the PCR was negative for adenovirus. No bacterial cultures were performed. All positive real-time results were available within 2 to 3 days from sampling, and this increased to 4 to 5 days if the initial real-time PCR was inconclusive and required additional PCR testing.
Discussion Although conjunctivitis typically is caused by a virus, bacteria, or allergy, adenovirus is the most common cause of both viral and infectious conjunctivitis. Japanese studies have found that adenovirus comprised 90% of all viral cases of conjunctivitis,24 whereas worldwide, adenovirus repre-
238 sents 15% to 70% of all cases of infectious conjunctivitis.24-33 Other viruses, such as the herpes simplex virus, may present as an indistinguishable acute conjunctivitis without associated lid ulcers or keratitis in 2.3% to 4.3% of all ocular herpes simplex infections.24,27-30,32,34,35 It is often difficult to clinically distinguish adenoviral disease from other etiologies of conjunctivitis, and studies have found that the clinical diagnostic accuracy compared with laboratory studies of acute conjunctivitis ranges between 40% and 75%.25-27 The use of in-office testing, such as the RPS Adeno Detector, may aid the eye doctor in making a more accurate diagnosis. Correctly identifying patients with adenoviral conjunctivitis may reduce the spread of disease and limit the toxicity, allergy, and antibiotic resistance associated with unnecessary empiric treatments. Our study found a prevalence of adenoviral conjunctivitis of 62% (31 of 50) of all patients presenting with a clinical diagnosis of infectious conjunctivitis to the WEH ER from July 2003 to October 2003. Because adenoviral demonstrates seasonal variability, it often is higher during the summer months and is thought to be related to the increased risk of transfer seen with summer-related activities such as swimming and day camps.36 Additionally, the urban population and the increased likelihood of poor hygiene and overcrowding may explain the high prevalence of adenoviral conjunctivitis. With the advent of new laboratory techniques such as PCR the ability to analyze tear samples from the inferior palpebral fornix has improved dramatically. PCR can identify more pathogens than routine virus isolation. Most likely, the previous assessments of both viral conjunctivitis and, in particular, adenoviral conjunctivitis, represent underestimates of their true prevalence. Many of the older studies show 18% to 45%25-31 of acute conjunctivitis that had no identifiable etiology. Based on the relatively increased sensitivity of PCR over viral isolation, it seems likely that PCR analysis during the aforementioned studies may have resulted in more substantiated cases of viral conjunctivitis.
Conclusion There is a current and ongoing need for the rapid, accurate diagnosis of ocular infection. Although PCR provides significant improvements in both sensitivity and specificity of tear sampling, it is still expensive, requires technical equipment not readily available as well as expertise, is relatively time consuming, and does not allow for a point-of-care diagnosis. Missing the diagnosis of viral conjunctivitis also is important because of the high risk of the contagion. Also, adenoviral conjunctivitis is associated with significant complications such as subepithelial infiltrates,37-40 lacrimal drainage abnormalities,41 and symblepharon formation.42 Adenovirus is the most frequent cause of conjunctivitis. For the busy clinician, an ideal rapid diagnostic test to determine ocular pathogens would be an inexpensive test,
Optometry, Vol 78, No 5, May 2007 the result of which is available before the patient leaves the provider’s office so that treatment can be appropriately instituted. Improved in-office immunoassays, such as the RPS Adeno Detector,22 may provide for highly sensitive and specific diagnostic capabilities for detecting ocular pathogens at the point of care. The rapid, accurate diagnosis of adenoviral ocular infections would not only limit the transmission of virus within the community but also would avoid expensive, unnecessary, and ineffective antibiotic therapy.
Acknowledgments The authors thank Rapid Pathogen Screening, Inc. for providing funding for the polymerase chain reaction studies. Robert P. Sambursky, M.D., serves as the chief medical officer for Rapid Pathogen Screening, Inc. Nicole Fram, M.D., and Elisabeth J. Cohen, M.D., have no financial interest.
References 1. Baum J. Infections of the eye. Clin Infect Dis 1995;21:479-86. 2. Pring-Åkerblom P, Adrian T. Type- and group-specific polymerase chain reaction for adenovirus detection. Res Virol 1994;145:25-35. 3. Kinchington PR, Turse SE, Kowalski RP, et al. Use of polymerase chain amplification reaction for the detection of adenoviruses in ocular swab specimens. Invest Ophthalmol Vis Sci 1994;35:4126-34. 4. Schnurr D, Dondero ME. Two new candidate adenovirus serotypes. Intervirol 1993;36:79-83. 5. Wood SR, Sharp IR, Caul EO, et al. Rapid detection and serotyping of adenovirus by direct immunofluorescence. J Med Virol 1997;51: 198-201. 6. Takeuchi S, Itoh N, Uchio E, et al. Serotyping of adenoviruses on conjunctival scrapings by PCR and sequence analysis. J Clin Microbiol 1999;37:1839-45. 7. Saitoh-Inagawa W, Oshima A, Aoki K, et al. Rapid diagnosis of adenoviral polymerase chain reaction assay for rapid diagnosis of conjunctivitis. Invest Ophthalmol Vis Sci 1999;40:90-5. 8. Roba LA, Kowalski RP, Gordon AT, et al. Adenoviral ocular isolates demonstrate serotype-dependent differences in in-vitro infectivity titers and clinical course. Cornea 1995;14:388-93. 9. Chien L, Llaues-Rodas R. Application of immunofluorescent staining technique to the study of pathogenesis and rapid diagnosis of viral infections. Am J Clin Pathol 1972;57:829-34. 10. Van Rij G, Klepper L, Perkamp E, et al. Immune electron microscopy and a cultural test in the diagnosis of adenovirus ocular infection. Br J Ophthalmol 1982;66:317-9. 11. Wadell G, Allard A, Hierholzer JC. Adenoviruses. In: Murray PR, Baron EJ, Pfaller MA, et al (eds). Manual of clinical microbiology, ed 7. Washington, DC: American Society for Microbiology, 1999; 970-82. 12. Elnifro EM, Cooper RJ, Klapper PE, et al. Diagnosis of viral and chlamydial keratoconjunctivitis: which laboratory test? Br J Ophthalmol 1999;83:622-7. 13. Knopf HL, Hierholzer JC. Clinical and immunologic responses in patients with viral keratoconjunctivitis. Am J Ophthalmol 1975;80: 661-72.
Sambursky et al
Clinical Research
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