Cytomegalovirus can be detected in some endotheliitis cases

Polymerase chain reaction may be able to provide a fast, reliable means of detecting infection in the aqueous.

Cytomegalovirus is not normally a first consideration as a cause of endotheliitis in immunocompetent individuals, but polymerase chain reaction has detected the virus in some cases.

Endotheliitis, which wears away the thin, irreplaceable endothelium, is a potentially sight-threatening disease, and therapy aimed at the wrong virus can delay recovery.

However, a physician would not normally initially treat cytomegalovirus (CMV) as the cause of endotheliitis without verification — first, because its presentation does not differ from that of endotheliitis caused by other pathogens, and second, because treatment is specific, costly and has side effects.

Keratic precipitates indicating CMV. Image: Chee SP

Treatment aimed at eradicating herpes simplex virus (HSV) or varicella zoster virus (VZV), two more likely causes of endotheliitis, is not effective against CMV and vice versa. However, polymerase chain reaction (PCR) may be able to provide a fast, reliable means of detecting CMV infection in the aqueous.

In one case published in Cornea of persistent endotheliitis that had manifested after keratoplasty, PCR detected CMV in the aqueous. Treatment, which had been acyclovir and steroids, was changed to ganciclovir to fight CMV, resulting in the disappearance of the hallmark keratic precipitates.

In another case published in Ocular Immunology and Inflammation, a patient with hypertensive keratouveitis and endotheliitis was given valganciclovir after PCR analysis showed the CMV genome. Within a week, the patient’s ocular hypertension disappeared, as did the CMV DNA after 3 months.

Mechanism of CMV infection

Anterior chamber-associated immune deviation has been hypothesized as the mechanism of corneal infection with CMV. In anterior chamber-associated immune deviation, a latent infection is dormant in the adjacent trabecular

meshwork or ciliary body, and when reactivated, it breaches the otherwise primarily avascular immune-protected region of the cornea.

Because the CMV serology is positive for IgG antibodies and negative for IgM antibodies, Soon-Phaik Chee, FRCOphth, FRCS(G), said that CMV endotheliitis may result from reactivation of a latent infection.

“These patients are CMV cytospin negative, meaning that the CMV antigen is not detected in the blood,” Dr. Chee said in an interview with Ocular Surgery News.

PCR and other testing

Dr. Chee and colleagues published a study in Ophthalmology on 10 patients with endotheliitis. The researchers used tetraplex PCR assay to test for CMV, HSV, VZV and Toxoplasma gondii. In 11 of 12 eyes, CMV was the only pathogen identified.

The main advantage of multiplex PCR testing is that one 0.1-mL aqueous sample is used to test for four microorganisms, and the cost is reasonable, Dr. Chee said. She said she prefers testing for multiple organisms using real-time PCR, but the set-up is costly.

Other methods that detect ocular CMV include culture, which takes weeks to find out results, and Goldmann-Witmer coefficient. In immunocompetent patients, Goldmann-Witmer coefficient may be a more sensitive test than PCR for viruses because the eye overcomes the infection, producing antibodies and rapidly reducing viral DNA. Thus, the viral antigen phase is short-lived and may be missed by PCR, Dr. Chee said. In the case of CMV, however, she said that studies have demonstrated that PCR is more sensitive than the Goldmann-Witmer coefficient regardless of immune status.

“We have just started using the confocal microscope to examine these eyes,” Dr. Chee said, speculating that the tool will be used for screening or confirming CMV infection by identifying owl’s eye inclusions in the endothelium.

“Certainly, when the owl’s eye inclusions in the endothelium are present, one would strongly recommend aqueous sampling for CMV to confirm the diagnosis before offering treatment. Japanese authors have reported the presence of coin-like lesions. However, we have not observed this in our cases,” Dr. Chee said.

PCR detects CMV, other viruses in posterior uveitis

A study in American Journal of Ophthalmology assessed results for CMV and other viruses in PCR analysis of intraocular fluid as a test for infectious uveitis of the posterior segment. The study retrospectively analyzed the results of PCR testing in 133 patients presenting with possible chorioretinitis.

The predictive value of a negative test was 67.9%. Conversely, the positive predictive value was 98.7%. Inflammation resolved in 25 of 26 cases of posterior uveitis after treatment was refined based on PCR and serologic results.

According to study author Janet L. Davis, MD, “The clinician is still the arbiter for all diagnoses and treatment choices. A negative PCR result with a strong clinical suspicion is not going to invalidate a working diagnosis. It is certainly a reason to keep looking back over your shoulder for whatever it is you might have missed. Sometimes there may not be a good second-line test, but if only PCRs for viruses were done initially, the next round might include toxoplasmosis.”

Dr. Davis said that PCR cannot be used routinely for all cases of unknown posterior uveitis, but that it should be used only when there is a good chance that the unknown is something that is actually diagnosable by PCR, namely intraocular infection from CMV, HSV, VZV, toxoplasmosis and possibly Epstein-Barr virus.

“As long as aqueous humor is being accessed and not vitreous, the morbidity related to specimen acquisition is minimal — essentially none in the currently published series of several hundred diagnostic paracenteses,” she said.

Role of PCR in treatment decisions

“I feel strongly that anti-CMV treatment should only begin after obtaining a confirmatory PCR result because of potential toxicity issues and cost,” Dr. Chee said.

“Today, we screen endotheliitis eyes using the tetraplex PCR and confirm this with real-time PCR before offering anti-CMV treatment. I would certainly perform PCR testing for all patients under my care with endotheliitis, as viruses other than CMV may be responsible,” she said.

In cases of posterior segment infectious uveitis, Dr. Davis said, “We have a technological solution [PCR] that enables precise diagnosis in at least some cases of posterior uveitis, which is fantastic. Even knowing the difference between HSV-ARN [acute retinal necrosis] and VZV-ARN is useful in selecting drug doses and clarifying the clinical course. Properly used, this is a great technique.” - by Pat Nale

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References:

• Chee SP, Bacsal K, Jap A, Se-Thoe SY, Cheng CL, Tan BH. Clinical features of cytomegalovirus anterior uveitis in immunocompetent patients. Am J Ophthalmol. 2008;145(5):834-840.
• Chee SP, Bascal K, Jap A, Se-Thoe SY, Cheng CL, Tan BH. Corneal endotheliitis associated with evidence of cytomegalovirus infection. Ophthalmology. 2007;114(4):798-803.
• Harper TW, Miller D, Schiffman JC, Davis JL. Polymerase chain reaction analysis of aqueous and vitreous specimens in the diagnosis of posterior segment infectious uveitis. Am J Ophthalmol. 2009;147(1):140-147.
• Koizumi N, Suzuki T, Uno T, et al. Cytomegalovirus as an etiologic factor in corneal endotheliitis. Ophthalmology. 2008;115(2):292-297.
• Suzuki T, Hara Y, Uno T, Ohashi Y. DNA of cytomegalovirus detected by PCR in aqueous of patient with corneal endotheliitis after penetrating keratoplasty. Cornea. 2007;26(3):370-372.
• Yamauchi Y, Suzuki J, Sakai J, Sakamoto S, Iwasaki T, Usui M. A case of hypertensive keratouveitis with endotheliitis associated with cytomegalovirus. Ocul Immunol Inflamm. 2007;15(5):399-401.

• Soon-Phaik Chee, FRCOphth, FRCS(G), can be reached at Singapore National Eye Centre, 11 Third Hospital Ave., Singapore 168751, Republic of Singapore; 65-6227-7255; fax: 65-6227-7290; e-mail: chee.soon.phaik@snec.com.sg.
• Janet L. Davis, MD, can be reached at Bascom Palmer Eye Institute, 900 NW 17th St., Miami, FL 33136; 305-326-6377; 305-326-6071; e-mail: jdavis@med.miami.edu.