Chronic congenital cytomegalovirus is fairly common, occurring in approximately one in every 150 newborns, and it's relatively harmless, to boot, except in those with weakened immune systems. But when CMV is acquired during pregnancy, as it is for one in every 25 women, it can be devastating to the developing baby.
Cytomegalovirus can cause a number of medical and developmental problems, including cognitive delays and cerebral palsy, but its most common complication is hearing loss. That estimate is borne out by a recent case-control study in the Archives of Otolaryngology and Head and Neck Surgery. (2011;137:47-53.) Stephanie Misono, MD, and colleagues at the University of Washington found that children with hearing loss in Washington State had a much higher rate of CMV infection (9.9 percent) than those without hearing loss (1.4 percent). They estimated that about 8.9 percent of hearing loss in children in the state can be attributed to congenital CMV.
Congenital cytomegalovirus is probably the most common non-genetic cause of hearing loss in children, said Karen Fowler, DrPH, of the Department of Pediatrics at the University of Alabama-Birmingham and the lead investigator of the largest study to date on the connection between CMV and hearing loss. The trial has enrolled nearly 100,000 infants and children so far.
Unfortunately, the virus frequently goes undetected, as does the hearing loss, until the child is much older. The typical newborn hearing screening that all infants must undergo before leaving the hospital does not identify all children with CMV-related hearing loss because it's not apparent yet.
“About half of all children with hearing loss from CMV infection have it at birth while in the remaining half, it will not appear until later,” Fowler said. “And hearing loss in CMV is also quite variable in terms of its severity and whether it is unilateral or bilateral. There is no typical pattern.”
Now, Fowler's team has developed a relatively simple and inexpensive assay that appears to detect CMV-infected newborns accurately. Two different variations on the assay had high sensitivity and specificity for detecting CMV in newborns, according to a study published in the New England Journal of Medicine. (2011;364 :2111-2118.)
TRIAL AND ERROR
Originally, Fowler's team wanted to use blood spot testing to detect CMV because all babies already have blood spots collected as part of their routine metabolic screening. “If that worked, we wouldn't have to institute another program to collect specimens,” said study author Suresh Boppana, MD, Professor of Pediatric Infectious Diseases at the University of Alabama-Birmingham.
The team conducted a real-time polymerase chain reaction (PCR) assay with rapid culture of the blood samples, hoping for accuracy. “Unfortunately, our data show that this is not effective,” Boppana said. “Only about 35 percent of all babies with CMV would have a positive blood spot test.”
The researchers next turned to saliva samples, which have the advantage of being easy to collect. The saliva was collected from nearly 35,000 infants using a mouth swab. The swab was either stored in a liquid solution for transportation to the lab, or simply air dried, placed in a tube and transported at room temperature.
Both methods were highly accurate. The liquid-medium storage method yielded sensitivity of 100 percent and a specificity of 99.9 percent, while the dry storage resulted in 97.4 percent sensitivity and 99.9 percent specificity.
“Dry storage is a bit less sensitive, but the advantage for many institutions is that you don't need any sample preparation at all,” Boppana said. Another plus: Most PCR assays require some sample preparation for DNA extraction, but Fowler and Boppana's group found that the saliva samples can be assayed for CMV infection without DNA extraction, making the process much simpler and less expensive.
NOT READY FOR THE CLINIC
Newborn screening for CMV isn't yet mandatory, but Misono said the Alabama team's assay could make implementing such a requirement much easier. “The development of a reliable, noninvasive, low-cost screening method does facilitate the possibility of newborn screening,” she said. “Given the excellent sensitivities and specificities, saliva-based PCR screening could be an extremely powerful and useful tool. That the specimens can be collected noninvasively, stored at room temperature, and transported relatively easily are also major advantages.
“And given the potential variety and severity of clinical problems associated with congenital CMV infection, newborn screening for congenital CMV could have a considerably positive impact,” she said.
Although an accurate test may have been identified, Fowler acknowledged that their results must still be replicated in other labs. Questions about what to do after that also remain. “There's no standard of care for CMV,” Fowler said. “Symptomatic children can be treated with antivirals, but they have side effects that we might not want to use with children who aren't symptomatic. That's always been the stopping point for broader testing: What can we do with the results?”
Although it might not be possible to treat the infection and prevent or minimize the hearing loss that may result, identifying at-risk children still offers great benefits. If children infected with chronic CMV pass their newborn hearing test only to develop hearing loss later, the signs might well be missed until they're in school, when they are already behind in language and other developmental skills.
“Studies show that intervention at the time of language development is crucial. You want children to get a hearing aid or a cochlear implant when they're developing their language skills,” Fowler said. “As long as we know how to monitor [children's hearing loss], they can get into early intervention and specialized programs [and] get hearing aids, and they won't miss a beat.”
Misono recommended that children diagnosed with congenital CMV receive regular audiograms because hearing loss related to congenital CMV can change or progress over time. “At the Seattle Children's Hospital, typical recommendations for children who are CMV-positive and have hearing loss include ear-specific assessment of auditory function every three to six months until at least 5 years of age, or until their hearing has been stable for two years,” she said. “Once hearing stability has been established, then annual follow-up is recommended.”
Future research from the Alabama team aims to identify predictors of which infants are at increased risk of hearing loss from CMV infection. “We know that only a small number of babies born with congenital CMV ever develop hearing loss,” Boppana said. “Right now, we don't know what might predict those who are at increased risk of sustaining hearing loss from their infection. Until we have that information, if we ever do, I think the best option is to screen all babies.”
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