Study of hearing loss could offer clues to cytomegalovirus
by Mary Silva
There are eight herpes viruses that infect humans. Each has its own characteristics and method of transmission; each targets different cell types within the body. All share an astonishing ability to adapt and survive at our expense.
Cytomegalovirus (CMV) is human herpes virus number five. Like the rest of the herpes family, it is sneaky and persistent. The virus moves in quickly and sets up house for a lifetime in the body’s welcoming environment. It causes no obvious problems as long as we are healthy. But for the vulnerable – people with HIV, for instance, or who are undergoing organ or stem cell transplants, or newborns – it can wreak havoc.
Rhonda Cardin, PhD, is a researcher in the Division of Infectious Diseases. Along with her colleagues David Bernstein, MD, Fernando Bravo, MD, and Dan Choo, MD, she studies CMV and its effect on infants who are infected with the virus before or during birth. Human CMV can cross the placenta during pregnancy.
“About 44,000 of all live births per year in the U.S. are CMV-positive at birth,” says Cardin. “If a woman has an active infection while pregnant, she can transmit the infection to the fetus.”
PREYING ON THE VULNERABLE
First-time CMV infection during pregnancy can cause problems for a developing fetus and lead to severe complications in newborn infants.
“If a woman has previously been infected and her virus reactivates during pregnancy, because she has had an immune response, the infection may not be as severe,” Cardin says. “But a woman who already has built antibodies to one strain of the virus can be infected with a new strain while pregnant and transmit it to her baby.”
THE IMPACT OF CMV
Cardin says about 10 percent of babies born with CMV have symptoms that include neurological deficits, hydrocephaly and hearing loss. The other 90 percent of CMV-positive babies show no symptoms at all – at least not at first.
“Around 18 months to 2 years of age, a number of these children can exhibit hearing loss or learning impairment,” says Cardin. “CMV is a leading cause of infection-related hearing loss and mental retardation in children.”
For now, Cardin and her colleagues are focusing their research on CMV’s impact on hearing loss. She says between seven and 25 percent of asymptomatic children born with CMV develop “progressive sensorineural hearing loss.”
CREATING A HUMAN-LIKE MODEL
Cardin’s research team uses guinea pigs, the only small animal model in which CMV crosses the placenta during pregnancy.
They infect pregnant guinea pigs with CMV between the second and third trimester and have seen a 90 to 100 percent transmission of the virus to the pups.
VIRUS TRAVELS TO THE COCHLEA
“Within 7 days of birth, we can measure virus spread throughout the animals,” Cardin says. “Our latest results show that cochleas are infected in the newborn pups.”
The researchers have also tested the hearing of the pups infected with CMV both in utero and just after birth, and have found delayed onset of hearing loss in both by measuring auditory-evoked brainstem responses, similar to detecting hearing loss in children.
“In 50 percent of pups, we see progressive hearing loss. This gives us a model to evaluate how CMV infection in the cochlea leads to hearing loss,” says Cardin.
This finding is significant, she says, because researchers also have found CMV in the cochlea of newborn babies born with high levels of CMV infection and in the cochlea of some older children who require cochlear implants.
Cardin hopes to use the animal models to understand what structures and cell types within the cochlea are infected and what leads to the hearing loss.
MEDICINES THAT MODULATE
Cardin and Bernstein are also exploring treatments and vaccines that might limit the severity of CMV transmission and infection of the fetus. They have evaluated one drug, CMX 001, which is currently in Phase III human clinical trials.
In animal studies by Choo, use of the anti-viral medication ganciclovir also has stopped CMV-related hearing loss when caught early; a clinical study is in the planning stages (see related story).
Finding a vaccine that prevents CMV infection altogether is the ultimate goal, but one that has eluded researchers to date.
“It’s very difficult to develop vaccines against the herpes viruses,” says Cardin. “These viruses have evolved with their hosts and know all the tricks to maintain themselves or evade the immune response.”
Clinical Trial Hopes To Catch, Halt CMV Hearing Loss Early
“Clinically, CMV-related hearing loss is one of the few hearing loss conditions in kids that you can treat and reverse,” says Daniel Choo, MD. “If you catch it early enough and treat it with antiviral drugs, you can potentially rescue a child’s hearing.”
The key is catching it early. Newborns are not currently tested for CMV. The state of Ohio, however, does require that all newborns have a hearing screen before they leave the hospital. If the screen indicates hearing loss, the babies are referred to an audiologist for a follow-up test.
Choo, Director of Otolaryngology / Head and Neck Surgery, is awaiting IRB approval of a clinical study that could benefit infants seen for this follow up test at Cincinnati Children’s. The audiologist conducting the test would perform simple, non-invasive cheek swabs to test infants for CMV. Those testing positive for CMV could receive antiviral therapy.
Choo is basing the study on his successful NIH-funded pre-clinical trial of the antiviral drug ganciclovir. Because antiviral drugs can have side effects when given systemically, Choo and his fellow researchers administered the drug directly into the ears of guinea pigs with CMV-induced hearing loss. Direct injection avoided the side effects and stopped or reversed hearing loss in the animals.
“Our clinical trial proposes that we will follow an infant who is CMV positive and put the child on an oral antiviral,” Choo says, adding that many children tolerate the medication well. “But if the infant starts to show side effects, we will put a tube in his ear and send him home with antiviral eardrops. The drops go right into the tubes and diffuse into the ear.”
Although early detection and treatment of CMV-related hearing loss offers the best chance of correction, the problem often goes undetected until later in childhood, when the damage has progressed. But even those children can be helped, says Choo.
“Regardless of what causes a child’s hearing loss, we can fit them with hearing aids to compensate. If their hearing is still poor, we can do a cochlear implant. Children do really well with cochlear implants. Somehow we can always make them hear."