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Exploring the dynamics of the herpesvirus family
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Human herpesviruses and the diseases they cause have been leading to a great burden of disease in the United States for decades.
The human herpesvirus family is divided into three groups — the alpha herpesviruses, the beta herpesviruses and the gamma herpesviruses.
“The herpesvirus family is noted mainly because once you acquire it, [it] remains in your body,”
The alpha herpesviruses include the herpes simplex viruses and varicella-zoster virus (HHV-3); beta herpesviruses include cytomegalovirus (CMV; HHV-5), HHV-6A and HHV-6B, and HHV-7; gamma herpesviruses include Epstein-Barr virus (EBV; HHV-4) and Kaposi’s sarcoma-associated herpesvirus (HHV-8).
According to
Philip Pellett, PhD, professor
of immunology and microbiology
at Wayne State University, said
geographic differences exist
for the viruses.
Photo courtesy of Mary Simmons,
Wayne State University School of Medicine
“They are about 90% identical, and there’s been a big battle for 20 years among virologists over whether they should be called separate viruses,” he said. “There are now nine different human herpesviruses, although we only number them up to eight.”
Infectious Diseases in Children spoke with several experts to discuss the details of the different human herpesviruses, excluding HSV-1 and HSV-2.
Pediatric varicella-zoster infections
The primary infection of varicella is a highly contagious disease and was one of the most common childhood diseases before varicella vaccine (Varivax, Merck) was licensed in 1995.
In 2006, the Advisory Committee on Immunization Practices recommended that two doses of varicella vaccine be administered to children aged 4 to 6 years, with at least 3 months after the first dose, as well as administration of catch-up second doses to older children.
“That has decreased the amount of chickenpox we have seen in the United States, and we now have fewer hospitalizations and fewer deaths,”
VZV is the only herpesvirus that has a vaccine licensed for use in the United States. Currently, the varicella vaccine is a live vaccine, but according to Gowtham, there is ongoing research in terms of developing an inactive vaccine that appears to be promising.
Recently, strains of varicella virus have been collected from around the world and over 40 genomes have been sequenced. After analysis of these genomes by Grose and others, it is now know that a strain of varicella virus relatively similar to the current varicella virus was present in early humans as they emigrated out of Africa over 100,000 years ago. Thus, the VZV genome mutates very slowly. For this reason, the varicella vaccine is effective in human populations everywhere.
“The (live) vaccine is contraindicated in a subset of immunocompromised patients,” Gowtham said.
According to Gershon, about 15% of children who receive just one dose of the varicella vaccine develop breakthrough chickenpox after exposure to wild-type varicella.
“It’s usually a mild case, but it does serve to transmit the virus. So when we were giving one dose routinely, we had a lot of school outbreaks,” she said.
Varicella typically presents as relatively mild among healthy patients. They commonly develop an itchy, blister-like rash within 10 to 21 days of acquiring the virus, and most patients will develop a low-grade fever before the virus is out of their system.
A patient with chickenpox can be treated with antiviral therapy, specifically acyclovir.
“There was a lot of controversy with drug use when they first came out because the studies showed there was a benefit, but it wasn’t anything spectacular,” Gershon said. “A lot of people just said, ‘Why spend the money?’ Now, chickenpox is becoming so rare that many people will treat if you get chickenpox, particularly if the person was not vaccinated.”
Varicella in special populations
Gershon said varicella is more likely to be severe in immunocompromised patients who are not able to receive the vaccine, which was most likely one of the reasons the vaccine was eventually developed.
“It’s not because chickenpox itself is so severe but because the virus couldn’t be controlled before the vaccine, and immunocompromised people would end up getting sick,” she said.
Gershon also said, rarely, a congenital varicella syndrome can occur if a pregnant women becomes infected with varicella before 20 weeks’ gestation.
“The main thing that distinguishes varicella from other congenital infections is that the fetus can get cutaneous manifestations,” Gowtham said. “They can have scars, big bulbous lesions, and even limb deformities.”
It is also possible for an infant to develop disseminated varicella, right before delivery, which is considered neonatal varicella and can be severe.
Epstein-Barr virus
EBV presents as the classic mononucleosis and is mostly prevalent among adolescents. According to the AAP, most people will become infected with EBV at some point in their lives, but the virus typically remains latent in the system. EBV transmission occurs through infected saliva and presents with fever, sore throat, swollen lymph glands and fatigue.
“What has been talked about in the literature remains true,” Grose said. “Not a whole lot has changed with the virus over the last 5 to 10 years.”
However, Grose said, of all of the human herpesviruses, EBV has the longest incubation period — at about 40 days. This long incubation period often leads teenagers to blame the wrong person for giving them EBV, otherwise known as the “kissing disease,” according to Grose.
Splenomegaly is also common in adolescents who acquire EBV infection.
“If an adolescent is involved in any contact sports, we do an ultrasound of the abdomen to check for splenomegaly,” Grose said. “If they have it, we do not allow them to play any contact sports during that time, which is usually 1 to 2 months. It’s usually advice that is not eagerly accepted.”
Grose said EBV can also occur in younger children, typically in the day care setting.
“In general, it causes mild symptoms, usually a low-grade fever for perhaps 3 to 4 weeks,” he said. “There are no major problems, but it’s just bothersome. There are no other complications of having it at an earlier age.”
Cytomegalovirus
In the United States, CMV is the most common congenital herpes infection, according to AAP, and usually infects most people at some point in their life. Gowtham said the most significant manifestation of congenital CMV is hearing loss: “It has nothing to do with the way your ear conducts the tympanic membrane or how it conducts sounds, it has to do with how the brain perceives the sounds. Fifteen percent of babies who acquire congenital CMV will have sensory neural hearing loss.”
Gowtham also said the hearing loss is usually not discovered until patients are aged 3 years.
“There’s currently ongoing research to see if we can do anything with testing before 3 years of age to see if that would help with hearing loss,” she said.
It is also typically transmitted through body fluids, including breast milk.
“Reactivation of CMV in normal, healthy patients with a normal immune system doesn’t really cause any issues,” Gowtham said. “You don’t really notice it; small bouts of the virus could be present in the blood, but the body is able to control it.”
At ID Week 2013,
“Babies receiving 6 months of treatment had better audiologic outcomes compared with those receiving 6 weeks of treatment,” Kimberlin said. “It appears, at this time, that valganciclovir is the safer way to deliver the drug and that longer-term therapy gives better outcomes.”
David W. Kimberlin
According to data from Kimberlin’s presentation, congenital CMV is also the most frequent viral cause of mental retardation.
Gowtham said CMV can occur during childhood, typically in the day care setting.
“These children can get a mononucleosis-like picture, fever, mild rash, mild hepatitis, etc.,” she said. “Most people, when they get CMV, may or may not have any symptoms, even as younger children. It generally has to do with your socioeconomic status. If you’re from a lower socioeconomic status you have a higher risk than people in a higher socioeconomic status, but as you age you generally get exposed to CMV.”
HHV-6 and HHV-7
HHV-6 was known for years to cause roseola, however, once 6A and 6B were recognized as separate species, it became evident that 6B was the main cause of roseola. Most children are infected before aged 3 to 4 years and about 30% have the classic fever-rash presentation of roseola. Most of the other experience a variety of symptoms, such as fever without rash, rash without fever, and others.
“We actually don’t even know what disease HHV-6A causes,” Grose said. “It’s a real mystery with regard to those two viruses because they’re about 90% similar at a genetic level, but it appears that HHV-6B is the one that causes the disease that most of us will be familiar with in the United States and Europe.”
However, according to
“Studies done in South Africa found HHV-6A in children with fevers,” he said. “Symptomatically, those illnesses presented similarly to HHV-6B. In other parts of the world, for the most part, roseola symptoms match as does the spectrum of disease and connects it to HHV-6B.”
In a study published in Epilepsia in 2012, researchers found that one-third of all children who have severe febrile seizures also have an active infection with HHV-6B.
“This is a striking observation because febrile seizures are sort of the bane of parents who try to do everything right in the care of their children; they just pop up,” Grose said. “It’s frightening, and there hasn’t been, up to this point, any specific etiology associated with the fever.”
According to the Manual of Clinical Microbiology, 11th edition (still in press), roseola symptoms include an abrupt rise in temperature lasting for 2 to 5 days and “coincides with onset of a maculopapular rash (only rarely vesicular), which resolves in 1 to 3 days.” In a recent study, HHV-7 seroprevalence ranges from 60% to 90% in healthy adults in the United States.
In children, after the waning of maternal antibodies, seroprevalence increases to more than 50% by age 2 years and progresses to the adult level through childhood.
According to Pellett, about 5% of roseola cases are caused by HHV-7 and the virus can cause other febrile illnesses.
“HHV-7 has primary disease that basically makes it look like the disease is roseola and makes it indistinguishable from HHV-6B primary infection,” Pellett said. “A larger subset of those kids have febrile convulsions during their primary infections that can also occur for HHV-6B.”
Testing for both HHV-6 and HHV-7 can be done using cultures, but Pellett said that is rarely performed other than in research settings.
“Even in kids with roseola, it would be very uncommon for a physician to order a laboratory test,” Pellett said. “Physicians can typically diagnose it clinically. Treatment using ganciclovir is also typically the same for both viruses, but less is known about outcomes when it is used for HHV-7.”
Kaposi’s sarcoma
HHV-8 is known as Kaposi’s sarcoma-associated herpesvirus and was first discovered in adults with HIV before there was adequate HIV treatment.
It most commonly presents as reddish brown plaque or nodular skin lesions on the skin or on oral muscosa or internal organs. It can be diagnosed by pathologic examination of affected tissues.
According to Grose, HHIV-8 infection in HIV patients seems to be mainly transmitted sexually.
“In adults, now though, who are adequately being treated for HIV infection, it doesn’t appear as if HHV-8 causes any additional disease,” he said.
Grose said HHV-8 is commonly found around the Mediterranean, for reasons that are still unknown. In those countries, it is present in both adults and children even if they do not have HIV. However, he said the virus does not seem to have any consequences in children. Transmission appears to occur by exchange of saliva among family members.
Pellett also said in the central African region, half of the adults have been infected with HHV-8 and they commonly pass it along to their children. — by Amber Cox
AAP. Cytomegalovirus (CMV) Infections. Available at: http://www.healthychildren.org/English/health-issues/conditions/infections/pages/Cytomegalovirus-CMV-Infections.aspx. Accessed March 31, 2014.
AAP. Mononucleosis. Available at: www.healthychildren.org/English/health-issues/conditions/infections/pages/Mononucleosis.aspx. Accessed March 31, 2014.
AAP. Varicella (Chickenpox). Available at: www.healthychildren.org/English/health-issues/vaccine-preventable-diseases/Pages/Varicella-ChickenPox.aspx. Accessed March 31, 2014.
CDC. MMWR. 2007;56(RR04):1-40.
Epstein LG. Epilepsia. 2012;53:1481-1488.
Grose C. J Virol. 2012;86:9558-9565.
Pellet PE, Tipples G. Human Herpesviruses 6, 7, and 8. In: Versalovic J, Carroll KC, Jorgensen JH, Landry ML, Warnock DW, eds. Manual of Clinical Microbiology. 11th ed. Washington, DC: ASM Press; In press.
For more information:
Swathi Gowtham, MD, did not release contact information.
Charles Grose, MD, can be reached at charles-grose@uiowa.edu.
Philip E. Pellett, PhD, can be reached at ppellett@med.wayne.edu
Disclosure: Gershon, Grose, Kimberlin and Pellett report no relevant financial disclosures. Gowtham did not disclose financial relationships to Infectious Diseases in Children.
Should all newborns be tested for cytomegalovirus?
Yes, if the patient meets the criteria.
Criteria for newborn screening programs have been proposed. In general, they state that screening should be performed if the benefits of identification outweigh the costs and potential harms. Specific criteria relate to (1) prevalence; (2) availability of suitable screening tests; and (3) accessibility of safe, effective therapies. If we apply these criteria to congenital cytomegalovirus (cCMV), we find the following:
1.) Certainly, the prevalence of cCMV and the subsequent sequelae justify a screening program. Congenital CMV is the most common congenital virus infection worldwide, with a prevalence of approximately 0.7%. It causes hearing loss and other neurological disabilities in 15% to 20% of infected infants; both outcomes being more common than diseases currently included in our screening program. These sequelae are seen more commonly in infants symptomatic at birth but also occur in those without symptoms at birth (ie, those who will be detected only by a screening program). The newborn hearing screens currently in use will identify about 50% of cCMV infants who will develop hearing loss, but unfortunately the other 50% have later-onset disease and will be missed without a specific screening program for cCMV. Hearing loss in cCMV is a progressive disease whose onset may be delayed for years after birth.
2.) Screening tests that have been evaluated include culture and PCR of urine, saliva and blood. The use of dried blood spots would simplify screening as the process is already in place, but there are concerns about its sensitivity. Saliva and PCR may be the optimal approach. Because swabs can be shipped dry to a central laboratory, this method should be easily adapted to widespread use. While a general screening program is not without controversy, good clinical practice dictates that infants identified with hearing loss should be screened for cCMV promptly so that cCMV can be distinguished from post-natal CMV acquisition.
3.) IV ganciclovir and, more recently, oral valganciclovir (Valcyte, Hoffmann-La Roche) have been evaluated in moderately large studies of infants with cCMV and neurologic involvement. Therapy reduced the progression and hearing loss and improved the neurologic outcome. However, it must be emphasized that these studies were restricted to infants with cCMV and neurologic involvement, and there are no large studies involving asymptomatic infants. Further, these drugs are not without side effects, which include neutropenia and concern for carcinogenicity and reproductive health. Improvement in the drugs available and our ability to predict which asymptomatic infants will go on to develop problems would simplify the choice of when to use these drugs. However, what is not controversial is that early management for those with hearing loss is beneficial and can improve language development. Thus, there is a strong rational for identifying cCMV-infected infants early, monitoring frequently for hearing problems and intervening when hearing loss is first noted.
In summary, cCMV is common, detection methods that can be automated are available and early intervention can improve the outcome. In 1992, Drs. Yow and Demmler (N Engl J Med. 1992; 326: 702-703.) appealed: “Congenital CMV disease: 20 years is long enough.” Surely after another 20 years it is time.
David I. Bernstein, MD, is director of the Division of Infectious Diseases at Cincinnati Children’s Hospital. Disclosure: Bernstein reports no relevant financial disclosures.
Time to screen for cCMV infection? No, Not yet.
Congenital CMV infection is a worldwide public health problem that often is clinically inapparent but may result in substantial sequelae, mainly sensorineural hearing loss. Although screening for cCMV infection is a long-sought goal, the time for such screening is not yet here. Certainly, cCMV screening conforms to the basic definition of a screening strategy, that is, one that is used in a population to detect a disease in individuals without signs or symptoms of that particular disease. As many as 90% of newborns infected with CMV have latent infection and are not identified in the neonatal period, yet, months to years later, about 5% to 10% will develop late-onset sensorineural hearing loss. Other criteria for a screening test as recommended by WHO also apply, namely that the condition should be an important health problem (yes!) and there should be an agreed-upon policy for treatment of the condition. For cCMV infection, the current treatment recommendation is provision of antiviral therapy only for those neonates who have signs of central nervous system involvement. This treatment recommendation soon may change after publication of the results of a recent randomized, placebo-controlled study of valganciclovir treatment of neonates with any clinical or laboratory abnormality of cCMV infection. Preliminary results showed improvement in hearing outcomes as well as language composite and receptive communication scores by Bayley III testing at 2 years of age. However, for the completely normal neonate with cCMV infection, no treatment beyond hearing screening every 6 months up to 4 years of age and then yearly is recommended.
The recent results of the CMV & Hearing Multicenter Screening (CHIMES) Study sponsored by the National Institute on Deafness and Other Communication Disorders suggest that simple addition of CMV screening to the already collected newborn dried blood spots is grossly inadequate — this strategy would identify at best 30% of infected newborns. These investigators showed that saliva screening for CMV DNA by PCR is optimal — certainly doable, but yet another test that needs to be performed before nursery discharge. The saliva swabs would be sent to the state health department laboratory for CMV DNA PCR testing, similar to how dried blood spots are processed, but the cost effect remains to be evaluated properly. Such a screening test would appear to be acceptable to the population, in that mothers are often frustrated by their previous lack of knowledge of CMV and the effects that it may have on their child. In addition, the natural history of hearing loss associated with cCMV infection is being evaluated by the CHIMES study, another important prerequisite for institution of universal screening.
Although much progress has been made toward screening for cCMV infection, challenges remain. A continuing and unresolved dilemma is how best to evaluate the neonate who screens positive for CMV infection — beyond hearing and ophthalmologic evaluations, there is no consensus, even among pediatric infectious diseases specialists, as to what tests should be performed. Should all of these neonates have complete blood cell and platelet counts, liver enzymes, and/or neuroimaging? The results of more expanded evaluation ultimately may influence treatment decisions. Yet, predicting which neonate with clinically inapparent infection will develop sequelae is not yet known, and a biomarker to identify such infants is urgently needed to help guide optimal and appropriate management.
Andrea Ronchi, MD, is with the University of Texas Southwestern Medical Center in Dallas. Pablo J. Sanchez, MD, is with the department of infectious diseases and neonatology at Nationwide Children’s Hospital. He is also a member of the Infectious Diseases in Children Editorial Board. Disclosure: Ronchi and Sanchez report no relevant financial disclosures.