The Journal of Pediatrics
Volume 143, Issue 1 , Pages 4-6, July 2003

Congenital cytomegalovirus (CMV) infections: hats off to Alabama

  • Charles G. Prober, MD

      Affiliations

    • Corresponding Author InformationReprint requests: Charles G. Prober, MD, Professor of Pediatrics, Microbiology and Immunology, Scientific Director, Glaser Pediatric Research Network, Stanford University School of Medicine, Stanford, CA 94305-5208.
    • ,
  • Andrea M. Enright, MD

Stanford University School of Medicine, Stanford, CA 94305-5208, USA

See related article, p 17

Article Outline

Abbreviations: CASG, Collaborative Antiviral Study Group, CMV, Cytomegalovirus, gB, Glycoprotein B, HSV, Herpes simplex virus, VZV, Varicella zoster virus

 

Cytomegalovirus (CMV), herpes simplex virus (HSV) types 1 and 2, and varicella zoster virus (VZV) are three Herpesviridae that cause congenital and perinatal infections.1 Whereas neonatal infections caused by VZV and HSV are uncommon, neonatal infections caused by CMV are relatively common. Vertical transmission of CMV to the fetus can occur during pregnancy, at delivery, or after birth through exposure to breast milk or other body secretions. Infants with congenital CMV infection can be symptomatic or asymptomatic at birth. Symptomatic infections are seen in approximately 10% of infants with congenital CMV infection; these infants suffer substantially. Mortality for such infants can reach 30%, and survivors can have mental retardation, sensorineural hearing loss, chorioretinitis, and other significant medical problems.2 Congenitally infected newborns who are asymptomatic at birth also can have significant sequelae, with as many as 15% developing sensorineural hearing loss.3 In contrast, infants infected with CMV perinatally and postnatally generally do well.

Much of our understanding of maternal transmission of CMV to infants is based on a number of carefully conducted studies, led by investigators at the University of Alabama over a period exceeding 30 years!2., 4., 5., 6., 7. We have learned that the incidence of congenital CMV infection in the United States ranges from 0.2% to 2.2% of all live births; this translates into 10,000 to 80,000 infants born each year with congenital CMV infection. Among pregnant women in Alabama, the risk of congenital CMV after maternal primary infection exceeds 30%.5 Fortunately, transmission rates are reduced in the setting of pre-existing maternal antibody to CMV.8., 9., 10. In Alabama, the risk of congenital infection is approximately 1% for infants born to mothers who have antibodies to CMV before pregnancy.9 Despite the greater fetal attack rate after maternal primary, rather than recurrent, infection, more infants contract congenital infection as a result of exposure to maternal recurrent infection. This is because of the high prevalence of latent maternal CMV among women of child-bearing age and the failure of maternal antibody to prevent transmission during pregnancy.9

The significance of congenital CMV infections lies in the potential to cause long-term neurologic dysfunction including sensorineural hearing loss, cognitive impairment, behavioral disorders, cerebral palsy, and visual impairment.3., 4. Congenital CMV infection is one of the most common causes of nongenetic sensorineural hearing loss and the leading infectious cause of central nervous system damage in children in the United States.4., 11. The estimated annual societal cost of supporting children with congenital CMV approaches $2 billion (1991 US dollars).12

On the basis of an analysis of the cost of disease and its impact on quality-adjusted life-years, the Institute of Medicine of the National Academy of Sciences identified the development of a vaccine for prevention of congenital CMV infection as a top priority.13 Despite more than 30 years of continued research, no vaccine is currently available. Limited studies of an attenuated CMV viral vaccine failed to demonstrate protection from CMV disease in initially CMV-seronegative women.14 Furthermore, because of concerns that attenuated vaccine viruses might be reactivated in pregnancy with the risk of fetal transmission, subunit vaccines have been developed.15., 16. One of the best candidate subunit vaccines, studied by the Alabama investigators and others, utilizes envelope glycoprotein B (gB).16 In its purified form, gB vaccine induces neutralizing antibodies and lymphocyte proliferation.16 Research on the CMV vaccines is ongoing.

The likelihood of serious sequelae from congenital CMV infection depends, to a large degree, on the presence or absence of symptoms at birth. Pass et al from Alabama reported a series of 34 patients with symptomatic congenital CMV infection at birth; 10 died and 21 of the 23 survivors had substantial morbidity.2 Morbidity included microcephaly (70%), mental retardation (61%), neuromuscular disorders (35%), hearing loss (30%), and visual disorders including chorioretinitis or optic atrophy (22%). In a more recent study, Alabama investigators documented hearing impairment in nearly 50% of newborns whose congenital CMV infection was symptomatic at birth.17 Compared with the poor outcomes of neonates with symptomatic CMV infection at birth, sequelae are less frequent and more subtle among congenitally infected infants who lack symptoms at birth. However, an estimated 7% to 15% of these asymptomatic infants will have sensorineural hearing loss and 7% will have some degree of learning impairment.18., 19.

Because infants with symptomatic congenital CMV infection have the greatest mortality and long-term morbidity, evaluation of antiviral therapy initially has focused on such infants. Studies conducted by the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group (CASG), led by investigators from Alabama, were designed to address the impact of antiviral therapy on symptomatic congenital CMV infection with central nervous system involvement. The first studies conducted by CASG in infants with symptomatic congenital CMV determined the safety and pharmacokinetics of ganciclovir in this population.20., 21. The subsequent phase II, CASG study evaluated the toxicity, virologic response, and clinical outcomes in newborns with symptomatic congenital CMV infection receiving 6 weeks of parenteral ganciclovir therapy.22 The majority of these infants had thrombocytopenia and neutropenia attributed to the ganciclovir therapy. Although the amount of CMV excreted in urine decreased during therapy, viruria returned to near pretreatment levels after therapy was stopped. Hearing improvement or stabilization was evident in 16% of 30 infants at ≥6 months of age.

This issue of The Journal presents the results of the phase III randomized double-blind study of parenteral ganciclovir in neonates with symptomatic congenital CMV infection.23 This trial was not placebo-controlled because it would not have been ethical to insert a central catheter for prolonged intravenous administration of a placebo. This trial was incredibly difficult for the investigators to conduct; they should be commended for their determination, persistence, and dedication to conducting important clinical research in children. Enrollment at the 18 CASG sites spanned 8 years. Only 42 of the 100 subjects enrolled could be evaluated for the primary endpoint, hearing function as measured by brainstem-evoked response audiometry at six months. Unfortunately, as the authors pointed out, the large proportion of unevaluable patients raises concerns of follow-up bias and weakens the strength of their conclusions. Concerns of bias are increased by the authors' observation that a statistically significantly higher percentage of nonevaluable ganciclovir-treated recipients were black and premature; such patients might be expected to have poorer outcomes. Thus, the exclusion of these patients from primary outcome analysis likely favors a good outcome in the treatment group.

It is a tribute to the authors that they have been so forthright regarding the limitations of their data. Notwithstanding the limitations, the authors' conclusion that six weeks of ganciclovir therapy begun in the neonatal period in infants with symptomatic congenital CMV infection prevents hearing deterioration at 6 months (and perhaps even at ≥12 months) of age is plausible. Unfortunately, because developmental outcomes were not assessed, the impact of the study's findings on hearing are unclear. The morbidity associated with microcephaly and other central nervous system involvement may overwhelm the modest beneficial effects on hearing. The side effects associated with ganciclovir also may dampen enthusiasm for the widespread use of this therapy. Almost two thirds of ganciclovir recipients developed neutropenia, severe enough to require dosage modifications in 14 of 29 patients, additional therapy with granulocyte colony-stimulating factor in two patients and treatment for gram-negative septicemia in one newborn. Thus, it is prudent for the authors to suggest that ganciclovir therapy be considered for neonates with symptomatic congenital CMV disease involving the central nervous system. Engaging the family in a dialogue to determine the most appropriate course of therapy, if any, is critical. The intravenous administration of a drug for six weeks through a central catheter requires a substantial commitment of time and resources. This commitment combined with the knowledge of the known toxicity of the medication, its potential long-term gonadal toxicity and carcinogenicity, and unknown effects of the drug on developmental outcome must be weighed against the potential benefits on hearing. The Committee on Infectious Diseases of the American Academy of Pediatrics states the following in the 2003 edition of the Red Book, “One study of ganciclovir therapy of congenitally infected newborns with central nervous system disease suggested that treatment decreases the risk of hearing impairment. However, because of the potential toxicity of long-term ganciclovir therapy, additional study is necessary before a recommendation can be made.”24

So where do we go from here? It is possible that a more prolonged course of therapy would result in greater benefits, although skeptics would argue that antiviral therapy is unlikely to reverse the adverse effects of infection if the infant has evidence of severe central nervous system involvement at birth (microcephaly, intracranial calcifications, and abnormal cerebrospinal fluid). Because an oral bioavailable form of ganciclovir (valganciclovir) has been developed, it is now easier and safer logistically to test the hypothesis that a longer duration of antiviral therapy might be more beneficial than six weeks of parenteral therapy. Valganciclovir has not yet been studied in neonates but it does appear to be as effective as intravenous ganciclovir for induction treatment and long-term management of cytomegalovirus retinitis in adults with acquired immunodeficiency syndrome.25 The availability of oral therapy also raises the possibility of conducting studies in congenitally infected infants who are asymptomatic at birth, especially if audiologic assessments demonstrate hearing impairment. In the meantime, it is clear that the search for a safe and effective vaccine against CMV must continue. The burden of disease associated with congenital CMV infection remains unacceptably high and what we have to offer remains limited.

Our hats are off to our colleagues in Alabama and to the three generations of patients whom they have studied. They have taught us a great deal about the epidemiology, consequences, and management of congenital CMV infections over the last 30 years; for this we are indebted.

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References 

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PII: S0022-3476(03)00290-7

doi:10.1016/S0022-3476(03)00290-7

The Journal of Pediatrics
Volume 143, Issue 1 , Pages 4-6, July 2003

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