PEDIATRICS Vol. 111 No. 1 January 2003, pp. 218-220
Why No Effect of Maternal Respiratory Syncytial Virus-Neutralizing Antibody?
To the Editor.—The impact of respiratory syncytial virus (RSV) infection on the morbidity and mortality of young infants is significant.1,2 No effective method of prevention is currently available for otherwise healthy infants, who represent the majority of cases of RSV during a typical respiratory virus season. However, a number of studies have demonstrated the protective effects of maternally derived antibodies against serious RSV disease.3–6 Passive polyclonal or monoclonal RSV-specific antibodies administered to premature infants at greatest risk is an effective method of prevention of severe RSV disease in this vulnerable population,7–9 underscoring the importance of high concentrations of antibody in decreasing the risk of RSV infection or severe disease in the first year of life.
The study of Bulkow et al,10 published in the February 2002 issue of Pediatrics, failed to find an association between maternal RSV-neutralizing antibody levels in the cord blood of Alaskan infants and hospitalization for RSV-associated disease. The study population (infants <3 years of age) is described as having high RSV infection and the highest annual hospitalization rates ever described. Factors associated with increased risk were considered to be mostly environmental in nature, although similar social/environmental conditions were common in both case and control subjects. Because of the living conditions described for these families, adults are also likely to be infected with RSV. Acute RSV infection in women during pregnancy is likely to boost maternal RSV antibody that can be transmitted transplacentally to the infant, providing protection early in life. The protective effect of passively transmitted serum maternal antibody was not apparent, yet the authors describe an association between the frequency of breastfeeding and a lower risk for RSV hospitalization. What is the biological explanation for these findings?
There are several factors in the study that could have led to these results. Although the authors made great efforts in attempting to enroll well-matched controls for each case, it is evident in the description of methods that this was not achieved adequately. Only 50.6% of the control subjects came from the same village as the cases. Given the population size of the villages (some as small as 50 people), the distances, and the transportation difficulties in the area, it is unlikely that control children had similar RSV exposure as the cases. When matching by age, a difference of 30 to 60 days is significant when the effects of maternally derived antibodies in infants are evaluated. The half-life of maternal RSV-neutralizing antibody in infants has been estimated to be approximately 26 days.11 Cord serum concentrations of RSV-neutralizing antibody were measured in cases versus controls under 6 months of age as a group, without taking into consideration the age of the infants at the time of their first infection and the maternal antibody kinetics in the first months of life. A protective effect is more likely to be noted in the first 1 to 3 months of life, and less so at or beyond 6 months of age, depending on the starting antibody concentration.
The authors failed to consider the interval between birth and the time of culture-proven infection. Because of the natural decay of maternal antibodies, a direct correlation between level of neutralizing antibodies at birth and age at time of infection is hypothesized, as previously described by Glezen et al3 in 1981 (Table 1). When Bulkow et al10 considered the most severe cases, a trend was observed for lower neutralizing antibody concentrations in cases (geometric mean titer: 193.8 and 63% <1:250) versus controls (geometric mean titer: 357.5 and 33% <1:250), as expected. This difference probably would have been significant with a larger number of subjects. It is possible, as the authors suggested, that a high inoculum in this setting may have overwhelmed the infants’ defense mechanisms, but we suggest that the analysis is not complete without examining the correlation between neutralizing antibody level and age at the time of culture-positive infection.
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Flor M. Munoz, MD
W. Paul Glezen, MD
Molecular Virology and Microbiology
Baylor College of Medicine
Houston, TX 77030, USA
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[Abstract/Free Full Text] - Bulkow LR, Singleton RJ, Karron RA, Harrison LH, and the Alaska RSV Study Group. Risk factors for severe respiratory syncytial virus infection among Alaska native children.
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In Reply.—
We agree with Drs Munoz and Glezen that our inability to demonstrate a protective effect of passively transmitted serum maternal antibody in Alaska Native infants was perplexing. We will attempt to answer questions Drs Munoz and Glezen posed about potential study design factors that may have led to these results.
- Inadequate matching. Although only 50.6% of control subjects came from the same village as the cases, 100% of the controls came from the same subregion of southwestern Alaska (out of 9 subregions defined by village proximity and travel patterns). During an RSV epidemic in fall 1994 we demonstrated that the majority of RSV cases within a given subregion occurred over a relatively short time period of 2 to 4 weeks while RSV circulated in the entire region over a period of over 16 weeks (Fig 1). We find no evidence that any subregions are spared during the RSV season.
- Age at first infection. Although we only reported cord serum concentrations of RSV-neutralizing antibody in cases versus controls under 6 months, we did analyze the concentrations by month of age as shown below (Table 1).
- Small sample size. We agree with the authors that the difference in neutralizing antibodies when considering the most severe cases probably would have been significant with a larger number of subjects; ie, it is likely that neutralizing antibody protects against severe RSV disease in this population. This would be in agreement with our earlier findings regarding the relationship between level of cord neutralizing antibody and disease severity in a large subset of infants hospitalized with RSV.1 In this earlier study, RSV cord blood-neutralizing antibody titers were available from 79 of 219 infants
6 months old. In the multiple logistic regression model, neutralizing antibody titers <1200 were significantly more common in children with severe disease (86% vs 49%; odds ratio: 6.2; P = .03) using a previously described severity index.2
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There are 3 possible explanations for our inability to demonstrate a protective effect of passively transmitted serum RSV maternal antibody in Alaska Native infants. One explanation is that measurement of neutralizing antibodies in cord blood may not have provided an accurate picture of levels at the time of infection. Another possible explanation is that the high viral inoculum in this setting may have overwhelmed the infants’ defense mechanisms. A third possible explanation is that levels of maternal-neutralizing antibodies may have actually been a surrogate marker for the presence or absence of RSV in the community at the time of the infant’s birth. It is possible that women with high titers of RSV-neutralizing antibody were infected with RSV shortly before giving birth. We know from our previous study that RSV epidemics are relatively brief but intense in individual villages1 (Fig 1). Because of close contact with potentially infected community members, these infants born with higher maternal antibody titers may have been more likely to have been exposed to RSV early in life. Even considering potential differences in analysis, the proportion of children in our study with high cord serum-neutralizing antibody concentrations was much higher in our study participants than in Dr Glezen’s study, suggesting that exposure to RSV may be more common and more intense in our population.
Despite our findings, we have subsequently documented a dramatic decrease in RSV hospitalization rates in premature infants in this region routinely receiving palivizumab prophylaxis during 1998–2001, compared with premature infants in 1993–1996, while RSV hospitalization rates for all infants have remained static. This also supports the protective role of RSV-neutralizing antibody in this population (Arctic Investigations Program, National Centers for Infectious Disease, Centers for Disease Control, unpublished data, 2001).
Rosalyn Singleton, MD
Lisa R. Bulkow, MS
Arctic Investigations Program
National Centers for Infectious Diseases
Centers for Disease Control and Prevention
Anchorage, AK 99508, USA
Ruth A. Karron, MD
Department of International Health
Johns Hopkins University School of Hygiene and Public Health
Baltimore, MD, USA
Lee H. Harrison, MD
Infectious Diseases Epidemiology Research Unit
University of Pittsburgh Graduate School of Public Health and School of Medicine
Pittsburgh, PA, USA
PEDIATRICS (ISSN 1098-4275). ©2003 by the American Academy of Pediatrics
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