Why No Effect of Maternal Respiratory Syncytial Virus-Neutralizing Antibody?

aperture original speculum—the optimal size for children younger than 4 or 5 months.

Thus, in the era of antibiotic-resistant bacteria and inculcated judicious antibiotic usage, clinicians who employ the widely used Welch-Allyn square-head otoscope must ensure that the specu-lums supplied and used are appropriately sized, tapered, and shiny enough to optimally visualize the TM. They should elect to use either the original speculums, which can be wiped clean with an alcohol swab after each patient, or the not-so-shiny but appro-priately sized (apertures: 2.5, 3.0, 4.0 mm) disposable speculums from Otrec, Inc. (Dyersburg, TN). The currently available Welch-Allyn disposable speculums for the square-head otoscope should be disposed of, or better yet “pre-disposed.” Their use is tanta-mount to committing the bacterial original sin of over- and un-derdiagnosis of AOM. And, like original sin, everyone will even-tually pay for your diagnostic peccadilloes.

Stan L. Block, MD

Bardstown, KY 40004

REFERENCES

1. Steinbach WJ, Sectish TC. Pediatric resident training in the diagnosis and treatment of acute otitis media.Pediatrics.2002;109:404 – 408

In Reply.—

Thank you for your support of our work to begin the change needed regarding otitis media training in pediatric residency ed-ucation. We remain amazed that the most common problem in pediatrics garners so little time in residency. You are correct that most medical schools rarely discuss the issue, and we found that many residency programs devote only a few lectures per year to the subject. We all assume such a ubiquitous outpatient problem will be learned by simple osmosis and will not require any struc-tured training. We feel that pointing out the contrary is merely the proverbial tip of the iceberg.

This is not to say that there are many programs where otitis media education is alive and well, but there are so many more where the demands of critical care medicine or other subspecial-ities are stealing time from understanding and correctly executing a very basic clinical skill: the otoscopic examination. All pediatri-cians— generalists and subspecialists—need a core set of clinical skills; we believe that otoscopic examination is one of these cores skills. Dr Block is of course referring to his past comments to “dispose of the disposables” (Pediatr Infect Dis J.1998;17:1179 – 1180). His witty prose in his letter to the editor is matched only by his passion to teach the correct diagnostic examination of

chil-dren’s ears. For that, we thank him and certainly welcome any thoughts to improve pediatric resident and pediatrician education on otitis media.

William J. Steinbach, MD

Division of Pediatric Infectious Diseases Duke University School of Medicine Winston-Salem, NC

Theodore C. Sectish, MD

Division of General Pediatrics

Stanford University School of Medicine Stanford, CA

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 ofPediatrics,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 fam-ilies, 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 in-fant, providing protection early in life. The protective effect of passively transmitted serum maternal antibody was not apparent, Fig 2. 2.5-mm aperture original

equip-ment speculum (L) versus 2.5 mm aper-ture (actual 2.0 mm) disposable specu-lum (R).

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 attempt-ing 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 approx-imately 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 neu-tralizing antibodies at birth and age at time of infection is hypoth-esized, 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 com-plete without examining the correlation between neutralizing an-tibody level and age at the time of culture-positive infection.

Flor M. Munoz, MD W. Paul Glezen, MD

Molecular Virology and Microbiology Baylor College of Medicine

Houston, TX 77030

REFERENCES

1. Shay DK, Holman RC, Newman RD, Liu LL, Stout JW, Anderson LJ. Bronchiolitis associated hospitalizations among US children, 1980 –1996.

JAMA.1999;282:1440 –1446

2. Shay DK, Holman RC, Roosevelt GE, Clarke MJ, Anderson LJ.

Bronchi-olitis associated mortality and estimates of respiratory syncytial virus associated deaths among US children, 1979 –1997.J Infect Dis.2001;183: 16 –22

3. Glezen WP, Paredes A, Allison JE, Taber LH, Frank AL. Risk of respi-ratory syncytial virus infection for infants from low-income families in relationship to age, sex, ethnic group, and maternal antibody level.

J Pediatr.1981;98:708 –715

4. Lamprech CL, Krause HE, Mufson MA. Role of maternal antibody in pneumonia and bronchiolitis due to respiratory syncytial virus.J Infect Dis.1976;134:211–217

5. Ogilvie MM, Vathenen AS, Radford M, Codd J, Kay S. Maternal anti-body and respiratory syncytial virus infection in infancy.J Med Virol.

1981;7:263–271

6. Bruhn FW, Yeager AS. Respiratory syncytial virus in early infancy: circulating antibody and respiratory syncytial virus infection.Am J Dis Child.1977;131:145–148

7. Groothuis JR, Simoes EAF, Levin MJ, et al. Prophylactic administration of respiratory syncytial virus immune globulin to high risk infants and young children.N Engl J Med.1993;329:1524 –1530

8. The PREVENT Study Group. Reduction of respiratory syncytial virus hospitalization among premature infants and infants with bronchopul-monary dysplasia using respiratory syncytial virus immune globulin prophylaxis.Pediatrics.1997;99:93–99

9. The Impact-RSV Study Group. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from re-spiratory syncytial virus infection in high-risk infants.Pediatrics.1998; 102:531–537

10. Bulkow LR, Singleton RJ, Karron RA, Harrison LH, and the Alaska RSV Study Group. Risk factors for severe respiratory syncytial virus infec-tion among Alaska native children.Pediatrics.2002;109:210 –216 11. Brandenburg AH, Groen J, van Steensel-Moll HA, et al. Respiratory

syncytial virus specific serum antibodies in infants under six months of age: limited serological response upon infection.J Med Virol.1997;52: 97–104

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.

1. 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 circu-lated 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.

2. 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).

3. Small sample size. We agree with the authors that the differ-ence 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}

anti-body titers were available from 79 of 219 infantsⱕ6 months old. In the multiple logistic regression model, neutralizing an-tibody titers⬍1200 were significantly more common in chil-dren with severe disease (86% vs 49%; odds ratio: 6.2;P⫽.03) using a previously described severity index.2

There are 3 possible explanations for our inability to demon-strate a protective effect of passively transmitted serum RSV ma-ternal 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. TABLE 1. RSV-Neutralizing Antibody Titer in Cord Serum

Correlated With Age at the Time of Culture-Proven Infection in Infants⬍6 Months of Age, Houston, 1975–1978

Cord Antibody

Titer

No. of Infants by Age Group (Weeks)

Total

2–8 9–17 18–26

16 2 1 3 6

32 6 3 1 10

64 6 8 3 17

128 5 11 1 17

256 1* 10 4 15

512 0 0 1 1

1024 0 1* 1 2

Total 20 34 14 68

GMT 58† 118 100 92

Titerⱖ256‡ 1 (5%) 11 (32%) 6 (43%) 18 (26%) GMT indicates geometric mean titer.

* Infants hospitalized with unexplained fever.

†P⬍.01 (Wilcoxon) versus infants older than 8 weeks. ‡ Distribution of titersⱖ256;P⬍.05.

Source: Table adapted from Glezen et al.J Pediatr.1981;98:708 – 715.

LETTERS TO THE EDITOR 219

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Another possible explanation is that the high viral inoculum in this setting may have overwhelmed the infants’ defense mecha-nisms. 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 be-fore 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 commu-nity 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-neutral-izing 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 in-fants 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, Na-tional 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

Ruth A. Karron, MD

Department of International Health

Johns Hopkins University School of Hygiene and Public Health

Baltimore, MD

Lee H. Harrison, MD

Infectious Diseases Epidemiology Research Unit University of Pittsburgh Graduate School of Public

Health and School of Medicine Pittsburgh, PA

Glucagon Infusion for Treatment of

Hypoglycemia: Efficacy and Safety in Sick,

Preterm Infants

To the Editor.—

Treatment of sick, preterm infants with persistent hypoglyce-mia is challenging because of fluid limitations and the need for multiple infusions. An intravenous glucagon infusion can be an effective treatment for hypoglycemia.1 _{Recently, its safety has}

been questioned when as association with hyponatremia and thrombocytopenia was reported inPediatrics.2_{For this reason, we}

examined our experience with the efficacy and safety of glucagon infusions in the preterm infant.

METHODS

We retrospectively reviewed the charts of all preterm infants with persistent hypoglycemia who were treated with glucagon Fig 1. RSV hospitalizations by week in 5 subregions, October 1994 –February 1995.

TABLE 1. Cord Serum Concentrations of RSV-Neutralizing Antibody in RSV Cases and Controls by Month of Age for Children⬍6 Months of Age

Age

(Months) ⬎1200

Odds Ratio (PValue)

Cases Controls Combining by

2-Month Groups

0 9/10 (90%) 8/13 (62%) 4.11 (.200) 2.16 (.264)

1 14/16 (88%) 19/23 (83%) 1.16 (.876)

2 7/9 (78%) 12/14 (86%) 0.71 (.733) 0.71 (.676)

3 6/7 (85%) 9/10 (90%) 0.71 (.809)

4 5/7 (72%) 8/9 (89%) 0.39 (.448) 0.39 (.448)

5 5/5 (100%) 6/6 (100%) —

DOI: 10.1542/peds.111.1.218

2003;111;218

Pediatrics

Flor M. Munoz and W. Paul Glezen

Why No Effect of Maternal Respiratory Syncytial Virus-Neutralizing Antibody?

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DOI: 10.1542/peds.111.1.218

2003;111;218

Pediatrics

Flor M. Munoz and W. Paul Glezen

Why No Effect of Maternal Respiratory Syncytial Virus-Neutralizing Antibody?

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