LETTERS

Respiratory Syncytial Virus in Indonesian Children

To the Editors: lobally, respiratory syncytial virus (RSV) is estimated to cause between 66,000 and 199,000 deaths among young children every year.1 Several factors, including a better understanding of RSV disease burden, improvements and vaccine technology and the remarkable success of vaccines such as rotavirus vaccines, have led to a renaissance in interest in RSV vaccine development. Currently, there are more than a dozen RSV vaccine candidates in preclinical or early clinical development. One of the critical questions about RSV vaccines is whether they can be effective early enough in life to prevent the most severe disease. Studies in industrialized as well as developing nations suggest that the highest incidence of hospitalization for RSV is in the first 6 months of life, and in particular, during the second and third month of life.25 Developing vaccines to induce active immunity at such a young age would be challenging. The study by Simes et al6 in Septembers Pediatric Infectious Disease Journal presents an intriguing finding from a study conducted in Indonesia a decade earlierthat fewer than 5% of cases of RSV lower respiratory infection among periurban and semirural Sundanese infants occur in the first 6 months of life. If true, and if this pattern occurs in other developing world settings, this opens the possibility that an RSV vaccine that does not become effective until age 6 months could prevent the bulk of serious RSV-related disease in those settings. Given this remarkable finding and implications for RSV vaccination, some additional clarification would help readers to better evaluate the study:

TO THE

EDITOR
the low number of cases during the first 6 months of life in this group. Confirming this finding would have important implications for RSV vaccine development. Division of Viral Diseases National Center for Immunization and Respiratory Diseases Centers for Disease Control and Prevention Atlanta, GA REFERENCES
1. Nair H, Nokes DJ, Gessner BD, et al. Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis. Lancet. 2010;375:15451555. 2. Hall CB, Weinberg GA, Iwane MK, et al. The burden of respiratory syncytial virus infection in young children. N Engl J Med. 2009;360: 588598. 3. McCormick J, Tubman R. Readmission with respiratory syncytial virus (RSV) infection among graduates from a neonatal intensive care unit. Pediatr Pulmonol. 2002;34:262266. 4. Nokes DJ, Ngama M, Bett A, et al. Incidence and severity of respiratory syncytial virus pneumonia in rural Kenyan children identified through hospital surveillance. Clin Infect Dis. 2009;49:13411349. 5. Djelantik IG, Gessner BD, Soewignjo S, et al. Incidence and clinical features of hospitalization because of respiratory syncytial virus lower respiratory illness among children less than two years of age in a rural Asian setting. Pediatr Infect Dis J. 2003;22:150157. 6. Simes EA, Mutyara K, Soh S, et al. The epidemiology of respiratory syncytial virus lower respiratory tract infections in children less than 5 years of age in Indonesia. Pediatr Infect Dis J. 2011;30:778784.

section, Newborn Cohort) or 3 years (as stated in the discussion). The data in Table 2 are internally inconsistent in that the incidence rates are not equal to what one would calculate based on the child-years of observation and the number of RSV lower respiratory infection cases in the table. Could this discrepancy be explained or the numbers corrected? The results section states that in the second and third years, more RSV was detected because of the use of PCR. The methods section describes technical details of the polymerase chain reaction (PCR) testing but does not state that the testing was used for only part of the study. When did PCR testing begin in the study, and what testing was used before PCR was used in the study? The recruitment rate of newborn infants during the latter part of the study (382 in 16 months) was about half that in the first part of the study (558 per 12 months). As it is unlikely that the birth rate fell by half during a 1-year time period, what is the explanation for the lower recruitment rate in the second half of the study, and is it true, as stated in the discussion, that the study recruited virtually all newborn babies in the first 3 years in cohort (almost 1000) ? In Figure 2, because of the study design, there may have been substantial differences in the proportion of children in the various age groups in the 7 time periods. One way to account for this would be to adjust each observation for the number of child-years of observation represented in the particular time point and age group.

Gregory L. Armstrong, MD

Reply:

The methods section states that infants 02 months of age were not recruited in the longitudinal cohort. Was this the case and what was the rationale for the exclusion? Also, note that the age groups in the first year of life are at 3-month intervals, not 2-month intervals, as stated throughout the manuscript. The study appears to have lasted 28 months (as stated in the methods section, Longitudinal Cohort), but parts of the manuscript suggest it lasted 24 months (as stated in the methods
The author has no conflicts of interest or funding to disclose.

In general, because risk of RSV disease can vary greatly during the first year of life and because RSV can be very seasonal, results of cohort studies such as the one presented here may be influenced by study design. For example, in the United States, one could consider a study that recruited a cohort of infants during the month of November, the start of the annual RSV season, and followed this cohort for a year. Such a study would tend to find most RSV infections occurring at a young age, as there would be little transmission of RSV during the second half of the study (ie, May through October). In contrast, a similar study that recruited infants only during the month of May would find infections occurring at an older age. Either study would be misleading. Although this phenomenon may have played a role in skewing the age distribution of RSV lower respiratory infection cases in this study, and the use of PCR testing only in the latter half of the study may have had a similar effect, neither of these would explain

e thank Dr Armstrong for the thorough perusal of the manuscript. He raises the same questions that we had regarding the paucity of serious lower respiratory tract disease caused by the respiratory syncytial virus (RSV) in infants less than 6 months of age, and the possibility of vaccinating children in developing countries. There were several queries, mostly relating to study design and analysis. We did not recruit infants less than 2 months of age in the longitudinal cohort because we did not want to overrepresent this group (knowing that we were going to recruit newborns in that cohort). We had aimed to eventually have similar child-years of observation in the 4 age groups in the first year of life, which cumulatively (1047) were similar to the 12- to 23-month group (1079) and slightly more per year than for the 24- to 59-month

This work was supported by a grant from the WHO Global Programme for Vaccines and Immunizations, Division of Vaccine Research and Development. The authors have no other funding or conflicts of interest to disclose.

The Pediatric Infectious Disease Journal Volume 31, Number 5, May 2012

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Letters to the Editor

The Pediatric Infectious Disease Journal Volume 31, Number 5, May 2012

TABLE 1. Child-years of Observation

Seasons RSV season Non-RSV season
mo indicates months.

Age Groups 02 mo 104 143 35 mo 78 169 68 mo 110 158 911 mo 144 148 1223 mo 432 647 2459 mo 548 738

age group. We designed our subject recruitment to have sufficient child-years of observation for all of our predefined age groups. For examination of risk factors, we chose not to recruit children in the same households, as these children would have been considered the same epidemiologic unit. This contributed, in part, to the decline in recruitment of newborns in the latter part of the study. The data in Table 2 are inconsistent, because, as stated in the statistical analysis section of the article, these were adjusted rates. Polymerase chain reaction testing for RSV was done at the end of the study; however, some earlier specimens were either not preserved adequately or were depleted in the rapid tests. All specimens were, however, tested using the Abbott Pak test (also stated in the methods section). We concur that one of the concerns in studies of seasonal infections is that the child-years of observation in each of the seasons, may bias study results. In fact, this is the reason for Figure 2 in the original manuscript. However, given the intensity of surveillance (weekly home visits), the relatively large size of the active surveillance (2014 subjects), that we recruited the newborn cohort throughout the study period, and that we covered 3 respiratory seasons, we did not expect this to be an issue. Because there were three 4-month RSV seasons in the 28-month study, the child-years of observation in the RSV season was proportionate to the non-RSV season (Table.). Hence, we do not suspect this biased our observations. Although the lack of RSV lower respiratory tract infection in those less than 2 months of age is a real observation in this population, the observation that severe RSV lower respiratory tract infection occurs in infants older than 6 months is well recognized1,2 especially in developing countries.37 How much impact this strategy of vaccinating older infants may have will be determined by prospective vaccine trials, but several studies from developing countries suggest that this may be a viable strategy.

Cissy B. Kartasasmita MD, PhD

Health Research Unit Faculty of Medicine Padjadjaran University/Hasan Sadikin General Hospital Bandung West Java, Indonesia REFERENCES
1. Simes EA, Mutyara K, Soh S, et al. The epidemiology of respiratory syncytial virus lower respiratory tract infections in children less than 5 years of age in Indonesia. Pediatr Infect Dis J. 2011;30:778784. 2. Hall CB, Weinberg GA, Iwane MK, et al. The burden of respiratory syncytial virus infection in young children. N Engl J Med. 2009;360: 588598. 3. Cherian T, Simoes EA, Steinhoff MC, et al. Bronchiolitis in tropical south India. Am J Dis Child. 1990;144:10261030. 4. John TJ, Cherian T, Steinhoff MC, et al. Etiology of acute respiratory infections in children in tropical southern India. Rev Infect Dis. 1991;13 (suppl 6):S463S469. 5. Weber MW, Dackour R, Usen S, et al. The clinical spectrum of respiratory syncytial virus disease in The Gambia. Pediatr Infect Dis J. 1998;17:224230. 6. Madhi SA, Kuwanda L, Cutland C, et al. Fiveyear cohort study of hospitalization for respiratory syncytial virus associated lower respiratory tract infection in African children. J Clin Virol. 2006;36:215221. 7. Nokes DJ, Okiro EA, Ngama M, et al. Respiratory syncytial virus infection and disease in infants and young children observed from birth in Kilifi District, Kenya. Clin Infect Dis. 2008;46:5057.

White Blood Cell Counts in Neonatal Early-Onset Sepsis

To the Editor: e read with interest the article of Murphy and Weiner1 who reported on 100% sensitivity and 100% negative predictive value of 2 normal white blood cell counts (WBC) within 812 hours and a negative blood culture at 24 hours for ruling out early-onset sepsis (EOS) in the neonate. A normal WBC count was defined as values between 6000 and 30,000/L, and an immature to total neutrophil ratio as less
The authors have no funding or conflicts of interest to disclose.

Eric A. F. Simes, MB BS, DCH, MD Phyllis J. Carosone-Link, MS, MSPH

Department of Pediatrics Section of Infectious Diseases University of Colorado Denver and Childrens Hospital Colorado Aurora, CO

than 0.2. The strength of the study was the large number of patients (n = 3213) included that retrospectively was identified by an electronic database during a 10-year period. Data revealed an overall low culture-proven EOS rate of 0.73%. The findings are astonishing by the way that to date no single or combined hematologic index was reported to be sensitive and specific enough to discriminate infected from noninfected symptomatic term and preterm neonates.2 By means of a retrospective cohort analysis of preterm and term neonates admitted to our neonatal intensive care unit between 2004 and 2007, including 737 of a total of 1301 neonates who had at least 1 WBC count determination during the first 72hours of life, we sought to prove the usefulness of leukocyte counts in the evaluation of EOS. WBC counts were performed in 19times per case (mean 1.65). Median gestational age was 34 weeks and median birth weight was 2137 g, and the number of preterm to term-born infants ratio was 236:501. Culture-proven EOS was diagnosed in 39 neonates (5.3%), and pathogens yielded Group B streptococci in 51%, Ureaplasma urealyticum in 26%, Escherichia coli in 10%, Staphylococcus aureus in 5% and single cases with Enterococci (3%), Chlamydia (3%) and Klebsiella (3%) infections. Defining normal WBC counts as between 9000 and 34,000/L3 revealed that 39% of cases with culture-proven EOS had abnormal values. By a second approach defining normal WBC counts between 8500 and 21,500/L calculated using the Youden index (0.29 for optimal cutoff values, sensitivity 64% and specificity 66%) data revealed 59% of cases had abnormal values. Sensitivity of WBC counts decreased when performed at 024 hours compared with 4872 hours of age. The immature to total neutrophil ratio showed sensitivity, specificity, positive predictive and negative predictive values (95% confidence interval) of 14% (529), 97% (9599), 36% (1365) and 92% (8994), respectively. Considering that blood cultures often do not reveal positive results before 72 hours of age, low sample volumes obtained in very low birth weight infants result in negative cultures and different rates of false-negative (approximately 20%) and false-positive results have been reported,3 collectively question the reliability of a negative blood culture result after 24 hours. Even when rapid automated blood culture systems were used, 97% and 99% of cultures were positive by 2436 hours of incubation when only pretherapy (before antibiotic therapy) cultures were evaluated.4 Risk factors associated with clinical symptoms and signs of sepsis seem to be more important in predicting culture-proven EOS than are any adjunct laboratory test.5 2012 Lippincott Williams & Wilkins

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