PEER-REVIEWED ARTICLE

Epidemiology of Respiratory Syncytial Virus in Various Regions Within North Carolina During Multiple Seasons David A. Wilfret, MD; Brent T. Baker, MD; Elizabeth Palavecino, MD; Cassandra Moran, DO; Daniel K. Benjamin Jr., MD, PhD Abstract Background: The Centers for Disease Control and Prevention (CDC) monitors the occurrence of respiratory syncytial virus (RSV) in the United States and has historically reported on activity at the regional level. Prior to the 2007-2008 RSV season, the CDC did not report seasonal RSV data for cities within North Carolina or for the state. The purpose of the present study is to characterize RSV seasonal activity within North Carolina and to determine the appropriate months in which at-risk children should receive prophylaxis. Methods: We prospectively collected RSV test data monthly over three seasons (fall through spring), from September 2003 through July 2006, from a diverse group of hospitals and a community pediatric practice located within five regions throughout North Carolina. Results: Approximately 14,000 laboratory tests, including 23.7% that were RSV positive, were evaluated over the three seasons, and RSV was detected within the state during all but three months of the study. Seasonal variation in the onset (October-November) of RSV activity and duration (six to seven months) of the RSV season according to the specified definition of seasonality was noted yearly within individual regions and among regions. On average over the study period, the greatest percentage of positive tests (33.8%) statewide occurred during January. Conclusions: Our data suggest the RSV season in North Carolina is longer than the national average, and RSV epidemics persist during months that fall outside of those in which RSV prophylaxis is given to high-risk children. Guidelines on the administration of RSV prophylaxis should ideally be based on results of local RSV test data. Keywords: respiratory syncytial virus (RSV); surveillance; seasonality; palivizumab; North Carolina

R

espiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections among young children1 and is responsible for more hospitalizations—approximately 2.4 per 100 births yearly—than any other disease during infancy.2,3 RSV affects nearly all children at least once by age 2.4 Those born prematurely or with either a history of chronic lung disease or significant congenital heart disease are at highest risk for severe disease.5 Potential consequences of RSV-related infection include recurrent wheezing and asthma through later life6 and deaths.7 This underscores the need for adequate preventive measures. There are no vaccines currently available against RSV, but the severity of infection and likelihood for hospitalization are reduced in at-risk children who are administered palivizumab prior to and during the RSV season.5,8,9

Recommendations on the use of palivizumab are issued periodically by the Committee on Infectious Diseases and published in the Redbook.5 The most current guideline states that palivizumab should be administered as a series of five monthly injections beginning in November and ending in March. However, these recommendations do not take into consideration the substantial seasonal variability in the onset and duration of RSV epidemics noted over time within a given geographic area or among different regions of the country.10 The Centers for Disease Control and Prevention (CDC) has monitored temporal and geographic trends for RSV activity through a passive surveillance system (i.e., National Respiratory and Enteric Virus Surveillance System [NREVSS]) that includes approximately 70 laboratories located throughout the

David A. Wilfret, MD, is a research fellow in the Department of Pediatrics at Duke University Medical Center. Brent T. Baker, MD, is a pediatrician for the North Carolina Respiratory Syncytial Virus Study Team. Elizabeth Palavecino, MD, is a medical microbiologist for the North Carolina Respiratory Syncytial Virus Study Team. Cassandra Moran, DO, is an instructor in the Department of Pediatrics at Duke University Medical Center. Daniel K. Benjamin Jr., MD, PhD, is an associate professor in the Department of Pediatrics at Duke University Medical Center. He can be reached at danny.benjamin (at) duke.edu.

NC Med J November/December 2008, Volume 69, Number 6

447

country. Results of RSV test data from participating sites for the 2003 through 2006 RSV seasons were grouped into one of four regions, and seasonal data were reported by region and not state, with the exception of Florida.11 There has been increased interest by individual state departments of health12,13 and independent investigators14-17 to gain a better understanding of the seasonality of RSV at the local level and to place less reliance on regional data. As a result, more than 20 state health departments have some form of RSV surveillance program. Recognizing the need for better reporting of local data, the number of reporting laboratories within the NREVSS has been greatly expanded and state data are currently available (i.e., as of the 2007-2008 RSV season) through the network. At the time of our study, North Carolina did not have any formal coordinated RSV monitoring program, and to our knowledge there were no available published data on the seasonality of RSV within the state. The purpose of this study was to identify when RSV was present in epidemic levels within different regions of the state over time and to determine the appropriate timing and duration of RSV prophylaxis specific to North Carolina.

METHODS We prospectively collected RSV test data monthly from children over three seasons (fall through spring), beginning September 2003 and ending July 2006 from a diverse group of academic and community hospitals and a group of pediatric primary care offices. The purpose of the study was to determine the onset, peak, duration, and conclusion of each RSV season within various regions of the state and in the state overall. A further objective was to determine appropriate timing and duration of palivizumab prophylaxis specific for North Carolina. Laboratory tests from patients were reported monthly and the number of positive tests was divided by the total number of tests to determine the percent of positive tests by region and for the state. The onset of the RSV season was defined as the first of consecutive months in which 10% or more of RSV tests were positive and at least 10 tests were reported. If fewer than 10 tests were reported, RSV was considered not to be present during the month. The conclusion of the RSV season was defined as the first month following successive epidemic months in which 10% positive tests and more than 10 samples were reported. c Fewer than 10 samples reported in this month.

Monthly data tabulated from all regions monitored within the state revealed that the onset of the RSV season occurred either in October or November and ended in March, April, or May. During 2003-2004 and 2004-2005, the RSV season lasted six months and during 2005-2006 was seven months long, beginning in November and ending in May (see Figure 1). Peak months for RSV activity differed annually and included February in the 2003-2004 season, January in the 2004-2005 season, and December in the 2005-2006 season. Overall statewide data yielded a six month RSV season from October through March with peak activity in January (see Figure 1). Of interest, in all three time periods there was a noticeable increase in the percentage of positive RSV tests from June to July including two seasons in which threshold limits were exceeded. It is unclear whether this result is a function of small sample size or high circulating levels of RSV in local communities. Nevertheless, it indicates that RSV is present in North Carolina during months outside of the traditionally-reported season. Greensboro/Winston-Salem The four hospitals within this region—Forsyth Medical Center, High Point Regional Hospital, Moses H. Cone Memorial Hospital, and Baptist Medical Center—tested 6,438 samples from inpatients and outpatients, contributing 46.3% of the total. Combined results from all hospitals in this region revealed two RSV seasons lasting six months, beginning in either October or November and concluding in March or April with a peak in

January and a third RSV season of four months with peak activity in January (see Figure 2). Wake Medical Center This facility tested 4,565 samples or 32.8% of the total. Results showed six month RSV seasons the first two years, starting in October and concluding in March (see Figure 3). Unfortunately, data for 2004-2005 were not reported for the months April through June; therefore it is possible that this RSV season could have been longer than reported. As with the first two seasons, the 2005-2006 season started in October but was of five months duration as the percent of positive RSV tests dipped to 9.7% in March. In the first season, the peak lasted essentially for two months, spanning January and February. In seasons two and three, peak activity occurred in December (see Figure 3). Pitt County Memorial Hospital This hospital contributed 1,139 samples, 8.2% of the total, over two RSV seasons. Data from this site differs from the others in that in both time periods the RSV season was short, lasting three months in 2003-2004, starting in October, and only two months in 2004-2005, beginning in January (see Figure 4). Carolinas Medical Center and Hendersonville Pediatrics Sites in these two regions each participated for one season and provided 1,778 or 12.8% of the samples. The Hendersonville practice contributed data for a full year from

NC Med J November/December 2008, Volume 69, Number 6

449

three locations and reported a seven-month RSV season during 2005-2006 including three months during which 50% or more of RSV tests were positive, including January, the peak month (see Figure 4). These findings should be interpreted cautiously as the high positivity rates are based on the fewest number of tests (367) per all regions and could also reflect a very strict test screening process. It is difficult to draw conclusions for Carolinas Medical Center as there is no general pattern to their data, which was reported over a period of only eight months.

Figure 1. RSV Test Data in North Carolina for Years 2003-2006

DISCUSSION RSV epidemics occur yearly throughout the United States, and a select group of infants and young children are at The RSV season in both of these states, and in Hawaii18,19 and increased risk for severe disease and hospitalization. Results of Alaska,15 is longer than that reported for other parts of the recent studies provide strong evidence that hospitalizations for country. The National Respiratory and Enteric Virus RSV-related illness parallel RSV virology data reported in the Surveillance System (NREVSS) has expanded the network of community.14,15 At the time of our study, the CDC monitored reporting laboratories, and data for the 2007-2008 RSV season RSV outbreaks through the NREVSS, which consisted of a is available for North Carolina (16 reporting laboratories) and limited number of laboratories in North Carolina. Data from other states on the CDC website. Several of the laboratories participating laboratories in individual states that were part of that are currently within the NREVSS network were included the NREVSS were arbitrarily grouped into four distinct in our study. In contrast to the data now available on the CDC regions; North Carolina was part of the south reporting region. website with NREVSS-reported data for the entire state, our Analyses of regional data reported by the CDC indicated that data is regional within North Carolina and statewide. Without the onset and duration of the RSV season varied substantially knowing the total number of laboratory tests ordered and the by year and location.10,14 Data were not available Figure 2. at the state level from RSV Test Data for Greensboro/Winston-Salem Study Sites for Years 2003-2006 the CDC. Given the variability in the timing of RSV outbreaks, there has been an increase in RSV surveillance monitoring at the local level.15,17 At least 20 state health departments presently have some form of RSV surveillance program.12 Two states—Florida and Georgia—monitor RSV in several regions within their states and report results on a statesupported website.12,13

450

NC Med J November/December 2008, Volume 69, Number 6

number positive per site, it is Figure 3. possible that there could be RSV Test Data for Wake Medical Center for Years 2003-2006 inherent biases in the statewide data reported by NREVSS. In North Carolina, RSV prophylaxis is typically given between November and March and longer if deemed medically necessary by the CDC or a local health department. For the 20072008 RSV season, North Carolina Medicaid, the main provider of palivizumab in the state, has approved palivizumab for no more than five monthly doses, while some insurance carriers will reimburse for six doses if that is supported by virology data. Our results suggest that the RSV season in North Carolina during the time of our study was at least six months long, including periods that extended outside of the came from large metropolitan areas. The imbalance of data from months recommended by the American Academy of Pediatrics these centers could limit generalizations about statewide results. Our data suggest that the RSV season in regions of North (AAP) for palivizumab administration. There are inherent strengths and weaknesses to our study. Carolina may be longer than the national average reported by the We reported results of almost 14,000 RSV tests, which is a CDC. Additionally, RSV epidemics can persist during months considerably larger study sample than that reported by other that fall outside of those in which RSV prophylaxis is recommended investigators.17 RSV activity was monitored from five regions by American Academy of Pediatrics for high-risk children. within the state over a period of three seasons and included Guidelines on the administration of RSV prophylaxis should cities with the largest populations within the state. Thus, we ideally be based on results of local RSV test data. NCMJ were able to determine trends in RSV activity within some Figure 4. regions and for the state over RSV Test Data From Each Study Site in North Carolina for Years 2003-2006 time. We acknowledge the following limitations, which could have biased study outcomes. Results of antigen testing were used to determine the presence of RSV in communities as only one site reported results of viral cultures; nevertheless, numerous state health departments and the NREVSS use similar testing methodology. The decision to test individual patients for RSV was left to the discretion of each clinician involved in the study, and data were reported by month rather than by week. As can be expected, the overwhelming majority of data NC Med J November/December 2008, Volume 69, Number 6

451

Financial Disclosure: MedImmune, Inc., provided funding for data management. None of the participating principal investigators received any monetary compensation. Acknowledgment: The authors and North Carolina RSV Study Team acknowledge the efforts of Dr. Jay H. Bauman, Scientific and Technical Evaluation, of Pharmaceuticals, Inc., for his analysis and assistance with manuscript preparation.

North Carolina RSV Study Team Member Brent T. Baker, MD Joy Barwick, MT, (ASCP) Danny Benjamin, MD, PhD Rosemary Billings Louise Hester Sue Knost, MS, (ASCP) Cassandra Moran, DO Elizabeth Palavecino, MD Mitzi Rumley David Wilfret, MD

Institution Hendersonville Pediatrics Pitt County Memorial Hospital Duke University Wake Medical Center Wake Forest University Baptist Medical Center Carolinas Medical Center Duke University Wake Forest University Baptist Medical Center Spectrum Lab Duke University

REFERENCES 1 Shay DK, Holman RC, Newman RD, et al. Bronchiolitisassociated hospitalizations among US children, 1980-1986. JAMA. 1999;282:1440-1446. 2 Leader S, Kohlhase K. Recent trends in severe respiratory syncytial virus (RSV) among US infants, 1997 to 2000. J Pediatr. 2003;143:S127-S132. 3 McLaurin K, Leader S. Growing impact of RSV hospitalizations among infants in the US, 1997-2002. Paper presented at: Pediatric Academic Societies Annual Meeting; May 2005; Washington, DC. 4 Glezen WP, Taber LH, Frank AL, Kasel JA. Risk of primary infection and reinfection with respiratory syncytial virus. Am J Dis Child. 1986;140:543-546. 5 American Academy of Pediatrics. Respiratory Syncytial Virus. In: Pickering KL, ed. Redbook: 2006 Report of the Committee on Infectious Diseases. 27th ed. Elk Grove Village: American Academy of Pediatrics; 2006:560-566. 6 Sigurs N, Gustafsson PM, Bjarnason R, et al. Severe respiratory syncytial virus bronchiolitis in infancy and asthma and allergy at age 13. Am J Respir Crit Care Med. 2005;171:137-141. 7 Thompson WW, Shay DK, Weintraub E, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA. 2003;289:179-186. 8 Feltes TF, Cabalka AK, Meissner C, et al. Palivizumab prophylaxis reduces hospitalization due to respiratory syncytial virus in young children with hemodynamically significant heart disease. J Pediatr. 2003;143:532-540. 9 Connor EM, Impact-RSV Study Group. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics. 1998;102:531-537. 10 Mullins JA, Lamonte AC, Bresee JS, Anderson LJ. Substantial variability in community respiratory syncytial virus season timing. Pediatr Infect Dis J. 2003;22:857-862.

452

11 Centers for Disease Control and Prevention. Brief report: respiratory syncytial virus activity—United States, 2005-2006. MMWR Morb Mortal Wkly Rep. 2006;55:1277-1279. 12 Bauman J, Eggleston M, Oquist N, Malinoski F. Respiratory syncytial virus: seasonal data for regions of Florida and implications for palivizumab. South Med. 2007;100:669-676. 13 Eggleston M, Bauman J. Regional respiratory syncytial virus surveillance data for Georgia and implications for prophylactic administration of palivizumab. Paper presented at: American Academy of Pediatrics National Conference and Exhibition; October 2007; San Francisco, CA. 14 Fergie J, Purcell K. Respiratory syncytial virus laboratory surveillance and hospitalization. Pediatr Infect Dis J. 2007;26(suppl):S51-S54. 15 Singleton RJ, Bruden D, Bulkow LR, Varney G, Butler JC. Decline in respiratory syncytial virus hospitalizations in a region with high hospitalization rates and prolonged season. Pediatr Infect Dis J. 2006;25:1116-1122. 16 Ellis SE, Coffey CS, Mitchel EF, Dittus RS, Griffin MR. Influenza—and respiratory syncytial virus—associated morbidity and mortality in the nursing home population. J Am Geriatr Soc. 2003;51:761-767. 17 Halstead DC, Jenkins SG. Continuous non-seasonal epidemic of respiratory syncytial virus infection in the southeast United States. South Med J. 1998;91:433-436. 18 Reese PE, Marchette NJ. Respiratory syncytial virus infection and prevalence of subgroups A and B in Hawaii. J Clin Microbiol. 1991;29:2614-2615. 19 Consensus Committee. Guidelines for prophylaxis for RSV infections in high-risk infants in Hawaii. Hawaii Academy of American Pediatric Organization website. http://www.hawaiiaap.org/pdfs/ConsensusStatement31AUG20 07.pdf. Accessed August 31, 2007.

NC Med J November/December 2008, Volume 69, Number 6