Singleton, Rosalyn J. MD*†; Bruden, Dana MS†; Bulkow, Lisa R. MS†
Previous studies suggest that American Indian and Alaska Native (AN) infants and children have higher rates of hospitalization attributable to respiratory syncytial virus (RSV) bronchiolitis and pneumonia than the general U.S. population.1–3 We present information on rates of RSV hospitalizations from 1993 to 2004 in an Alaskan population with high rates of RSV hospitalization. We also describe risk factors for hospitalization and the impact of interventions such as palivizumab prophylaxis on high-risk infants in this population.
There is substantial variability in the timing of RSV seasons by year and geographic regions. Mullins et al4 calculated the RSV season onset and offset from 1990 to 2000 for the entire United States and determined a median duration of 15 weeks with significant regional variation. Data for northern latitudes suggest that RSV seasons may be prolonged in northern populations.5–9 We present data on the prolonged RSV season in Alaska.
MATERIALS AND METHODS
The Yukon-Kuskokwim (YK) Delta region in southwestern Alaska encompasses 75,000 square miles of coastal wetlands and tundra, an area approximately the size of South Dakota. The annual birth cohort is 600 to 620 births with 6–12% of infants born prematurely. The year 2000 population of approximately 25,000 comprises primarily Yup'ik Eskimos (85%), who live in 52 villages and the regional town, Bethel (population 6000). The villages are typically connected to one another only by airplane, boat, or snow machine, and the entire region is not connected to the remainder of the state by road. The lifestyle of the people living in these villages is primarily subsistence, with a heavy reliance on local fishing and hunting. Commercial fishing is the main export industry of the area. Most homes are small and many homes are without running water. The YK Delta Regional Hospital, a 50-bed primary care facility, is the only hospital in the region. Children requiring tertiary care are transferred to hospitals in Anchorage. Primary healthcare in village clinics is provided by certified Community Health Aides (CHAs) who receive standardized training and act on standing orders and phone communication with YK Delta Regional Hospital physicians.
RSV Surveillance: 1993–1996 and 1997–2004.
We conducted active laboratory-based surveillance for lower respiratory tract infection (LRTI) hospitalization in children from the YK Delta younger than 3 years of age who were hospitalized between October 1, 1993 and September 30, 1996.10 Nasopharyngeal aspirates were tested for RSV by rapid antigen enzyme immunoassay test pack (Abbott, Oak Park, IL) or by direct immunofluorescence assay (Bartels, Issaquah, WA) and cultured. In addition, we collected discharge diagnoses and clinical information.11
From October 1, 1996 to June 30, 2004, we abstracted clinical and laboratory information for children younger than 3 years of age residing in YK Delta who were hospitalized in Bethel or Anchorage.12 During this time period, RSV was diagnosed using rapid antigen testing, primarily with Directogen RSV (Becton Dickenson, Cockeysville, MD). Rapid antigen testing was performed for 83% of LRTIs in children 1 year of age and younger.
Case-Control Study—Risk Factors for RSV Hospitalization: 1993–1996.
To understand the factors associated with RSV hospitalization in AN infants younger than 1 year of age who are from the YK Delta, we conducted a case-control study with infants who were hospitalized with RSV between 1993 and 1996 and matched control infants.13
Impact of Palivizumab on RSV Hospitalizations.
Palivizumab use for high-risk infants14 began in Alaska in the fall of 1998. On the basis of local laboratory surveillance data, palivizumab has been administered during most years from October 1 through May 31. We compared RSV hospitalization rates in YK premature infants before (1993–1996) and after palivizumab (1998–2001).7 Between October 1, 1998 and September 30, 2001, all AN children who received palivizumab were entered into a centralized statewide registry. Data collected included demographic information, hospitalization dates, and palivizumab administration dates. We compared the RSV hospitalization rate within 32 days after palivizumab (“protected period”) and 32 days or more after palivizumab (“unprotected period”) during the 1998–2001 RSV seasons for 335 AN high-risk children around the state who received palivizumab through tribal health facilities.7
From 1998 to 2003, palivizumab was administered in YK Delta high-risk infants either at the regional hospital or by public health nurses traveling to the local villages. Difficulties in travel within the region and scheduling problems resulted in low compliance, and a pilot project to train the local CHAs to administer palivizumab was initiated. In 2003, CHAs received a 4-day training on RSV and palivizumab. Subsequently, palivizumab doses were shipped by the pharmacist to the village for administration by the CHA in the village clinic. We evaluated compliance comparing the projected number of palivizumab injections (based on month of first dose) to the actual number administered. We also calculated the proportion of protected days within the RSV season before (1998–2001) and after the CHA training project (2003–2004).15
We applied the methodology used by Mullins et al,4 to RSV hospitalization surveillance data for the YK Delta from 1994 to 2004 to calculate median RSV onset and offset weeks.12 To examine the RSV season length the year started on July 1. Season onset and offset were defined as the first and last of 2 consecutive weeks, respectively, with RSV detected in 2 or more specimens and higher than 10% of all submitted specimens. We modified the Mullins et al definition to additionally require the peak week to have more than 5 RSV tests performed.
RSV Surveillance: 1993–1996.
Using active laboratory surveillance from 1993 to 1996, we showed that AN infants younger than 1 year of age from the YK Delta experienced a RSV hospitalization rate of 156 per 1000 per year, 5 times the rate in the U.S. general infant population (Fig. 1).1,2,10,16 During this period, all LRTIs accounted for 67% of all hospitalizations for infants in this region and 32% of all infant hospitalizations were associated with RSV infection.
Risk Factors for RSV Hospitalization: 1993–1996.
Several household and environmental factors that affect respiratory virus transmission seem to contribute to the high rates of RSV hospitalization in AN infants younger than 1 year of age from the YK Delta. In a nested case-control study conducted during active surveillance, the average study household had more than 6 persons, higher than 50% of households lacked running water or flush toilets, and higher than 50% of households included a smoker.17 In the multivariate analysis, risk of RSV hospitalization was greater for children with underlying medical conditions (primarily prematurity) [odds ratio (OR) 6.63, P < 0.001], whereas risk was decreased in children breast-fed more than half of feeds (OR 0.38, P < 0.001).13 Risk of RSV hospitalization was also greater for those with 4 or more additional children younger than 12 years of age in the household (OR 2.13, P = 0.011), and those with a household crowding index of 2 or more persons per room (OR 1.72, P = 0.024).
Impact of Palivizumab.
Palivizumab was administered to high-risk infants who met the American Academy of Pediatrics criteria for prophylaxis.14 The RSV hospitalization rate among high-risk YK premature infants younger than 36 weeks gestation decreased from 439 per 1000 infants/yr during the preprophylaxis period (1993–1996) to 150 per 1000 infants/yr during 1998–2001 [risk ratio (RR) 0.34, P < 0.01]. In contrast, the rate in nonpremature YK infants older than 36 weeks gestation was similar from 1993 to 1996 (148 per 1000 infants/yr) and from 1998 to 2001 (142 per 1000/yr) (Fig. 2).7 The rate of first RSV hospitalization during the RSV season among YK children receiving palivizumab was 1.28 per 1000 protected days and 3.12 per 1000 unprotected days (RR 0.41, P = 0.02).7 For all AN children receiving palivizumab, the rate of first RSV hospitalization was 0.55 per 1000 protected days and 1.07 per 1000 unprotected days (RR 0.52, P = 0.03).7
CHA Palivizumab Project.
From 1998 to 2001, only 74.0% of projected palivizumab doses were administered to palivizumab recipients in the YK Delta. During the following 2003–2004 RSV season, after the CHA training project, 90.4% of projected palivizumab doses were administered. In addition, palivizumab recipients were protected during 85.1% of the RSV season days during the 2003–2004 season, compared with 67.3% during the 1998–2001 seasons.15
LRTI and RSV Hospitalizations: 1994–2004.
The rate of RSV hospitalization in YK Delta children younger than 1 year of age decreased from 178 per 1000 infants/yr (1994–1997) to 104 per 1000 infants/yr (2001–2004) (P < 0.001), whereas the rate of non-RSV LRTI hospitalizations increased from 153 to 215 per 1000 infants/yr (P < 0.001), and the overall LRTI hospitalization rate remained stable at 284 per 1000 infants/yr from 1994 to 1997 and 282 from 2001 to 2004 (Table 1). 12 Despite the reduction in RSV hospitalization rate, the 2001–2004 rate of 104 per 1000 infants/yr remained more than 3 times the RSV hospitalization rate reported for the general U.S. infant population.16 During this time period, children with an LRTI hospitalization at younger than 1 year of age were 3.2 (95% confidence interval, 2.6, 3.8) times more likely to be hospitalized for an LRTI during their second year of life than children without an LRTI at younger than 1 year of age. The median length of stay for an RSV hospitalization was 4 days and 4.0% of hospitalizations required mechanical ventilation.
Seasonality of RSV Infections in the YK Delta.
The earliest week of RSV season onset was July 8 to 14 (1998–1999 season and 1999–2000 season) and the week of March 17 to 23 (2002–2003 season) was the latest. The RSV peak week ranged from December 16 to 22 (1994–1995 season) to May 5 to 11 (2002–2003 season) (Fig. 3). The RSV offset week ranged from February 17–23 (2001–2002 season) to June 23–30 (1998–1999 season). The median RSV onset, peak, and offset weeks for the YK Delta region were October 14–20, February 20–26, and May 19–25, respectively (Table 2). Over the 10 seasons, 13% (n = 169; yearly range, 2–26%) of RSV cases occurred during the summer months (June 1–September 30). The RSV season varied in length from 12 weeks (2002–2003) to 51 weeks (1998–1999) with a median of 30.5 weeks.12 This is twice as long as the median RSV season in the contiguous United States, which lasts from late December to late March with a median season length of 15 weeks (Table 2).4
The prolonged seasonality of RSV in YK Delta has implications for the duration of palivizumab prophylaxis. Although the 2003 Report of the American Academy of Pediatrics Committee on Infectious Diseases14 (Redbook) recommended that the duration of RSV prophylaxis be based on local epidemiology, the 2006 Report18 did not include this recommendation. This decision was based on national data showing that variations occur within the overall patterns of RSV outbreaks, between November and March or April. However, in Alaska, median onset (October 14-20) and offset (May 19–25) dates fall outside these limits and support the prolonged prophylaxis strategies (from October to May) recommended by Alaska healthcare providers.19 The unusual RSV season length in Alaska suggests a need for the Redbook Committee to consider including some recommendation to individualize prophylaxis duration based on local epidemiology. In addition to extending the timing of palivizumab to provide coverage for the prolonged RSV seasons, training CHAs to administer palivizumab doses in the village eliminated the monthly plane trip to the regional center and resulted in improved compliance and a savings in time and money.15
Several factors, such as household crowding, exposure to environmental tobacco smoke, maternal smoking during pregnancy, low educational level, and indoor air pollution have been well-documented to increase the risk of LRTI and pneumonia in children.13,20–22 Aboriginal race was associated with more complicated RSV hospitalization in Canada.23 We previously reported that household crowding, underlying medical conditions, and lack of breast-feeding were associated with increased RSV hospitalization.13
Other factors that may contribute to increased RSV hospitalizations in this region include lack of running water or flush toilets in some villages and high rates of adult smokers.24 Alaska has the lowest proportion of homes with piped water and wastewater disposal service in the United States (93.7% for Alaska versus 99.4% for the United States). In rural YK Delta, some communities lack these services entirely. The Arctic Investigations Program and Alaska Division of Public Health conducted independent analyses of the association of piped water and LRTI hospitalizations.25 Using statewide data, Alaska Division of Public Health found that communities that had a lower proportion of houses with piped water experienced higher LRTI hospitalization rates (P < 0.001) after adjusting for potential confounding factors. Likewise, in the Arctic Investigations Program analysis of YK Delta communities, the hospitalization rates due to LRTI were progressively lower with higher piped water service levels. The lack of running water is likely to be a surrogate marker for reduced hand hygiene practice in the home, resulting in greater viral transmission. Addressing critical issues such as lack of piped water will be essential to reducing the disparity in LRTI hospitalizations in YK infants.
The typical RSV season in the YK Delta is twice as long as in the contiguous United States. Factors such as household crowding and lack of running water contribute to RSV hospitalization rates in YK Delta infants that were 5-fold higher than the general U.S. population. Monthly immunoprophylaxis with palivizumab lowered RSV hospitalizations in premature infants 3-fold. During the time of this study, RSV hospitalization rates seemed to be declining whereas non-RSV LRTI hospitalization rates were increasing. Palivizumab prophylaxis may be partly responsible for the decrease in RSV hospitalization rates; however, information about the etiology of non-RSV LRTIs in YK infants will be critical to determining what other specific measures (eg, influenza vaccination) will contribute to decreasing overall rates of LRTIs. A study is in progress to assess the role of viruses other than RSV in LRTI hospitalizations among YK children who are younger than 3 years of age. Preliminary data from this study suggest that, in addition to RSV, parainfluenza virus and human metapneumovirus contribute significantly to LRTI hospitalizations among YK children.
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