Effectiveness of Respiratory Syncytial Virus Immunoprophylaxis in Reducing Bronchiolitis Hospitalizations Among High-Risk Infants

Effectiveness of Respiratory Syncytial Virus Immunoprophylaxis in Reducing Bronchiolitis... Abstract We sought to determine the real-world effectiveness of respiratory syncytial virus (RSV) immunoprophylaxis in a population-based cohort to inform policy. The study population included infants born during 1996–2008 and enrolled in the Kaiser Permanente Northern California integrated health-care delivery system. During the RSV season (November–March), the date of RSV immunoprophylaxis administration and the following 30 days were defined as RSV immunoprophylaxis protected period(s), and all other days were defined as unprotected period(s). Numbers of bronchiolitis hospitalizations were determined using International Classification of Diseases, Ninth Revision, codes during RSV season. We used a proportional hazards model to estimate risk of bronchiolitis hospitalization when comparing infants’ protected period(s) with unprotected period(s). Infants who had ever received RSV immunoprophylaxis had a 32% decreased risk of bronchiolitis hospitalization (adjusted hazard ratio = 0.68, 95% confidence interval: 0.46, 1.00) when protected periods were compared with unprotected periods. Infants with chronic lung disease (CLD) had a 52% decreased risk of bronchiolitis hospitalization (adjusted hazard ratio = 0.48, 95% confidence interval: 0.25, 0.94) when protected periods were compared with unprotected periods. Under the new 2014 American Academy of Pediatrics (AAP) guidelines, 48% of infants eligible for RSV immunoprophylaxis on the basis of AAP guidelines in place at birth would no longer be eligible, but nearly all infants with CLD would remain eligible. RSV immunoprophylaxis is effective in decreasing hospitalization. This association is greatest for infants with CLD, a group still recommended for receipt of RSV immunoprophylaxis under the new AAP guidelines. bronchiolitis, bronchiolitis hospitalization, high-risk infants, immunoprophylaxis, infancy, lower respiratory tract infection, respiratory syncytial virus Respiratory syncytial virus (RSV) infection is the leading cause of viral lower respiratory tract infections, such as bronchiolitis, in infants and young children (1–3). No effective treatment for RSV exists, nor is there an efficacious RSV vaccine yet available for the prevention of serious RSV infection. The only available pharmacological preventive strategy for severe RSV infection is the administration of an RSV monoclonal antibody licensed for use in high-risk infants (4, 5). Randomized clinical trials (RCTs) have demonstrated that passive RSV immunoprophylaxis is efficacious in reducing RSV-related hospitalizations in infants who are at increased risk for RSV infection (6–9). The US Food and Drug Administration first approved the use of RSV immunoprophylaxis in 1996 (10), and the American Academy of Pediatrics (AAP) issued recommendations for RSV immunoprophylaxis for selected high-risk infants in 1997 (4), with subsequent updates (5, 11–14). Guidelines regarding eligibility for, and timing of receipt of, RSV immunoprophylaxis have changed over time; it has been recommended that infants with chronic lung disease (CLD), congenital heart disease, and premature birth receive immunoprophylaxis during the winter RSV season of their first year of life (5, 11, 13). The AAP updated its guidelines in 2009 (12) and 2014 (5) with modified infant eligibility. The proportion of infants impacted and the real-world effectiveness across eligibility groups are not known. While RCTs have established efficacy, what is needed to further inform policy on this costly preventive therapy is current real-world effectiveness studies of immunoprophylaxis. The likelihood of administration and timing of receipt of immunoprophylaxis, even among recommended high-risk infants, varies based upon the infants’ risk for RSV infection, which depends on the severity and timing of the actual RSV seasons (15). Additionally, CLD of prematurity has significantly changed since the efficacy studies were conducted (16, 17). Our objective in this study was to obtain data needed for policy and clinical-care decisions by assessing the effectiveness of RSV immunoprophylaxis in reducing numbers of bronchiolitis hospitalizations among infants who were eligible and/or received RSV immunoprophylaxis, as well as to examine the proportion of infants likely to be affected by the new 2014 guidelines (5). Critical to such analyses of observational data is the application of methods of adjustment for treatment indication bias, the duration of effect of immunoprophylaxis, and the temporal relationship between receipt of RSV immunoprophylaxis, bronchiolitis hospitalizations, and the epidemic circulation and risk of RSV infection. METHODS Study population A cohort of 211,098 infants born between 1996 and 2008 and continuously enrolled during the first year of life in Kaiser Permanente Northern California (KPNC), an integrated health-care delivery system, were included (Figure 1) (15). We categorized infants into 5 mutually exclusive and hierarchical eligibility groups based on the in-place AAP guidelines recommended during our study period, as described previously: 1) CLD that required medical therapy in the 6 months preceding the RSV season; 2) prematurity of <29 completed weeks’ gestation; 3) prematurity of 29–31 weeks’ gestation; 4) other eligibility (e.g., 32- to 34-week infants with 2 or more risk factors, infants with congenital heart disease, etc.); and 5) ineligible for RSV immunoprophylaxis. Infants in groups 1–4 were considered eligible for RSV immunoprophylaxis based on the literature and guidelines (5, 11, 13). The study protocol was approved by the KPNC and Vanderbilt University institutional review boards and the State of California Committee for the Protection of Human Subjects. Figure 1. View largeDownload slide Distribution of the study population according to eligibility for and receipt of respiratory syncytial virus (RSV) immunoprophylaxis, Kaiser Permanente Northern California, 1996–2008. AAP, American Academy of Pediatrics; CLD, chronic lung disease. Figure 1. View largeDownload slide Distribution of the study population according to eligibility for and receipt of respiratory syncytial virus (RSV) immunoprophylaxis, Kaiser Permanente Northern California, 1996–2008. AAP, American Academy of Pediatrics; CLD, chronic lung disease. RSV season, immunoprophylaxis receipt, and protected/unprotected periods We defined RSV season as November–March in order to capture RSV-specific morbidity by minimizing misclassification of events caused by viruses other than RSV, which is also consistent with the AAP-defined season for receipt of RSV immunoprophylaxis for most US areas, including California (5). We captured data on administration of RSV immunoprophylaxis using a pharmacy database that included information on outpatient visits, medications, and the dates of immunoprophylaxis administration (see Web Figure 1A, available at https://academic.oup.com/aje). RSV immunoprophylaxis is efficacious for eligible infants during the RSV season, and dosing is recommended every 30 days for such infants (5, 18). We defined the 30-day interval following administration of RSV immunoprophylaxis as the protected period. All days during the RSV season that did not fall within a protected period were defined as the unprotected period (Figure 2 and Web Figure 2). We distinguished and identified 2 different types of unprotected periods. One was the unprotected period for infants who never received any RSV immunoprophylaxis; the other was the unprotected period for those infants who received at least 1 dose of immunoprophylaxis but did not receive it every 30 days. Figure 2. View largeDownload slide Data-processing strategy for creating analysis records during each infant’s first 5-month respiratory syncytial virus (RSV) season following birth, Kaiser Permanente Northern California, 1996–2008. The start of follow-up was the first day on which infants were eligible for RSV immunoprophylaxis based on American Academy of Pediatrics guidelines, the first day after birth hospitalization discharge, or the start of the RSV season (November 1), whichever came last. The end of follow-up was the last day on which infants were eligible for RSV immunoprophylaxis, the infant’s first birthday, or the end of the RSV season (March 31), whichever came first. Circles denote bronchiolitis hospitalization, and diamonds denote administration of RSV immunoprophylaxis. Figure 2. View largeDownload slide Data-processing strategy for creating analysis records during each infant’s first 5-month respiratory syncytial virus (RSV) season following birth, Kaiser Permanente Northern California, 1996–2008. The start of follow-up was the first day on which infants were eligible for RSV immunoprophylaxis based on American Academy of Pediatrics guidelines, the first day after birth hospitalization discharge, or the start of the RSV season (November 1), whichever came last. The end of follow-up was the last day on which infants were eligible for RSV immunoprophylaxis, the infant’s first birthday, or the end of the RSV season (March 31), whichever came first. Circles denote bronchiolitis hospitalization, and diamonds denote administration of RSV immunoprophylaxis. Bronchiolitis hospitalizations Numbers of bronchiolitis hospitalizations during the 5-month RSV season of each infant’s first 12 months of life were captured using International Classification of Diseases, Ninth Revision, codes (466.1 and 480.1) for bronchiolitis (Web Figure 1B). Our definition of bronchiolitis hospitalization has been validated previously (19–21). Statistical analysis We expressed descriptive statistics as proportions for categorical variables and as means and standard deviations or medians and interquartile ranges for continuous variables, as appropriate. We assessed the effectiveness of RSV immunoprophylaxis by comparing bronchiolitis hospitalization incidence rates between protected and unprotected periods. The incidence rate ratio was estimated within eligibility groups, as well as among infants who received at least 1 dose of immunoprophylaxis. We limited the estimation of effectiveness of RSV immunoprophylaxis to the 3,210 infants who received at least 1 dose of immunoprophylaxis. A Cox proportional hazards regression model with repeated measures was fitted adjusting for both fixed and time-dependent covariates (22). Type of immunoprophylaxis period (protected or unprotected) was considered as a time-dependent variable. Similar models were developed for each eligibility group. Detailed information on the regression models can be found in the Web Appendix. Additional sensitivity analyses regarding the 30-day protection window were conducted (Web Appendix, Web Figure 3). Two types of RSV immunoprophylaxis, RSV immune globulin intravenous (licensed in 1996) and palivizumab (licensed in 1998), were available during the study period. KPNC administered palivizumab almost exclusively starting in 1998. We conducted a subgroup analysis of children born in 1998 and afterwards to determine the palivizumab-specific association with bronchiolitis hospitalization. The AAP subsequently updated its guidelines for RSV immunoprophylaxis in 2009 (12) and 2014 (5), modifying the criteria for infant eligibility and the number of doses an eligible infant should receive. We estimated the proportions of infants who were eligible and ineligible under the old and new guidelines and the effectiveness of immunoprophylaxis in the 2 subgroups. All analyses were performed using R software, version 3.1.2 (R Foundation for Statistical Computing, Vienna, Austria; www.r-project.org), and SAS software, version 9.3 (SAS Institute, Inc., Cary, North Carolina). RESULTS Receipt of RSV immunoprophylaxis There were 211,098 infants born and enrolled in the cohort over the 13-year study period (1996–2008) (Table 1). Among those infants, 3,444 (1.63%) were eligible for RSV immunoprophylaxis based on the guidelines in place at birth, and 3,210 infants (1.52%) received at least 1 dose. Infants in the CLD and <29-weeks’-gestation eligibility groups were the most likely to receive immunoprophylaxis (76.5% and 78.6%, respectively), while infants in the “other” eligibility group were the least likely to receive it (15.6%) (Table 1). Among infants who ever received immunoprophylaxis, the median number of doses received was 4 (interquartile range, 3–5). Table 1. Maternal and Infant Characteristics of Infants Enrolled in Kaiser Permanente Northern California According to Eligibility for Respiratory Syncytial Virus Immunoprophylaxis, 1996–2008 Characteristic  Eligibility Group  Ineligible Group  Chronic Lung Disease  Prematurity at <29 Weeks  Prematurity at <32 Weeks  Other Eligible Group  No. of Persons  %  No. of Persons  %  No. of Persons  %  No. of Persons  %  No. of Persons  %  Total  324  0.2  1,016  0.5  1,752  0.8  352  0.2  207,654  98.4  Estimated gestational age, weeksa  28 (26–30)  27 (26–28)  30 (30–31)  34 (33–34)  39 (38–40)  Birth weight, ga  1,000 (769–1,323)  925 (783–1,115)  1,455 (1,239–1,670)  2,170 (1,834–2,591)  3,415 (3,070–3,755)  Small-for-gestational-age birth (<5th percentile)  16  4.9  16  1.6  6  4.3  13  3.7  2,964  1.4  Birth hospitalization length of stay, daysa  78 (56–103)  71 (57–87)  37 (29–47)  13 (7–20)  3 (2–3)  Male infant sexb  212  65.4  470  46.3  940  53.7  185  52.6  106,540  51.3  Infant race/ethnicityc                       White  121  37.3  378  37.3  704  40.2  163  46.3  85,839  41.4   African-American  70  21.6  155  15.3  243  13.9  61  17.3  17,334  8.4   Latino  58  17.9  222  21.9  352  20.1  61  17.3  44,437  21.4   Asian  48  14.8  149  14.7  270  15.4  35  9.9  42,346  20.4   Other  27  8.3  110  10.8  183  10.4  32  9.1  17,499  8.4  Congenital heart disease  190  58.6  498  49.0  359  20.5  117  33.2  2,596  1.3  Neuromuscular disorder  30  9.3  27  2.7  22  1.3  11  3.1  330  0.2  Receipt of ≥1 dose of RSV immunoprophylaxis  248  76.5  799  78.6  1,159  66.2  352  15.6  949  0.5  No. of living siblings at homed                       0  127  39.2  497  48.9  816  46.6  62  17.6  90,768  43.7   1  115  35.5  308  30.3  531  30.3  152  43.2  71,025  34.2   >1  82  25.3  211  20.8  404  23.1  138  39.2  45,727  22.0  Maternal smoking during pregnancy  25  7.7  85  8.4  121  6.9  249  70.7  14,197  6.8  Maternal age at delivery, yearsa,e  30 (25–35)  31 (26–35)  31 (26–36)  30 (25–35)  30 (26–34)  Maternal education, years                       <12  90  27.8  355  34.9  553  31.6  156  44.3  65,167  31.4   12  76  23.5  213  21.0  361  20.6  101  28.7  43,220  20.8   >12  158  48.8  448  44.1  838  47.8  95  27.0  99,267  47.8  Characteristic  Eligibility Group  Ineligible Group  Chronic Lung Disease  Prematurity at <29 Weeks  Prematurity at <32 Weeks  Other Eligible Group  No. of Persons  %  No. of Persons  %  No. of Persons  %  No. of Persons  %  No. of Persons  %  Total  324  0.2  1,016  0.5  1,752  0.8  352  0.2  207,654  98.4  Estimated gestational age, weeksa  28 (26–30)  27 (26–28)  30 (30–31)  34 (33–34)  39 (38–40)  Birth weight, ga  1,000 (769–1,323)  925 (783–1,115)  1,455 (1,239–1,670)  2,170 (1,834–2,591)  3,415 (3,070–3,755)  Small-for-gestational-age birth (<5th percentile)  16  4.9  16  1.6  6  4.3  13  3.7  2,964  1.4  Birth hospitalization length of stay, daysa  78 (56–103)  71 (57–87)  37 (29–47)  13 (7–20)  3 (2–3)  Male infant sexb  212  65.4  470  46.3  940  53.7  185  52.6  106,540  51.3  Infant race/ethnicityc                       White  121  37.3  378  37.3  704  40.2  163  46.3  85,839  41.4   African-American  70  21.6  155  15.3  243  13.9  61  17.3  17,334  8.4   Latino  58  17.9  222  21.9  352  20.1  61  17.3  44,437  21.4   Asian  48  14.8  149  14.7  270  15.4  35  9.9  42,346  20.4   Other  27  8.3  110  10.8  183  10.4  32  9.1  17,499  8.4  Congenital heart disease  190  58.6  498  49.0  359  20.5  117  33.2  2,596  1.3  Neuromuscular disorder  30  9.3  27  2.7  22  1.3  11  3.1  330  0.2  Receipt of ≥1 dose of RSV immunoprophylaxis  248  76.5  799  78.6  1,159  66.2  352  15.6  949  0.5  No. of living siblings at homed                       0  127  39.2  497  48.9  816  46.6  62  17.6  90,768  43.7   1  115  35.5  308  30.3  531  30.3  152  43.2  71,025  34.2   >1  82  25.3  211  20.8  404  23.1  138  39.2  45,727  22.0  Maternal smoking during pregnancy  25  7.7  85  8.4  121  6.9  249  70.7  14,197  6.8  Maternal age at delivery, yearsa,e  30 (25–35)  31 (26–35)  31 (26–36)  30 (25–35)  30 (26–34)  Maternal education, years                       <12  90  27.8  355  34.9  553  31.6  156  44.3  65,167  31.4   12  76  23.5  213  21.0  361  20.6  101  28.7  43,220  20.8   >12  158  48.8  448  44.1  838  47.8  95  27.0  99,267  47.8  Abbreviation: RSV, respiratory syncytial virus. a Values are expressed as median (interquartile range). b Sex was unknown for 30 (<0.1%) of the infants. c Race/ethnicity was unknown for 201 (0.1%) of the infants. d Number of living siblings at home was unknown for 135 (0.1%) of the infants. e Maternal age at delivery was unknown for 1 (<0.1%) of the infants. Table 1. Maternal and Infant Characteristics of Infants Enrolled in Kaiser Permanente Northern California According to Eligibility for Respiratory Syncytial Virus Immunoprophylaxis, 1996–2008 Characteristic  Eligibility Group  Ineligible Group  Chronic Lung Disease  Prematurity at <29 Weeks  Prematurity at <32 Weeks  Other Eligible Group  No. of Persons  %  No. of Persons  %  No. of Persons  %  No. of Persons  %  No. of Persons  %  Total  324  0.2  1,016  0.5  1,752  0.8  352  0.2  207,654  98.4  Estimated gestational age, weeksa  28 (26–30)  27 (26–28)  30 (30–31)  34 (33–34)  39 (38–40)  Birth weight, ga  1,000 (769–1,323)  925 (783–1,115)  1,455 (1,239–1,670)  2,170 (1,834–2,591)  3,415 (3,070–3,755)  Small-for-gestational-age birth (<5th percentile)  16  4.9  16  1.6  6  4.3  13  3.7  2,964  1.4  Birth hospitalization length of stay, daysa  78 (56–103)  71 (57–87)  37 (29–47)  13 (7–20)  3 (2–3)  Male infant sexb  212  65.4  470  46.3  940  53.7  185  52.6  106,540  51.3  Infant race/ethnicityc                       White  121  37.3  378  37.3  704  40.2  163  46.3  85,839  41.4   African-American  70  21.6  155  15.3  243  13.9  61  17.3  17,334  8.4   Latino  58  17.9  222  21.9  352  20.1  61  17.3  44,437  21.4   Asian  48  14.8  149  14.7  270  15.4  35  9.9  42,346  20.4   Other  27  8.3  110  10.8  183  10.4  32  9.1  17,499  8.4  Congenital heart disease  190  58.6  498  49.0  359  20.5  117  33.2  2,596  1.3  Neuromuscular disorder  30  9.3  27  2.7  22  1.3  11  3.1  330  0.2  Receipt of ≥1 dose of RSV immunoprophylaxis  248  76.5  799  78.6  1,159  66.2  352  15.6  949  0.5  No. of living siblings at homed                       0  127  39.2  497  48.9  816  46.6  62  17.6  90,768  43.7   1  115  35.5  308  30.3  531  30.3  152  43.2  71,025  34.2   >1  82  25.3  211  20.8  404  23.1  138  39.2  45,727  22.0  Maternal smoking during pregnancy  25  7.7  85  8.4  121  6.9  249  70.7  14,197  6.8  Maternal age at delivery, yearsa,e  30 (25–35)  31 (26–35)  31 (26–36)  30 (25–35)  30 (26–34)  Maternal education, years                       <12  90  27.8  355  34.9  553  31.6  156  44.3  65,167  31.4   12  76  23.5  213  21.0  361  20.6  101  28.7  43,220  20.8   >12  158  48.8  448  44.1  838  47.8  95  27.0  99,267  47.8  Characteristic  Eligibility Group  Ineligible Group  Chronic Lung Disease  Prematurity at <29 Weeks  Prematurity at <32 Weeks  Other Eligible Group  No. of Persons  %  No. of Persons  %  No. of Persons  %  No. of Persons  %  No. of Persons  %  Total  324  0.2  1,016  0.5  1,752  0.8  352  0.2  207,654  98.4  Estimated gestational age, weeksa  28 (26–30)  27 (26–28)  30 (30–31)  34 (33–34)  39 (38–40)  Birth weight, ga  1,000 (769–1,323)  925 (783–1,115)  1,455 (1,239–1,670)  2,170 (1,834–2,591)  3,415 (3,070–3,755)  Small-for-gestational-age birth (<5th percentile)  16  4.9  16  1.6  6  4.3  13  3.7  2,964  1.4  Birth hospitalization length of stay, daysa  78 (56–103)  71 (57–87)  37 (29–47)  13 (7–20)  3 (2–3)  Male infant sexb  212  65.4  470  46.3  940  53.7  185  52.6  106,540  51.3  Infant race/ethnicityc                       White  121  37.3  378  37.3  704  40.2  163  46.3  85,839  41.4   African-American  70  21.6  155  15.3  243  13.9  61  17.3  17,334  8.4   Latino  58  17.9  222  21.9  352  20.1  61  17.3  44,437  21.4   Asian  48  14.8  149  14.7  270  15.4  35  9.9  42,346  20.4   Other  27  8.3  110  10.8  183  10.4  32  9.1  17,499  8.4  Congenital heart disease  190  58.6  498  49.0  359  20.5  117  33.2  2,596  1.3  Neuromuscular disorder  30  9.3  27  2.7  22  1.3  11  3.1  330  0.2  Receipt of ≥1 dose of RSV immunoprophylaxis  248  76.5  799  78.6  1,159  66.2  352  15.6  949  0.5  No. of living siblings at homed                       0  127  39.2  497  48.9  816  46.6  62  17.6  90,768  43.7   1  115  35.5  308  30.3  531  30.3  152  43.2  71,025  34.2   >1  82  25.3  211  20.8  404  23.1  138  39.2  45,727  22.0  Maternal smoking during pregnancy  25  7.7  85  8.4  121  6.9  249  70.7  14,197  6.8  Maternal age at delivery, yearsa,e  30 (25–35)  31 (26–35)  31 (26–36)  30 (25–35)  30 (26–34)  Maternal education, years                       <12  90  27.8  355  34.9  553  31.6  156  44.3  65,167  31.4   12  76  23.5  213  21.0  361  20.6  101  28.7  43,220  20.8   >12  158  48.8  448  44.1  838  47.8  95  27.0  99,267  47.8  Abbreviation: RSV, respiratory syncytial virus. a Values are expressed as median (interquartile range). b Sex was unknown for 30 (<0.1%) of the infants. c Race/ethnicity was unknown for 201 (0.1%) of the infants. d Number of living siblings at home was unknown for 135 (0.1%) of the infants. e Maternal age at delivery was unknown for 1 (<0.1%) of the infants. Across all eligibility groups, higher-risk infants were more likely to receive RSV immunoprophylaxis (Table 2 and Web Table 1). Compared with infants who did not receive any immunoprophylaxis, infants who received at least 1 dose were more likely to be male and to have a lower gestational age, a lower birth weight, a longer birth hospitalization length of stay, other siblings at home, mothers who smoked during pregnancy, and less educated mothers (P < 0.01). Infants who received at least 1 dose were also more likely to have congenital heart disease or a neuromuscular disorder than infants who did not receive any immunoprophylaxis. Table 2. Maternal and Infant Characteristics of Infants Enrolled in Kaiser Permanente Northern California According to Eligibility for and Receipt of Respiratory Syncytial Virus Immunoprophylaxis (Ever vs. Never), 1996–2008 Characteristic  Eligible Group (n = 3,444)  Ineligible Group (n = 207,654)  Ever Receiveda  Never Receivedb  Ever Received  Never Received  No. of Persons  %  No. of Persons  %  No. of Persons  %  No. of Persons  %  Total  2,261  65.7  1,183  34.3  949  0.5  206,705  99.5  Estimated gestational age, weeksc  29 (27–31)  31 (29–32)  32 (32–35)  39 (38–40)  Birth weight, gc  1,194 (912–1,510)  1,550 (1,160–1,935)  1,950 (1,645–2,470)  3,416 (3,075–3,755)  Small-for-gestational-age birth (<5th percentile)  79  3.5  42  3.6  63  6.6  2,901  1.4  Birth hospitalization length of stay, daysc  52 (36–73)  32 (18–52)  21 (13–29)  3 (2–3)  Male infant sexd  1,186  52.5  621  52.5  508  53.6  106,032  51.3  Infant race/ethnicitye                   White  876  38.8  490  41.4  386  40.7  85,453  41.4   African-American  321  14.2  208  17.6  74  7.8  17,260  8.4   Latino  474  21.0  219  18.5  210  22.1  44,227  21.4   Asian  341  15.1  161  13.6  181  19.1  42,165  20.4   Other  247  10.9  105  8.9  98  10.3  17,401  8.4  Congenital heart disease  868  38.4  296  25.0  208  21.9  2,388  1.2  Neuromuscular disorder  67  3.0  23  1.9  18  1.9  312  0.2  No. of living siblings at homef                   0  1,040  46.0  462  39.0  405  42.7  90,363  43.7   1  717  31.7  389  32.9  309  32.6  70,716  34.2   >1  503  22.3  332  28.1  234  24.7  45,493  22.0  Maternal smoking during pregnancy  187  8.3  293  24.8  35  3.7  14,162  6.9  Maternal age at delivery, yearsc,g  31 (26–35)  31 (25–35)  31 (27–35)  30 (26–34)  Maternal education, years                   <12  766  33.9  388  32.8  333  35.1  64,834  31.4   12  442  19.5  309  26.1  162  17.1  43,058  20.8   >12  1,053  46.6  486  41.1  454  47.8  98,813  47.8  Characteristic  Eligible Group (n = 3,444)  Ineligible Group (n = 207,654)  Ever Receiveda  Never Receivedb  Ever Received  Never Received  No. of Persons  %  No. of Persons  %  No. of Persons  %  No. of Persons  %  Total  2,261  65.7  1,183  34.3  949  0.5  206,705  99.5  Estimated gestational age, weeksc  29 (27–31)  31 (29–32)  32 (32–35)  39 (38–40)  Birth weight, gc  1,194 (912–1,510)  1,550 (1,160–1,935)  1,950 (1,645–2,470)  3,416 (3,075–3,755)  Small-for-gestational-age birth (<5th percentile)  79  3.5  42  3.6  63  6.6  2,901  1.4  Birth hospitalization length of stay, daysc  52 (36–73)  32 (18–52)  21 (13–29)  3 (2–3)  Male infant sexd  1,186  52.5  621  52.5  508  53.6  106,032  51.3  Infant race/ethnicitye                   White  876  38.8  490  41.4  386  40.7  85,453  41.4   African-American  321  14.2  208  17.6  74  7.8  17,260  8.4   Latino  474  21.0  219  18.5  210  22.1  44,227  21.4   Asian  341  15.1  161  13.6  181  19.1  42,165  20.4   Other  247  10.9  105  8.9  98  10.3  17,401  8.4  Congenital heart disease  868  38.4  296  25.0  208  21.9  2,388  1.2  Neuromuscular disorder  67  3.0  23  1.9  18  1.9  312  0.2  No. of living siblings at homef                   0  1,040  46.0  462  39.0  405  42.7  90,363  43.7   1  717  31.7  389  32.9  309  32.6  70,716  34.2   >1  503  22.3  332  28.1  234  24.7  45,493  22.0  Maternal smoking during pregnancy  187  8.3  293  24.8  35  3.7  14,162  6.9  Maternal age at delivery, yearsc,g  31 (26–35)  31 (25–35)  31 (27–35)  30 (26–34)  Maternal education, years                   <12  766  33.9  388  32.8  333  35.1  64,834  31.4   12  442  19.5  309  26.1  162  17.1  43,058  20.8   >12  1,053  46.6  486  41.1  454  47.8  98,813  47.8  Abbreviation: RSV, respiratory syncytial virus. a Child received at least 1 dose of RSV immunoprophylaxis during infancy. b Child received no doses of RSV immunoprophylaxis during infancy. c Values are expressed as median (interquartile range). d Sex was unknown for 30 (<0.1%) of the infants. e Race/ethnicity was unknown for 201 (0.1%) of the infants. f Number of living siblings at home was unknown for 135 (0.1%) of the infants. g Maternal age at delivery was unknown for 1 (<0.1%) of the infants. Table 2. Maternal and Infant Characteristics of Infants Enrolled in Kaiser Permanente Northern California According to Eligibility for and Receipt of Respiratory Syncytial Virus Immunoprophylaxis (Ever vs. Never), 1996–2008 Characteristic  Eligible Group (n = 3,444)  Ineligible Group (n = 207,654)  Ever Receiveda  Never Receivedb  Ever Received  Never Received  No. of Persons  %  No. of Persons  %  No. of Persons  %  No. of Persons  %  Total  2,261  65.7  1,183  34.3  949  0.5  206,705  99.5  Estimated gestational age, weeksc  29 (27–31)  31 (29–32)  32 (32–35)  39 (38–40)  Birth weight, gc  1,194 (912–1,510)  1,550 (1,160–1,935)  1,950 (1,645–2,470)  3,416 (3,075–3,755)  Small-for-gestational-age birth (<5th percentile)  79  3.5  42  3.6  63  6.6  2,901  1.4  Birth hospitalization length of stay, daysc  52 (36–73)  32 (18–52)  21 (13–29)  3 (2–3)  Male infant sexd  1,186  52.5  621  52.5  508  53.6  106,032  51.3  Infant race/ethnicitye                   White  876  38.8  490  41.4  386  40.7  85,453  41.4   African-American  321  14.2  208  17.6  74  7.8  17,260  8.4   Latino  474  21.0  219  18.5  210  22.1  44,227  21.4   Asian  341  15.1  161  13.6  181  19.1  42,165  20.4   Other  247  10.9  105  8.9  98  10.3  17,401  8.4  Congenital heart disease  868  38.4  296  25.0  208  21.9  2,388  1.2  Neuromuscular disorder  67  3.0  23  1.9  18  1.9  312  0.2  No. of living siblings at homef                   0  1,040  46.0  462  39.0  405  42.7  90,363  43.7   1  717  31.7  389  32.9  309  32.6  70,716  34.2   >1  503  22.3  332  28.1  234  24.7  45,493  22.0  Maternal smoking during pregnancy  187  8.3  293  24.8  35  3.7  14,162  6.9  Maternal age at delivery, yearsc,g  31 (26–35)  31 (25–35)  31 (27–35)  30 (26–34)  Maternal education, years                   <12  766  33.9  388  32.8  333  35.1  64,834  31.4   12  442  19.5  309  26.1  162  17.1  43,058  20.8   >12  1,053  46.6  486  41.1  454  47.8  98,813  47.8  Characteristic  Eligible Group (n = 3,444)  Ineligible Group (n = 207,654)  Ever Receiveda  Never Receivedb  Ever Received  Never Received  No. of Persons  %  No. of Persons  %  No. of Persons  %  No. of Persons  %  Total  2,261  65.7  1,183  34.3  949  0.5  206,705  99.5  Estimated gestational age, weeksc  29 (27–31)  31 (29–32)  32 (32–35)  39 (38–40)  Birth weight, gc  1,194 (912–1,510)  1,550 (1,160–1,935)  1,950 (1,645–2,470)  3,416 (3,075–3,755)  Small-for-gestational-age birth (<5th percentile)  79  3.5  42  3.6  63  6.6  2,901  1.4  Birth hospitalization length of stay, daysc  52 (36–73)  32 (18–52)  21 (13–29)  3 (2–3)  Male infant sexd  1,186  52.5  621  52.5  508  53.6  106,032  51.3  Infant race/ethnicitye                   White  876  38.8  490  41.4  386  40.7  85,453  41.4   African-American  321  14.2  208  17.6  74  7.8  17,260  8.4   Latino  474  21.0  219  18.5  210  22.1  44,227  21.4   Asian  341  15.1  161  13.6  181  19.1  42,165  20.4   Other  247  10.9  105  8.9  98  10.3  17,401  8.4  Congenital heart disease  868  38.4  296  25.0  208  21.9  2,388  1.2  Neuromuscular disorder  67  3.0  23  1.9  18  1.9  312  0.2  No. of living siblings at homef                   0  1,040  46.0  462  39.0  405  42.7  90,363  43.7   1  717  31.7  389  32.9  309  32.6  70,716  34.2   >1  503  22.3  332  28.1  234  24.7  45,493  22.0  Maternal smoking during pregnancy  187  8.3  293  24.8  35  3.7  14,162  6.9  Maternal age at delivery, yearsc,g  31 (26–35)  31 (25–35)  31 (27–35)  30 (26–34)  Maternal education, years                   <12  766  33.9  388  32.8  333  35.1  64,834  31.4   12  442  19.5  309  26.1  162  17.1  43,058  20.8   >12  1,053  46.6  486  41.1  454  47.8  98,813  47.8  Abbreviation: RSV, respiratory syncytial virus. a Child received at least 1 dose of RSV immunoprophylaxis during infancy. b Child received no doses of RSV immunoprophylaxis during infancy. c Values are expressed as median (interquartile range). d Sex was unknown for 30 (<0.1%) of the infants. e Race/ethnicity was unknown for 201 (0.1%) of the infants. f Number of living siblings at home was unknown for 135 (0.1%) of the infants. g Maternal age at delivery was unknown for 1 (<0.1%) of the infants. Effectiveness of RSV immunoprophylaxis The effectiveness of RSV immunoprophylaxis was studied among infants who were either eligible based on AAP guidelines or received at least 1 dose of immunoprophylaxis (Table 3). Compared with eligible infants who never received immunoprophylaxis, infants who received at least 1 dose had an increased risk of bronchiolitis hospitalization during the unprotected periods (incidence rate ratio (IRR) = 1.49, 95% confidence interval (CI): 1.00, 2.24) but not during the protected periods (IRR = 0.97, 95% CI: 0.68, 1.39). These results were consistent when we limited the analysis to eligible-only infant groups. Such results were most likely due to indication bias in which infants at higher risk for infection were more likely to receive immunoprophylaxis. This was also evident in the subgroup of ineligible infants, where receipt of immunoprophylaxis significantly increased the risk of bronchiolitis hospitalization in both protected and unprotected periods compared with infants who never received immunoprophylaxis. Table 3. Incidence Rates of Bronchiolitis Hospitalization Among Infants Enrolled in Kaiser Permanente Northern California, by Eligibility Group and History of Respiratory Syncytial Virus Immunoprophylaxis in the Last 30 Days, 1996–2008a Eligibility Group and Immunoprophylaxis Status (Ever Receivedb/Never Receivedc)  Immunoprophylaxis-Protected Time (Yes/No)  Total Follow-up Timed, years  Total No. of Hospitalizations  Incidence Rate (per 1,000 Person-Years)  Reference Group  Unprotected Periods of Infants Who Never Received Immunoprophylaxis  Unprotected Periods of Infants Who Ever Received Immunoprophylaxis  IRRe  95% CI  IRRe  95% CI  Infants who were eligible for or ever received immunoprophylaxis                 Never received  No  429.91  51  118.63  1  Referent       Ever received  No  287.69  51  177.27  1.49  1.00, 2.24  1  Referent   Ever received  Yes  823.79  95  115.32  0.97  0.68, 1.39  0.65  0.46, 0.93  Infants who ever received Immunoprophylaxis                   Never received  No                 Ever received  No  287.69  51  177.27      1  Referent   Ever received  Yes  823.79  95  115.32      0.65  0.46, 0.93  Eligible infants                   Never received  No  429.91  51  118.63  1  Referent       Ever received  No  181.31  26  143.40  1.21  0.74, 1.97  1  Referent   Ever received  Yes  572.64  64  111.76  0.94  0.64, 1.38  0.78  0.49, 1.25  Chronic lung disease                   Never received  No  24.09  20  830.21  1         Ever received  No  15.65  15  958.49  1.16  0.59, 2.26  1  Referent   Ever received  Yes  58.58  24  409.72  0.49  0.27, 0.90  0.43  0.23, 0.81  Prematurity at <29 weeks                   Never received  No  72.91  5  68.57  1         Ever received  No  49.09  1  20.37  0.30  0.04, 2.54  1  Referent   Ever received  Yes  202.93  22  108.41  1.58  0.59, 4.25  5.32  0.71, 39.86  Prematurity at 29–31 weeks                   Never received  No  217.14  13  59.87  1  Referent       Ever received  No  109.91  9  81.88  1.37  0.59, 3.18  1  Referent   Ever received  Yes  297.72  17  57.10  0.95  0.47, 1.95  0.70  0.31, 1.56  Other eligible groupf                   Never received  No  115.77  13  112.29  1  Referent       Ever received  No  6.66  1  150.25  1.34  0.18, 10.09  1  Referent   Ever received  Yes  13.40  1  74.60  0.66  0.09, 5.10  0.50  0.03, 7.92  Ineligible group                   Never received  No  84,167.24  1,964  23.33  1  Referent       Ever received  No  106.38  25  235.00  10.07  6.65, 15.24  1  Referent   Ever received  Yes  251.16  31  123.43  5.29  3.57, 7.84  0.53  0.30, 0.93  Eligibility Group and Immunoprophylaxis Status (Ever Receivedb/Never Receivedc)  Immunoprophylaxis-Protected Time (Yes/No)  Total Follow-up Timed, years  Total No. of Hospitalizations  Incidence Rate (per 1,000 Person-Years)  Reference Group  Unprotected Periods of Infants Who Never Received Immunoprophylaxis  Unprotected Periods of Infants Who Ever Received Immunoprophylaxis  IRRe  95% CI  IRRe  95% CI  Infants who were eligible for or ever received immunoprophylaxis                 Never received  No  429.91  51  118.63  1  Referent       Ever received  No  287.69  51  177.27  1.49  1.00, 2.24  1  Referent   Ever received  Yes  823.79  95  115.32  0.97  0.68, 1.39  0.65  0.46, 0.93  Infants who ever received Immunoprophylaxis                   Never received  No                 Ever received  No  287.69  51  177.27      1  Referent   Ever received  Yes  823.79  95  115.32      0.65  0.46, 0.93  Eligible infants                   Never received  No  429.91  51  118.63  1  Referent       Ever received  No  181.31  26  143.40  1.21  0.74, 1.97  1  Referent   Ever received  Yes  572.64  64  111.76  0.94  0.64, 1.38  0.78  0.49, 1.25  Chronic lung disease                   Never received  No  24.09  20  830.21  1         Ever received  No  15.65  15  958.49  1.16  0.59, 2.26  1  Referent   Ever received  Yes  58.58  24  409.72  0.49  0.27, 0.90  0.43  0.23, 0.81  Prematurity at <29 weeks                   Never received  No  72.91  5  68.57  1         Ever received  No  49.09  1  20.37  0.30  0.04, 2.54  1  Referent   Ever received  Yes  202.93  22  108.41  1.58  0.59, 4.25  5.32  0.71, 39.86  Prematurity at 29–31 weeks                   Never received  No  217.14  13  59.87  1  Referent       Ever received  No  109.91  9  81.88  1.37  0.59, 3.18  1  Referent   Ever received  Yes  297.72  17  57.10  0.95  0.47, 1.95  0.70  0.31, 1.56  Other eligible groupf                   Never received  No  115.77  13  112.29  1  Referent       Ever received  No  6.66  1  150.25  1.34  0.18, 10.09  1  Referent   Ever received  Yes  13.40  1  74.60  0.66  0.09, 5.10  0.50  0.03, 7.92  Ineligible group                   Never received  No  84,167.24  1,964  23.33  1  Referent       Ever received  No  106.38  25  235.00  10.07  6.65, 15.24  1  Referent   Ever received  Yes  251.16  31  123.43  5.29  3.57, 7.84  0.53  0.30, 0.93  Abbreviations: AAP, American Academy of Pediatrics; CI, confidence interval; IRR, incidence rate ratio; RSV, respiratory syncytial virus. a Infants described in this table were either eligible for RSV immunoprophylaxis on the basis of in-place AAP guidelines during the study period in which they were born or received at least 1 dose of RSV immunoprophylaxis. b Child received at least 1 dose of RSV immunoprophylaxis during infancy. c Child received no doses of RSV immunoprophylaxis during infancy. d Follow-up time during the 5-month RSV season in infancy. e IRRs were calculated within each eligibility group, among all eligible subjects, all subjects who ever received immunoprophylaxis, and infants who either were eligible or ever received immunoprophylaxis. Within each group, IRRs were calculated using either the unprotected periods of subjects who never received RSV immunoprophylaxis or the unprotected periods of subjects who ever received RSV immunoprophylaxis as the reference group. f “Other eligible group” included infants who were born at 32–34 weeks of gestation with 2 or more additional risk factors and infants who had congenital heart disease. Table 3. Incidence Rates of Bronchiolitis Hospitalization Among Infants Enrolled in Kaiser Permanente Northern California, by Eligibility Group and History of Respiratory Syncytial Virus Immunoprophylaxis in the Last 30 Days, 1996–2008a Eligibility Group and Immunoprophylaxis Status (Ever Receivedb/Never Receivedc)  Immunoprophylaxis-Protected Time (Yes/No)  Total Follow-up Timed, years  Total No. of Hospitalizations  Incidence Rate (per 1,000 Person-Years)  Reference Group  Unprotected Periods of Infants Who Never Received Immunoprophylaxis  Unprotected Periods of Infants Who Ever Received Immunoprophylaxis  IRRe  95% CI  IRRe  95% CI  Infants who were eligible for or ever received immunoprophylaxis                 Never received  No  429.91  51  118.63  1  Referent       Ever received  No  287.69  51  177.27  1.49  1.00, 2.24  1  Referent   Ever received  Yes  823.79  95  115.32  0.97  0.68, 1.39  0.65  0.46, 0.93  Infants who ever received Immunoprophylaxis                   Never received  No                 Ever received  No  287.69  51  177.27      1  Referent   Ever received  Yes  823.79  95  115.32      0.65  0.46, 0.93  Eligible infants                   Never received  No  429.91  51  118.63  1  Referent       Ever received  No  181.31  26  143.40  1.21  0.74, 1.97  1  Referent   Ever received  Yes  572.64  64  111.76  0.94  0.64, 1.38  0.78  0.49, 1.25  Chronic lung disease                   Never received  No  24.09  20  830.21  1         Ever received  No  15.65  15  958.49  1.16  0.59, 2.26  1  Referent   Ever received  Yes  58.58  24  409.72  0.49  0.27, 0.90  0.43  0.23, 0.81  Prematurity at <29 weeks                   Never received  No  72.91  5  68.57  1         Ever received  No  49.09  1  20.37  0.30  0.04, 2.54  1  Referent   Ever received  Yes  202.93  22  108.41  1.58  0.59, 4.25  5.32  0.71, 39.86  Prematurity at 29–31 weeks                   Never received  No  217.14  13  59.87  1  Referent       Ever received  No  109.91  9  81.88  1.37  0.59, 3.18  1  Referent   Ever received  Yes  297.72  17  57.10  0.95  0.47, 1.95  0.70  0.31, 1.56  Other eligible groupf                   Never received  No  115.77  13  112.29  1  Referent       Ever received  No  6.66  1  150.25  1.34  0.18, 10.09  1  Referent   Ever received  Yes  13.40  1  74.60  0.66  0.09, 5.10  0.50  0.03, 7.92  Ineligible group                   Never received  No  84,167.24  1,964  23.33  1  Referent       Ever received  No  106.38  25  235.00  10.07  6.65, 15.24  1  Referent   Ever received  Yes  251.16  31  123.43  5.29  3.57, 7.84  0.53  0.30, 0.93  Eligibility Group and Immunoprophylaxis Status (Ever Receivedb/Never Receivedc)  Immunoprophylaxis-Protected Time (Yes/No)  Total Follow-up Timed, years  Total No. of Hospitalizations  Incidence Rate (per 1,000 Person-Years)  Reference Group  Unprotected Periods of Infants Who Never Received Immunoprophylaxis  Unprotected Periods of Infants Who Ever Received Immunoprophylaxis  IRRe  95% CI  IRRe  95% CI  Infants who were eligible for or ever received immunoprophylaxis                 Never received  No  429.91  51  118.63  1  Referent       Ever received  No  287.69  51  177.27  1.49  1.00, 2.24  1  Referent   Ever received  Yes  823.79  95  115.32  0.97  0.68, 1.39  0.65  0.46, 0.93  Infants who ever received Immunoprophylaxis                   Never received  No                 Ever received  No  287.69  51  177.27      1  Referent   Ever received  Yes  823.79  95  115.32      0.65  0.46, 0.93  Eligible infants                   Never received  No  429.91  51  118.63  1  Referent       Ever received  No  181.31  26  143.40  1.21  0.74, 1.97  1  Referent   Ever received  Yes  572.64  64  111.76  0.94  0.64, 1.38  0.78  0.49, 1.25  Chronic lung disease                   Never received  No  24.09  20  830.21  1         Ever received  No  15.65  15  958.49  1.16  0.59, 2.26  1  Referent   Ever received  Yes  58.58  24  409.72  0.49  0.27, 0.90  0.43  0.23, 0.81  Prematurity at <29 weeks                   Never received  No  72.91  5  68.57  1         Ever received  No  49.09  1  20.37  0.30  0.04, 2.54  1  Referent   Ever received  Yes  202.93  22  108.41  1.58  0.59, 4.25  5.32  0.71, 39.86  Prematurity at 29–31 weeks                   Never received  No  217.14  13  59.87  1  Referent       Ever received  No  109.91  9  81.88  1.37  0.59, 3.18  1  Referent   Ever received  Yes  297.72  17  57.10  0.95  0.47, 1.95  0.70  0.31, 1.56  Other eligible groupf                   Never received  No  115.77  13  112.29  1  Referent       Ever received  No  6.66  1  150.25  1.34  0.18, 10.09  1  Referent   Ever received  Yes  13.40  1  74.60  0.66  0.09, 5.10  0.50  0.03, 7.92  Ineligible group                   Never received  No  84,167.24  1,964  23.33  1  Referent       Ever received  No  106.38  25  235.00  10.07  6.65, 15.24  1  Referent   Ever received  Yes  251.16  31  123.43  5.29  3.57, 7.84  0.53  0.30, 0.93  Abbreviations: AAP, American Academy of Pediatrics; CI, confidence interval; IRR, incidence rate ratio; RSV, respiratory syncytial virus. a Infants described in this table were either eligible for RSV immunoprophylaxis on the basis of in-place AAP guidelines during the study period in which they were born or received at least 1 dose of RSV immunoprophylaxis. b Child received at least 1 dose of RSV immunoprophylaxis during infancy. c Child received no doses of RSV immunoprophylaxis during infancy. d Follow-up time during the 5-month RSV season in infancy. e IRRs were calculated within each eligibility group, among all eligible subjects, all subjects who ever received immunoprophylaxis, and infants who either were eligible or ever received immunoprophylaxis. Within each group, IRRs were calculated using either the unprotected periods of subjects who never received RSV immunoprophylaxis or the unprotected periods of subjects who ever received RSV immunoprophylaxis as the reference group. f “Other eligible group” included infants who were born at 32–34 weeks of gestation with 2 or more additional risk factors and infants who had congenital heart disease. The adjusted analysis was then limited to infants who received at least 1 dose of RSV immunoprophylaxis, as we had previously recognized bias for receipt of immunoprophylaxis in a prior study with inability to adequately adjust for differential propensity for prescribing (15, 23). Among infants who received any RSV immunoprophylaxis, receipt of immunoprophylaxis decreased the risk of bronchiolitis hospitalization during protected periods as compared with unprotected periods (IRR = 0.65, 95% CI: 0.46, 0.93). This protective association was consistent after adjustment for covariates (adjusted hazard ratio (aHR) = 0.68, 95% CI: 0.46, 1.00) (Table 4). Prior receipt of immunoprophylaxis in the same season was associated with a decreased risk of bronchiolitis hospitalization after controlling for the 30-day protected periods after administration (aHR = 0.49, 95% CI: 0.28, 0.88). Table 4. Risk of Bronchiolitis Hospitalization Among Infants Enrolled in Kaiser Permanente Northern California According to Eligibility for Respiratory Syncytial Virus Immunoprophylaxis, 1996–2008a Eligibility Group  No. of Children Who Received RSV Immunoprophylaxis  No. of Bronchiolitis Hospitalization Events  Adjusted HRb  95% CI  Infants who ever received immunoprophylaxisc  3,205  146  0.68  0.46, 1.00  All eligible infants  2,261  90  0.76  0.44, 1.31  Infants with chronic lung disease  248  39  0.48  0.25, 0.94  Prematurity at <29 weeks  797  23  5.96  0.56, 63.66  Prematurity at 29–31 weeks  1,158  26  0.72  0.28, 1.84  Other eligible groupd  55  2  —e  —  Ineligible group  947  56  0.51  0.30, 0.86  Eligibility Group  No. of Children Who Received RSV Immunoprophylaxis  No. of Bronchiolitis Hospitalization Events  Adjusted HRb  95% CI  Infants who ever received immunoprophylaxisc  3,205  146  0.68  0.46, 1.00  All eligible infants  2,261  90  0.76  0.44, 1.31  Infants with chronic lung disease  248  39  0.48  0.25, 0.94  Prematurity at <29 weeks  797  23  5.96  0.56, 63.66  Prematurity at 29–31 weeks  1,158  26  0.72  0.28, 1.84  Other eligible groupd  55  2  —e  —  Ineligible group  947  56  0.51  0.30, 0.86  Abbreviations: CI, confidence interval; HR, hazard ratio; KPNC, Kaiser Permanente Northern California; RSV, respiratory syncytial virus. a Infants included in these analyses received at least 1 dose of RSV immunoprophylaxis. b Cox proportional hazards models adjusted for both fixed and time-dependent covariates, including infant age at receipt of RSV immunoprophylaxis, prior receipt of RSV immunoprophylaxis (during the same RSV season), prior history of bronchiolitis hospitalization, infant birth weight (g), gestational age (in completed weeks), infant race/ethnicity, sex, infant birth season, length of birth hospitalization stay, number of living siblings, singleton birth, maternal age at delivery (in years), maternal education (in years), maternal smoking during pregnancy, and RSV immunoprophylaxis eligibility group. The RSV immunoprophylaxis-unprotected period served as the reference category for each eligibility group. c Five infants were removed from multivariable analyses because of unknown sex (1 infant), missing race/ethnicity (2 infants), and missing number of living siblings (2 infants). The 5 infants removed did not experience any bronchiolitis hospitalizations during the 5-month follow-up time in infancy. d “Other eligible group” included infants who were born at 32–34 weeks of gestation with 2 or more additional risk factors and infants who had congenital heart disease. e HR and 95% CI were not calculated because of the limited number of events among subjects within-group. Table 4. Risk of Bronchiolitis Hospitalization Among Infants Enrolled in Kaiser Permanente Northern California According to Eligibility for Respiratory Syncytial Virus Immunoprophylaxis, 1996–2008a Eligibility Group  No. of Children Who Received RSV Immunoprophylaxis  No. of Bronchiolitis Hospitalization Events  Adjusted HRb  95% CI  Infants who ever received immunoprophylaxisc  3,205  146  0.68  0.46, 1.00  All eligible infants  2,261  90  0.76  0.44, 1.31  Infants with chronic lung disease  248  39  0.48  0.25, 0.94  Prematurity at <29 weeks  797  23  5.96  0.56, 63.66  Prematurity at 29–31 weeks  1,158  26  0.72  0.28, 1.84  Other eligible groupd  55  2  —e  —  Ineligible group  947  56  0.51  0.30, 0.86  Eligibility Group  No. of Children Who Received RSV Immunoprophylaxis  No. of Bronchiolitis Hospitalization Events  Adjusted HRb  95% CI  Infants who ever received immunoprophylaxisc  3,205  146  0.68  0.46, 1.00  All eligible infants  2,261  90  0.76  0.44, 1.31  Infants with chronic lung disease  248  39  0.48  0.25, 0.94  Prematurity at <29 weeks  797  23  5.96  0.56, 63.66  Prematurity at 29–31 weeks  1,158  26  0.72  0.28, 1.84  Other eligible groupd  55  2  —e  —  Ineligible group  947  56  0.51  0.30, 0.86  Abbreviations: CI, confidence interval; HR, hazard ratio; KPNC, Kaiser Permanente Northern California; RSV, respiratory syncytial virus. a Infants included in these analyses received at least 1 dose of RSV immunoprophylaxis. b Cox proportional hazards models adjusted for both fixed and time-dependent covariates, including infant age at receipt of RSV immunoprophylaxis, prior receipt of RSV immunoprophylaxis (during the same RSV season), prior history of bronchiolitis hospitalization, infant birth weight (g), gestational age (in completed weeks), infant race/ethnicity, sex, infant birth season, length of birth hospitalization stay, number of living siblings, singleton birth, maternal age at delivery (in years), maternal education (in years), maternal smoking during pregnancy, and RSV immunoprophylaxis eligibility group. The RSV immunoprophylaxis-unprotected period served as the reference category for each eligibility group. c Five infants were removed from multivariable analyses because of unknown sex (1 infant), missing race/ethnicity (2 infants), and missing number of living siblings (2 infants). The 5 infants removed did not experience any bronchiolitis hospitalizations during the 5-month follow-up time in infancy. d “Other eligible group” included infants who were born at 32–34 weeks of gestation with 2 or more additional risk factors and infants who had congenital heart disease. e HR and 95% CI were not calculated because of the limited number of events among subjects within-group. We further estimated the effectiveness of immunoprophylaxis in each eligibility group (Tables 3 and 4). Infants in the CLD eligibility group had the largest risk reduction during the protected period(s), with a risk of bronchiolitis hospitalization that was decreased by 57% (IRR = 0.43, 95% CI: 0.23, 0.81) in the unadjusted analysis and by 52% after adjustment for covariates (aHR = 0.48, 95% CI: 0.25, 0.94). Among infants in the ineligible but treated group (who nevertheless received at least some immunoprophylaxis), the risks in the protected periods were decreased by 47% (IRR = 0.53, 95% CI: 0.30, 0.93) and 49% (aHR = 0.51, 95% CI: 0.30, 0.86), respectively. There was no similar significantly decreased risk of bronchiolitis hospitalization with RSV immunoprophylaxis in the 2 premature eligibility groups or the “other” eligibility group (Tables 3 and 4). In sensitivity analyses, results were unchanged when we extended the RSV immunoprophylaxis-protected time from 30 days to 35 days or when we delayed the starting time of the protective period to 4 days following administration (Web Tables 2–4). The association was consistent when we limited the analyses to infants born in 1998 and afterward, when infants almost exclusively received palivizumab (Web Tables 3 and 5). Analysis of infants following the 2009 and 2014 AAP guideline updates The AAP updated its recommendations for the use of RSV immunoprophylaxis in 2009 (12) and 2014 (5). Among 3,444 infants who were eligible on the basis of pre-2009 AAP guidelines, 1,783 infants (52%) would have been continuously eligible for RSV immunoprophylaxis based on the most recent guidelines (Web Table 6). Among them, 75% (n = 1,332) received at least 1 dose of immunoprophylaxis, and 4% (n = 75) experienced at least 1 bronchiolitis hospitalization (Web Table 7). The risk of bronchiolitis hospitalization was nonsignificantly decreased (aHR = 0.94, 95% CI: 0.44, 2.03) among the infants who had ever received immunoprophylaxis. Of the 1,661 infants (48%) who would no longer be eligible on the basis of the current guidelines, 56% (n = 929) received at least 1 dose of immunoprophylaxis, and 3% (n = 53) experienced 56 bronchiolitis hospitalizations in total (Web Tables 6 and 7). Risk of bronchiolitis hospitalization was nonsignificantly decreased by 36% (aHR = 0.64, 95% CI: 0.29, 1.40) among infants who ever received immunoprophylaxis. DISCUSSION To our knowledge, this was the first population-based study of the effectiveness of RSV immunoprophylaxis in reducing infant bronchiolitis morbidity that accounted for indication bias, duration of effect of treatment, and the temporal relationship between treatment and outcome during the annual RSV epidemic and that assessed the impact of the updated 2009 and 2014 AAP guidelines for use of RSV immunoprophylaxis. In this study population, infants who received at least 1 dose of RSV immunoprophylaxis had a 32% decrease in risk of bronchiolitis hospitalization within 30 days of administration, independent of prior immunoprophylaxis receipt. While the decreased risk associated with receipt of RSV immunoprophylaxis observed in this study was smaller than the 55% reduction reported in the RCTs of efficacy (9), reduced effectiveness in comparison with corresponding efficacy in RCTs is common, as real-world effectiveness studies often include different populations and decreased adherence (24). Within one RSV season, prior receipt of any immunoprophylaxis was independently associated with a decreased risk of bronchiolitis hospitalization, even during unprotected periods. Thus, infants were less likely to experience a bronchiolitis hospitalization during the unprotected period if they had a preceding protected period/receipt of immunoprophylaxis. The smaller reduction in effectiveness as compared with efficacy may be due to the extended protection conferred by RSV immunoprophylaxis in a study comparing protected and unprotected periods, but it also may be due to the type of intervention, which requires in-person administration during pediatrician visits, resulting in high adherence and known receipt of drug in comparison with most real-world effectiveness studies. This result is consistent with previous findings that subsequent use (days 1–30 of each subsequent dose) and former use (days 31–60 after any dose if delays or no readministration occurred) significantly reduced the risk of RSV-related hospitalization (25). Our findings are also consistent with the elevated trough serum concentrations measured after the third and fourth monthly injections (26). CLD is one of the strongest known risk factors for severe RSV infection, and it was also a significant determinant of enhanced adherence to immunoprophylaxis in this study. Among infants with CLD, receipt of RSV immunoprophylaxis was associated with a 52% decrease in risk of bronchiolitis hospitalization. Such a significant reduction in risk of bronchiolitis hospitalization was supported by decreasing hospitalization rates in this population over the course of the study period as the proportion receiving immunoprophylaxis increased over time (Web Figure 4) (15). It is noteworthy that rates of bronchiolitis hospitalization in infants with CLD who ever and never received immunoprophylaxis were 16% and 26%, respectively, which is a much higher rate than that observed in children with bronchopulmonary dysplasia enrolled in the IMpact-RSV Study (8% and 13% in the immunoprophylaxis and placebo groups, respectively) (9). The difference is likely due to an evolving definition, evolving diagnosis, and different pathophysiology of CLD/bronchopulmonary dysplasia as management has changed over time. Children defined as having CLD in our study were probably different from and sicker than children enrolled in previous studies (16, 17, 27). Second, the higher rate observed in our study may in part be secondary to non-RSV pathogens. Nevertheless, the significant reduction we observed demonstrates that RSV immunoprophylaxis is effective in reducing bronchiolitis hospitalization in this population. Premature birth is another significant and known risk factor for severe RSV infection. Extreme prematurity (birth at <29 weeks) was also a significant determinant of enhanced adherence to immunoprophylaxis. However, there were no differences in the risks of bronchiolitis hospitalization between protected and unprotected periods in the subgroups of infants born at less than 29 completed weeks of gestation and between 29 and 31 weeks of gestation. The nonsignificant result is different from the 78% risk reduction reported in the IMpact-RSV Study (9) and might be due to the limited sample size and small number of bronchiolitis hospitalizations observed in our study. Compared with the 2% and 8% prevalences of RSV hospitalization observed in immunoprophylaxis-treated and placebo groups among premature infants enrolled in the RCT, we observed 2.5% (n = 49) and 2.2% (n = 18) prevalences of bronchiolitis hospitalization among premature infants who had ever and never received immunoprophylaxis, respectively. The small numbers observed might have been due to the significant improvement in premature infant medical care and outcomes over the past 20 years, with marked decreases in mortality, major changes in how care for premature infants is managed, advances in maternal immunization and nutrition, and changes in the pathophysiology of prematurity (28, 29). All of these important changes have resulted in healthier preterm infants and in larger numbers of lower-gestational-age preterm infants who survive and whose vulnerability to RSV is likely different from that of 20 years ago. Interestingly, we observed a large decrease in risk associated with receipt of RSV immunoprophylaxis in 949 low-risk infants who received immunoprophylaxis (aHR = 0.51, 95% CI: 0.30, 0.86). The median gestational age of these infants was 32 weeks (interquartile range, 32–35). Twenty-six percent of them (n = 243) had congenital heart disease or CLD. The fact that those infants were similar to eligible infants in many ways (Table 2) suggests either misclassification of high-risk eligibility groupings, with some high-risk infants being misclassified as low-risk ineligible infants, or the presence of infants who were very similar to high-risk infants but failed to meet specific eligibility criteria. The AAP updated its RSV immunoprophylaxis guidelines in 2009 (12) and 2014 (5), which now results in eligibility for about half of the previously eligible infants. Our results indicated that the real-world receipt of RSV immunoprophylaxis tracks with these guidelines. The majority of the infants eligible under both older and current guidelines received at least 1 dose of immunoprophylaxis, while only about half of infants who would no longer be eligible under the up-to-date guidelines received at least 1 dose. The strengths of this study include the large population, with detailed information on the timing of and adherence to RSV immunoprophylaxis. Previous observational studies on RSV immunoprophylaxis often included only subjects who were receiving, or had received, immunoprophylaxis as compared with subjects who did not receive immunoprophylaxis (30, 31). There are significant problems with this approach, as pointed out above. Importantly, we demonstrated that administration of RSV immunoprophylaxis is itself an indication of increased risk of infection, and there is significant differential propensity for receipt, even within high-risk eligibility groups (Table 2, Web Table 1) (32). Thus, our approach to dealing with confounding by indication is critical to assessing real-world effectiveness. Another strength of this study was consideration of the protection window and the temporal relationship of immunoprophylaxis receipt and bronchiolitis visits to the RSV epidemic, something that has not been accounted for in prior observational studies. This is important, as it makes biological sense to account for presumed protection during periods following dosing, as well as higher and lower risks of infection depending on timing within the RSV season. Lastly, we assessed the association with RSV immunoprophylaxis using the unprotected periods of subjects who received at least 1 dose of immunoprophylaxis in order to minimize bias due to infants’ differential risks of RSV infection and seasonal variation (Web Table 8, Web Figure 5). There are several important limitations of this work to consider. We lacked virological confirmation of the etiology of bronchiolitis. Bronchiolitis captured by International Classification of Diseases, Ninth Revision, codes might not be due to RSV; therefore, the effect of RSV immunoprophylaxis might have been diluted (33, 34). To minimize the misclassification of bronchiolitis caused by viruses other than RSV, we limited the RSV season to November–March. Approximately 50%–70% of infant bronchiolitis hospitalizations occurring during the winter season were due to RSV (18, 35–37). KPNC started to test for RSV using the polymerase chain reaction method in 2006. Among 544 bronchiolitis hospitalization episodes that infants experienced during November–March from 2006 to 2009, 64% (n = 350 episodes) tested RSV-positive (Kedir Turi, Vanderbilt University, unpublished data, 2018). Further, it is also possible that infants who receive RSV immunoprophylaxis are protected against viral agents other than RSV as a result of their protection against severe RSV infection (6). Therefore, the association detected in this study reflected the true real-world effectiveness of immunoprophylaxis. It must also be noted that the innate risk of RSV infection among study subjects was highly variable and that the decision to administer RSV immunoprophylaxis was influenced by known risk factors as well as subjective risk factors. This makes confounding by treatment indication (i.e., sicker or higher-risk infants being more likely to receive treatment) a particular problem in observational studies such as this one (32). It is for this reason that our main analyses were restricted to patients who received at least 1 dose of immunoprophylaxis. There were several additional limitations. Two types of immunoprophylaxis with different mechanisms, RSV immune globulin intravenous (licensed in 1996) and palivizumab (licensed in 1998), were available during the study period. We could not determine type of immunoprophylaxis or differentiate between the 2 types of immunoprophylaxis available during the study period. KPNC administrated palivizumab almost exclusively in 1998 and afterwards; therefore, our results were mainly driven by the effect of palivizumab (Web Tables 3 and 5). Lastly, despite the fact that this is one of the largest population-based studies on the effectiveness of immunoprophylaxis to have been carried out to date, the study lacked statistical power for several high-risk subgroups. However, the groupings were based on the inclusion criteria from RCTs, and it may be that studies such as this can provide important data on groups who most benefit from this costly preventive intervention, particularly as numbers of RSV bronchiolitis events appear to be decreasing. In summary, in this real-world effectiveness study of RSV immunoprophylaxis, we have demonstrated that administration of RSV immunoprophylaxis was associated with a decreased risk of bronchiolitis hospitalization among high-risk infants, with infants with CLD, a group still recommended for receipt under the new 2014 AAP guidelines (5), experiencing the greatest risk reduction. Immunoprophylaxis was effective in reducing RSV-related morbidity during the 30 days following dosing regardless of prior receipt, supporting the importance of adherence to immunoprophylaxis therapy to provide protection in high-risk infants (38–40). The additional protective effect of prior receipt of immunoprophylaxis suggests that a longer dosing schedule might be as effective as current monthly dosing recommendations. Lastly, approximately half of the infants previously eligible under the prior guidelines were no longer eligible under the updated 2014 guidelines for use of RSV immunoprophylaxis. However, the burden of disease and the effectiveness of RSV immunoprophylaxis were greatest in the population that is still covered under the latest guidelines. Until a vaccine for RSV is available, these up-to-date data on the effectiveness of RSV prophylaxis may aid in informing use of this preventive intervention among high-risk infants (41). ACKNOWLEDGMENTS Author affiliations: Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee (Pingsheng Wu, Tina V. Hartert); Department of Inpatient Pediatrics, Kaiser Permanente Medical Center, Walnut Creek, California (Gabriel J. Escobar); Perinatal Research Unit, Division of Research, Kaiser Permanente Northern California, Oakland, California (Gabriel J. Escobar, Sherian X. Li, Eileen M. Walsh); Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee (Pingsheng Wu, Tebeb Gebretsadik, William D. Dupont, Chang Yu, Jeffrey R. Horner); Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee (Kecia N. Carroll); Department of Health Policy, Vanderbilt University Medical Center, Nashville, Tennessee (Edward F. Mitchel, William D. Dupont); and Department of Health Science, College of Life Sciences, Brigham Young University, Provo, Utah (Chantel Sloan). This work was funded by the Agency for Healthcare Research and Quality (grant R01 HS018454) and the National Institutes of Health (grants K24 AI77930, RC4 MH092755, R21 HL123829, R21 HL129020, and UL1 RR024975 (now 2 UL1 TR000445)). We thank Drs. Marie Griffin, Carlos Grijalva, and Kathryn Edwards of Vanderbilt University Medical Center for their assistance with critical revision of the manuscript. We are indebted to the Kaiser Permanente Division of Research for providing the data on the study cohort. This work was presented in part at the 8th Asian Conference on Pharmaceopidemiology (Hong Kong SAR, People’s Republic of China, October 25–27, 2013) and at the 2016 American Thoracic Society International Conference (San Francisco, California, May 13–18, 2016). G.J.E, S.X.L, E.M.W., and T.V.H. report receipt of past grant support from MedImmune LLC (Gaithersburg, Maryland). G.J.E. has also received grant support from Novartis International AG (Basel, Switzerland) for other projects. Drs. Marie Griffin, Carlos Grijalva, and Kathryn Edwards did not receive any compensation for their contribution to this article. Abbreviations AAP American Academy of Pediatrics aHR adjusted hazard ratio CI confidence interval CLD chronic lung disease IRR incidence rate ratio KPNC Kaiser Permanente Northern California RCT randomized clinical trial RSV respiratory syncytial virus. REFERENCES 1 Glezen WP, Taber LH, Frank AL, et al.  . Risk of primary infection and reinfection with respiratory syncytial virus. Am J Dis Child . 1986; 140( 6): 543– 546. Google Scholar PubMed  2 Hall CB. Respiratory syncytial virus and parainfluenza virus. N Engl J Med . 2001; 344( 25): 1917– 1928. Google Scholar CrossRef Search ADS PubMed  3 Shay DK, Holman RC, Newman RD, et al.  . Bronchiolitis-associated hospitalizations among US children, 1980–1996. JAMA . 1999; 282( 15): 1440– 1446. Google Scholar CrossRef Search ADS PubMed  4 American Academy of Pediatrics Committee on Infectious Diseases, Committee on Fetus and Newborn. Respiratory syncytial virus immune globulin intravenous: indications for use. Pediatrics . 1997; 99( 4): 645– 650. CrossRef Search ADS PubMed  5 American Academy of Pediatrics Committee on Infectious Diseases; American Academy of Pediatrics Bronchiolitis Guidelines Committee. Updated guidance for palivizumab prophylaxis among infants and young children at increased risk of hospitalization for respiratory syncytial virus infection. Pediatrics . 2014; 134( 2): 415– 420. CrossRef Search ADS PubMed  6 Blanken MO, Rovers MM, Molenaar JM, et al.  . Respiratory syncytial virus and recurrent wheeze in healthy preterm infants. N Engl J Med . 2013; 368( 19): 1791– 1799. Google Scholar CrossRef Search ADS PubMed  7 Groothuis JR, Simoes EA, Levin MJ, et al.  . Prophylactic administration of respiratory syncytial virus immune globulin to high-risk infants and young children. The Respiratory Syncytial Virus Immune Globulin Study Group. N Engl J Med . 1993; 329( 21): 1524– 1530. Google Scholar CrossRef Search ADS PubMed  8 O’Brien KL, Chandran A, Weatherholtz R, et al.  . Efficacy of motavizumab for the prevention of respiratory syncytial virus disease in healthy Native American infants: a phase 3 randomised double-blind placebo-controlled trial. Lancet Infect Dis . 2015; 15( 12): 1398– 1408. Google Scholar CrossRef Search ADS PubMed  9 The 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( 3): 531– 537. CrossRef Search ADS   10 Nightingale SL. First product available for preventing serious RSV disease. JAMA . 1996; 275( 12): 902. Google Scholar CrossRef Search ADS PubMed  11 American Academy of Pediatrics Committee on Infectious Diseases and Committee on Fetus and Newborn. Prevention of respiratory syncytial virus infections: indications for the use of palivizumab and update on the use of RSV-IGIV. Pediatrics . 1998; 102( 5): 1211– 1216. CrossRef Search ADS PubMed  12 Committee on Infectious Diseases. From the American Academy of Pediatrics: policy statements—modified recommendations for use of palivizumab for prevention of respiratory syncytial virus infections. Pediatrics . 2009; 124( 6): 1694– 1701. CrossRef Search ADS PubMed  13 Pickering LK, Baker CJ, Long SS, et al.  ., eds. Red Book: 2006 Report of the Committee on Infectious Diseases . 27th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2006. 14 Canfield SD, Simoes EA. Prevention of respiratory syncytial virus (RSV) infection: RSV immune globulin intravenous and palivizumab. (American Academy of Pediatrics). Pediatr Ann . 1999; 28( 8): 507– 514. Google Scholar CrossRef Search ADS PubMed  15 Escobar GJ, Gebretsadik T, Carroll K, et al.  . Adherence to immunoprophylaxis regimens for respiratory syncytial virus infection in insured and Medicaid populations. J Pediatric Infect Dis Soc . 2013; 2( 3): 205– 214. Google Scholar CrossRef Search ADS PubMed  16 Islam JY, Keller RL, Aschner JL, et al.  . Understanding the short- and long-term respiratory outcomes of prematurity and bronchopulmonary dysplasia. Am J Respir Crit Care Med . 2015; 192( 2): 134– 156. Google Scholar CrossRef Search ADS PubMed  17 Poindexter BB, Feng R, Schmidt B, et al.  . Comparisons and limitations of current definitions of bronchopulmonary dysplasia for the prematurity and respiratory outcomes program. Ann Am Thorac Soc . 2015; 12( 12): 1822– 1830. Google Scholar CrossRef Search ADS PubMed  18 Subramanian KN, Weisman LE, Rhodes T, et al.  . Safety, tolerance and pharmacokinetics of a humanized monoclonal antibody to respiratory syncytial virus in premature infants and infants with bronchopulmonary dysplasia. MEDI-493 Study Group. Pediatr Infect Dis J . 1998; 17( 2): 110– 115. Google Scholar CrossRef Search ADS PubMed  19 Carroll KN, Wu P, Gebretsadik T, et al.  . Season of infant bronchiolitis and estimates of subsequent risk and burden of early childhood asthma. J Allergy Clin Immunol . 2009; 123( 4): 964– 966. Google Scholar CrossRef Search ADS PubMed  20 Wu P, Dupont WD, Griffin MR, et al.  . Evidence of a causal role of winter virus infection during infancy in early childhood asthma. Am J Respir Crit Care Med . 2008; 178( 11): 1123– 1129. Google Scholar CrossRef Search ADS PubMed  21 Schanzer DL, Langley JM, Tam TW. Hospitalization attributable to influenza and other viral respiratory illnesses in Canadian children. Pediatr Infect Dis J . 2006; 25( 9): 795– 800. Google Scholar CrossRef Search ADS PubMed  22 Therneau TM, Grambsch PM. Modeling Survival Data: Extending the Cox Model . New York, NY: Springer Science & Business Media; 2000. Google Scholar CrossRef Search ADS   23 Carroll KN, Gebretsadik T, Escobar GJ, et al.  . Respiratory syncytial virus immunoprophylaxis in high-risk infants and development of childhood asthma. J Allergy Clin Immunol . 2017; 139( 1): 66.e3– 71.e3. Google Scholar CrossRef Search ADS   24 Eaglstein WH, Kirsner RS. Expectations for comparative effectiveness and efficacy research: with welcomed questions may come unwelcome answers. JAMA Dermatol . 2013; 149( 1): 18– 19. Google Scholar CrossRef Search ADS PubMed  25 Winterstein AG, Hampp C, Saidi A. Effectiveness of palivizumab prophylaxis in infants and children in Florida. Pharmacoepidemiol Drug Saf . 2012; 21( 1): 53– 60. Google Scholar CrossRef Search ADS PubMed  26 MedImmune LLC. Synagis. Palivizumab. (Package insert). Gaithersburg, MD: MedImmune LLC; 2014. 27 Sahni R, Ammari A, Suri MS, et al.  . Is the new definition of bronchopulmonary dysplasia more useful? J Perinatol . 2005; 25( 1): 41– 46. Google Scholar CrossRef Search ADS PubMed  28 Ehrenkranz RA, Walsh MC, Vohr BR, et al.  . Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia. Pediatrics . 2005; 116( 6): 1353– 1360. Google Scholar CrossRef Search ADS PubMed  29 Fanaroff AA, Stoll BJ, Wright LL, et al.  . Trends in neonatal morbidity and mortality for very low birthweight infants. Am J Obstet Gynecol . 2007; 196( 2): 147.e1– 147e8. Google Scholar CrossRef Search ADS   30 Atkins JT, Karimi P, Morris BH, et al.  . Prophylaxis for respiratory syncytial virus with respiratory syncytial virus-immunoglobulin intravenous among preterm infants of thirty-two weeks gestation and less: reduction in incidence, severity of illness and cost. Pediatr Infect Dis J . 2000; 19( 2): 138– 143. Google Scholar CrossRef Search ADS PubMed  31 Pedraz C, Carbonell-Estrany X, Figueras-Aloy J, et al.  . Effect of palivizumab prophylaxis in decreasing respiratory syncytial virus hospitalizations in premature infants. Pediatr Infect Dis J . 2003; 22( 9): 823– 827. Google Scholar CrossRef Search ADS PubMed  32 Boyce TG, Yogev R, DeVincenzo JP, et al.  . Confounding by indication limits conclusions of study of palivizumab effectiveness. Pediatrics . 2017; 139( 3): e20164247A. Google Scholar CrossRef Search ADS PubMed  33 Hall CB, Weinberg GA, Blumkin AK, et al.  . Respiratory syncytial virus-associated hospitalizations among children less than 24 months of age. Pediatrics . 2013; 132( 2): e341– e348. Google Scholar CrossRef Search ADS PubMed  34 Makari D, Staat MA, Henrickson KJ, et al.  . The underrecognized burden of respiratory syncytial virus among infants presenting to US emergency departments. Clin Pediatr (Phila) . 2015; 54( 6): 594– 597. Google Scholar CrossRef Search ADS PubMed  35 Henrickson KJ, Hoover S, Kehl KS, et al.  . National disease burden of respiratory viruses detected in children by polymerase chain reaction. Pediatr Infect Dis J . 2004; 23( 1 suppl): S11– S18. Google Scholar CrossRef Search ADS PubMed  36 Meissner HC. Viral bronchiolitis in children. N Engl J Med . 2016; 374( 1): 62– 72. Google Scholar CrossRef Search ADS PubMed  37 Smyth RL, Openshaw PJ. Bronchiolitis. Lancet . 2006; 368( 9532): 312– 322. Google Scholar CrossRef Search ADS PubMed  38 Krilov LR, Masaquel AS, Weiner LB, et al.  . Partial palivizumab prophylaxis and increased risk of hospitalization due to respiratory syncytial virus in a Medicaid population: a retrospective cohort analysis. BMC Pediatr . 2014; 14: 261. Google Scholar CrossRef Search ADS PubMed  39 La Via WV, Notario GF, Yu XQ, et al.  . Three monthly doses of palivizumab are not adequate for 5-month protection: a population pharmacokinetic analysis. Pulm Pharmacol Ther . 2013; 26( 6): 666– 671. Google Scholar CrossRef Search ADS PubMed  40 Robbie GJ, Zhao L, Mondick J, et al.  . Population pharmacokinetics of palivizumab, a humanized anti-respiratory syncytial virus monoclonal antibody, in adults and children. Antimicrob Agents Chemother . 2012; 56( 9): 4927– 4936. Google Scholar CrossRef Search ADS PubMed  41 Andabaka T, Nickerson JW, Rojas-Reyes MX, et al.  . Monoclonal antibody for reducing the risk of respiratory syncytial virus infection in children. Cochrane Database Syst Rev . 2013;( 4): CD006602. © The Author(s) 2018. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. 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Effectiveness of Respiratory Syncytial Virus Immunoprophylaxis in Reducing Bronchiolitis Hospitalizations Among High-Risk Infants

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Abstract

Abstract We sought to determine the real-world effectiveness of respiratory syncytial virus (RSV) immunoprophylaxis in a population-based cohort to inform policy. The study population included infants born during 1996–2008 and enrolled in the Kaiser Permanente Northern California integrated health-care delivery system. During the RSV season (November–March), the date of RSV immunoprophylaxis administration and the following 30 days were defined as RSV immunoprophylaxis protected period(s), and all other days were defined as unprotected period(s). Numbers of bronchiolitis hospitalizations were determined using International Classification of Diseases, Ninth Revision, codes during RSV season. We used a proportional hazards model to estimate risk of bronchiolitis hospitalization when comparing infants’ protected period(s) with unprotected period(s). Infants who had ever received RSV immunoprophylaxis had a 32% decreased risk of bronchiolitis hospitalization (adjusted hazard ratio = 0.68, 95% confidence interval: 0.46, 1.00) when protected periods were compared with unprotected periods. Infants with chronic lung disease (CLD) had a 52% decreased risk of bronchiolitis hospitalization (adjusted hazard ratio = 0.48, 95% confidence interval: 0.25, 0.94) when protected periods were compared with unprotected periods. Under the new 2014 American Academy of Pediatrics (AAP) guidelines, 48% of infants eligible for RSV immunoprophylaxis on the basis of AAP guidelines in place at birth would no longer be eligible, but nearly all infants with CLD would remain eligible. RSV immunoprophylaxis is effective in decreasing hospitalization. This association is greatest for infants with CLD, a group still recommended for receipt of RSV immunoprophylaxis under the new AAP guidelines. bronchiolitis, bronchiolitis hospitalization, high-risk infants, immunoprophylaxis, infancy, lower respiratory tract infection, respiratory syncytial virus Respiratory syncytial virus (RSV) infection is the leading cause of viral lower respiratory tract infections, such as bronchiolitis, in infants and young children (1–3). No effective treatment for RSV exists, nor is there an efficacious RSV vaccine yet available for the prevention of serious RSV infection. The only available pharmacological preventive strategy for severe RSV infection is the administration of an RSV monoclonal antibody licensed for use in high-risk infants (4, 5). Randomized clinical trials (RCTs) have demonstrated that passive RSV immunoprophylaxis is efficacious in reducing RSV-related hospitalizations in infants who are at increased risk for RSV infection (6–9). The US Food and Drug Administration first approved the use of RSV immunoprophylaxis in 1996 (10), and the American Academy of Pediatrics (AAP) issued recommendations for RSV immunoprophylaxis for selected high-risk infants in 1997 (4), with subsequent updates (5, 11–14). Guidelines regarding eligibility for, and timing of receipt of, RSV immunoprophylaxis have changed over time; it has been recommended that infants with chronic lung disease (CLD), congenital heart disease, and premature birth receive immunoprophylaxis during the winter RSV season of their first year of life (5, 11, 13). The AAP updated its guidelines in 2009 (12) and 2014 (5) with modified infant eligibility. The proportion of infants impacted and the real-world effectiveness across eligibility groups are not known. While RCTs have established efficacy, what is needed to further inform policy on this costly preventive therapy is current real-world effectiveness studies of immunoprophylaxis. The likelihood of administration and timing of receipt of immunoprophylaxis, even among recommended high-risk infants, varies based upon the infants’ risk for RSV infection, which depends on the severity and timing of the actual RSV seasons (15). Additionally, CLD of prematurity has significantly changed since the efficacy studies were conducted (16, 17). Our objective in this study was to obtain data needed for policy and clinical-care decisions by assessing the effectiveness of RSV immunoprophylaxis in reducing numbers of bronchiolitis hospitalizations among infants who were eligible and/or received RSV immunoprophylaxis, as well as to examine the proportion of infants likely to be affected by the new 2014 guidelines (5). Critical to such analyses of observational data is the application of methods of adjustment for treatment indication bias, the duration of effect of immunoprophylaxis, and the temporal relationship between receipt of RSV immunoprophylaxis, bronchiolitis hospitalizations, and the epidemic circulation and risk of RSV infection. METHODS Study population A cohort of 211,098 infants born between 1996 and 2008 and continuously enrolled during the first year of life in Kaiser Permanente Northern California (KPNC), an integrated health-care delivery system, were included (Figure 1) (15). We categorized infants into 5 mutually exclusive and hierarchical eligibility groups based on the in-place AAP guidelines recommended during our study period, as described previously: 1) CLD that required medical therapy in the 6 months preceding the RSV season; 2) prematurity of <29 completed weeks’ gestation; 3) prematurity of 29–31 weeks’ gestation; 4) other eligibility (e.g., 32- to 34-week infants with 2 or more risk factors, infants with congenital heart disease, etc.); and 5) ineligible for RSV immunoprophylaxis. Infants in groups 1–4 were considered eligible for RSV immunoprophylaxis based on the literature and guidelines (5, 11, 13). The study protocol was approved by the KPNC and Vanderbilt University institutional review boards and the State of California Committee for the Protection of Human Subjects. Figure 1. View largeDownload slide Distribution of the study population according to eligibility for and receipt of respiratory syncytial virus (RSV) immunoprophylaxis, Kaiser Permanente Northern California, 1996–2008. AAP, American Academy of Pediatrics; CLD, chronic lung disease. Figure 1. View largeDownload slide Distribution of the study population according to eligibility for and receipt of respiratory syncytial virus (RSV) immunoprophylaxis, Kaiser Permanente Northern California, 1996–2008. AAP, American Academy of Pediatrics; CLD, chronic lung disease. RSV season, immunoprophylaxis receipt, and protected/unprotected periods We defined RSV season as November–March in order to capture RSV-specific morbidity by minimizing misclassification of events caused by viruses other than RSV, which is also consistent with the AAP-defined season for receipt of RSV immunoprophylaxis for most US areas, including California (5). We captured data on administration of RSV immunoprophylaxis using a pharmacy database that included information on outpatient visits, medications, and the dates of immunoprophylaxis administration (see Web Figure 1A, available at https://academic.oup.com/aje). RSV immunoprophylaxis is efficacious for eligible infants during the RSV season, and dosing is recommended every 30 days for such infants (5, 18). We defined the 30-day interval following administration of RSV immunoprophylaxis as the protected period. All days during the RSV season that did not fall within a protected period were defined as the unprotected period (Figure 2 and Web Figure 2). We distinguished and identified 2 different types of unprotected periods. One was the unprotected period for infants who never received any RSV immunoprophylaxis; the other was the unprotected period for those infants who received at least 1 dose of immunoprophylaxis but did not receive it every 30 days. Figure 2. View largeDownload slide Data-processing strategy for creating analysis records during each infant’s first 5-month respiratory syncytial virus (RSV) season following birth, Kaiser Permanente Northern California, 1996–2008. The start of follow-up was the first day on which infants were eligible for RSV immunoprophylaxis based on American Academy of Pediatrics guidelines, the first day after birth hospitalization discharge, or the start of the RSV season (November 1), whichever came last. The end of follow-up was the last day on which infants were eligible for RSV immunoprophylaxis, the infant’s first birthday, or the end of the RSV season (March 31), whichever came first. Circles denote bronchiolitis hospitalization, and diamonds denote administration of RSV immunoprophylaxis. Figure 2. View largeDownload slide Data-processing strategy for creating analysis records during each infant’s first 5-month respiratory syncytial virus (RSV) season following birth, Kaiser Permanente Northern California, 1996–2008. The start of follow-up was the first day on which infants were eligible for RSV immunoprophylaxis based on American Academy of Pediatrics guidelines, the first day after birth hospitalization discharge, or the start of the RSV season (November 1), whichever came last. The end of follow-up was the last day on which infants were eligible for RSV immunoprophylaxis, the infant’s first birthday, or the end of the RSV season (March 31), whichever came first. Circles denote bronchiolitis hospitalization, and diamonds denote administration of RSV immunoprophylaxis. Bronchiolitis hospitalizations Numbers of bronchiolitis hospitalizations during the 5-month RSV season of each infant’s first 12 months of life were captured using International Classification of Diseases, Ninth Revision, codes (466.1 and 480.1) for bronchiolitis (Web Figure 1B). Our definition of bronchiolitis hospitalization has been validated previously (19–21). Statistical analysis We expressed descriptive statistics as proportions for categorical variables and as means and standard deviations or medians and interquartile ranges for continuous variables, as appropriate. We assessed the effectiveness of RSV immunoprophylaxis by comparing bronchiolitis hospitalization incidence rates between protected and unprotected periods. The incidence rate ratio was estimated within eligibility groups, as well as among infants who received at least 1 dose of immunoprophylaxis. We limited the estimation of effectiveness of RSV immunoprophylaxis to the 3,210 infants who received at least 1 dose of immunoprophylaxis. A Cox proportional hazards regression model with repeated measures was fitted adjusting for both fixed and time-dependent covariates (22). Type of immunoprophylaxis period (protected or unprotected) was considered as a time-dependent variable. Similar models were developed for each eligibility group. Detailed information on the regression models can be found in the Web Appendix. Additional sensitivity analyses regarding the 30-day protection window were conducted (Web Appendix, Web Figure 3). Two types of RSV immunoprophylaxis, RSV immune globulin intravenous (licensed in 1996) and palivizumab (licensed in 1998), were available during the study period. KPNC administered palivizumab almost exclusively starting in 1998. We conducted a subgroup analysis of children born in 1998 and afterwards to determine the palivizumab-specific association with bronchiolitis hospitalization. The AAP subsequently updated its guidelines for RSV immunoprophylaxis in 2009 (12) and 2014 (5), modifying the criteria for infant eligibility and the number of doses an eligible infant should receive. We estimated the proportions of infants who were eligible and ineligible under the old and new guidelines and the effectiveness of immunoprophylaxis in the 2 subgroups. All analyses were performed using R software, version 3.1.2 (R Foundation for Statistical Computing, Vienna, Austria; www.r-project.org), and SAS software, version 9.3 (SAS Institute, Inc., Cary, North Carolina). RESULTS Receipt of RSV immunoprophylaxis There were 211,098 infants born and enrolled in the cohort over the 13-year study period (1996–2008) (Table 1). Among those infants, 3,444 (1.63%) were eligible for RSV immunoprophylaxis based on the guidelines in place at birth, and 3,210 infants (1.52%) received at least 1 dose. Infants in the CLD and <29-weeks’-gestation eligibility groups were the most likely to receive immunoprophylaxis (76.5% and 78.6%, respectively), while infants in the “other” eligibility group were the least likely to receive it (15.6%) (Table 1). Among infants who ever received immunoprophylaxis, the median number of doses received was 4 (interquartile range, 3–5). Table 1. Maternal and Infant Characteristics of Infants Enrolled in Kaiser Permanente Northern California According to Eligibility for Respiratory Syncytial Virus Immunoprophylaxis, 1996–2008 Characteristic  Eligibility Group  Ineligible Group  Chronic Lung Disease  Prematurity at <29 Weeks  Prematurity at <32 Weeks  Other Eligible Group  No. of Persons  %  No. of Persons  %  No. of Persons  %  No. of Persons  %  No. of Persons  %  Total  324  0.2  1,016  0.5  1,752  0.8  352  0.2  207,654  98.4  Estimated gestational age, weeksa  28 (26–30)  27 (26–28)  30 (30–31)  34 (33–34)  39 (38–40)  Birth weight, ga  1,000 (769–1,323)  925 (783–1,115)  1,455 (1,239–1,670)  2,170 (1,834–2,591)  3,415 (3,070–3,755)  Small-for-gestational-age birth (<5th percentile)  16  4.9  16  1.6  6  4.3  13  3.7  2,964  1.4  Birth hospitalization length of stay, daysa  78 (56–103)  71 (57–87)  37 (29–47)  13 (7–20)  3 (2–3)  Male infant sexb  212  65.4  470  46.3  940  53.7  185  52.6  106,540  51.3  Infant race/ethnicityc                       White  121  37.3  378  37.3  704  40.2  163  46.3  85,839  41.4   African-American  70  21.6  155  15.3  243  13.9  61  17.3  17,334  8.4   Latino  58  17.9  222  21.9  352  20.1  61  17.3  44,437  21.4   Asian  48  14.8  149  14.7  270  15.4  35  9.9  42,346  20.4   Other  27  8.3  110  10.8  183  10.4  32  9.1  17,499  8.4  Congenital heart disease  190  58.6  498  49.0  359  20.5  117  33.2  2,596  1.3  Neuromuscular disorder  30  9.3  27  2.7  22  1.3  11  3.1  330  0.2  Receipt of ≥1 dose of RSV immunoprophylaxis  248  76.5  799  78.6  1,159  66.2  352  15.6  949  0.5  No. of living siblings at homed                       0  127  39.2  497  48.9  816  46.6  62  17.6  90,768  43.7   1  115  35.5  308  30.3  531  30.3  152  43.2  71,025  34.2   >1  82  25.3  211  20.8  404  23.1  138  39.2  45,727  22.0  Maternal smoking during pregnancy  25  7.7  85  8.4  121  6.9  249  70.7  14,197  6.8  Maternal age at delivery, yearsa,e  30 (25–35)  31 (26–35)  31 (26–36)  30 (25–35)  30 (26–34)  Maternal education, years                       <12  90  27.8  355  34.9  553  31.6  156  44.3  65,167  31.4   12  76  23.5  213  21.0  361  20.6  101  28.7  43,220  20.8   >12  158  48.8  448  44.1  838  47.8  95  27.0  99,267  47.8  Characteristic  Eligibility Group  Ineligible Group  Chronic Lung Disease  Prematurity at <29 Weeks  Prematurity at <32 Weeks  Other Eligible Group  No. of Persons  %  No. of Persons  %  No. of Persons  %  No. of Persons  %  No. of Persons  %  Total  324  0.2  1,016  0.5  1,752  0.8  352  0.2  207,654  98.4  Estimated gestational age, weeksa  28 (26–30)  27 (26–28)  30 (30–31)  34 (33–34)  39 (38–40)  Birth weight, ga  1,000 (769–1,323)  925 (783–1,115)  1,455 (1,239–1,670)  2,170 (1,834–2,591)  3,415 (3,070–3,755)  Small-for-gestational-age birth (<5th percentile)  16  4.9  16  1.6  6  4.3  13  3.7  2,964  1.4  Birth hospitalization length of stay, daysa  78 (56–103)  71 (57–87)  37 (29–47)  13 (7–20)  3 (2–3)  Male infant sexb  212  65.4  470  46.3  940  53.7  185  52.6  106,540  51.3  Infant race/ethnicityc                       White  121  37.3  378  37.3  704  40.2  163  46.3  85,839  41.4   African-American  70  21.6  155  15.3  243  13.9  61  17.3  17,334  8.4   Latino  58  17.9  222  21.9  352  20.1  61  17.3  44,437  21.4   Asian  48  14.8  149  14.7  270  15.4  35  9.9  42,346  20.4   Other  27  8.3  110  10.8  183  10.4  32  9.1  17,499  8.4  Congenital heart disease  190  58.6  498  49.0  359  20.5  117  33.2  2,596  1.3  Neuromuscular disorder  30  9.3  27  2.7  22  1.3  11  3.1  330  0.2  Receipt of ≥1 dose of RSV immunoprophylaxis  248  76.5  799  78.6  1,159  66.2  352  15.6  949  0.5  No. of living siblings at homed                       0  127  39.2  497  48.9  816  46.6  62  17.6  90,768  43.7   1  115  35.5  308  30.3  531  30.3  152  43.2  71,025  34.2   >1  82  25.3  211  20.8  404  23.1  138  39.2  45,727  22.0  Maternal smoking during pregnancy  25  7.7  85  8.4  121  6.9  249  70.7  14,197  6.8  Maternal age at delivery, yearsa,e  30 (25–35)  31 (26–35)  31 (26–36)  30 (25–35)  30 (26–34)  Maternal education, years                       <12  90  27.8  355  34.9  553  31.6  156  44.3  65,167  31.4   12  76  23.5  213  21.0  361  20.6  101  28.7  43,220  20.8   >12  158  48.8  448  44.1  838  47.8  95  27.0  99,267  47.8  Abbreviation: RSV, respiratory syncytial virus. a Values are expressed as median (interquartile range). b Sex was unknown for 30 (<0.1%) of the infants. c Race/ethnicity was unknown for 201 (0.1%) of the infants. d Number of living siblings at home was unknown for 135 (0.1%) of the infants. e Maternal age at delivery was unknown for 1 (<0.1%) of the infants. Table 1. Maternal and Infant Characteristics of Infants Enrolled in Kaiser Permanente Northern California According to Eligibility for Respiratory Syncytial Virus Immunoprophylaxis, 1996–2008 Characteristic  Eligibility Group  Ineligible Group  Chronic Lung Disease  Prematurity at <29 Weeks  Prematurity at <32 Weeks  Other Eligible Group  No. of Persons  %  No. of Persons  %  No. of Persons  %  No. of Persons  %  No. of Persons  %  Total  324  0.2  1,016  0.5  1,752  0.8  352  0.2  207,654  98.4  Estimated gestational age, weeksa  28 (26–30)  27 (26–28)  30 (30–31)  34 (33–34)  39 (38–40)  Birth weight, ga  1,000 (769–1,323)  925 (783–1,115)  1,455 (1,239–1,670)  2,170 (1,834–2,591)  3,415 (3,070–3,755)  Small-for-gestational-age birth (<5th percentile)  16  4.9  16  1.6  6  4.3  13  3.7  2,964  1.4  Birth hospitalization length of stay, daysa  78 (56–103)  71 (57–87)  37 (29–47)  13 (7–20)  3 (2–3)  Male infant sexb  212  65.4  470  46.3  940  53.7  185  52.6  106,540  51.3  Infant race/ethnicityc                       White  121  37.3  378  37.3  704  40.2  163  46.3  85,839  41.4   African-American  70  21.6  155  15.3  243  13.9  61  17.3  17,334  8.4   Latino  58  17.9  222  21.9  352  20.1  61  17.3  44,437  21.4   Asian  48  14.8  149  14.7  270  15.4  35  9.9  42,346  20.4   Other  27  8.3  110  10.8  183  10.4  32  9.1  17,499  8.4  Congenital heart disease  190  58.6  498  49.0  359  20.5  117  33.2  2,596  1.3  Neuromuscular disorder  30  9.3  27  2.7  22  1.3  11  3.1  330  0.2  Receipt of ≥1 dose of RSV immunoprophylaxis  248  76.5  799  78.6  1,159  66.2  352  15.6  949  0.5  No. of living siblings at homed                       0  127  39.2  497  48.9  816  46.6  62  17.6  90,768  43.7   1  115  35.5  308  30.3  531  30.3  152  43.2  71,025  34.2   >1  82  25.3  211  20.8  404  23.1  138  39.2  45,727  22.0  Maternal smoking during pregnancy  25  7.7  85  8.4  121  6.9  249  70.7  14,197  6.8  Maternal age at delivery, yearsa,e  30 (25–35)  31 (26–35)  31 (26–36)  30 (25–35)  30 (26–34)  Maternal education, years                       <12  90  27.8  355  34.9  553  31.6  156  44.3  65,167  31.4   12  76  23.5  213  21.0  361  20.6  101  28.7  43,220  20.8   >12  158  48.8  448  44.1  838  47.8  95  27.0  99,267  47.8  Characteristic  Eligibility Group  Ineligible Group  Chronic Lung Disease  Prematurity at <29 Weeks  Prematurity at <32 Weeks  Other Eligible Group  No. of Persons  %  No. of Persons  %  No. of Persons  %  No. of Persons  %  No. of Persons  %  Total  324  0.2  1,016  0.5  1,752  0.8  352  0.2  207,654  98.4  Estimated gestational age, weeksa  28 (26–30)  27 (26–28)  30 (30–31)  34 (33–34)  39 (38–40)  Birth weight, ga  1,000 (769–1,323)  925 (783–1,115)  1,455 (1,239–1,670)  2,170 (1,834–2,591)  3,415 (3,070–3,755)  Small-for-gestational-age birth (<5th percentile)  16  4.9  16  1.6  6  4.3  13  3.7  2,964  1.4  Birth hospitalization length of stay, daysa  78 (56–103)  71 (57–87)  37 (29–47)  13 (7–20)  3 (2–3)  Male infant sexb  212  65.4  470  46.3  940  53.7  185  52.6  106,540  51.3  Infant race/ethnicityc                       White  121  37.3  378  37.3  704  40.2  163  46.3  85,839  41.4   African-American  70  21.6  155  15.3  243  13.9  61  17.3  17,334  8.4   Latino  58  17.9  222  21.9  352  20.1  61  17.3  44,437  21.4   Asian  48  14.8  149  14.7  270  15.4  35  9.9  42,346  20.4   Other  27  8.3  110  10.8  183  10.4  32  9.1  17,499  8.4  Congenital heart disease  190  58.6  498  49.0  359  20.5  117  33.2  2,596  1.3  Neuromuscular disorder  30  9.3  27  2.7  22  1.3  11  3.1  330  0.2  Receipt of ≥1 dose of RSV immunoprophylaxis  248  76.5  799  78.6  1,159  66.2  352  15.6  949  0.5  No. of living siblings at homed                       0  127  39.2  497  48.9  816  46.6  62  17.6  90,768  43.7   1  115  35.5  308  30.3  531  30.3  152  43.2  71,025  34.2   >1  82  25.3  211  20.8  404  23.1  138  39.2  45,727  22.0  Maternal smoking during pregnancy  25  7.7  85  8.4  121  6.9  249  70.7  14,197  6.8  Maternal age at delivery, yearsa,e  30 (25–35)  31 (26–35)  31 (26–36)  30 (25–35)  30 (26–34)  Maternal education, years                       <12  90  27.8  355  34.9  553  31.6  156  44.3  65,167  31.4   12  76  23.5  213  21.0  361  20.6  101  28.7  43,220  20.8   >12  158  48.8  448  44.1  838  47.8  95  27.0  99,267  47.8  Abbreviation: RSV, respiratory syncytial virus. a Values are expressed as median (interquartile range). b Sex was unknown for 30 (<0.1%) of the infants. c Race/ethnicity was unknown for 201 (0.1%) of the infants. d Number of living siblings at home was unknown for 135 (0.1%) of the infants. e Maternal age at delivery was unknown for 1 (<0.1%) of the infants. Across all eligibility groups, higher-risk infants were more likely to receive RSV immunoprophylaxis (Table 2 and Web Table 1). Compared with infants who did not receive any immunoprophylaxis, infants who received at least 1 dose were more likely to be male and to have a lower gestational age, a lower birth weight, a longer birth hospitalization length of stay, other siblings at home, mothers who smoked during pregnancy, and less educated mothers (P < 0.01). Infants who received at least 1 dose were also more likely to have congenital heart disease or a neuromuscular disorder than infants who did not receive any immunoprophylaxis. Table 2. Maternal and Infant Characteristics of Infants Enrolled in Kaiser Permanente Northern California According to Eligibility for and Receipt of Respiratory Syncytial Virus Immunoprophylaxis (Ever vs. Never), 1996–2008 Characteristic  Eligible Group (n = 3,444)  Ineligible Group (n = 207,654)  Ever Receiveda  Never Receivedb  Ever Received  Never Received  No. of Persons  %  No. of Persons  %  No. of Persons  %  No. of Persons  %  Total  2,261  65.7  1,183  34.3  949  0.5  206,705  99.5  Estimated gestational age, weeksc  29 (27–31)  31 (29–32)  32 (32–35)  39 (38–40)  Birth weight, gc  1,194 (912–1,510)  1,550 (1,160–1,935)  1,950 (1,645–2,470)  3,416 (3,075–3,755)  Small-for-gestational-age birth (<5th percentile)  79  3.5  42  3.6  63  6.6  2,901  1.4  Birth hospitalization length of stay, daysc  52 (36–73)  32 (18–52)  21 (13–29)  3 (2–3)  Male infant sexd  1,186  52.5  621  52.5  508  53.6  106,032  51.3  Infant race/ethnicitye                   White  876  38.8  490  41.4  386  40.7  85,453  41.4   African-American  321  14.2  208  17.6  74  7.8  17,260  8.4   Latino  474  21.0  219  18.5  210  22.1  44,227  21.4   Asian  341  15.1  161  13.6  181  19.1  42,165  20.4   Other  247  10.9  105  8.9  98  10.3  17,401  8.4  Congenital heart disease  868  38.4  296  25.0  208  21.9  2,388  1.2  Neuromuscular disorder  67  3.0  23  1.9  18  1.9  312  0.2  No. of living siblings at homef                   0  1,040  46.0  462  39.0  405  42.7  90,363  43.7   1  717  31.7  389  32.9  309  32.6  70,716  34.2   >1  503  22.3  332  28.1  234  24.7  45,493  22.0  Maternal smoking during pregnancy  187  8.3  293  24.8  35  3.7  14,162  6.9  Maternal age at delivery, yearsc,g  31 (26–35)  31 (25–35)  31 (27–35)  30 (26–34)  Maternal education, years                   <12  766  33.9  388  32.8  333  35.1  64,834  31.4   12  442  19.5  309  26.1  162  17.1  43,058  20.8   >12  1,053  46.6  486  41.1  454  47.8  98,813  47.8  Characteristic  Eligible Group (n = 3,444)  Ineligible Group (n = 207,654)  Ever Receiveda  Never Receivedb  Ever Received  Never Received  No. of Persons  %  No. of Persons  %  No. of Persons  %  No. of Persons  %  Total  2,261  65.7  1,183  34.3  949  0.5  206,705  99.5  Estimated gestational age, weeksc  29 (27–31)  31 (29–32)  32 (32–35)  39 (38–40)  Birth weight, gc  1,194 (912–1,510)  1,550 (1,160–1,935)  1,950 (1,645–2,470)  3,416 (3,075–3,755)  Small-for-gestational-age birth (<5th percentile)  79  3.5  42  3.6  63  6.6  2,901  1.4  Birth hospitalization length of stay, daysc  52 (36–73)  32 (18–52)  21 (13–29)  3 (2–3)  Male infant sexd  1,186  52.5  621  52.5  508  53.6  106,032  51.3  Infant race/ethnicitye                   White  876  38.8  490  41.4  386  40.7  85,453  41.4   African-American  321  14.2  208  17.6  74  7.8  17,260  8.4   Latino  474  21.0  219  18.5  210  22.1  44,227  21.4   Asian  341  15.1  161  13.6  181  19.1  42,165  20.4   Other  247  10.9  105  8.9  98  10.3  17,401  8.4  Congenital heart disease  868  38.4  296  25.0  208  21.9  2,388  1.2  Neuromuscular disorder  67  3.0  23  1.9  18  1.9  312  0.2  No. of living siblings at homef                   0  1,040  46.0  462  39.0  405  42.7  90,363  43.7   1  717  31.7  389  32.9  309  32.6  70,716  34.2   >1  503  22.3  332  28.1  234  24.7  45,493  22.0  Maternal smoking during pregnancy  187  8.3  293  24.8  35  3.7  14,162  6.9  Maternal age at delivery, yearsc,g  31 (26–35)  31 (25–35)  31 (27–35)  30 (26–34)  Maternal education, years                   <12  766  33.9  388  32.8  333  35.1  64,834  31.4   12  442  19.5  309  26.1  162  17.1  43,058  20.8   >12  1,053  46.6  486  41.1  454  47.8  98,813  47.8  Abbreviation: RSV, respiratory syncytial virus. a Child received at least 1 dose of RSV immunoprophylaxis during infancy. b Child received no doses of RSV immunoprophylaxis during infancy. c Values are expressed as median (interquartile range). d Sex was unknown for 30 (<0.1%) of the infants. e Race/ethnicity was unknown for 201 (0.1%) of the infants. f Number of living siblings at home was unknown for 135 (0.1%) of the infants. g Maternal age at delivery was unknown for 1 (<0.1%) of the infants. Table 2. Maternal and Infant Characteristics of Infants Enrolled in Kaiser Permanente Northern California According to Eligibility for and Receipt of Respiratory Syncytial Virus Immunoprophylaxis (Ever vs. Never), 1996–2008 Characteristic  Eligible Group (n = 3,444)  Ineligible Group (n = 207,654)  Ever Receiveda  Never Receivedb  Ever Received  Never Received  No. of Persons  %  No. of Persons  %  No. of Persons  %  No. of Persons  %  Total  2,261  65.7  1,183  34.3  949  0.5  206,705  99.5  Estimated gestational age, weeksc  29 (27–31)  31 (29–32)  32 (32–35)  39 (38–40)  Birth weight, gc  1,194 (912–1,510)  1,550 (1,160–1,935)  1,950 (1,645–2,470)  3,416 (3,075–3,755)  Small-for-gestational-age birth (<5th percentile)  79  3.5  42  3.6  63  6.6  2,901  1.4  Birth hospitalization length of stay, daysc  52 (36–73)  32 (18–52)  21 (13–29)  3 (2–3)  Male infant sexd  1,186  52.5  621  52.5  508  53.6  106,032  51.3  Infant race/ethnicitye                   White  876  38.8  490  41.4  386  40.7  85,453  41.4   African-American  321  14.2  208  17.6  74  7.8  17,260  8.4   Latino  474  21.0  219  18.5  210  22.1  44,227  21.4   Asian  341  15.1  161  13.6  181  19.1  42,165  20.4   Other  247  10.9  105  8.9  98  10.3  17,401  8.4  Congenital heart disease  868  38.4  296  25.0  208  21.9  2,388  1.2  Neuromuscular disorder  67  3.0  23  1.9  18  1.9  312  0.2  No. of living siblings at homef                   0  1,040  46.0  462  39.0  405  42.7  90,363  43.7   1  717  31.7  389  32.9  309  32.6  70,716  34.2   >1  503  22.3  332  28.1  234  24.7  45,493  22.0  Maternal smoking during pregnancy  187  8.3  293  24.8  35  3.7  14,162  6.9  Maternal age at delivery, yearsc,g  31 (26–35)  31 (25–35)  31 (27–35)  30 (26–34)  Maternal education, years                   <12  766  33.9  388  32.8  333  35.1  64,834  31.4   12  442  19.5  309  26.1  162  17.1  43,058  20.8   >12  1,053  46.6  486  41.1  454  47.8  98,813  47.8  Characteristic  Eligible Group (n = 3,444)  Ineligible Group (n = 207,654)  Ever Receiveda  Never Receivedb  Ever Received  Never Received  No. of Persons  %  No. of Persons  %  No. of Persons  %  No. of Persons  %  Total  2,261  65.7  1,183  34.3  949  0.5  206,705  99.5  Estimated gestational age, weeksc  29 (27–31)  31 (29–32)  32 (32–35)  39 (38–40)  Birth weight, gc  1,194 (912–1,510)  1,550 (1,160–1,935)  1,950 (1,645–2,470)  3,416 (3,075–3,755)  Small-for-gestational-age birth (<5th percentile)  79  3.5  42  3.6  63  6.6  2,901  1.4  Birth hospitalization length of stay, daysc  52 (36–73)  32 (18–52)  21 (13–29)  3 (2–3)  Male infant sexd  1,186  52.5  621  52.5  508  53.6  106,032  51.3  Infant race/ethnicitye                   White  876  38.8  490  41.4  386  40.7  85,453  41.4   African-American  321  14.2  208  17.6  74  7.8  17,260  8.4   Latino  474  21.0  219  18.5  210  22.1  44,227  21.4   Asian  341  15.1  161  13.6  181  19.1  42,165  20.4   Other  247  10.9  105  8.9  98  10.3  17,401  8.4  Congenital heart disease  868  38.4  296  25.0  208  21.9  2,388  1.2  Neuromuscular disorder  67  3.0  23  1.9  18  1.9  312  0.2  No. of living siblings at homef                   0  1,040  46.0  462  39.0  405  42.7  90,363  43.7   1  717  31.7  389  32.9  309  32.6  70,716  34.2   >1  503  22.3  332  28.1  234  24.7  45,493  22.0  Maternal smoking during pregnancy  187  8.3  293  24.8  35  3.7  14,162  6.9  Maternal age at delivery, yearsc,g  31 (26–35)  31 (25–35)  31 (27–35)  30 (26–34)  Maternal education, years                   <12  766  33.9  388  32.8  333  35.1  64,834  31.4   12  442  19.5  309  26.1  162  17.1  43,058  20.8   >12  1,053  46.6  486  41.1  454  47.8  98,813  47.8  Abbreviation: RSV, respiratory syncytial virus. a Child received at least 1 dose of RSV immunoprophylaxis during infancy. b Child received no doses of RSV immunoprophylaxis during infancy. c Values are expressed as median (interquartile range). d Sex was unknown for 30 (<0.1%) of the infants. e Race/ethnicity was unknown for 201 (0.1%) of the infants. f Number of living siblings at home was unknown for 135 (0.1%) of the infants. g Maternal age at delivery was unknown for 1 (<0.1%) of the infants. Effectiveness of RSV immunoprophylaxis The effectiveness of RSV immunoprophylaxis was studied among infants who were either eligible based on AAP guidelines or received at least 1 dose of immunoprophylaxis (Table 3). Compared with eligible infants who never received immunoprophylaxis, infants who received at least 1 dose had an increased risk of bronchiolitis hospitalization during the unprotected periods (incidence rate ratio (IRR) = 1.49, 95% confidence interval (CI): 1.00, 2.24) but not during the protected periods (IRR = 0.97, 95% CI: 0.68, 1.39). These results were consistent when we limited the analysis to eligible-only infant groups. Such results were most likely due to indication bias in which infants at higher risk for infection were more likely to receive immunoprophylaxis. This was also evident in the subgroup of ineligible infants, where receipt of immunoprophylaxis significantly increased the risk of bronchiolitis hospitalization in both protected and unprotected periods compared with infants who never received immunoprophylaxis. Table 3. Incidence Rates of Bronchiolitis Hospitalization Among Infants Enrolled in Kaiser Permanente Northern California, by Eligibility Group and History of Respiratory Syncytial Virus Immunoprophylaxis in the Last 30 Days, 1996–2008a Eligibility Group and Immunoprophylaxis Status (Ever Receivedb/Never Receivedc)  Immunoprophylaxis-Protected Time (Yes/No)  Total Follow-up Timed, years  Total No. of Hospitalizations  Incidence Rate (per 1,000 Person-Years)  Reference Group  Unprotected Periods of Infants Who Never Received Immunoprophylaxis  Unprotected Periods of Infants Who Ever Received Immunoprophylaxis  IRRe  95% CI  IRRe  95% CI  Infants who were eligible for or ever received immunoprophylaxis                 Never received  No  429.91  51  118.63  1  Referent       Ever received  No  287.69  51  177.27  1.49  1.00, 2.24  1  Referent   Ever received  Yes  823.79  95  115.32  0.97  0.68, 1.39  0.65  0.46, 0.93  Infants who ever received Immunoprophylaxis                   Never received  No                 Ever received  No  287.69  51  177.27      1  Referent   Ever received  Yes  823.79  95  115.32      0.65  0.46, 0.93  Eligible infants                   Never received  No  429.91  51  118.63  1  Referent       Ever received  No  181.31  26  143.40  1.21  0.74, 1.97  1  Referent   Ever received  Yes  572.64  64  111.76  0.94  0.64, 1.38  0.78  0.49, 1.25  Chronic lung disease                   Never received  No  24.09  20  830.21  1         Ever received  No  15.65  15  958.49  1.16  0.59, 2.26  1  Referent   Ever received  Yes  58.58  24  409.72  0.49  0.27, 0.90  0.43  0.23, 0.81  Prematurity at <29 weeks                   Never received  No  72.91  5  68.57  1         Ever received  No  49.09  1  20.37  0.30  0.04, 2.54  1  Referent   Ever received  Yes  202.93  22  108.41  1.58  0.59, 4.25  5.32  0.71, 39.86  Prematurity at 29–31 weeks                   Never received  No  217.14  13  59.87  1  Referent       Ever received  No  109.91  9  81.88  1.37  0.59, 3.18  1  Referent   Ever received  Yes  297.72  17  57.10  0.95  0.47, 1.95  0.70  0.31, 1.56  Other eligible groupf                   Never received  No  115.77  13  112.29  1  Referent       Ever received  No  6.66  1  150.25  1.34  0.18, 10.09  1  Referent   Ever received  Yes  13.40  1  74.60  0.66  0.09, 5.10  0.50  0.03, 7.92  Ineligible group                   Never received  No  84,167.24  1,964  23.33  1  Referent       Ever received  No  106.38  25  235.00  10.07  6.65, 15.24  1  Referent   Ever received  Yes  251.16  31  123.43  5.29  3.57, 7.84  0.53  0.30, 0.93  Eligibility Group and Immunoprophylaxis Status (Ever Receivedb/Never Receivedc)  Immunoprophylaxis-Protected Time (Yes/No)  Total Follow-up Timed, years  Total No. of Hospitalizations  Incidence Rate (per 1,000 Person-Years)  Reference Group  Unprotected Periods of Infants Who Never Received Immunoprophylaxis  Unprotected Periods of Infants Who Ever Received Immunoprophylaxis  IRRe  95% CI  IRRe  95% CI  Infants who were eligible for or ever received immunoprophylaxis                 Never received  No  429.91  51  118.63  1  Referent       Ever received  No  287.69  51  177.27  1.49  1.00, 2.24  1  Referent   Ever received  Yes  823.79  95  115.32  0.97  0.68, 1.39  0.65  0.46, 0.93  Infants who ever received Immunoprophylaxis                   Never received  No                 Ever received  No  287.69  51  177.27      1  Referent   Ever received  Yes  823.79  95  115.32      0.65  0.46, 0.93  Eligible infants                   Never received  No  429.91  51  118.63  1  Referent       Ever received  No  181.31  26  143.40  1.21  0.74, 1.97  1  Referent   Ever received  Yes  572.64  64  111.76  0.94  0.64, 1.38  0.78  0.49, 1.25  Chronic lung disease                   Never received  No  24.09  20  830.21  1         Ever received  No  15.65  15  958.49  1.16  0.59, 2.26  1  Referent   Ever received  Yes  58.58  24  409.72  0.49  0.27, 0.90  0.43  0.23, 0.81  Prematurity at <29 weeks                   Never received  No  72.91  5  68.57  1         Ever received  No  49.09  1  20.37  0.30  0.04, 2.54  1  Referent   Ever received  Yes  202.93  22  108.41  1.58  0.59, 4.25  5.32  0.71, 39.86  Prematurity at 29–31 weeks                   Never received  No  217.14  13  59.87  1  Referent       Ever received  No  109.91  9  81.88  1.37  0.59, 3.18  1  Referent   Ever received  Yes  297.72  17  57.10  0.95  0.47, 1.95  0.70  0.31, 1.56  Other eligible groupf                   Never received  No  115.77  13  112.29  1  Referent       Ever received  No  6.66  1  150.25  1.34  0.18, 10.09  1  Referent   Ever received  Yes  13.40  1  74.60  0.66  0.09, 5.10  0.50  0.03, 7.92  Ineligible group                   Never received  No  84,167.24  1,964  23.33  1  Referent       Ever received  No  106.38  25  235.00  10.07  6.65, 15.24  1  Referent   Ever received  Yes  251.16  31  123.43  5.29  3.57, 7.84  0.53  0.30, 0.93  Abbreviations: AAP, American Academy of Pediatrics; CI, confidence interval; IRR, incidence rate ratio; RSV, respiratory syncytial virus. a Infants described in this table were either eligible for RSV immunoprophylaxis on the basis of in-place AAP guidelines during the study period in which they were born or received at least 1 dose of RSV immunoprophylaxis. b Child received at least 1 dose of RSV immunoprophylaxis during infancy. c Child received no doses of RSV immunoprophylaxis during infancy. d Follow-up time during the 5-month RSV season in infancy. e IRRs were calculated within each eligibility group, among all eligible subjects, all subjects who ever received immunoprophylaxis, and infants who either were eligible or ever received immunoprophylaxis. Within each group, IRRs were calculated using either the unprotected periods of subjects who never received RSV immunoprophylaxis or the unprotected periods of subjects who ever received RSV immunoprophylaxis as the reference group. f “Other eligible group” included infants who were born at 32–34 weeks of gestation with 2 or more additional risk factors and infants who had congenital heart disease. Table 3. Incidence Rates of Bronchiolitis Hospitalization Among Infants Enrolled in Kaiser Permanente Northern California, by Eligibility Group and History of Respiratory Syncytial Virus Immunoprophylaxis in the Last 30 Days, 1996–2008a Eligibility Group and Immunoprophylaxis Status (Ever Receivedb/Never Receivedc)  Immunoprophylaxis-Protected Time (Yes/No)  Total Follow-up Timed, years  Total No. of Hospitalizations  Incidence Rate (per 1,000 Person-Years)  Reference Group  Unprotected Periods of Infants Who Never Received Immunoprophylaxis  Unprotected Periods of Infants Who Ever Received Immunoprophylaxis  IRRe  95% CI  IRRe  95% CI  Infants who were eligible for or ever received immunoprophylaxis                 Never received  No  429.91  51  118.63  1  Referent       Ever received  No  287.69  51  177.27  1.49  1.00, 2.24  1  Referent   Ever received  Yes  823.79  95  115.32  0.97  0.68, 1.39  0.65  0.46, 0.93  Infants who ever received Immunoprophylaxis                   Never received  No                 Ever received  No  287.69  51  177.27      1  Referent   Ever received  Yes  823.79  95  115.32      0.65  0.46, 0.93  Eligible infants                   Never received  No  429.91  51  118.63  1  Referent       Ever received  No  181.31  26  143.40  1.21  0.74, 1.97  1  Referent   Ever received  Yes  572.64  64  111.76  0.94  0.64, 1.38  0.78  0.49, 1.25  Chronic lung disease                   Never received  No  24.09  20  830.21  1         Ever received  No  15.65  15  958.49  1.16  0.59, 2.26  1  Referent   Ever received  Yes  58.58  24  409.72  0.49  0.27, 0.90  0.43  0.23, 0.81  Prematurity at <29 weeks                   Never received  No  72.91  5  68.57  1         Ever received  No  49.09  1  20.37  0.30  0.04, 2.54  1  Referent   Ever received  Yes  202.93  22  108.41  1.58  0.59, 4.25  5.32  0.71, 39.86  Prematurity at 29–31 weeks                   Never received  No  217.14  13  59.87  1  Referent       Ever received  No  109.91  9  81.88  1.37  0.59, 3.18  1  Referent   Ever received  Yes  297.72  17  57.10  0.95  0.47, 1.95  0.70  0.31, 1.56  Other eligible groupf                   Never received  No  115.77  13  112.29  1  Referent       Ever received  No  6.66  1  150.25  1.34  0.18, 10.09  1  Referent   Ever received  Yes  13.40  1  74.60  0.66  0.09, 5.10  0.50  0.03, 7.92  Ineligible group                   Never received  No  84,167.24  1,964  23.33  1  Referent       Ever received  No  106.38  25  235.00  10.07  6.65, 15.24  1  Referent   Ever received  Yes  251.16  31  123.43  5.29  3.57, 7.84  0.53  0.30, 0.93  Eligibility Group and Immunoprophylaxis Status (Ever Receivedb/Never Receivedc)  Immunoprophylaxis-Protected Time (Yes/No)  Total Follow-up Timed, years  Total No. of Hospitalizations  Incidence Rate (per 1,000 Person-Years)  Reference Group  Unprotected Periods of Infants Who Never Received Immunoprophylaxis  Unprotected Periods of Infants Who Ever Received Immunoprophylaxis  IRRe  95% CI  IRRe  95% CI  Infants who were eligible for or ever received immunoprophylaxis                 Never received  No  429.91  51  118.63  1  Referent       Ever received  No  287.69  51  177.27  1.49  1.00, 2.24  1  Referent   Ever received  Yes  823.79  95  115.32  0.97  0.68, 1.39  0.65  0.46, 0.93  Infants who ever received Immunoprophylaxis                   Never received  No                 Ever received  No  287.69  51  177.27      1  Referent   Ever received  Yes  823.79  95  115.32      0.65  0.46, 0.93  Eligible infants                   Never received  No  429.91  51  118.63  1  Referent       Ever received  No  181.31  26  143.40  1.21  0.74, 1.97  1  Referent   Ever received  Yes  572.64  64  111.76  0.94  0.64, 1.38  0.78  0.49, 1.25  Chronic lung disease                   Never received  No  24.09  20  830.21  1         Ever received  No  15.65  15  958.49  1.16  0.59, 2.26  1  Referent   Ever received  Yes  58.58  24  409.72  0.49  0.27, 0.90  0.43  0.23, 0.81  Prematurity at <29 weeks                   Never received  No  72.91  5  68.57  1         Ever received  No  49.09  1  20.37  0.30  0.04, 2.54  1  Referent   Ever received  Yes  202.93  22  108.41  1.58  0.59, 4.25  5.32  0.71, 39.86  Prematurity at 29–31 weeks                   Never received  No  217.14  13  59.87  1  Referent       Ever received  No  109.91  9  81.88  1.37  0.59, 3.18  1  Referent   Ever received  Yes  297.72  17  57.10  0.95  0.47, 1.95  0.70  0.31, 1.56  Other eligible groupf                   Never received  No  115.77  13  112.29  1  Referent       Ever received  No  6.66  1  150.25  1.34  0.18, 10.09  1  Referent   Ever received  Yes  13.40  1  74.60  0.66  0.09, 5.10  0.50  0.03, 7.92  Ineligible group                   Never received  No  84,167.24  1,964  23.33  1  Referent       Ever received  No  106.38  25  235.00  10.07  6.65, 15.24  1  Referent   Ever received  Yes  251.16  31  123.43  5.29  3.57, 7.84  0.53  0.30, 0.93  Abbreviations: AAP, American Academy of Pediatrics; CI, confidence interval; IRR, incidence rate ratio; RSV, respiratory syncytial virus. a Infants described in this table were either eligible for RSV immunoprophylaxis on the basis of in-place AAP guidelines during the study period in which they were born or received at least 1 dose of RSV immunoprophylaxis. b Child received at least 1 dose of RSV immunoprophylaxis during infancy. c Child received no doses of RSV immunoprophylaxis during infancy. d Follow-up time during the 5-month RSV season in infancy. e IRRs were calculated within each eligibility group, among all eligible subjects, all subjects who ever received immunoprophylaxis, and infants who either were eligible or ever received immunoprophylaxis. Within each group, IRRs were calculated using either the unprotected periods of subjects who never received RSV immunoprophylaxis or the unprotected periods of subjects who ever received RSV immunoprophylaxis as the reference group. f “Other eligible group” included infants who were born at 32–34 weeks of gestation with 2 or more additional risk factors and infants who had congenital heart disease. The adjusted analysis was then limited to infants who received at least 1 dose of RSV immunoprophylaxis, as we had previously recognized bias for receipt of immunoprophylaxis in a prior study with inability to adequately adjust for differential propensity for prescribing (15, 23). Among infants who received any RSV immunoprophylaxis, receipt of immunoprophylaxis decreased the risk of bronchiolitis hospitalization during protected periods as compared with unprotected periods (IRR = 0.65, 95% CI: 0.46, 0.93). This protective association was consistent after adjustment for covariates (adjusted hazard ratio (aHR) = 0.68, 95% CI: 0.46, 1.00) (Table 4). Prior receipt of immunoprophylaxis in the same season was associated with a decreased risk of bronchiolitis hospitalization after controlling for the 30-day protected periods after administration (aHR = 0.49, 95% CI: 0.28, 0.88). Table 4. Risk of Bronchiolitis Hospitalization Among Infants Enrolled in Kaiser Permanente Northern California According to Eligibility for Respiratory Syncytial Virus Immunoprophylaxis, 1996–2008a Eligibility Group  No. of Children Who Received RSV Immunoprophylaxis  No. of Bronchiolitis Hospitalization Events  Adjusted HRb  95% CI  Infants who ever received immunoprophylaxisc  3,205  146  0.68  0.46, 1.00  All eligible infants  2,261  90  0.76  0.44, 1.31  Infants with chronic lung disease  248  39  0.48  0.25, 0.94  Prematurity at <29 weeks  797  23  5.96  0.56, 63.66  Prematurity at 29–31 weeks  1,158  26  0.72  0.28, 1.84  Other eligible groupd  55  2  —e  —  Ineligible group  947  56  0.51  0.30, 0.86  Eligibility Group  No. of Children Who Received RSV Immunoprophylaxis  No. of Bronchiolitis Hospitalization Events  Adjusted HRb  95% CI  Infants who ever received immunoprophylaxisc  3,205  146  0.68  0.46, 1.00  All eligible infants  2,261  90  0.76  0.44, 1.31  Infants with chronic lung disease  248  39  0.48  0.25, 0.94  Prematurity at <29 weeks  797  23  5.96  0.56, 63.66  Prematurity at 29–31 weeks  1,158  26  0.72  0.28, 1.84  Other eligible groupd  55  2  —e  —  Ineligible group  947  56  0.51  0.30, 0.86  Abbreviations: CI, confidence interval; HR, hazard ratio; KPNC, Kaiser Permanente Northern California; RSV, respiratory syncytial virus. a Infants included in these analyses received at least 1 dose of RSV immunoprophylaxis. b Cox proportional hazards models adjusted for both fixed and time-dependent covariates, including infant age at receipt of RSV immunoprophylaxis, prior receipt of RSV immunoprophylaxis (during the same RSV season), prior history of bronchiolitis hospitalization, infant birth weight (g), gestational age (in completed weeks), infant race/ethnicity, sex, infant birth season, length of birth hospitalization stay, number of living siblings, singleton birth, maternal age at delivery (in years), maternal education (in years), maternal smoking during pregnancy, and RSV immunoprophylaxis eligibility group. The RSV immunoprophylaxis-unprotected period served as the reference category for each eligibility group. c Five infants were removed from multivariable analyses because of unknown sex (1 infant), missing race/ethnicity (2 infants), and missing number of living siblings (2 infants). The 5 infants removed did not experience any bronchiolitis hospitalizations during the 5-month follow-up time in infancy. d “Other eligible group” included infants who were born at 32–34 weeks of gestation with 2 or more additional risk factors and infants who had congenital heart disease. e HR and 95% CI were not calculated because of the limited number of events among subjects within-group. Table 4. Risk of Bronchiolitis Hospitalization Among Infants Enrolled in Kaiser Permanente Northern California According to Eligibility for Respiratory Syncytial Virus Immunoprophylaxis, 1996–2008a Eligibility Group  No. of Children Who Received RSV Immunoprophylaxis  No. of Bronchiolitis Hospitalization Events  Adjusted HRb  95% CI  Infants who ever received immunoprophylaxisc  3,205  146  0.68  0.46, 1.00  All eligible infants  2,261  90  0.76  0.44, 1.31  Infants with chronic lung disease  248  39  0.48  0.25, 0.94  Prematurity at <29 weeks  797  23  5.96  0.56, 63.66  Prematurity at 29–31 weeks  1,158  26  0.72  0.28, 1.84  Other eligible groupd  55  2  —e  —  Ineligible group  947  56  0.51  0.30, 0.86  Eligibility Group  No. of Children Who Received RSV Immunoprophylaxis  No. of Bronchiolitis Hospitalization Events  Adjusted HRb  95% CI  Infants who ever received immunoprophylaxisc  3,205  146  0.68  0.46, 1.00  All eligible infants  2,261  90  0.76  0.44, 1.31  Infants with chronic lung disease  248  39  0.48  0.25, 0.94  Prematurity at <29 weeks  797  23  5.96  0.56, 63.66  Prematurity at 29–31 weeks  1,158  26  0.72  0.28, 1.84  Other eligible groupd  55  2  —e  —  Ineligible group  947  56  0.51  0.30, 0.86  Abbreviations: CI, confidence interval; HR, hazard ratio; KPNC, Kaiser Permanente Northern California; RSV, respiratory syncytial virus. a Infants included in these analyses received at least 1 dose of RSV immunoprophylaxis. b Cox proportional hazards models adjusted for both fixed and time-dependent covariates, including infant age at receipt of RSV immunoprophylaxis, prior receipt of RSV immunoprophylaxis (during the same RSV season), prior history of bronchiolitis hospitalization, infant birth weight (g), gestational age (in completed weeks), infant race/ethnicity, sex, infant birth season, length of birth hospitalization stay, number of living siblings, singleton birth, maternal age at delivery (in years), maternal education (in years), maternal smoking during pregnancy, and RSV immunoprophylaxis eligibility group. The RSV immunoprophylaxis-unprotected period served as the reference category for each eligibility group. c Five infants were removed from multivariable analyses because of unknown sex (1 infant), missing race/ethnicity (2 infants), and missing number of living siblings (2 infants). The 5 infants removed did not experience any bronchiolitis hospitalizations during the 5-month follow-up time in infancy. d “Other eligible group” included infants who were born at 32–34 weeks of gestation with 2 or more additional risk factors and infants who had congenital heart disease. e HR and 95% CI were not calculated because of the limited number of events among subjects within-group. We further estimated the effectiveness of immunoprophylaxis in each eligibility group (Tables 3 and 4). Infants in the CLD eligibility group had the largest risk reduction during the protected period(s), with a risk of bronchiolitis hospitalization that was decreased by 57% (IRR = 0.43, 95% CI: 0.23, 0.81) in the unadjusted analysis and by 52% after adjustment for covariates (aHR = 0.48, 95% CI: 0.25, 0.94). Among infants in the ineligible but treated group (who nevertheless received at least some immunoprophylaxis), the risks in the protected periods were decreased by 47% (IRR = 0.53, 95% CI: 0.30, 0.93) and 49% (aHR = 0.51, 95% CI: 0.30, 0.86), respectively. There was no similar significantly decreased risk of bronchiolitis hospitalization with RSV immunoprophylaxis in the 2 premature eligibility groups or the “other” eligibility group (Tables 3 and 4). In sensitivity analyses, results were unchanged when we extended the RSV immunoprophylaxis-protected time from 30 days to 35 days or when we delayed the starting time of the protective period to 4 days following administration (Web Tables 2–4). The association was consistent when we limited the analyses to infants born in 1998 and afterward, when infants almost exclusively received palivizumab (Web Tables 3 and 5). Analysis of infants following the 2009 and 2014 AAP guideline updates The AAP updated its recommendations for the use of RSV immunoprophylaxis in 2009 (12) and 2014 (5). Among 3,444 infants who were eligible on the basis of pre-2009 AAP guidelines, 1,783 infants (52%) would have been continuously eligible for RSV immunoprophylaxis based on the most recent guidelines (Web Table 6). Among them, 75% (n = 1,332) received at least 1 dose of immunoprophylaxis, and 4% (n = 75) experienced at least 1 bronchiolitis hospitalization (Web Table 7). The risk of bronchiolitis hospitalization was nonsignificantly decreased (aHR = 0.94, 95% CI: 0.44, 2.03) among the infants who had ever received immunoprophylaxis. Of the 1,661 infants (48%) who would no longer be eligible on the basis of the current guidelines, 56% (n = 929) received at least 1 dose of immunoprophylaxis, and 3% (n = 53) experienced 56 bronchiolitis hospitalizations in total (Web Tables 6 and 7). Risk of bronchiolitis hospitalization was nonsignificantly decreased by 36% (aHR = 0.64, 95% CI: 0.29, 1.40) among infants who ever received immunoprophylaxis. DISCUSSION To our knowledge, this was the first population-based study of the effectiveness of RSV immunoprophylaxis in reducing infant bronchiolitis morbidity that accounted for indication bias, duration of effect of treatment, and the temporal relationship between treatment and outcome during the annual RSV epidemic and that assessed the impact of the updated 2009 and 2014 AAP guidelines for use of RSV immunoprophylaxis. In this study population, infants who received at least 1 dose of RSV immunoprophylaxis had a 32% decrease in risk of bronchiolitis hospitalization within 30 days of administration, independent of prior immunoprophylaxis receipt. While the decreased risk associated with receipt of RSV immunoprophylaxis observed in this study was smaller than the 55% reduction reported in the RCTs of efficacy (9), reduced effectiveness in comparison with corresponding efficacy in RCTs is common, as real-world effectiveness studies often include different populations and decreased adherence (24). Within one RSV season, prior receipt of any immunoprophylaxis was independently associated with a decreased risk of bronchiolitis hospitalization, even during unprotected periods. Thus, infants were less likely to experience a bronchiolitis hospitalization during the unprotected period if they had a preceding protected period/receipt of immunoprophylaxis. The smaller reduction in effectiveness as compared with efficacy may be due to the extended protection conferred by RSV immunoprophylaxis in a study comparing protected and unprotected periods, but it also may be due to the type of intervention, which requires in-person administration during pediatrician visits, resulting in high adherence and known receipt of drug in comparison with most real-world effectiveness studies. This result is consistent with previous findings that subsequent use (days 1–30 of each subsequent dose) and former use (days 31–60 after any dose if delays or no readministration occurred) significantly reduced the risk of RSV-related hospitalization (25). Our findings are also consistent with the elevated trough serum concentrations measured after the third and fourth monthly injections (26). CLD is one of the strongest known risk factors for severe RSV infection, and it was also a significant determinant of enhanced adherence to immunoprophylaxis in this study. Among infants with CLD, receipt of RSV immunoprophylaxis was associated with a 52% decrease in risk of bronchiolitis hospitalization. Such a significant reduction in risk of bronchiolitis hospitalization was supported by decreasing hospitalization rates in this population over the course of the study period as the proportion receiving immunoprophylaxis increased over time (Web Figure 4) (15). It is noteworthy that rates of bronchiolitis hospitalization in infants with CLD who ever and never received immunoprophylaxis were 16% and 26%, respectively, which is a much higher rate than that observed in children with bronchopulmonary dysplasia enrolled in the IMpact-RSV Study (8% and 13% in the immunoprophylaxis and placebo groups, respectively) (9). The difference is likely due to an evolving definition, evolving diagnosis, and different pathophysiology of CLD/bronchopulmonary dysplasia as management has changed over time. Children defined as having CLD in our study were probably different from and sicker than children enrolled in previous studies (16, 17, 27). Second, the higher rate observed in our study may in part be secondary to non-RSV pathogens. Nevertheless, the significant reduction we observed demonstrates that RSV immunoprophylaxis is effective in reducing bronchiolitis hospitalization in this population. Premature birth is another significant and known risk factor for severe RSV infection. Extreme prematurity (birth at <29 weeks) was also a significant determinant of enhanced adherence to immunoprophylaxis. However, there were no differences in the risks of bronchiolitis hospitalization between protected and unprotected periods in the subgroups of infants born at less than 29 completed weeks of gestation and between 29 and 31 weeks of gestation. The nonsignificant result is different from the 78% risk reduction reported in the IMpact-RSV Study (9) and might be due to the limited sample size and small number of bronchiolitis hospitalizations observed in our study. Compared with the 2% and 8% prevalences of RSV hospitalization observed in immunoprophylaxis-treated and placebo groups among premature infants enrolled in the RCT, we observed 2.5% (n = 49) and 2.2% (n = 18) prevalences of bronchiolitis hospitalization among premature infants who had ever and never received immunoprophylaxis, respectively. The small numbers observed might have been due to the significant improvement in premature infant medical care and outcomes over the past 20 years, with marked decreases in mortality, major changes in how care for premature infants is managed, advances in maternal immunization and nutrition, and changes in the pathophysiology of prematurity (28, 29). All of these important changes have resulted in healthier preterm infants and in larger numbers of lower-gestational-age preterm infants who survive and whose vulnerability to RSV is likely different from that of 20 years ago. Interestingly, we observed a large decrease in risk associated with receipt of RSV immunoprophylaxis in 949 low-risk infants who received immunoprophylaxis (aHR = 0.51, 95% CI: 0.30, 0.86). The median gestational age of these infants was 32 weeks (interquartile range, 32–35). Twenty-six percent of them (n = 243) had congenital heart disease or CLD. The fact that those infants were similar to eligible infants in many ways (Table 2) suggests either misclassification of high-risk eligibility groupings, with some high-risk infants being misclassified as low-risk ineligible infants, or the presence of infants who were very similar to high-risk infants but failed to meet specific eligibility criteria. The AAP updated its RSV immunoprophylaxis guidelines in 2009 (12) and 2014 (5), which now results in eligibility for about half of the previously eligible infants. Our results indicated that the real-world receipt of RSV immunoprophylaxis tracks with these guidelines. The majority of the infants eligible under both older and current guidelines received at least 1 dose of immunoprophylaxis, while only about half of infants who would no longer be eligible under the up-to-date guidelines received at least 1 dose. The strengths of this study include the large population, with detailed information on the timing of and adherence to RSV immunoprophylaxis. Previous observational studies on RSV immunoprophylaxis often included only subjects who were receiving, or had received, immunoprophylaxis as compared with subjects who did not receive immunoprophylaxis (30, 31). There are significant problems with this approach, as pointed out above. Importantly, we demonstrated that administration of RSV immunoprophylaxis is itself an indication of increased risk of infection, and there is significant differential propensity for receipt, even within high-risk eligibility groups (Table 2, Web Table 1) (32). Thus, our approach to dealing with confounding by indication is critical to assessing real-world effectiveness. Another strength of this study was consideration of the protection window and the temporal relationship of immunoprophylaxis receipt and bronchiolitis visits to the RSV epidemic, something that has not been accounted for in prior observational studies. This is important, as it makes biological sense to account for presumed protection during periods following dosing, as well as higher and lower risks of infection depending on timing within the RSV season. Lastly, we assessed the association with RSV immunoprophylaxis using the unprotected periods of subjects who received at least 1 dose of immunoprophylaxis in order to minimize bias due to infants’ differential risks of RSV infection and seasonal variation (Web Table 8, Web Figure 5). There are several important limitations of this work to consider. We lacked virological confirmation of the etiology of bronchiolitis. Bronchiolitis captured by International Classification of Diseases, Ninth Revision, codes might not be due to RSV; therefore, the effect of RSV immunoprophylaxis might have been diluted (33, 34). To minimize the misclassification of bronchiolitis caused by viruses other than RSV, we limited the RSV season to November–March. Approximately 50%–70% of infant bronchiolitis hospitalizations occurring during the winter season were due to RSV (18, 35–37). KPNC started to test for RSV using the polymerase chain reaction method in 2006. Among 544 bronchiolitis hospitalization episodes that infants experienced during November–March from 2006 to 2009, 64% (n = 350 episodes) tested RSV-positive (Kedir Turi, Vanderbilt University, unpublished data, 2018). Further, it is also possible that infants who receive RSV immunoprophylaxis are protected against viral agents other than RSV as a result of their protection against severe RSV infection (6). Therefore, the association detected in this study reflected the true real-world effectiveness of immunoprophylaxis. It must also be noted that the innate risk of RSV infection among study subjects was highly variable and that the decision to administer RSV immunoprophylaxis was influenced by known risk factors as well as subjective risk factors. This makes confounding by treatment indication (i.e., sicker or higher-risk infants being more likely to receive treatment) a particular problem in observational studies such as this one (32). It is for this reason that our main analyses were restricted to patients who received at least 1 dose of immunoprophylaxis. There were several additional limitations. Two types of immunoprophylaxis with different mechanisms, RSV immune globulin intravenous (licensed in 1996) and palivizumab (licensed in 1998), were available during the study period. We could not determine type of immunoprophylaxis or differentiate between the 2 types of immunoprophylaxis available during the study period. KPNC administrated palivizumab almost exclusively in 1998 and afterwards; therefore, our results were mainly driven by the effect of palivizumab (Web Tables 3 and 5). Lastly, despite the fact that this is one of the largest population-based studies on the effectiveness of immunoprophylaxis to have been carried out to date, the study lacked statistical power for several high-risk subgroups. However, the groupings were based on the inclusion criteria from RCTs, and it may be that studies such as this can provide important data on groups who most benefit from this costly preventive intervention, particularly as numbers of RSV bronchiolitis events appear to be decreasing. In summary, in this real-world effectiveness study of RSV immunoprophylaxis, we have demonstrated that administration of RSV immunoprophylaxis was associated with a decreased risk of bronchiolitis hospitalization among high-risk infants, with infants with CLD, a group still recommended for receipt under the new 2014 AAP guidelines (5), experiencing the greatest risk reduction. Immunoprophylaxis was effective in reducing RSV-related morbidity during the 30 days following dosing regardless of prior receipt, supporting the importance of adherence to immunoprophylaxis therapy to provide protection in high-risk infants (38–40). The additional protective effect of prior receipt of immunoprophylaxis suggests that a longer dosing schedule might be as effective as current monthly dosing recommendations. Lastly, approximately half of the infants previously eligible under the prior guidelines were no longer eligible under the updated 2014 guidelines for use of RSV immunoprophylaxis. However, the burden of disease and the effectiveness of RSV immunoprophylaxis were greatest in the population that is still covered under the latest guidelines. Until a vaccine for RSV is available, these up-to-date data on the effectiveness of RSV prophylaxis may aid in informing use of this preventive intervention among high-risk infants (41). ACKNOWLEDGMENTS Author affiliations: Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee (Pingsheng Wu, Tina V. Hartert); Department of Inpatient Pediatrics, Kaiser Permanente Medical Center, Walnut Creek, California (Gabriel J. Escobar); Perinatal Research Unit, Division of Research, Kaiser Permanente Northern California, Oakland, California (Gabriel J. Escobar, Sherian X. Li, Eileen M. Walsh); Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee (Pingsheng Wu, Tebeb Gebretsadik, William D. Dupont, Chang Yu, Jeffrey R. Horner); Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee (Kecia N. Carroll); Department of Health Policy, Vanderbilt University Medical Center, Nashville, Tennessee (Edward F. Mitchel, William D. Dupont); and Department of Health Science, College of Life Sciences, Brigham Young University, Provo, Utah (Chantel Sloan). This work was funded by the Agency for Healthcare Research and Quality (grant R01 HS018454) and the National Institutes of Health (grants K24 AI77930, RC4 MH092755, R21 HL123829, R21 HL129020, and UL1 RR024975 (now 2 UL1 TR000445)). We thank Drs. Marie Griffin, Carlos Grijalva, and Kathryn Edwards of Vanderbilt University Medical Center for their assistance with critical revision of the manuscript. We are indebted to the Kaiser Permanente Division of Research for providing the data on the study cohort. This work was presented in part at the 8th Asian Conference on Pharmaceopidemiology (Hong Kong SAR, People’s Republic of China, October 25–27, 2013) and at the 2016 American Thoracic Society International Conference (San Francisco, California, May 13–18, 2016). G.J.E, S.X.L, E.M.W., and T.V.H. report receipt of past grant support from MedImmune LLC (Gaithersburg, Maryland). G.J.E. has also received grant support from Novartis International AG (Basel, Switzerland) for other projects. Drs. Marie Griffin, Carlos Grijalva, and Kathryn Edwards did not receive any compensation for their contribution to this article. Abbreviations AAP American Academy of Pediatrics aHR adjusted hazard ratio CI confidence interval CLD chronic lung disease IRR incidence rate ratio KPNC Kaiser Permanente Northern California RCT randomized clinical trial RSV respiratory syncytial virus. REFERENCES 1 Glezen WP, Taber LH, Frank AL, et al.  . Risk of primary infection and reinfection with respiratory syncytial virus. Am J Dis Child . 1986; 140( 6): 543– 546. Google Scholar PubMed  2 Hall CB. Respiratory syncytial virus and parainfluenza virus. N Engl J Med . 2001; 344( 25): 1917– 1928. Google Scholar CrossRef Search ADS PubMed  3 Shay DK, Holman RC, Newman RD, et al.  . Bronchiolitis-associated hospitalizations among US children, 1980–1996. JAMA . 1999; 282( 15): 1440– 1446. Google Scholar CrossRef Search ADS PubMed  4 American Academy of Pediatrics Committee on Infectious Diseases, Committee on Fetus and Newborn. Respiratory syncytial virus immune globulin intravenous: indications for use. Pediatrics . 1997; 99( 4): 645– 650. CrossRef Search ADS PubMed  5 American Academy of Pediatrics Committee on Infectious Diseases; American Academy of Pediatrics Bronchiolitis Guidelines Committee. Updated guidance for palivizumab prophylaxis among infants and young children at increased risk of hospitalization for respiratory syncytial virus infection. Pediatrics . 2014; 134( 2): 415– 420. CrossRef Search ADS PubMed  6 Blanken MO, Rovers MM, Molenaar JM, et al.  . Respiratory syncytial virus and recurrent wheeze in healthy preterm infants. N Engl J Med . 2013; 368( 19): 1791– 1799. Google Scholar CrossRef Search ADS PubMed  7 Groothuis JR, Simoes EA, Levin MJ, et al.  . Prophylactic administration of respiratory syncytial virus immune globulin to high-risk infants and young children. The Respiratory Syncytial Virus Immune Globulin Study Group. N Engl J Med . 1993; 329( 21): 1524– 1530. Google Scholar CrossRef Search ADS PubMed  8 O’Brien KL, Chandran A, Weatherholtz R, et al.  . Efficacy of motavizumab for the prevention of respiratory syncytial virus disease in healthy Native American infants: a phase 3 randomised double-blind placebo-controlled trial. Lancet Infect Dis . 2015; 15( 12): 1398– 1408. Google Scholar CrossRef Search ADS PubMed  9 The 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( 3): 531– 537. CrossRef Search ADS   10 Nightingale SL. First product available for preventing serious RSV disease. JAMA . 1996; 275( 12): 902. Google Scholar CrossRef Search ADS PubMed  11 American Academy of Pediatrics Committee on Infectious Diseases and Committee on Fetus and Newborn. Prevention of respiratory syncytial virus infections: indications for the use of palivizumab and update on the use of RSV-IGIV. Pediatrics . 1998; 102( 5): 1211– 1216. CrossRef Search ADS PubMed  12 Committee on Infectious Diseases. From the American Academy of Pediatrics: policy statements—modified recommendations for use of palivizumab for prevention of respiratory syncytial virus infections. Pediatrics . 2009; 124( 6): 1694– 1701. CrossRef Search ADS PubMed  13 Pickering LK, Baker CJ, Long SS, et al.  ., eds. Red Book: 2006 Report of the Committee on Infectious Diseases . 27th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2006. 14 Canfield SD, Simoes EA. Prevention of respiratory syncytial virus (RSV) infection: RSV immune globulin intravenous and palivizumab. (American Academy of Pediatrics). Pediatr Ann . 1999; 28( 8): 507– 514. Google Scholar CrossRef Search ADS PubMed  15 Escobar GJ, Gebretsadik T, Carroll K, et al.  . Adherence to immunoprophylaxis regimens for respiratory syncytial virus infection in insured and Medicaid populations. J Pediatric Infect Dis Soc . 2013; 2( 3): 205– 214. Google Scholar CrossRef Search ADS PubMed  16 Islam JY, Keller RL, Aschner JL, et al.  . Understanding the short- and long-term respiratory outcomes of prematurity and bronchopulmonary dysplasia. Am J Respir Crit Care Med . 2015; 192( 2): 134– 156. Google Scholar CrossRef Search ADS PubMed  17 Poindexter BB, Feng R, Schmidt B, et al.  . Comparisons and limitations of current definitions of bronchopulmonary dysplasia for the prematurity and respiratory outcomes program. Ann Am Thorac Soc . 2015; 12( 12): 1822– 1830. Google Scholar CrossRef Search ADS PubMed  18 Subramanian KN, Weisman LE, Rhodes T, et al.  . Safety, tolerance and pharmacokinetics of a humanized monoclonal antibody to respiratory syncytial virus in premature infants and infants with bronchopulmonary dysplasia. MEDI-493 Study Group. Pediatr Infect Dis J . 1998; 17( 2): 110– 115. Google Scholar CrossRef Search ADS PubMed  19 Carroll KN, Wu P, Gebretsadik T, et al.  . Season of infant bronchiolitis and estimates of subsequent risk and burden of early childhood asthma. J Allergy Clin Immunol . 2009; 123( 4): 964– 966. Google Scholar CrossRef Search ADS PubMed  20 Wu P, Dupont WD, Griffin MR, et al.  . Evidence of a causal role of winter virus infection during infancy in early childhood asthma. Am J Respir Crit Care Med . 2008; 178( 11): 1123– 1129. Google Scholar CrossRef Search ADS PubMed  21 Schanzer DL, Langley JM, Tam TW. Hospitalization attributable to influenza and other viral respiratory illnesses in Canadian children. Pediatr Infect Dis J . 2006; 25( 9): 795– 800. Google Scholar CrossRef Search ADS PubMed  22 Therneau TM, Grambsch PM. Modeling Survival Data: Extending the Cox Model . New York, NY: Springer Science & Business Media; 2000. Google Scholar CrossRef Search ADS   23 Carroll KN, Gebretsadik T, Escobar GJ, et al.  . Respiratory syncytial virus immunoprophylaxis in high-risk infants and development of childhood asthma. J Allergy Clin Immunol . 2017; 139( 1): 66.e3– 71.e3. Google Scholar CrossRef Search ADS   24 Eaglstein WH, Kirsner RS. Expectations for comparative effectiveness and efficacy research: with welcomed questions may come unwelcome answers. JAMA Dermatol . 2013; 149( 1): 18– 19. Google Scholar CrossRef Search ADS PubMed  25 Winterstein AG, Hampp C, Saidi A. Effectiveness of palivizumab prophylaxis in infants and children in Florida. Pharmacoepidemiol Drug Saf . 2012; 21( 1): 53– 60. Google Scholar CrossRef Search ADS PubMed  26 MedImmune LLC. Synagis. Palivizumab. (Package insert). Gaithersburg, MD: MedImmune LLC; 2014. 27 Sahni R, Ammari A, Suri MS, et al.  . Is the new definition of bronchopulmonary dysplasia more useful? J Perinatol . 2005; 25( 1): 41– 46. Google Scholar CrossRef Search ADS PubMed  28 Ehrenkranz RA, Walsh MC, Vohr BR, et al.  . Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia. Pediatrics . 2005; 116( 6): 1353– 1360. Google Scholar CrossRef Search ADS PubMed  29 Fanaroff AA, Stoll BJ, Wright LL, et al.  . Trends in neonatal morbidity and mortality for very low birthweight infants. Am J Obstet Gynecol . 2007; 196( 2): 147.e1– 147e8. Google Scholar CrossRef Search ADS   30 Atkins JT, Karimi P, Morris BH, et al.  . Prophylaxis for respiratory syncytial virus with respiratory syncytial virus-immunoglobulin intravenous among preterm infants of thirty-two weeks gestation and less: reduction in incidence, severity of illness and cost. Pediatr Infect Dis J . 2000; 19( 2): 138– 143. Google Scholar CrossRef Search ADS PubMed  31 Pedraz C, Carbonell-Estrany X, Figueras-Aloy J, et al.  . Effect of palivizumab prophylaxis in decreasing respiratory syncytial virus hospitalizations in premature infants. Pediatr Infect Dis J . 2003; 22( 9): 823– 827. Google Scholar CrossRef Search ADS PubMed  32 Boyce TG, Yogev R, DeVincenzo JP, et al.  . Confounding by indication limits conclusions of study of palivizumab effectiveness. Pediatrics . 2017; 139( 3): e20164247A. Google Scholar CrossRef Search ADS PubMed  33 Hall CB, Weinberg GA, Blumkin AK, et al.  . Respiratory syncytial virus-associated hospitalizations among children less than 24 months of age. Pediatrics . 2013; 132( 2): e341– e348. Google Scholar CrossRef Search ADS PubMed  34 Makari D, Staat MA, Henrickson KJ, et al.  . The underrecognized burden of respiratory syncytial virus among infants presenting to US emergency departments. Clin Pediatr (Phila) . 2015; 54( 6): 594– 597. Google Scholar CrossRef Search ADS PubMed  35 Henrickson KJ, Hoover S, Kehl KS, et al.  . National disease burden of respiratory viruses detected in children by polymerase chain reaction. Pediatr Infect Dis J . 2004; 23( 1 suppl): S11– S18. Google Scholar CrossRef Search ADS PubMed  36 Meissner HC. Viral bronchiolitis in children. N Engl J Med . 2016; 374( 1): 62– 72. Google Scholar CrossRef Search ADS PubMed  37 Smyth RL, Openshaw PJ. Bronchiolitis. Lancet . 2006; 368( 9532): 312– 322. Google Scholar CrossRef Search ADS PubMed  38 Krilov LR, Masaquel AS, Weiner LB, et al.  . Partial palivizumab prophylaxis and increased risk of hospitalization due to respiratory syncytial virus in a Medicaid population: a retrospective cohort analysis. BMC Pediatr . 2014; 14: 261. Google Scholar CrossRef Search ADS PubMed  39 La Via WV, Notario GF, Yu XQ, et al.  . Three monthly doses of palivizumab are not adequate for 5-month protection: a population pharmacokinetic analysis. Pulm Pharmacol Ther . 2013; 26( 6): 666– 671. Google Scholar CrossRef Search ADS PubMed  40 Robbie GJ, Zhao L, Mondick J, et al.  . Population pharmacokinetics of palivizumab, a humanized anti-respiratory syncytial virus monoclonal antibody, in adults and children. Antimicrob Agents Chemother . 2012; 56( 9): 4927– 4936. Google Scholar CrossRef Search ADS PubMed  41 Andabaka T, Nickerson JW, Rojas-Reyes MX, et al.  . Monoclonal antibody for reducing the risk of respiratory syncytial virus infection in children. Cochrane Database Syst Rev . 2013;( 4): CD006602. © The Author(s) 2018. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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American Journal of EpidemiologyOxford University Press

Published: Jan 17, 2018

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