**3.5 How effective is palivizumab prophylaxis in late preterm infants?**

Palivizumab has proven effective in late preterm infants, reducing the incidence of RSVH by up to 82% in prospective, comparative studies (**Table 2**) [8, 10, 11, 39, 54]. A *post-hoc* analysis of the pivotal IMpact study, a randomized clinical trial including 724 preterm infants, showed the effectiveness of palivizumab to be similar in <29 wGA and 32–35 wGA infants (relative risk reduction: 80.4 vs. 82.1%, respectively) [11]. The Spanish FLIP-2 study, which reported a 68.3% reduction in RSVH with prophylaxis, found that not receiving palivizumab was an independent risk factor for RSVH (OR: 0.25; 95% CI: 0.13–0.49) in 32–35 wGA infants [39]. Registry data have confirmed the efficacy of palivizumab, with the Palivizumab Outcomes Registry from the US reporting RSVH rates of 0.2–1.6% in 32–35 wGA infants across four RSV seasons (2000–2004) [55], compared to 10.1% in the placebo arm of the IMpact trial [11]. Similar results were seen in the Canadian Registry of Palivizumab (CARESS) [56], with a RSVH incidence of 1.4% in 33–35 wGA infants during the 2006–2011 RSV seasons, compared to 8.2% (untreated subjects) in the IMpact study [11]. A propensity score weighted regression analysis based on a prospective, international trial (*n* = 849), showed that palivizumab prophylaxis significantly reduced RSVHs by 74.1% in 29–35 wGA infants, without comorbidities, aged ≤6 months [57].

Some studies have indicated that restricting palivizumab to ≤29 wGA infants does not increase the overall RSVH rate in children <2 years, while saving money on palivizumab prescriptions [58, 59]. A retrospective US study reported no difference in RSVH rates following introduction of the AAP 2014 policy (pre: 5.37/1000 vs. post: 5.78/1000; *p* = 0.622) [58]. Similar results were reported in Italy following introduction of the same policy in 2016, with the RSVH rate being 6.3/1000 before implementation and 5.5/1000 afterwards [59]. Other studies, however, have reported RSVH rates to have increased by up to 103% following implementation of a more restrictive policy [60–63].

Several studies have indicated that, by preventing RSV infection, palivizumab can reduce subsequent wheezing in premature children, including those born late preterm [48, 54, 64–66]. In the MAKI study, a randomized, placebo-controlled trial of palivizumab that included 429 infants born at 32–35 wGA, the proportion of children with wheezing was reduced by 41.9% in the palivizumab group at 6 years (11.6 vs. 19.9% for placebo) [48]. Similar results were seen in the Japanese CREW study (*n* = 444; 349 received palivizumab ≤1 year), where recurrent wheezing was significantly lower in palivizumab-treated, 33–35 wGA infants than chronologically age-matched untreated infants (15.3 vs. 31.6%, respectively; *p* = 0.003) [65].


*RRR: relative risk reduction; RSVH: Respiratory-syncytial-virus-related hospitalization; wGA: weeks' gestational age.*

#### **Table 2.**

*Prospective, comparative studies on the effectiveness of palivizumab prophylaxis in reducing RSVH in late preterm infants.*

#### **3.6 Can the use of risk factors target infants at highest risk for RSV infection and improve the cost-effectiveness of prophylaxis in the late preterm population?**

A key argument for restricting the use of palivizumab to <29 wGA infants is cost-effectiveness. Late preterm infants represent approximately 85% of preterm births [6], and it is unrealistic that prophylaxis of all these infants would ever be cost-effective. For this reason, the use of risk factors, to identify infants at the highest risk of RSVH, appears a pragmatic approach. There have been several RSTs developed and validated, including those in Canada [17], Spain [18], and the Netherlands [41]. Recently, a RST, involving 32–35 wGA infants, was published using pooled, individual patient data (*n* = 13,475) from six prospective, observational studies across the Northern Hemisphere [16], which included Canada [40], Italy [42], the Netherlands [41], Spain [39], the US [44], and a multinational cohort comprising subjects from Europe, the Middle East, North America, and Asia [45]. The RST was externally validated against a further study from Ireland (*n* = 1078) [43]. The RST includes three risk factors: birth 3 months before and 2 months after the RSV season start date; smokers in the household and/or smoking during pregnancy; and siblings (excluding multiples) and/or (planned) day-care (**Figure 3**) [16]. Predictive accuracy was demonstrated to be good, with an area under the receiver operating characteristic curve (AUROC) of 0.773, and sensitivity/specificity of 68.9 and 73.0%, respectively. The RST provides cut-off scores for infants at low- (≤19; 1.0% RSVH rate), moderate- (20–45; 3.3%), and high-risk (50–56; 9.5%) for RSVH [16].

The cost-effectiveness of using the multinational RST has not been formally assessed; however, economic evaluations have been undertaken on the use of other RSTs or risk-factor based approaches to targeting prophylaxis in late preterm 33–35 wGA infants [19, 67, 68]. The Canadian RST, based on data from the PICNIC study [40], included seven variables: small for GA (<10th percentile); male sex; born early during the RSV season (November, December, January); family history without eczema; subject or siblings in daycare; >5 individuals in the home, including the subject; and, >1 smoker in the household [17]. The AUROC was 0.762 and sensitivity and specificity were 68.2 and 71.9%, respectively. The RST included cut-off scores of 0–48, 49–64, and 65–100 for low-, moderate-, and high-risk infants, respectively

#### **Figure 3.**

*Risk factor scoring tool for late preterm infants [16]. 0 = No/Not Present; 1 = Yes/Present for one risk factor; 2 = Yes/Present for both risk factors. Score—Low-risk:* ≤*19; Moderate-risk: 20–45; High-risk: 50–56.*

**37**

the ICERs still further.

**4. Conclusion**

available funding.

*Resolving the Debate on RSV Prophylaxis in Late Preterm Infants*

[17]. A cost-effective analysis from 2008, using a decision analytic model, reported incremental cost-effectiveness ratios (ICERs) of CDN\$179,699, CDN\$34,215, and CDN\$5765 per quality-adjusted life year (QALY) for low-, moderate-, and high-risk infants, respectively; the ICERs for moderate- and high-risk infants were considered cost-effective under the Canadian healthcare system (medications commonly adopted with ICERs per QALY of CDN\$50–75,000 at that time) [19]. The Dutch RST was based on data from the RISK study and included four variables: family atopy; birth Aug-14 to Dec-01; breastfeeding; and siblings or daycare attendance [41]. The AUROC was 0.703 and the cut-off score for low-risk was defined as <16 (3.5% RSVH rate) and for high-risk as ≥16 (10.0% RSVH rate) [41]. Assuming all high-risk infants would receive prophylaxis, a decision model analysis produced an ICER of €214,748 per QALY, for moderately preterm infants 32–35 wGA, which was considered not cost-effective at a threshold of €80,000 per QALY [67]. Another analysis on 33–35 wGA infants, using data from the Spanish FLIP-2 study [39], assessed costeffectiveness based on infants having either 2 major risk factors and 2 minor risk factors (group A), 2 major and 1 minor risk factors (B), or 2 major risk factors (C) [68]. Major risk factors included chronological age < 10 weeks at the start of the RSV season or being born during the first 10 weeks of the season, school-age siblings or daycare attendance; whereas minor risk factors included maternal smoking during pregnancy and male sex [69]. Again using a decision analytic model, the incremental cost-utility ratio of €11,550.37, €14,177.18 and €13,937.61 per QALY gained for groups A, B and C, respectively, were derived and were deemed all highly cost-effective based on a threshold of €30,000 per QALY from both a National Health System and societal perspective [68]. An Austrian analysis reported palivizumab prophylaxis to be cost-effective in 33–35 wGA infants at €21,862 per QALY from the healthcare system perspective, when administered to those <3 months of age with risk factors [70]. It is important to note that the Canadian, Spanish and Austrian analyses modeled the effects of long-term respiratory morbidity, using life-time (Canadian and Austrian) and 6-year time horizons (Spanish), while the Dutch study included follow-up to only 1 year of age [19, 67, 68, 70]. This could, in part, account for the differences in cost-effectiveness reported. It would be interesting to see the impact on the ICERs if the increased rates of wheezing in children with a history of RSVH at 6 years in the RISK study (27.7 vs. 17.6% for non-hospitalized) were incorporated into the Dutch cost-effectiveness analysis. The ICERs reported from all three studies reflect costs from the healthcare system or payer perspective; including the societal impact of RSVH could potentially reduce the ICERs by 15–40% [19, 68]. The models also do not include the impact of RSV in the community setting, which could reduce

There is a sizable body of evidence demonstrating that late preterm infants are at increased risk of RSVH, resulting in substantial morbidity, both in terms of acute hospitalization and longer-term respiratory sequelae. While we await the availability of a safe and effective vaccine or a newer monoclonal antibody with an extended half-life, palivizumab remains the only proven therapy for reducing the incidence of RSVH in late preterm infants, and may also reduce subsequent wheezing. The use of RSTs and risk factors provides a mechanism to cost-effectively target the most vulnerable of these infants to receive palivizumab. It is recommended that countries adopt the multinational RST (**Figure 3**) and adapt this with local data and cut-offs, as available, to meet country-specific requirements and

*DOI: http://dx.doi.org/10.5772/intechopen.85073*

*Resolving the Debate on RSV Prophylaxis in Late Preterm Infants DOI: http://dx.doi.org/10.5772/intechopen.85073*

*The Burden of Respiratory Syncytial Virus Infection in the Young*

**3.6 Can the use of risk factors target infants at highest risk for RSV infection and improve the cost-effectiveness of prophylaxis in the late preterm population?**

A key argument for restricting the use of palivizumab to <29 wGA infants is cost-effectiveness. Late preterm infants represent approximately 85% of preterm births [6], and it is unrealistic that prophylaxis of all these infants would ever be cost-effective. For this reason, the use of risk factors, to identify infants at the highest risk of RSVH, appears a pragmatic approach. There have been several RSTs developed and validated, including those in Canada [17], Spain [18], and the Netherlands [41]. Recently, a RST, involving 32–35 wGA infants, was published using pooled, individual patient data (*n* = 13,475) from six prospective, observational studies across the Northern Hemisphere [16], which included Canada [40], Italy [42], the Netherlands [41], Spain [39], the US [44], and a multinational cohort comprising subjects from Europe, the Middle East, North America, and Asia [45]. The RST was externally validated against a further study from Ireland (*n* = 1078) [43]. The RST includes three risk factors: birth 3 months before and 2 months after the RSV season start date; smokers in the household and/or smoking during pregnancy; and siblings (excluding multiples) and/or (planned) day-care (**Figure 3**) [16]. Predictive accuracy was demonstrated to be good, with an area under the receiver operating characteristic curve (AUROC) of 0.773, and sensitivity/specificity of 68.9 and 73.0%, respectively. The RST provides cut-off scores for infants at low- (≤19; 1.0% RSVH rate), moderate- (20–45; 3.3%), and high-risk (50–56;

The cost-effectiveness of using the multinational RST has not been formally assessed; however, economic evaluations have been undertaken on the use of other RSTs or risk-factor based approaches to targeting prophylaxis in late preterm 33–35 wGA infants [19, 67, 68]. The Canadian RST, based on data from the PICNIC study [40], included seven variables: small for GA (<10th percentile); male sex; born early during the RSV season (November, December, January); family history without eczema; subject or siblings in daycare; >5 individuals in the home, including the subject; and, >1 smoker in the household [17]. The AUROC was 0.762 and sensitivity and specificity were 68.2 and 71.9%, respectively. The RST included cut-off scores of 0–48, 49–64, and 65–100 for low-, moderate-, and high-risk infants, respectively

*Risk factor scoring tool for late preterm infants [16]. 0 = No/Not Present; 1 = Yes/Present for one risk factor; 2 = Yes/Present for both risk factors. Score—Low-risk:* ≤*19; Moderate-risk: 20–45; High-risk: 50–56.*

**36**

**Figure 3.**

9.5%) for RSVH [16].

[17]. A cost-effective analysis from 2008, using a decision analytic model, reported incremental cost-effectiveness ratios (ICERs) of CDN\$179,699, CDN\$34,215, and CDN\$5765 per quality-adjusted life year (QALY) for low-, moderate-, and high-risk infants, respectively; the ICERs for moderate- and high-risk infants were considered cost-effective under the Canadian healthcare system (medications commonly adopted with ICERs per QALY of CDN\$50–75,000 at that time) [19]. The Dutch RST was based on data from the RISK study and included four variables: family atopy; birth Aug-14 to Dec-01; breastfeeding; and siblings or daycare attendance [41]. The AUROC was 0.703 and the cut-off score for low-risk was defined as <16 (3.5% RSVH rate) and for high-risk as ≥16 (10.0% RSVH rate) [41]. Assuming all high-risk infants would receive prophylaxis, a decision model analysis produced an ICER of €214,748 per QALY, for moderately preterm infants 32–35 wGA, which was considered not cost-effective at a threshold of €80,000 per QALY [67]. Another analysis on 33–35 wGA infants, using data from the Spanish FLIP-2 study [39], assessed costeffectiveness based on infants having either 2 major risk factors and 2 minor risk factors (group A), 2 major and 1 minor risk factors (B), or 2 major risk factors (C) [68]. Major risk factors included chronological age < 10 weeks at the start of the RSV season or being born during the first 10 weeks of the season, school-age siblings or daycare attendance; whereas minor risk factors included maternal smoking during pregnancy and male sex [69]. Again using a decision analytic model, the incremental cost-utility ratio of €11,550.37, €14,177.18 and €13,937.61 per QALY gained for groups A, B and C, respectively, were derived and were deemed all highly cost-effective based on a threshold of €30,000 per QALY from both a National Health System and societal perspective [68]. An Austrian analysis reported palivizumab prophylaxis to be cost-effective in 33–35 wGA infants at €21,862 per QALY from the healthcare system perspective, when administered to those <3 months of age with risk factors [70]. It is important to note that the Canadian, Spanish and Austrian analyses modeled the effects of long-term respiratory morbidity, using life-time (Canadian and Austrian) and 6-year time horizons (Spanish), while the Dutch study included follow-up to only 1 year of age [19, 67, 68, 70]. This could, in part, account for the differences in cost-effectiveness reported. It would be interesting to see the impact on the ICERs if the increased rates of wheezing in children with a history of RSVH at 6 years in the RISK study (27.7 vs. 17.6% for non-hospitalized) were incorporated into the Dutch cost-effectiveness analysis. The ICERs reported from all three studies reflect costs from the healthcare system or payer perspective; including the societal impact of RSVH could potentially reduce the ICERs by 15–40% [19, 68]. The models also do not include the impact of RSV in the community setting, which could reduce the ICERs still further.

### **4. Conclusion**

There is a sizable body of evidence demonstrating that late preterm infants are at increased risk of RSVH, resulting in substantial morbidity, both in terms of acute hospitalization and longer-term respiratory sequelae. While we await the availability of a safe and effective vaccine or a newer monoclonal antibody with an extended half-life, palivizumab remains the only proven therapy for reducing the incidence of RSVH in late preterm infants, and may also reduce subsequent wheezing. The use of RSTs and risk factors provides a mechanism to cost-effectively target the most vulnerable of these infants to receive palivizumab. It is recommended that countries adopt the multinational RST (**Figure 3**) and adapt this with local data and cut-offs, as available, to meet country-specific requirements and available funding.
