4 International Journal of Pediatrics Table 3: Palivizumab prophylaxis in children with CHD and its impact on RSV hospitalization rate. Author (reference) Location Methodology Feltes et al. [9] Cohen et al. [37] Chang and Chen [38] California, USA Saji et al. [39] Saji et al. [40] ∗ Denotes statistical signiﬁcance. International USA Japan Japan Randomized, double-blind, placebo-controlled Prospective, observational Observational Questionnaire Questionnaire recipients and 4.2% in placebo recipients but this did not reach statistical signiﬁcance. An important clinical ﬁnding in this trial was that palivizumab serum concentrations were reduced 58% after cardiopulmonary bypass and therefore led to the recommendation that another 15 mg/kg dose of palivizumab should be administered after surgery [9]. Table 3 highlights studies that have reported on the impact of palivizumab prophylaxis in preventing RSV hospitalization rate in children with CHD. Table 4 highlights recommendations from the American Academy of Pediatrics for palivizumab administration in children with CHD. Adherence to the prophylaxis schedule is critical since children with CHD who receive adequate RSV prophylaxis are less likely to be hospitalized with an RSV infection. Lo´ pez et al. reported that children who received adequate RSV prophylaxis were 58% less likely to be hospital- ized than those that did not have adequate prophylaxis (3.3% vs. 7.9%) [5]. Children do not necessarily need to receive their ﬁrst dose of palivizumab prophylaxis in the hospital setting but can reliably receive it in an oﬃce-based or home-based setting [42]. A recent systematic review of compliance with palivizumab prophylaxis reported that home-based pro- grams are associated with improved compliance compared to oﬃce-based administration [43]. 3.2. Motavizumab. Motavizumab was developed by aﬃnity maturation of palivizumab, binds to the RSV fusion protein 70-fold better than palivizumab, and reduces pulmonary RSV titers up to 100-fold lower compared to palivizumab in cotton rats [44]. A multinational Phase 2 randomized, double-blind, palivizumab-controlled study of children ≤24 months en- rolled 1236 patients with hemodynamically signiﬁcant CHD, or acyanotic CHD with pulmonary hypertension and/or use of daily medication for congestive heart failure. The safety proﬁles of motavizumab and palivizumab were similar except motavizumab recipients had a signiﬁcantly higher incidents of skin events such as cutaneous hypersensitivity (1.6% vs. 0.3%, resp.; P = 0.038). Although the study was not suﬃciently powered to com- pare eﬃcacy between the two drugs, there was a nonsignif- icant diﬀerence in RSV-related hospitalizations between Hospitalization rate without prophylaxis Hospitalization rate with prophylaxis 9.7% 0.56% 4.42% 5.3% 1.9% 0.46% 4.6% 2.53% Relative reduction 45.4%∗ 17.9% 42.8% motavizumab and palivizumab (1.9% vs. 2.6%, resp.). There was no signiﬁcant diﬀerence between groups related to percentage of hospitalized patients requiring supplemental oxygen, number of intensive care unit admissions, need for mechanical ventilation, and the length of hospital stay. There was also no signiﬁcant diﬀerence in medically attended lower respiratory tract infections between motavizumab and palivizumab (1.0% vs. 1.9%, resp.). Mortality rates were also similar between motavizumab and palivizumab recipients (1.5% vs. 1.6%, resp.) [45]. Because RSV replication depends on an RNA polymerase that can have a high mutation rate, there has been concern that immunoprophylaxis may increase the potential of resistant RSV mutants. Although resistant RSV variants were detected in ∼5% of breakthrough cases, these did not appear to worsen the patient’s clinical outcome [46]. In patients who underwent cardiopulmonary bypass surgery, those who received an extra dose of motavizumab achieved a similar serum trough concentrations as those who did not undergo cardiopulmonary bypass, highlighting the need to redose motavizumab after cardiopulmonary bypass surgery. However, because of motavizumab’s lack of improved eﬃcacy over palivizumab and higher number of allergic reactions, it was not approved by the United States Food and Drug Administration and is not available for immunoprophylaxis against RSV. 3.3. Economic Considerations of Immunoprophylaxis. Al- though immunoprophylaxis has been showed to reduce hospital admissions related to RSV, there has not been evi- dence that mortality has improved. As a result, controversy regarding the cost-beneﬁt of administering palivizumab to all children <24 months of age with hemodynamically signiﬁcant congenital heart disease has been raised [47], especially since the RSV hospitalization rate in children with CHD is lower in children >12 months of age [5, 19, 48]. Cost-eﬀectiveness studies of palivizumab vary greatly in their methodology leading to disparate conclusions regarding their eﬀectiveness. The cost-beneﬁt of immunoprophylaxis is inﬂuenced by the rate of RSV hospitalization so that immunoprophylaxis given to an infant in the Canadian Inuit region, which has the highest rate of RSV infection