Compliance with the RSV immunoprophylaxis dosing schedule in the Polish registry for palivizumab (2008-2014)

Respiratory syncytial virus (RSV) is a highly contagious pathogen that infects over 90% of all children by two years of age. In healthy full-term infants in the second half-year of life and in older children, RSV infection may be a mild, self-limiting disease. However, in some cases, especially infants under 6 months of age and high-risk children, symptoms of lower respiratory tract infections (LRTIs) develop in the form of bronchitis, severe bronchiolitis or pneumonia with respiratory failure [1, 2, 3]. In these patients it may be necessary not only to be hospitalised in the intensive care unit, but also to use mechanical ventilation. Indeed, data on mortality in the course of infection indicate that despite advances in neonatal intensive care, RSV infection is a significant cause of infant deaths [4, 5]. An increased risk of a severe course of infection requiring hospitalisation and mechanical ventilation occurs primarily in children born prematurely, in infants with bronchopulmonary dysplasia (BPD) and in those with a hemodynamically significant congenital heart defect.

Due to the lack of effective methods for treating bronchiolitis caused by RSV, the prevention of infection plays a fundamental role. So far, no effective RSV vaccine has been developed and the only option to prevent RSV infection is immunoprophylaxis with palivizumab. Palivizumab is a humanised monoclonal immunoglobulin G class antibody that binds to the F (fusion) glycoprotein of the RSV, preventing its penetration into the airway epithelium. The immunoglobulin is given once a month at a dose of 15 mg/kg of body weight by intramuscular injection. Prophylaxis is carried out during the high-risk season, which in Poland occurs from October to April.

Since 2008, the Polish National Programme for RSV Immunoprophylaxis (OPZRSV) has been conducted in our country, under which all patients included in preventive treatment are closely monitored. Data on demographics, clinical outcomes and results of prophylaxis with palivizumab in infants are recorded. Published results of OPZRSV confirm the efficacy of the prophylaxis conducted [6]. Since the effectiveness of immunoprophylaxis depends on the compliance with the monthly dosing schedule, it is necessary to monitor adherence with the recommendations and to ascertain any factors that may affect it. The data published so far on adherence to the recommendations among children from the OPZRSV registry indicated the need for further research to determine new factors that may interfere with palivizumab use in the Polish population [7].

The study includes children enrolled into the OPZRSV who received at least one palivizumab dose financed by the National Health Fund (NFZ) over six consecutive RSV seasons (season I: 2008/09, season II: 2009/10, season III: 2010/11, season IV: 2011/12, season V: 2012/13 and season VI: 2013/14). The inclusion criteria were not identical for all the periods of prophylaxis and were subject to changes depending on updates to guidelines introduced by the Ministry of Health and the NFZ.

In the 2008/09 season, prophylaxis included infants with BPD who fulfilled one of the following conditions:

From 2009 to 2013 (seasons II–V), prophylaxis was also funded by the NFZ, but more restricted inclusion criteria were applied. The programme enrolled children with BPD who met one of the following criteria:

In season VI, prophylaxis was implemented in children who at the time of initiation of the immunisation did not complete their first year of life and met one of the following criteria:

BPD was defined as the necessity to use oxygen therapy with oxygen concentration above 21% for up to 28 days of life.

The exclusion criteria were: hypersensitivity to the active substance (palivizumab) or to any of the constituents present in the preparation; contraindications for passive immunisation; and lack of parental or legal guardian consent to the administration of immunoglobulin.

The study was retrospective, observational, multicentre, and non-interventional. During the six seasons, the study included 32 neonatal centres throughout the country. For each child enrolled for the prophylactic supply of palivizumab, demographic data were collected, and the neonatal course and details of palivizumab administration were analysed.

Compliance with the monthly dosing schedule of palivizumab is key to maintaining its therapeutic concentration and effective inhibition of RSV replication. Insufficient compliance significantly affects the effectiveness of immunoprophylaxis and may increase the risk of severe LRTIs caused by RSV [8]. For this reason, it is necessary to monitor the course of immunisation and identify factors affecting cooperation with the doctor and compliance with the dosage regimen.

The data from the six OPZRSV seasons presented in our study reveal that 81.7% of the children received all the expected doses, and 62.2% of the children received all their injections within the appropriate interdose interval. These results are similar to data from other published registers of large-scale national prevention programmes, which included from several thousands to over 10,000 patients. For example, over nine seasons (from 2005 to 2014), The Canadian Registry of Palivizumab (CARESS) estimated that 81.2% of children received all the expected doses, and 60.9% of infants received all injections within the appropriate interdose interval [8]. Likewise, in two studies presenting five seasons of the Palivizumab Outcomes Registry (i.e., from 1998 to 1999 and from 2000 to 2004), 79.8-86.0% of the children were compliant in terms of receiving all the expected doses [9, 10]. Data regarding the administration of all injections within the appropriate interdose interval were published for only four seasons (2000-2004), and amounted to 59.3% [9, 10]. Finally, based on six seasons of the German Palivizumab Registry (1999-2005), 73% of the patients received all doses within the appropriate interdose interval [11].

Our results also indicate that compliance changes along with the duration of OPZRSV, with the lowest compliance (as defined by the administration of all the expected doses) occurring in the first two seasons of the immunisation programme. A higher compliance in the subsequent years of the programme was also highlighted in the Canadian registry (CARESS), which may reflect an increase in the knowledge and experience of health professionals with respect to running the OPZRSV [8].

A higher probability of adherence was also observed in children who were younger at the start of the immunisation programme, which is in line with the results of the Italian cohort study and the Canadian registry [8, 12]. Since the predisposition to developing a severe LRTI caused by RSV is inversely proportional to the chronological age, the awareness of this threat among parents seems to be a factor conducive to compliance. However, in contrast to Italian researchers, we did not find a higher rate of adherence to the dosing regimen (as assessed by any method) among children with lower birth weight.

We did however, find the probability of non-compliance to be higher in male children. This is worrying because boys have shorter and narrower airways and are therefore more likely to develop bronchial obstruction in the case of RSV infection [13, 14]. In addition, male sex is a risk factor for hospitalisation associated with RSV infection in young children [15]. However, this knowledge is not common among parents. It seems that, on the contrary, male children can be perceived by the family as stronger and thus not requiring prophylaxis.

There are a few limitations of our study. First, this was an observational study without a comparative placebo arm. Second, administrative factors could adversely affect compliance with the dosage regimen. An example may be a situation in which an infant did not receive palivizumab during hospitalisation because the centre did not have accreditation to conduct the OPZRSV.

Our data from the OPZRSV are similar to prevention programmes conducted in other countries in terms of compliance with the monthly injection regimen during the RSV season. However, compliance rates do not reach >90%, as previously reported in randomised clinical trials. This difference between registries and randomised trials seems to be due to the reduction of compliance rates over time, that is, from the first injection to the last injection during the RSV season.

Educating parents about the risks associated with RSV infection, including the risk factors for a more severe disease course, along with the benefits of immunoprophylaxis is crucial for improving compliance with the palivizumab dosing schedule [12, 16, 17, 18]. Parents should be informed that this is passive immunisation and not vaccination, which is why a monthly supply of immunoprophylaxis over the RSV season is necessary for it to be effective.

In the current and previously published studies presenting data from the OPZRSV, there are no demographic or neonatal features affecting compliance except for sex and chronological age at the time of the first dose administration. Therefore, further actions aimed at optimising the prevention programme should be directed to the entire population covered by the prevention programme, taking into account the fact that the parents of boys should be aware of the risk related to their child’s sex.