Influenza vaccination in children at high risk of respiratory disease

Introduction

Influenza is a contagious respiratory illness the clinical course of which is mainly benign and usually self-limiting. However, epidemics of influenza can occur every couple of years, and can lead to complications ranging from pneumonia to severe respiratory failure, or even death in susceptible hosts [Bhat et al. 2005; Centers for Disease Control and Prevention, 2011; Esposito and Principi, 2009]. Young children, the elderly, and people with chronic underlying conditions are especially vulnerable to the complications of influenza [Centers for Disease Control and Prevention, 2011; Esposito and Principi, 2009], and it has been reported that children with chronic respiratory diseases (CRDs), including chronic lung disease (CLD) of prematurity, asthma and cystic fibrosis (CF), are at significant risk [Blumental et al. 2011; Coffin et al. 2007; Patria et al. 2012]. For this reason, all health authorities agree in recommending influenza vaccination for patients with CRDs, although actual coverage remains generally unsatisfactory [Centers for Disease Control and Prevention, 2011; Esposito et al. 2006; Esposito and Principi, 2009; ECDC, 2012; European Union Council, 2009].

There are different types of influenza vaccines available on the market. Influenza vaccines prepared for intramuscular use and based on traditional inactivated viruses (TIVs) have been available for more than 50 years, although the first preparations based on whole viruses have been replaced by subunit and split-virus vaccines in order to reduce the incidence of adverse events [Principi and Esposito, 2012b]. Various attempts have been made to increase the immunogenicity and the efficacy of TIVs: the composition of TIVs has been modified by adding adjuvants, the amount of antigen has been increased, and other routes of administration have been tried. The addition of adjuvants was the first method used to improve TIVs, and has been the most widely studied. Some of the new adjuvants (emulsions and virosomes) have been widely evaluated and the apparently good results have led to the registration of adjuvanted influenza vaccines for use in humans, at least in some countries and in some subjects [Principi and Esposito, 2012]. In order to overcome some of the limitations of TIVs, a live attenuated influenza vaccine (LAIV) has also been registered. This contains cold-adapted, temperature-sensitive, attenuated influenza viruses, the moderate replication rate of which usually prevents them from reaching disease-inducing concentrations [Esposito et al. 2012a]. A LAIV does not have to be injected because it is administered intranasally. Unlike a TIV, which can only induce a systemic response to chemically treated viral proteins, a LAIV elicits mucosal and systemic immunity against native hemagglutinin and neuraminidase glycoproteins by generating specific nasal and serum antibodies and T-cell responses similar to those induced by natural influenza infection. Consequently, it can lead to a more substantial immune response and provide protection not only against the viruses included in the vaccine, but also against mismatched strains [Esposito et al. 2012b].

The aim of this review is to analyze the impact of influenza on children at high risk of respiratory disease as well as the immunogenicity, safety and efficacy of influenza vaccination in such children. PubMed was used to select all of the studies published in the last 15 years using the following combinations of text words: ‘influenza’ and ‘chronic respiratory disease’ or ‘chronic lung disease’ or ‘preterm’ or ‘prematurity’ or ‘asthma’ or ‘cystic fibrosis’ or ‘ciliary dyskinesia’ or ‘bronchiectasis’ or ‘airway malformation’ or ‘pulmonary fibrosis’ or ‘recurrent respiratory infection’. More than 3000 articles were found, but only papers published in English, those related to neonates, children and adolescents as well as those showing evidence-based data or presenting recommendations from scientific societies were included.

Preterm neonates and infants

Influenza is not a frequent illness in newborns because of the presence of protective antibodies acquired through the placenta or from breast milk [Wilkinson et al. 2006]. However, it may cause considerable morbidity and even mortality during the neonatal period, especially in preterm babies (i.e. with a gestational age of <37 weeks) and those with a low birth weight (i.e. <2500 g), because of a low rate of transplacental immunoglobulin G (IgG) transfer and the prematurity of the newborn’s immune system [Iwane et al. 2004; Louie et al. 2010]. The clinical manifestations of neonatal influenza are not specific (ranging from mild-to-moderate symptoms to severe sepsis-like syndrome) [Martic et al. 2011], but respiratory symptoms are predominant, with fever and apnea being among the most common.

Despite the high level of vigilance, reduced contact with infected cases, and the use of strict preventive measures in neonatal intensive care units (NICUs), there have been a number of reports of outbreaks of nosocomial influenza. In a retrospective cohort study of 54 newborns admitted to an NICU during the 1998 influenza outbreak, 6/19 infants infected with influenza A were symptomatic and a 27-week gestation twin with a birth weight of 962 g died because of virus-related hemophagocytic syndrome [Cunney et al. 2000]. Univariate analysis indicated that gestational age was associated with the development of influenza, whereas multiple logistic regression analysis found that only mechanical ventilation [odds ratio (OR 6.2; p = 0.02) and twin pregnancy (OR 7.0; p = 0.04) remained significant risk factors [Cunney et al. 2000]. Sagrera and colleagues reported 30 cases of neonates admitted to an NICU with nosocomial influenza A, and identified a low birth weight, a short gestational period, twin pregnancy and mechanical ventilation as risk factors; however, all of the cases had a favorable outcome [Sagrera et al. 2002]. In a recent study of 652 infants hospitalized because of A/H1N1/2009 influenza, 82 (13%) were admitted to an NICU [Yen et al. 2012]. A total of 27 (35%) of the hospitalized infants were preterm and most of them were affected by CLD of prematurity (92%). Moreover, seven patients died, two of whom were preterm infants admitted to an NICU upon delivery [Yen et al. 2012]. Another large-scale multicentre surveillance study estimated the rates of hospitalization due to seasonal influenza and found that 15% of the 4015 hospitalized children with laboratory-confirmed influenza had a history of prematurity [Dawood et al. 2010]. Furthermore, a surveillance report on the 2003–2004 and 2004–2005 influenza seasons in California found that 160 children were admitted to pediatric ICUs because of severe influenza; of the 14 children who had been born prematurely (9%), two died [Louie et al. 2010].

All of these data support the fact that, regardless of the presence of CLD of prematurity, preterm neonates and infants are also at high risk of influenza infection after discharge and influenza vaccination is therefore the primary means of preventing it. Unfortunately, because influenza vaccines are only licensed from the age of 6 months regardless of gestational age [Esposito et al. 2012a], immunization of all household contacts should be recommended [Centers for Disease Control and Prevention, 2011; Esposito et al. 2012a]. However, as the actual rate of adult immunization is usually low [Shah and Caprio, 2007], neonatologists and pediatricians should consider it as a priority to inform parents that this is the case. Another preventive measure for neonates and infants aged less than 6 months is maternal influenza immunization during pregnancy, however, it is not known whether this strategy is effective in the case of prematurity [Esposito et al. 2012a; Rasmussen et al. 2012].

Preterm infants aged at least 6 months have significant hypogammaglobulinemia during the first year of life, but it has been observed that two doses of influenza vaccine one month apart can induce protective concentrations of influenza-specific antibodies [D’Angio et al. 2011; Esposito et al. 2011; Sasaki et al. 2006]. Sasaki and colleagues found that antibody responses to influenza A (H1N1 and H3N2) vaccine in 45 previously unvaccinated preterm infants aged 6–11 months seemed to be comparable with those of similarly aged full-term infants [Sasaki et al. 2006]. Furthermore, their multivariate analysis showed that serum IgG levels at the time of vaccination had no positive association with antibody responses, thus indicating that prolonged hypogammaglobulinemia had no effect on vaccine responses in preterm infants aged over 6 months [Sasaki et al. 2006]. These findings have been confirmed by a recent prospective multicentre study carried out by D’Angio and colleagues who found that the antibody responses to two doses of trivalent inactivated influenza vaccine in 36 preterm infants with a gestational age of 26–27 weeks were similar to, or greater than those of 33 full-term infants [D’Angio et al. 2011]. Esposito and colleagues found that influenza A/H1N1/2009 MF59-adjuvanted vaccine evoked a significant immune response in 105 children aged 6–23 months (35 with a gestational age of less than 32 weeks, 35 with a gestational age of 32–36 weeks and 35 full-term children), and had a good safety and tolerability profile [Esposito et al. 2011].

Although these data confirm that influenza vaccination is immunogenic and safe even in preterm infants, there is an urgent need for further research in a number of areas. It is essential to establish the best means of increasing influenza vaccination coverage in their household contacts, and there is a need for efficacy (not only immunogenicity) studies comparing the different influenza vaccines in premature infants aged at least 6 months and less than 6 months.

Children with asthma

Asthma is a common childhood disease, with a mean global prevalence of about 12% [Lai et al. 2009]. Influenza viruses play a role in wheezing and asthma exacerbation, although influenza infection seems to be less closely related to asthma than infections due to other viruses such as rhinovirus or respiratory syncytial virus [Bosis et al. 2006]. However, a number of studies have shown that a large proportion of children with laboratory-confirmed influenza who are hospitalized or attended an outpatient clinic because of acute respiratory illnesses have asthma; in addition, it was found that both outpatient attendance and hospitalization are more frequent among children with asthma [Glezen et al. 2000; Miller et al. 2008; Moineddin et al. 2008; Neuzil et al. 2000], whose annual rate of influenza-attributable hospitalization is two to four times higher than that of otherwise healthy children [Neuzil et al. 2000]. Furthermore, children with asthma and influenza are also more likely to have pneumonia, require intensive care or develop respiratory failure [Dawood et al. 2011]. The pandemic A/H1N1/2009 influenza virus has been associated with severe lung injury in patients with asthma [Libster et al. 2010; Jain et al. 2009]. More than 30% of the children experiencing an asthma attack due to pandemic A/H1N1/2009 virus were diagnosed as having pneumonia, required admission to an intensive care unit, needed mechanical ventilation or died [Hasegawa et al. 2011; Torres et al. 2012].

All health authorities recommend annual influenza vaccination for patients with asthma, including children [Centers for Disease Control and Prevention, 2011; Esposito et al. 2012b], but actual coverage is very low [Esposito et al. 2006; Patria et al. 2012]. Pediatricians tend to resist influenza vaccination because of the lack of convincing evidence concerning its efficacy in preventing asthma exacerbations (and concerns that it may even induce them) and its potentially severe complications [Esposito et al. 2006; Patria et al. 2012]. In terms of efficacy, some studies have shown that the current influenza vaccination status of children with asthma is associated with a significant reduction in the use of oral steroids [Lanthier et al. 2011], a lower rate of exacerbations [Ong et al. 2009; Smiths et al. 2002], and a decrease in acute respiratory diseases [Kramarz et al. 2001]. Other studies have found no decrease in the rate of influenza-associated exacerbations in influenza-vaccinated patients with asthma, although their duration was shorter than in those who had not been vaccinated [Bueving et al. 2004; Sugaya et al. 1994]. However, the lack of evidence of any clear efficacy in some clinical trials may have been due to their uncontrolled design, the size of the population of children with asthma, and the heterogeneous enrolment of asthma cases without adjusting for asthma severity.

Some studies have evaluated the immunogenicity of influenza vaccines in relation to steroid therapy. Some years ago, it was shown that influenza vaccination is safe and effective in children with asthma regardless of concomitant prednisone administration [Fairchok et al. 1998; Park et al. 1996]. Subsequently, a large-scale study found that the immune response to influenza A antigens was similar in patients receiving no or low-dose inhaled corticosteroids and those receiving medium- or high-dose inhaled or oral corticosteroids, but the response to influenza B antigen may be reduced in patients treated with high-dose inhaled corticosteroids [Hanania et al. 2004]. More recently, it has been observed that the use of a virosomal-adjuvanted influenza vaccine in children with asthma seems to lead to high and persistent seroprotection rates (87–90% after 1 month, and 74–77% after 6 months) regardless of steroid therapy [Zuccotti et al. 2007].

In terms of safety, there is extensive evidence that inactivated influenza vaccination is safe and well tolerated in children with asthma, and that there is no increase in the frequency of asthma exacerbations as a complication of its administration [American Lung Association Asthma Clinical Research Centers, 2001; Cates et al. 2008; Nicholson et al. 1998]. It has also been found that inactivated influenza vaccines are safe in subjects with severe egg allergy [Esposito et al. 2008; Greenhawt et al. 2011; Owens and MacGinnitie, 2011; Webb et al. 2011].

Recent studies have shown that a LAIV is more efficacious than a trivalent vaccine, and does not lead to any significant increase in adverse pulmonary outcomes even in children with moderate to severe asthma [Ashkenazi et al. 2006; Gaglani et al. 2008; Tennis et al. 2011]. In the European Union, a LAIV is approved for use in children with mild-to-moderate asthma, and further studies are needed to confirm its safety in severe asthma.

Another future action that needs to be taken is to increase influenza vaccination coverage, at least among children with moderate or severe asthma and frequent asthma exacerbations, and to evaluate the efficacy, immunogenicity and safety of adjuvanted influenza vaccines, which seem to be more effective than traditional inactivated vaccines and may reduce influenza-related complications in very young patients with asthma.

Children with cystic fibrosis

It is known that bacterial infections play a critical role in the development of significant lung damage [Dasenbrook et al. 2010; Waters et al. 2011], whereas the role of respiratory viruses in the pulmonary exacerbations of CF is still uncertain, as is the relationship between viral infections and the progression of lung damage. Previous studies may have underestimated the prevalence of viral infections because it is only recently that molecular-based techniques have improved the detection of respiratory viruses. In this regard, a recent cross-sectional study has found that children with CF are frequently positive for at least one respiratory virus during a pulmonary exacerbation, and that viral-related exacerbations are associated with more severe disease and a poorer quality of life [Asner et al. 2012]. Respiratory viruses may also contribute to the pathogenesis of bacterial exacerbations, and it has been suggested that respiratory viral infections facilitate the acquisition and colonization of Pseudomonas aeruginosa, thus affecting host pulmonary defenses [Armstrong et al. 1998; Johansen and Hoiby, 1992].

Early studies suggested that seasonal influenza viruses play a role in worsening the lung function of patients with CF [Conway et al. 2002; Pribble et al. 1990], however, more recent studies have not found any evidence that influenza is more frequent in patients with CF than in healthy subjects, or that influenza is responsible for bacterial exacerbations or changes in colonization [Olesen et al. 2006; Ortiz et al. 2010; Punch et al. 2005; Wat et al. 2008]. Two other studies have confirmed the limited role of influenza in respiratory exacerbations in children with CF, despite the widespread presence of at least one virus during their course [Asner et al. 2012; Burns et al. 2012].

The impact of pandemic A/H1N1/2009 influenza is also unclear because its role in worsening lung function is poorly understood. Published studies found pandemic A/H1N1/2009 infection in only a small percentage of cases (2–4%), however, some studies found that patients with CF with severe lung disease and in poor clinical condition were exposed to an increased risk of complications and unfavorable outcomes during the course of the disease [France et al. 2010; Nash et al. 2011; Viviani et al. 2011]. One study found that most patients experienced mild uncomplicated disease [Colombo et al. 2011]. The main limitations of the studies of the impact of influenza on patients with CF are their small sample sizes, the absence of a healthy control group, the lack of data concerning the severity of pulmonary deterioration, and the lack of information concerning influenza vaccination status. However, given the potential risks associated with influenza infection and the advantages of influenza vaccination, all health authorities recommend influenza vaccination in patients with CF [Centers for Disease Control and Prevention, 2011; Esposito et al. 2012b]. Over the last 10 years there has been a significant increase in the level of influenza vaccination coverage among patients with CF, which is now generally high although not optimal in some geographical areas. In 2009, 91.2% of the children with CF in Italy were vaccinated against influenza versus only 8.3% in the 2000–2001 season [Esposito et al. 2006; Pandolfi et al. 2011]. Coverage in France has been relatively stable but is less than in other countries (79.9% in the 2005–2006 season) [Murris-Espin et al. 2008], whereas 91% of the children with CF in the United States were vaccinated in the 2006–2007 season [Ortiz et al. 2010].

The immunogenic effect and safety of influenza vaccines in children with CF seems to be comparable with that in healthy individuals. A recent Cochrane analysis of four relatively old studies involving a total of 179 participants with CF (mainly children) concluded that all influenza vaccinations (live intranasal, trivalent inactivated, subunit with a split virus and virosomal with a subunit product) generated a satisfactory antibody response with no significant differences between them; the total adverse event rate was quite high, but none of the adverse reactions were severe [Dharmaraj and Smyth, 2009]. In another study, a single dose of the pandemic A/H1N1/2009 MF59-adjuvanted influenza vaccine led to a high seroconversion rate in patients with CF with good lung status and in generally good nutritional condition [Alghisi et al. 2011]. The vaccine was also well tolerated and the frequency of adverse events was comparable with the published data concerning other influenza vaccines [Alghisi et al. 2011]. Interestingly, Bodewes and colleagues studied influenza A virus-specific cellular and humoral responses, and observed that annually vaccinated patients with CF developed an optimal virus- specific CD4(+) T-cell and antibody response, but may have had lower cross-reactive virus-specific CD8+ T-cell responses to other subtypes of influenza A viruses [Bodewes et al. 2012]. These findings highlight the importance of developing broadly protective vaccines that provide protection against all influenza A viruses.

Overall, although the number of studies is limited and no efficacy data are available, influenza vaccines seem to be immunogenic and safe in patients with CF, although the immune response of undernourished patients with more advanced disease is not known. Further well constructed clinical studies are needed in order to assess the effectiveness of the available influenza vaccines in relation to major clinical outcome measures, such as pulmonary function and nutritional status.

Other respiratory diseases

Other rare CRDs include primary ciliary dyskinesia, non-CF bronchiectasis, airway malformation, idiopathic pulmonary fibrosis, and the respiratory involvement observed in neurological and neuromuscular diseases, congenital heart diseases and immunodeficiency. There is a lack of specific studies evaluating the impact of influenza on respiratory exacerbations in patients with these disorders or the benefits of vaccination. However, given the increasing evidence of the burden of influenza on the population as a whole and the benefits associated with vaccination, annual influenza vaccinations should be recommended in such patients (especially those with multiple pulmonary exacerbations) and the members of their households.

Another important group consists of children with recurrent respiratory tract infections (RRTIs), defined as at least eight episodes per year in children aged under 3 years, and at least six episodes per year in children aged at least 3 years [Principi et al. 2003]. RRTIs are quite common in childhood and have a considerable impact on healthcare systems. Recent studies have shown that children with RRTIs are at high risk for influenza infection and complications, and that this increases medical consultations and costs, antibiotic use, school absences and lost working days. In a retrospective study of 250 children with nonresponsive or recurrent community-acquired pneumonia (CAP) who underwent bronchoscopy with bronchoalveolar lavage, De Schutter and colleagues found a viral infection in 30.4%, with a high prevalence of respiratory syncytial virus, and influenza and para-influenza viruses [De Schutter et al. 2011]. Another study of 80 children with recurrent lower respiratory infections who underwent bronchoscopy with bronchoalveolar lavage detected viral genomes in 62.5% [Bugin et al. 2012].

Viral RRTIs may be associated with frequent and unnecessary antibiotic prescriptions [Principi et al. 2013], and this misuse may promote the growth of drug-resistant pathogenic bacteria, which is becoming a major threat to treatment efficacy [Esposito and Principi, 2002; File, 2002]. Consequently, greater priority has recently been given to preventing RRTIs by means of influenza vaccination. Esposito and colleagues studied 127 children aged between 6 months and 9 years with a history of RRTIs who were randomized to receive intranasal virosomal influenza vaccine or a control placebo [Esposito et al. 2003], and found that the vaccinated children had fewer respiratory infections and acute febrile respiratory illnesses, fewer prescribed antibiotics and antipyretics, and missed fewer school days than the controls. Similar benefits were also observed among the patients’ household contacts. The vaccine was well accepted by the children, and the adverse events were transient and mild to moderate, with fever being the most frequent symptom [Esposito et al. 2003]. Another study randomized children aged 6–71 months with a history of RRTIs to receive two doses of a LAIV or an inactivated influenza vaccine [Ashkenazi et al. 2006], and found that LAIV reduced the number of respiratory infection-related physician visits by 8.9% [90% confidence interval (CI) 1.5–15.8%), and the number of missed days of school, kindergarten or day care by 16.2% (90% CI 10.4–21.6%). These findings confirm that any type of influenza vaccination can lead to substantial health and economic benefits by reducing the number of respiratory recurrences in children with RRTIs and, in our opinion, such patients should be included in the list of those for whom influenza vaccination should be recommended.

Conclusion

Children at high risk of respiratory disease are a heterogeneous group of the pediatric population. However, there are few studies assessing the impact of influenza on respiratory exacerbations or the efficacy of influenza vaccine in such patients, which may explain why influenza vaccination coverage remains quite low in most categories. Table 1 summarizes knowledge and gaps on influenza vaccination in children at high risk of respiratory disease. The published data show that preterm neonates and infants are at significant risk of influenza-related complications, and that influenza vaccines are immunogenic and safe in such cases; however, no specific studies of their efficacy have been carried out. There is disagreement as to whether or not influenza infection increases asthma morbidity or whether or not influenza vaccination helps in preventing asthma exacerbations in children with asthma. Further studies are needed to clarify which patient subgroups are susceptible to influenza-related complications, and to demonstrate the efficacy, immunogenicity and safety of adjuvanted influenza vaccines in such patients. Recent data provide no evidence that influenza is more frequent in patients with CF than in healthy subjects, or that it is responsible for increased lower respiratory tract morbidity. However, once again, future studies should not only consider the efficacy of the different influenza vaccines but also their immunogenicity because there is a lack of any clear correlate of protection, especially in relation to adjuvanted vaccines and LAIVs. Furthermore, there is a need for well constructed clinical studies to assess the effectiveness of the available vaccines in patients with other rare CRDs and other chronic underlying diseases with possibly severe respiratory involvement. It is also important to determine whether children with RRTIs should be included in the list of those for whom influenza vaccination is recommended. In the meantime, despite the limitations of the available studies and bearing in mind the use of influenza prevention programs in healthy subjects, further efforts are needed to increase influenza vaccination coverage among children with CRDs, and to inform their families about the importance of influenza and the benefits of preventing it.

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Table 1.

Knowledge and gaps on influenza vaccination in children at high risk of respiratory disease.

Patients	Knowledge	Main gaps
Preterm neonates and infants	Regardless of the presence of chronic lung disease of prematurity, these patients have a significant risk of influenza-related complications; influenza vaccines are immunogenic and safe in such patients	To establish the best means of increasing influenza vaccination coverage in their household contacts; to perform efficacy studies comparing the different influenza vaccines in premature infants aged ≥6 and <6 months
Children and adolescents with asthma	Influenza infection increases asthma morbidity and influenza vaccination helps in preventing asthma exacerbations in children and adolescents with moderate to severe asthma	To clarify which patient subgroups are susceptible to influenza-related complications, and to demonstrate the efficacy, immunogenicity and safety of adjuvanted influenza vaccines in such patients
Pediatric patients with cystic fibrosis	No evidence that influenza is more frequent in cystic fibrosis patients than in healthy subjects, or that it is responsible for increased lower respiratory tract morbidity	To assess the effectiveness of the available influenza vaccines in relation to major clinical outcome measures such as pulmonary function and nutritional status
Pediatric patients with rare chronic respiratory disease or chronic underlying diseases with possibly severe respiratory involvement	There is a lack of specific studies evaluating the impact of influenza on respiratory exacerbations in patients with these disorders, or the benefits of vaccination	To assess the effectiveness of the available vaccines
Children with recurrent respiratory tract infections	These children are at high risk of influenza infection and complications, and influenza vaccination is associated with significant benefits	To determine whether these children should be included in the list of those for whom influenza vaccination is recommended