Respiratory syncytial virus (RSV) is the most common cause of serious respiratory disease in infants and children worldwide. Specific RSV antibodies are detected in 87% of children under 18 months and virtually all children by age 3 years.1,2 In regions with temperate climate there are annual outbreaks of RSV infection, which is the most common reason for hospital admission in children in the winter months in developed countries.1–3

Each year, RSV causes 3.4 million cases of disease severe enough to require hospital admission. Its clinical spectrum encompasses acute respiratory infections (ARIs) of the upper or lower respiratory tract; the lower respiratory tract infections (LRTIs), which include pneumonia and bronchiolitis, are associated with greater morbidity and mortality.2–4 Furthermore, children that experience severe LRTIs caused by RSV are at greater risk of asthma and recurrent wheezing throughout the lifespan.5

Patients with primary immunodeficiencies (PIDs) -currently named as inborn errors of immunity - are very vulnerable to serious and possibly life-threatening ARIs. Respiratory syncytial virus infections tend to be more severe in immunocompromised infants compared to healthy infants, characterised by prolonged viral shedding and development of potentially lethal LRTI.6 The literature describes severe courses of disease following infection by RSV infections in infants and children with primary and acquired immunodeficiencies, and in-depth studies have been conducted in patients with acquired immunodeficiency due to human immunodeficiency virus (HIV) infection, treated with antineoplastic drugs or under immunosuppressive therapy after solid organ transplantation.2,7–10 In the case of PIDs, there is a higher risk of hospitalization and an increased mortality due to RSV in affected patients compared to children with normal immune function.11,12

Environmental infection control measures are essential to reduce the spread of RSV during the epidemic season in hospitalized immunocompromised infants. Prophylaxis with palivizumab is recommended in high-risk infants born preterm and in children aged less than 2 years with bronchopulmonary dysplasia or haemodynamically significant congenital heart disease. Although some authors have proposed extending prophylaxis to infants with PID, routine prophylaxis is not recommended at present in this high-risk group.2,13 In some countries, like Japan, palivizumab is indicated for prophylaxis during the RSV season in immunocompromised children and in children with Down syndrome, and new guidelines on the use of palivizumab in children with acquired immunodeficiency have been published.14

Given the potential repercussions of community-acquired infection by RSV in very young children with PIDs, these patients could especially benefit from preventive strategies. However, to estimate the real burden of infection by RSV in patients with PIDs, we need to identify which patients are at high risk of increased morbidity and mortality in association with these infections.

Therefore, the aim of our non-interventional study was to evaluate the frequency of hospital admission due to RSV-related ARI (RSV-ARI admission) in children with PIDs in Spain, and to identify clinical predictors of severity.

Globally, ARIs remain one of the leading causes of morbidity and mortality in children under 5 years, and human RSV is the viral pathogen identified most frequently in children with ARI. It is estimated that 10% of episodes of RSV infection require hospital admission. Shi et al. estimated an annual rate of hospital admission due to RSV-related ARI of 0.16% (95% confidence interval, 0.1−0.25) in developed countries.17 In a nationwide survey conducted in Japan, children with PID were 10 times as likely to require admission due to RSV-related ARI (1.6% over a 10-year period, 15 patients out of 910).18 In our study, the overall incidence of RSV-ARI admission in children with one of the PIDs considered to carry a high-risk of hospitalization was 3.0% in a 5-year period. This was very similar to the frequency reported in other studies, including the one by Domínguez-Pinilla et al., who found an incidence of 6.5% in children under 15 years with acquired or primary immunodeficiency in a 5-year single centre retrospective study in Spain. However, only 1 of those children had a PID (SCID). The remaining 8 children had solid cancer (n = 3) or blood cancer (n = 5). Although roughly one third of patients in that study received palivizumab, which was consistent with our findings, half of the patients in the study had congenital heart defects.19

In our study, the median length of stay was 8.5 days, much lower compared to the median hospital stay in the study from Domínguez-Pinilla et al. (20 days)17 and in the Japanese nationwide survey of PID patients (10.5 days),16 but greater than the median length of stay described in children in the general population admitted to hospital due to RSV (3–6.9 days).20,21

In a cohort of 406 children hospitalized for RSV infection in the 1999–2007 period, Thorburn et al. observed that pre-existing diseases and comorbidities, including primary immunodeficiencies, were associated with an increased frequency of PICU admission and higher mortality.9 In a cohort study that included 117 immunocompromised paediatric patients with primary or acquired immunodeficiency and RSV infection carried out between 2006 and 2011, Asner et al. found a frequency of ICU admission greater than 20% and a mortality of 5%.22 Our findings were similar, as 4 of the patients admitted due to RSV-related ARI in our study (30.8%) required admission to the PICU during their stay, although there were no RSV-related deaths.

Cell-mediated immunity plays a more critical role in the control of most viral infections than antibody-mediated immunity. In this regard, there is evidence that deficiencies in systemic CD4+ and CD8 + T-cell responses may contribute to RSV susceptibility in the elderly, who have lower levels of RSV-specific CD4+ and CD8 + T cells compared to younger adults.23,24 Immunosuppressive drugs prescribed to solid organ transplant recipients may also have an inhibitory effect on T cells, thus impairing the ability of these patients to clear opportunistic RSV infections, which results in more severe disease.25 Similarly, haematopoietic stem cell transplant recipients are also at increased risk of severe RSV infection, and peripheral blood lymphopaenia has been identified as a specific risk factor for LRTI by RSV.26–28 In addition, conventional CD4 + T cells from infants infected by RSV produce low amounts of IL-2, which is required for the effective generation of effector and memory CD8 + T cells.29,30 In our study, nearly 80% of the patients hospitalized due to RSV-ARI had CID or CIDwASF, both classifications that include cellular immunodeficiencies.

One of the limitations of the study is its design, as we did not collect data on patients with PID that were not hospitalized.

The low incidence of RSV-ARI admission in children with PID also posed a barrier to learning about the risk factors for RSV-ARI. As a result, we were unable to properly pursue the secondary objective of the study, which was to assess RSV-related ARI severity in relation to risk factors previously found to be significantly associated with this disease, such as such as prematurity and low birth weight.31

The low admission rate was comparable to the rate observed in late preterm infants, but comorbidities in PID children are quite different.32,33 In addition, the incidence of RSV-ARI admission in children with PID could be even higher, as children with antibody deficiencies, who were not eligible for this study, could add to the number of RSV-related hospital admissions. However, it should also be taken into account that comorbidities can also contribute to hospitalization and to development of severe RSV-ARI and, therefore, increased risk of severe disease.

In conclusion, in the group of paediatric patients with PIDs, RSV infection requiring hospital admission is more frequent in patients with CID or CIDwASF. Special attention should be devoted to the prevention of RSV infection in patients with these disorders.

The results of this study suggest that the implementation of measures to prevent nosocomial RSV infections in paediatric patients with PID should be mandatory during epidemic seasons. Further studies are needed to confirm these results.

Funding for the study was provided by AbbVie. The authors did not receive any honoraria or payments in relation to this study.

Luis Ignacio González-Granado has no financial relationships relevant to this article to disclose.

Andrea Martín-Nalda has no financial relationships relevant to this article to disclose.

Laia Alsina has no financial relationships relevant to this article to disclose.

Olaf Neth has no financial relationships relevant to this article to disclose.

Manuel Santamaría has no financial relationships relevant to this article to disclose.

Pere Soler-Palacín has no financial relationships relevant to this article to disclose.

AbbVie participated in the study design and implementation, interpretation of the data, and manuscript revision and approval for publication.

Doctors Luis Ignacio González-Granado, Andrea Martin-Nalda and Pere Soler-Palacín conceived and designed the study, participated in data collection, conducted the initial analysis, drafted the initial manuscript and revised the manuscript.

Doctors Laia Alsina, Olaf Neth, Manuel Santamaría and the SENTIR group participated in data collection and in the revision of the manuscript.

All authors approved the final article for submission and agreed to be accountable for all aspects of the work.