Introduction
Community-acquired pneumonia (CAP) is a leading infectious cause of hospitalizations and death among children <5 years of age globally [
2,
13]. Among the estimated in-hospital deaths, the majority (99%) occur in low-income countries. Although the disease burden from childhood pneumonia is lower in high-income countries, medical service utilization, emergency visits and antibiotic use and related costs remain substantial. Despite this, there are relatively few studies related to the clinical burden in hospitalized children with pneumonia in high-income countries [
12].
Major pathogens associated with childhood CAP include
Streptococcus pneumonia,
Haemophilus influenzae,
Staphylococcus aureus,
Chlamydophila pneumoniae and
Mycoplasma pneumoniae [
14,
21]. A number of viral pathogens including respiratory syncytial virus, rhinoviruses, human metapneumoviruses, adenoviruses and influenza have been acknowledged as important pathogens for CAP as well [
8,
13]. However, identifying the cause of paediatric CAP has been problematic due to poor sensitivity of conventional microbial tests, such as blood cultures and nasopharyngeal (NP) cultures, to accurately identify bacteria involved in the localized lung infection. Molecular methods for identification of both viruses and bacteria may improve sensitivity, but perhaps not accurately predict viral vs. bacterial origin of CAP, since it has been increasingly recognised that healthy children may also be carriers of viruses in NP samples [
16,
19]. The introduction of both
H. influenzae type b and more recently pneumococcal conjugate vaccines (PCV) has had a great impact on CAP hospitalizations and mortality in both low- and high-income countries [
5,
10,
11]. Pneumococcal conjugate vaccine PCV7, as the most studied vaccine so far, has repeatedly been reported to reduce hospitalizations due to pneumonia, which in most studies is defined as radiologically confirmed pneumonia, bacterial and non-bacterial pneumonia or cases identified through ICD codes. The range of reduction of all-cause pneumonia has been reported between 13 and 65% in countries as Italy, Poland, the US and Sweden after the introduction of PCV [
1,
5,
10,
18].
However, there are still some unresolved problems related to the prevention and management of paediatric CAP in high-income countries. Hospitalization of children with CAP is already recommended for moderate-severe pneumonia, children with unstable vital parameters and in children with comorbidities. The most common comorbidities associated with CAP and/or invasive pneumococcal disease (IPD) are immunodeficiency, any type of childhood cancer, congenital heart or lung disease and neurological diseases [
7,
8,
15]. Despite this, little data is available on the burden of CAP in children with comorbidities based on population data.
In Stockholm County, Sweden, PCV7 was offered on a 2 + 1 schedule at 3, 5 and 12 months of age to all children born since July 1, 2007. In January 2010, PCV7 was changed to PCV13 even for children who had received 1 or 2 doses of PCV7. No catch-up programme was implemented. High vaccine coverage was reached early on, and 98% of children born 2010 had received 3 doses of PCV [
10]. Using a population-based retrospective cohort of children residing in Stockholm County, we sought to describe underlying comorbidities in children less than 5 years of age, hospitalized with CAP before and after the introduction of PCV. In addition, we provide data on the clinical course and complications for children with and without comorbidities.
Material and methods
Data source
Data for this retrospective cohort study were retrieved from the Hospital Registry, which contains information on hospitalization and discharge diagnoses covering all paediatric admissions in the Stockholm County. The three paediatric hospitals located in Stockholm participated in the study, all with paediatric emergency departments and one serving as a referral centre for ICU cases for children from the Stockholm County, Sweden. Incidence of pneumonia was calculated with population data from the Regional Planning Office, Stockholm County Council for the respective time periods. The population of children <18 years increased from 416,000 in the pre-vaccination period to 451,000 in the post-vaccination period. In addition, to validate diagnoses and retrieve in-depth data on comorbidity, 50% of all medical records were reviewed. The Regional Ethical Board in Stockholm, Sweden, approved of the study (D-no.: 2011/44-31/1).
Patients
Children aged 0 to <5 years hospitalized for CAP were eligible for this study if they were residing in Stockholm county, discharged from the three participating hospitals between November 1, 2005 and April 30, 2007 (pre-vaccination period) and November 1, 2010 and April 30, 2012 (post-vaccination period). Subjects living in the Stockholm area were included if they were discharged with an ICD-10 code of J13-J18.9 which excludes a diagnosis of pneumonia of known viral origin. A readmission occurring within 30 days from first admission/discharge was checked through chart revision and excluded if considered a deterioration of the first episode. In the post-vaccination period, the vaccine up-take was estimated to 80% in our cohort based on the age of the child at admission in relation to the three-dose vaccine schedule. In children aged 2 to >5 years, 34 children (5.7%) were born before July 1 2007 and thus not offered PCV7.
Study definitions
Patients with chronic comorbid conditions were identified through their respective discharge diagnosis and through chart review. The underlying diseases within each risk group in this study are shown in Table
1. During chart review, the CAP cases were further classified as severe using a previously published classification scheme [
4]. For the pneumonia to be classified as severe, the child had to have ≥1 major criteria; need of mechanical ventilation, acute need of non-invasive positive pressure ventilation, hypoxemia (less than SpO2 below 90%) or >2 minor criteria; tachypnea greater than age-adjusted respiratory rates, apnoea, increased breathing work, altered mental status or unexplained metabolic acidosis [
4].
Table 1
Definitions of chronic comorbidity used in this study and their prevalence in the chart review (n = 621) conducted from the two time periods
Obstructive disease | Children with asthma or recurrent obstructive bronchitis | 85 | 94 |
Chronic lung disease | Children with bronchopulmonary dysplasia | 8 | 8 |
Neurological disease | Children with impaired muscular tonus, cerebral palsy or severe epilepsy | 21 | 28 |
Chronic heart disease | Children with congenital heart defects | 3 | 0 |
Congenital malformations and/or syndromes | Children with craniofacial malformations, lung malformations, esofageal artresia | 16 | 6 |
Other diseasesa
| Children with diabetes, cancer and primary immunodeficiency | 47 | 26 |
Statistics
Statistical analysis was done in SPSS 21.0 and Stata/IC 12.0. Fischer’s exact test and Chi square statistics were used to compare parameters in the pre- and post-period and to compare parameters between the children with and without risk factors. We stratified the subjects in two age groups (0 < 2 years of age, 2 to <5 years of age). Mann-Whitney tests were performed to compare median and mean values. A p value of <0.05 was considered significant.
Discussion
In this retrospective study, children admitted to hospital for pneumonia have been characterized with respect to comorbidities and severity of disease before and after the introduction of a PCV into the Swedish childhood immunization programme. We conclude that children with underlying comorbidities also have benefitted from the introduction of PCV similar to otherwise healthy children.
Since the introduction of PCV in Sweden, the incidence of pneumonia hospitalizations in children <5 years of age has decreased as previously reported by us and others [
10,
1] and is in accordance to several international studies [
3,
5,
12]. The study by Berglund et al. covered several parts of Sweden with slightly different vaccine strategies from 2010 and onwards. In our cohort, the largest effect was seen in children <2 years of age, and these young children <2 years had received PCV7 or PCV13 (introduced in Jan. 2010). On the other hand, some children 3–5 years of age in the older age group may not have been offered PCV at all. It is therefore likely that the positive vaccine effect may increase also in the older age group in the coming years when all children have been offered PCV13. Although the trend of a reduced hospitalizations rate is similar in our study compared to Berglund et al., it should be noted that the patient cohorts differed as children with viral pneumonia were excluded in our study.
To understand whether PCV has benefitted children with underlying diseases, we also registered comorbidities associated with CAP hospitalization. Previous studies from the USA [
7,
15] suggest that PCV has significantly lower efficacy in preventing IPD in children with some comorbidities such as immunodeficiency, chronic medical conditions and asthma compared with children with no underlying disease. However, our results suggest that children with comorbidities also benefit from the PCV vaccination since the proportion of children with comorbidities and pneumonia was similar before and after the universal introduction of PCV. In addition, it is also important to also stress that the actual number of children with comorbidities decreased in after the introduction of PCV and this was most evident for children with congenital heart disease/malformations/cancer and primary immunodeficiencies. However, one major difference between previous studies and ours is that our study was based on a discharge diagnosis of pneumonia coded as bacterial (J13-J18.9) and not based on culture-verified IPD. Our finding emphasizes the importance of a high vaccine coverage also in children with chronic diseases.
We next sought to elucidate whether the clinical course during hospitalization differed in children with comorbidities compared to otherwise healthy children. Chart review identified a higher proportion of children with comorbidities than the coded discharge diagnosis which emphasize the risk of only using ICD codes. Different routine for coding between institutions as well as the accuracy of the individual paediatrician may impact studies based on discharge diagnosis only. In our cohorts, obstructive disease predominated in the two study periods as also shown in two previous US studies [
8,
15]. More than one underlying disease was present in one-third of the children with comorbidity. In children <2 years of age, there were less children with congenital malformations/syndromes or with other diseases (cancer, immunosuppression, diabetes) in the post-immunization period. In the older age group, the distribution of children with comorbidities was rather similar.
Not surprisingly, children with comorbidities in our cohort more often presented with severe pneumonia were more often in need of PICU care. Unfortunately, it was not possible to ascertain from the chart review whether the children with more severe pneumonia actually had received PCV or not, which otherwise would have been interesting. The proportion of children in PICU was much lower in our study compared to recently published data from an active population-based surveillance study of CAP in the USA [
8]. Whether this reflects more severe or multiple comorbidities in the different populations or differences in management of severe cases is difficult to ascertain. In the study by Jain et al., 50% had underlying conditions, and 21% of admitted children were in need of ICU care although there may have been a selection bias since one third of possible cases declined participation. The frequency of direct complication to pneumonia (empyema/sepsis) did not change significantly between the study periods in our population contrary to what has been previously shown for empyema in the PCV post-immunization era [
6,
9]. Albeit it is possible that our cohort is too small to detect any changes compared to the international studies, the mortality in our selected cohort was low and occurred in children with underlying diseases, which is in accordance with other studies [
8,
12].
Several limitations exist with this study. Firstly, a limitation is that the individual vaccination data were not available. However, since data suggests a 98% high vaccine coverage for PCV in children born 2010 in Stockholm county, we think that our estimate of vaccine coverage based on age is reliable [
10]. We cannot exclude a selection bias for unvaccinated children with comorbidities, especially for the groups of children with perinatal disease such as BPD or congenital malformations/syndromes since these children may have received their immunizations later in life compared to healthy newborns. However, these children constituted a minor fraction of the children with comorbidities. PCV also has a herd effect in non-vaccinated groups, and this study was designed to evaluate the overall effect of the programme.
Secondly, a limitation is that the initial selection of cases has been made using ICD codes for pneumonia coded as bacterial and we know that there could be children who were given the wrong diagnosis or where comorbidities were not registered. However, to validate discharge diagnosis, we performed chart review in a substantial number of cases. Unfortunately, we could not establish the true aetiology of pneumonia due to incomplete data during chart review, but we know from other studies [
8,
17] that all cases were not true ‘bacterial pneumoniaʼ. It was also evident that sampling for microbiological diagnosis differed between the three hospitals included. Within the same time frame as our study, viral PCR diagnostics were introduced in 2007 [
20], which may have facilitated and correctly improved the diagnosis of viral pneumonia in children.
In conclusion, we show that all children have benefitted from the reduction of CAP hospitalization after introduction of PCV. In addition, we show that approximately half of all children hospitalized with CAP also have underlying comorbidities. Our data suggests that studies only based on discharge diagnosis may underestimate other important study variables as in our case.
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