CONTEXT:

Invasive pneumococcal disease (IPD) and pneumonia are a leading cause of morbidity and mortality throughout the world, and asthma is the most common chronic disease of childhood.

OBJECTIVE:

To evaluate the risk of IPD or pneumonia among children with asthma after the introduction of pneumococcal conjugate vaccines (PCVs).

DATA SOURCES:

Four electronic databases were searched.

STUDY SELECTION:

We selected all cohorts or case-control studies of IPD and pneumonia in populations who already received PCV (largely 7-valent pneumococcal conjugate vaccine), but not 23-valent pneumococcal polysaccharide, in which authors reported data for children with asthma and in which healthy controls were included, without language restriction.

DATA EXTRACTION:

Two reviewers independently reviewed all studies. Primary outcomes were occurrence of IPD and pneumonia. Secondary outcomes included mortality, hospital admissions, hospital length of stay, ICU admission, respiratory support, costs, and additional medication use.

RESULTS:

Five studies met inclusion criteria; of those, 3 retrospective cohorts (∼26 million person-years) and 1 case-control study (N = 3294 children) qualified for the meta-analysis. Children with asthma had 90% higher odds of IPD than healthy controls (odds ratio = 1.90; 95% confidence interval = 1.63–2.11; I2 = 1.7%). Pneumonia was also more frequent among children with asthma than among controls, and 1 study reported that pneumonia-associated costs increased by asthma severity.

LIMITATIONS:

None of the identified studies had information of asthma therapy or compliance.

CONCLUSIONS:

Despite PCV vaccination, children with asthma continue to have a higher risk of IPD than children without asthma. Further research is needed to assess the need for supplemental 23-valent pneumococcal polysaccharide vaccination in children with asthma, regardless of their use of oral steroids.

Streptococcus pneumoniae is still one of the most frequent causes of invasive disease, such as sepsis and meningitis, and a frequent cause of bacterial pneumonia, acute otitis media, and rhinosinusitis.1  Although these diseases can occur in both healthy children and those with chronic underlying diseases, their incidence and severity are significantly higher in those with chronic underlying disease.2 

Invasive pneumococcal disease (IPD) is a leading cause of morbidity and mortality throughout the world. In 2000, before the introduction of the 7-valent pneumococcal conjugate vaccine (PCV7), an estimated 14.5 million episodes of IPD occurred among children <5 years of age, resulting in an estimated 826 000 deaths (11% of all deaths in that age group).3  Pneumococcal conjugate vaccine (PCV) PCV7 was introduced in the United States in 2000, and 13-valent pneumococcal conjugate vaccine (PCV13) replaced it in 2010. Current guidelines from the US Centers for Disease Control and Prevention (CDC)4  and the American Academy of Pediatrics (AAP)5  recommend 4 doses of PCV13 (at 2, 4, 6, and 12–15 months of age) and a dose of the 23-valent pneumococcal polysaccharide vaccine (PPSV23) at 2 years of age for children with conditions considered high risk for IPD or as soon as possible after a diagnosis of chronic illness is made after the age of 2 years. High-risk conditions include cerebrospinal fluid leak or cochlear implants; diabetes; HIV infection or immunodeficiencies (congenital, acquired, or secondary to medications); anatomic or functional asplenia; sickle cell and other hemoglobinopathies; neoplasms; and chronic diseases including chronic heart, lung, kidney, or liver diseases. Currently, PPSV23 vaccination is recommended for patients with asthma only if they are treated with high-dose oral corticosteroid therapy.4,5 

Asthma is the most common chronic disease of childhood.6  It affects >6.5 million children in the United States alone,7  with millions more around the world, and its prevalence steadily increased from the 1980s to at least the 2000s.7  In a previous study in which authors reported increased risk of IPD in children with asthma and adults involved a period of time (1995–2002) in which most children would not have received PCV,8  and a systematic review of IPD in asthma included only 1 pediatric study in the PCV era.9  Here, we aim to evaluate current evidence on the risk of IPD in children with asthma after the introduction of PCV.

We searched 4 electronic databases (Medline, the Cochrane Collaboration clinical trials register, Latin American and Caribbean Health Sciences Literature, and Cumulative Index to Nursing and Allied Health Literature) up to October 2018. The search was conducted by using the following keywords: “(((pneumococcal infections) OR (invasive pneumococcal disease) OR (pneumococcal pneumonia)) AND ((asthma OR wheezing))),” as well as the corresponding Medical Subject Headings terms, restricted to children (birth to 18 years of age). We also searched the references of included publications as well as other nonbibliographic data sources such as pharmaceutical industry Web sites.

The inclusion criteria were (1) cohorts or case-control studies including children with and without asthma; (2) assessment of IPD (defined as the isolation of S pneumoniae from a normally sterile fluid [eg, blood, cerebrospinal fluid, pleural fluid, peritoneal fluid, pericardial fluid, surgical aspirate, bone or joint fluid by any laboratory diagnosis test]) with association of morbidity or mortality; (3) in populations who have already received PCV7, 10-valent pneumococcal conjugate vaccine, or PCV13, but not PPSV23; with (4) no language restriction. The exclusion criteria were (1) no specific data for children with asthma reported in the population analysis, (2) IPD morbidity or mortality description in children with asthma but in the absence of a control group, and (3) reviews, letters, abstracts, or articles lacking sufficient information in English for data synthesis or analysis. The primary outcomes were the occurrence of IPD, defined as above, and pneumococcal pneumonia. Secondary outcomes, if available, were hospital admissions, mortality, length of hospital stay, admission to the ICU, need for invasive respiratory support, additional medication use (ie, in addition to the patient’s baseline), all-cause pneumonia, and costs associated with disease.

Titles, abstracts, and citations were independently analyzed by 2 independent investigators (J.A.C.-R. and E.F.), and any disagreements were resolved by consensus after discussion. The reviewers independently assessed the full text of all studies for inclusion on the basis of the criteria for population intervention, study design, and outcomes. After obtaining full reports from potentially relevant studies, they independently reassessed eligibility. If the information was incomplete, we attempted to contact the authors. The risk of bias from including certain studies was assessed according to the Newcastle-Ottawa Scale.10,11 

When feasible, we calculated pooled odds ratios (ORs) with 95% confidence intervals (CIs). Heterogeneity was assessed by using the I2 test (≤25% absence of bias; 26%–39% unimportant; 40%–60% moderate; 60%–100% substantial bias).12  To address the variability across studies for each outcome of interest, a fixed-effects meta-analysis was used when low heterogeneity was present (I2 <40%), and a random-effects meta-analysis was performed when high heterogeneity was detected (I2 ≥40%). Meta-analyses were performed by using Stata version 14.0 (Stata Corp, College Station, TX) or Review Manager 5.3 software (2014; The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark).

A total of 125 studies were initially identified in the databases and other sources (Fig 1). After excluding duplicates, we reviewed 123 abstracts; 112 studies were excluded because they did not meet inclusion criteria. Eleven full-text articles were evaluated, and 5 of them1317  fulfilled the inclusion criteria for the qualitative synthesis, of which 41316  also fulfilled criteria for the quantitative synthesis or meta-analysis (Table 1). The other 6 studies were excluded because they were performed before introduction of PCV7 (n = 3),8,18,19  they provided no specific data by asthma status (n = 1),20  or they included no pediatric data (n = 2).21,22 

FIGURE 1

Flowchart of study selection. Two studies were reviewed but not included in the meta-analysis: Weycker et al16  (used data from the same cohort as Pelton et al14 ) and Hsu et al17  (insufficient data available).

FIGURE 1

Flowchart of study selection. Two studies were reviewed but not included in the meta-analysis: Weycker et al16  (used data from the same cohort as Pelton et al14 ) and Hsu et al17  (insufficient data available).

TABLE 1

Summary of Studies Included in the Qualitative Summary and Quantitative Analysis

Author (Year)Country (Region)Study DesignIncluded ParticipantsOutcomesMain Results, Notes, and Funding
Pilishvili et al13  (2010) United States (select counties in 8 US states) CC Children 3–59 mo old with IPD versus children without IPD of the same age living in same area. IPD defined on the basis of culture data from an active bacteria core surveillance system (2001–2004). Asthma was defined by report during questionnaires. IPD IPD = 27% with asthma; CG = 18% with asthma 
IPD cases: n = 782 Risk of IPD (asthma compared to the CG): aOR = 1.8 (95% CI = 1.5–2.2); P < .001 
CG: n = 2512 Multivariable model (controlling for multiple comorbidities): aOR = 1.5 (1.1–2.1) 
Funding: CDC, National Vaccine Program 
Pelton et al14  (2014)a United States (claims data covering providers in several states) RC Children <18 y of age with high-risk and at-risk conditions for IPD versus children without risk conditions in 3 integrated health care claims database (2007–2010). IPD, pneumococcal pneumonia, all-cause pneumonia RR for IPD among children with asthma: 
Children <5 y old: 6 million person-years. Age <5 y: aRR 1.6 (1.0–2.4) 
Children 5–17 y old: 20.5 million person-years; IPD and asthma defined by using the ICD-9Age 5–17 y: aRR 2.1 (1.4–3.2) 
RR for pneumococcal pneumonia among children with asthma: 
Age <5 y: aRR 3.5 (3.0–4.0) 
Age 5–17 y: aRR 2.8 (2.6–3.1) 
Funding: Pfizer, Inc 
Kwak et al15  (2015) Korea (whole-country database) RC Retrospective population-based cohort using Korean Health Insurance Review and Assessment database (2010–2011) IPD In children 0–18 y of age, odds of asthma among IPD cases: 
2010: 398 of 935 106 subjects had IPD. In 2010: aOR = 2.08 (1.25–3.45) 
2011: 428 of 952 295 subjects had IPD. In 2011: aOR = 3.26 (1.74–6.11) 
IPD and asthma were defined by using the ICD-10Unclear whether the risk pool overlapped between 2010 and 2011; also, ∼50% of subjects in each year had asthma, suggesting a matched CC design, but it was not stated in the methods 
Funding: Pfizer Korea Ltd 
Weycker et al16  (2016)a United States (claims data covering providers in several states) RC Review of 3 integrated health care claims repositories (2007–2010) IPD, all-cause pneumonia In children <18 y: 
Children <18 y old: 26.5 million person-years; IPD and asthma defined by using ICD-9 aRR of IPD among children with asthma: 1.5 (1.1–2.0); aRR of pneumonia among children with asthma: 2.9 (2.9–3.0) 
Funding: Pfizer, Inc 
Author (Year)Country (Region)Study DesignIncluded ParticipantsOutcomesMain Results, Notes, and Funding
Pilishvili et al13  (2010) United States (select counties in 8 US states) CC Children 3–59 mo old with IPD versus children without IPD of the same age living in same area. IPD defined on the basis of culture data from an active bacteria core surveillance system (2001–2004). Asthma was defined by report during questionnaires. IPD IPD = 27% with asthma; CG = 18% with asthma 
IPD cases: n = 782 Risk of IPD (asthma compared to the CG): aOR = 1.8 (95% CI = 1.5–2.2); P < .001 
CG: n = 2512 Multivariable model (controlling for multiple comorbidities): aOR = 1.5 (1.1–2.1) 
Funding: CDC, National Vaccine Program 
Pelton et al14  (2014)a United States (claims data covering providers in several states) RC Children <18 y of age with high-risk and at-risk conditions for IPD versus children without risk conditions in 3 integrated health care claims database (2007–2010). IPD, pneumococcal pneumonia, all-cause pneumonia RR for IPD among children with asthma: 
Children <5 y old: 6 million person-years. Age <5 y: aRR 1.6 (1.0–2.4) 
Children 5–17 y old: 20.5 million person-years; IPD and asthma defined by using the ICD-9Age 5–17 y: aRR 2.1 (1.4–3.2) 
RR for pneumococcal pneumonia among children with asthma: 
Age <5 y: aRR 3.5 (3.0–4.0) 
Age 5–17 y: aRR 2.8 (2.6–3.1) 
Funding: Pfizer, Inc 
Kwak et al15  (2015) Korea (whole-country database) RC Retrospective population-based cohort using Korean Health Insurance Review and Assessment database (2010–2011) IPD In children 0–18 y of age, odds of asthma among IPD cases: 
2010: 398 of 935 106 subjects had IPD. In 2010: aOR = 2.08 (1.25–3.45) 
2011: 428 of 952 295 subjects had IPD. In 2011: aOR = 3.26 (1.74–6.11) 
IPD and asthma were defined by using the ICD-10Unclear whether the risk pool overlapped between 2010 and 2011; also, ∼50% of subjects in each year had asthma, suggesting a matched CC design, but it was not stated in the methods 
Funding: Pfizer Korea Ltd 
Weycker et al16  (2016)a United States (claims data covering providers in several states) RC Review of 3 integrated health care claims repositories (2007–2010) IPD, all-cause pneumonia In children <18 y: 
Children <18 y old: 26.5 million person-years; IPD and asthma defined by using ICD-9 aRR of IPD among children with asthma: 1.5 (1.1–2.0); aRR of pneumonia among children with asthma: 2.9 (2.9–3.0) 
Funding: Pfizer, Inc 

aRR, adjusted risk rate; CC, case-control; CG, control group; ICD-10, International Classification of Diseases, 10th Revision; RC, retrospective cohort.

a

Pelton et al14  and Weycker et al16  reported on the same cohort.

The 5 identified studies were published from 2010 to 2016. One study was a case-control analysis of children with and without IPD13  and included 3294 children (45 with asthma; 782 with IPD and 2512 in the control group), 3 were retrospective cohorts,1416  and the fifth study was a retrospective study of microbiology laboratory reports from 586 IPD cases from 2001 to 2007.17  The latter study was not included for the quantitative synthesis. In none of the studies did the authors report separately the fluid site from which the pneumococcal infection was isolated.

Among the 4 studies included for the quantitative synthesis or meta-analysis (Table 1), 3 were conducted in the United States,13,14,16  and 1 was conducted in Korea.15  Pelton et al14  and Weycker et al16  reported on the same cohort, with a total of 26.5 million person-years of follow-up, including 1.23 million person-years in children with asthma. In the third retrospective cohort,15  the authors reported 398 IPD cases among 935 106 participants (467 294 with asthma) in 2010 and 428 IPD cases among 952 295 participants (482 155 with asthma) in 2011, but it was unclear whether the populations at risk were different for each of the 2 years. Pilishvili et al13  defined IPD on the basis of isolation of Pneumococcus from a normally sterile site in an active bacterial core surveillance program, and asthma was defined by questionnaires. Pelton et al14  and Weycker et al16  defined IPD and asthma by using International Classification of Diseases, Ninth Revision (ICD-9), codes, whereas Kwak et al15  used International Classification of Diseases, 10th Revision, codes.

Pilishvili et al13  included children <6 years of age, and Pelton et al14  reported separate estimates for children <5 and 5 to 17 years of age; in contrast, Kwak et al15  and Weycker et al16  reported estimates for children <18 years old. Pilishvili et al13  included children of an age group for which PCV7 was recommended and adjusted their analyses by receipt of ≥1 dose of PCV7, Pelton stated that study data were collected during a period when 89% of children <2 years old had received 3 PCV7 doses, and Kwak et al15  only mention that children not receiving oral steroids and children with asthma >6 years old were excluded from receiving PCV13 and PPSV23. A description of study quality assessment is presented in Table 2. Pilishvili et al13  was funded by the CDC and the National Vaccine Program Office, Pelton et al14  and Weycker et al16  were funded by Pfizer, Inc, and Kwak et al15  were funded by Pfizer Korea, Ltd.

TABLE 2

Study Quality Assessment

Newcastle-Ottawa Scale for Cohort StudiesPelton et al14  2014Kwak et al15  2015Weycker et al16  2016Pilishvili et al13  2010Hsu et al17  2011
Selection      
 Exposed representative of the community Adequate Adequate Adequate Adequate Adequate 
 Nonexposed selected from the same community Adequate Unclear or not reported Adequate Adequate Unclear or not reported 
 Exposure ascertained by secure records or structured interview Adequate Adequate Adequate Adequate Adequate 
 Demonstration that outcome of interest was not present at study start Adequate Adequate Adequate Adequate Adequate 
Comparability      
 Study controlled for most important factor(s) Inadequate Adequate Unclear or not reported Inadequate Inadequate 
 Study controlled for other factor(s) Inadequate Inadequate Inadequate Adequate Inadequate 
Outcome      
 Independent blind assessment or using record linkage Adequate Adequate Adequate Adequate Adequate 
 Follow-up long enough for outcome to occur Adequate Adequate Adequate Adequate Adequate 
 Subjects lost to follow-up unlikely to introduce bias Unclear or not reported Adequate Unclear or not reported Inadequate Inadequate 
Newcastle-Ottawa Scale for Cohort StudiesPelton et al14  2014Kwak et al15  2015Weycker et al16  2016Pilishvili et al13  2010Hsu et al17  2011
Selection      
 Exposed representative of the community Adequate Adequate Adequate Adequate Adequate 
 Nonexposed selected from the same community Adequate Unclear or not reported Adequate Adequate Unclear or not reported 
 Exposure ascertained by secure records or structured interview Adequate Adequate Adequate Adequate Adequate 
 Demonstration that outcome of interest was not present at study start Adequate Adequate Adequate Adequate Adequate 
Comparability      
 Study controlled for most important factor(s) Inadequate Adequate Unclear or not reported Inadequate Inadequate 
 Study controlled for other factor(s) Inadequate Inadequate Inadequate Adequate Inadequate 
Outcome      
 Independent blind assessment or using record linkage Adequate Adequate Adequate Adequate Adequate 
 Follow-up long enough for outcome to occur Adequate Adequate Adequate Adequate Adequate 
 Subjects lost to follow-up unlikely to introduce bias Unclear or not reported Adequate Unclear or not reported Inadequate Inadequate 

Authors of all 5 studies reported IPD.1317  Pilishvili et al13  reported that 27% of patients with IPD had asthma compared with 18% of patients in the control group, for an adjusted odds ratio (aOR) of 1.8 (95% CI = 1.50–2.22). Pelton et al14  reported IPD rates (per 100 000) of 11.6 for children <5 years of age with asthma (compared to 7.3 for healthy children) and 2.3 for children 5 to 17 years old with asthma (compared to 1.1 for healthy children); the adjusted rate ratios (RRs) were 1.6 (1.0–2.4) and 2.1 (1.4–3.2) for each age group, respectively. Kwak et al15  reported aORs of 2.08 (1.25–3.45) in 2010 and 3.26 (1.74–6.11) in 2011 for IPD among children with asthma versus children without asthma. Weycker et al16  reported an IPD rate of 3.7 per 100 000 for children with asthma (compared to 2.5 for healthy controls), with an adjusted RR of 1.5 (1.1–2.0).

The meta-analysis (Fig 2) of IPD revealed a pooled estimate of 1.90 (1.63–2.11) using a fixed-effects model and 1.90 (1.63–2.21) using a random-effects model. There was low heterogeneity (I2 = 1.7%; P = .40) among studies. The studies by Pelton et al14  and Weycker et al16  were reported on the same cohort. Only estimates reported by Pelton et al14  were included in the pooled analysis because they reported data on preschoolers and schoolchildren separately. In a sensitivity analysis including data from Weycker et al16  instead, the pooled estimate remained virtually unchanged (OR 1.86 [1.48–2.35]). Hsu et al17  was not included in the meta-analysis of IPD because they only reported data on pneumonia.

FIGURE 2

Meta-analysis of IPD in children with asthma compared with children without known risk factors. Please note that Pelton includes 2 different age groups (<5 years and 5–17 years), and Kwak et al15  included estimates for 2 years (2010 and 2011); thus, the studies have 2 separate entries in the analysis. ES, effect estimate for the OR. ID, identification.

FIGURE 2

Meta-analysis of IPD in children with asthma compared with children without known risk factors. Please note that Pelton includes 2 different age groups (<5 years and 5–17 years), and Kwak et al15  included estimates for 2 years (2010 and 2011); thus, the studies have 2 separate entries in the analysis. ES, effect estimate for the OR. ID, identification.

Authors in some of the included studies performed subgroup analyses. Pilishvili et al13  evaluated the risk of IPD from serotypes not covered by PCV7 and reported an aOR of 1.5 (1.1–2.1) for children with asthma compared with children in a control group. Pelton et al14  evaluated the risk of IPD by asthma severity and reported adjusted RRs of 0.9 (0.3–2.4), 1.4 (0.8–2.6), and 6.6 (3.0–14.8) for mild, moderate, and severe asthma, respectively, among children <5 years of age. For children 5 to 17 years old, the adjusted RRs were 1.7 (0.8–3.4) for mild asthma and 2.6 (1.5–4.3) for moderate asthma (severe asthma was not analyzed in that age group).14 

Authors of 3 studies also reported on the risk of pneumococcal or all-cause pneumonia in children with asthma.14,16,17  Among children <5 years of age, Pelton et al14  reported adjusted RRs of 3.5 (3.0–4.0) for pneumococcal pneumonia and of 3.0 (3.0–3.0) for all-cause pneumonia. For children ages 5 to 17 years, the RRs were 2.8 (2.6–3.1) and 3.5 (3.4–3.5), respectively.14  Using data from the same cohort, Weycker et al16  reported an adjusted RR of 2.9 (2.9–3.0) for all-cause pneumonia in children with asthma <18 years of age. Hsu et al17  reported that a higher proportion of children with asthma had pneumococcal pneumonia compared with children with no known risk factors (65% vs 31%; P < .05); of note, that study included only children with asthma who were not receiving corticosteroids. As mentioned before, Pelton et al14  and Weycker et al16  reported on the same population; thus, a meta-analysis was not performed.

In none of the included studies did authors report data on asthma for hospital admission, mortality, length of hospital stay, ICU admission, invasive respiratory support, or additional medication use. Weycker et al16  reported on costs associated with IPD and all-cause pneumonia. Estimated costs (per 100 000 person-years) for IPD were $100 020 for children with mild asthma, $172 002 for moderate asthma, and $638 452 for severe asthma (compared with $72 581 for healthy controls), with cost ratios of 1.4 (0.1–3.9), 2.4 (0.6–5.0), and 8.9 (0.0–33.9), respectively. For all-cause pneumonia, estimated costs per 100 000 person-years for mild, moderate, and severe asthma were $7.5, $14.6, and $46.8 million, respectively (compared with $1.7 million for healthy controls), and the respective cost ratios were 4.3 (3.8–4.9), 8.4 (7.7–9.1), and 26.8 (22.5–31.3).

This review reveals that children with asthma are at a higher risk of IPD and pneumonia than children without asthma, even after the introduction of PCV. For the first time, this meta-analysis reveals 90% increased odds of IPD among children with asthma in populations vaccinated with PCV7, 10-valent pneumococcal conjugate vaccine, and/or PCV13 but not PPSV23. If confirmed, these findings will bear clinical and public health importance because the CDC7  and AAP5  guidelines currently recommend the polysaccharide vaccine (PPSV23) after 2 years of age for children with asthma only “if treated with prolonged high-dose oral corticosteroids.” However, it is important to note that the pooled analysis was based on a small number of studies; thus, there is not sufficient evidence at this time to make any clinical or policy recommendations.

The reported results have biologically plausible explanations. In a case-control study, children with asthma receiving inhaled corticosteroid (ICS) therapy for at least 30 days (mean duration 8.6 months) had significantly higher prevalence of oropharyngeal colonization by S pneumoniae than those not being treated with ICS (adjusted prevalence ratio of 3.75 [1.72–8.18]).23  ICS deposition in the oropharynx may inhibit mucosal immune response and partially contribute to the risk of oropharyngeal candidiasis, a well-known local adverse event of ICS,24  and one could hypothesize that the same may be true of S pneumoniae. Thus, a higher carrier rate of S pneumoniae in the oropharynx, along with the impaired airway clearance that may be present in asthma, could potentially increase the risk of pneumococcal diseases such as pneumonia or IPD. Furthermore, S pneumoniae colonization may be common in all school-aged children and adolescents with asthma, regardless of the severity of the disease and the administration of PCV7 in the first years of life.25  A recent quasi-cohort study26  that included 152 412 patients with asthma aged 12 to 35 years (of whom 1928 had pneumonia during follow-up) revealed an increased risk of pneumonia associated with current use of ICSs (RR: 1.83 [1.57–2.14]) for an excess risk of 1.44 cases per 1000 person-years (rate difference [RD]: 1.44 [1.03–1.87]). There was an excess pneumonia risk with low doses (RD: 1.60 [1.06–2.45]), moderate doses (RD: 1.53 [1.12–2.08]), and high doses (RD: 1.96 [1.64–2.34]) of ICSs, and this increased risk was present for both budesonide and fluticasone. That study was done between 1990 and 2007 in Canada, where the PCV7 for children was implemented in 2001.26  Serotypes 19 F, 4, and 9V (all contained in PCV7) were the most frequently identified serotypes in vaccinated subjects, highlighting the limited protection against colonization provided by PCV7 and the issue of persistent colonization by the pneumococcal serotypes included in the vaccine, which could leave children with asthma at risk for infection.

Children with atopic conditions other than asthma may also have an impaired response to S pneumoniae.27  Among children ages 3 to 8 years, only 18% of those with eczema showed adequate antibody responses to PPSV23, compared with 57% of those without eczema (OR: 0.2 [0.05–0.84]; P = .03). On the other hand, however, Quezada et al28  recently reported that children with well-controlled asthma without a history of recurrent respiratory infections had pneumococcal antibody levels and percentages of serotype-specific protection to S pneumoniae comparable to those of healthy children. Rose et al29  enrolled preschoolers (2–5 years of age) with mild to moderate asthma to undergo sequential immunization with 1 dose of PCV7 followed by a single dose of PPSV23, with half of them randomly assigned to receiving PPSV23 8 weeks after PCV and the other half to a 10-month interval. They reported that although both sequential pneumococcal vaccine regimens were safe and immunogenic, immunogenicity was higher when the booster was given after 10 months compared to 8 weeks. Thus, limitations in serum antibody response may contribute to the increased rates of IPD among children with asthma.

Finally, a Canadian study designed to estimate the number needed to vaccinate (NNV) to prevent 1 case of IPD revealed for PPSV23 in children with asthma is higher than for healthy children and comparable to that of other high-risk conditions.30  The NNV for PPSV23 ranged from 905 to 1023 for healthy children, 581 to 677 for low-risk asthma, and 318 to 371 for high-risk asthma. On the basis of this finding, they concluded that it was warranted to add asthma to the list of high-risk conditions recommended for pneumococcal vaccination. Our results further highlight that the recommendation to administer PPSV23 to children with asthma should be regardless of asthma severity or chronic use of oral steroids.

This systematic review and meta-analysis have several limitations. First, there was a small number of studies available in the literature, with differences in design, study population, and reporting methodology. Given the small number of studies, we could not perform a formal assessment of publication bias. None of the identified studies had information of asthma therapy or compliance. None of our secondary outcomes were reported in the available studies. Given the small number of studies with information about pneumococcal pneumonia (most of them defined by International Classification of Diseases codes), we were not able to perform a quantitative analysis. Although in their study, Weycker et al16  reported markedly increased costs of treating all-cause pneumonia in children with asthma, there was no analysis on pneumococcal pneumonia, and the cost ratios for IPD were nonsignificant. Finally, 3 of 4 studies that reported funding were supported by pharmaceutical companies, and only 1 was funded by the CDC; although we cannot make any assertions to this regard on the basis of the available data, it will be important that future studies continue to be transparent about the role of the funding source in the study design, execution, interpretation, and publication.

Our review and meta-analysis revealed that children with asthma who received PCV as part of their regular immunization schedules still have 90% higher odds of IPD than children without asthma. Pneumococcal and all-cause pneumonia were also significantly more frequent in children with asthma. If further confirmed in large, independent studies, these findings would suggest that children with asthma >2 years of age should receive PPSV23 after their regular PCV vaccination schedule irrespective of the use of high-dose oral steroids indicated in the current CDC and AAP guidelines.

Dr Castro-Rodriguez conceptualized and designed the study, reviewed and collected the data, drafted the initial manuscript, and reviewed and revised the manuscript; Dr Abarca made a substantial contribution to the analysis and interpretation of data and critically revised the manuscript for important intellectual content; Dr Forno reviewed and collected the data, conducted and interpreted the meta-analyses, and reviewed and revised the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

FUNDING: Dr Castro-Rodriguez’s contribution was funded in part by Chilean Comisión Nacional de Investigación Científica y Tecnológica Programa de Investigacion Asociativa/Anillos de Ciencia y Tecnologia (grant ACT172097) from the Chilean Comisión Nacional de Investigación Científica y Tecnológica. Dr Forno’s contribution was funded in part by grant HL125666 from the US National Institutes of Health. Funded by the National Institutes of Health (NIH).

COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2019-3360.

     
  • AAP

    American Academy of Pediatrics

  •  
  • aOR

    adjusted odds ratio

  •  
  • CDC

    Centers for Disease Control and Prevention

  •  
  • CI

    confidence interval

  •  
  • ICD-9

    International Classification of Diseases, Ninth Revision

  •  
  • ICS

    inhaled corticosteroid

  •  
  • IPD

    invasive pneumococcal disease

  •  
  • NNV

    number needed to vaccinate

  •  
  • OR

    odds ratio

  •  
  • PCV

    pneumococcal conjugate vaccine

  •  
  • PCV7

    7-valent pneumococcal conjugate vaccine

  •  
  • PCV13

    13-valent pneumococcal conjugate vaccine

  •  
  • PPSV23

    23-valent pneumococcal polysaccharide vaccine

  •  
  • RD

    rate difference

  •  
  • RR

    rate ratio

1
Tan
TQ
.
Pediatric invasive pneumococcal disease in the United States in the era of pneumococcal conjugate vaccines
.
Clin Microbiol Rev
.
2012
;
25
(
3
):
409
419
2
Kaplan
SL
,
Mason
EO
 Jr
,
Wald
E
, et al
.
Six year multicenter surveillance of invasive pneumococcal infections in children
.
Pediatr Infect Dis J
.
2002
;
21
(
2
):
141
147
3
O’Brien
KL
,
Wolfson
LJ
,
Watt
JP
, et al;
Hib and Pneumococcal Global Burden of Disease Study Team
.
Burden of disease caused by Streptococcus pneumoniae in children younger than 5 years: global estimates
.
Lancet
.
2009
;
374
(
9693
):
893
902
4
Nuorti
JP
,
Whitney
CG
;
Centers for Disease Control and Prevention (CDC)
.
Prevention of pneumococcal disease among infants and children - use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine - recommendations of the Advisory Committee on Immunization Practices (ACIP)
.
MMWR Recomm Rep
.
2010
;
59
(
RR
):
1
18
5
American Academy of Pediatrics Committee on Infectious Diseases
.
Recommendations for the prevention of Streptococcus pneumoniae infections in infants and children: use of 13-valent pneumococcal conjugate vaccine (PCV13) and pneumococcal polysaccharide vaccine (PPSV23)
.
Pediatrics
.
2010
;
126
(
1
):
186
190
6
World Health Organization
.
Asthma Fact Sheet
.
Geneva, Switzerland
:
World Health Organization
;
2017
7
Centers for Disease Control and Prevention
.
Data, statistics, and surveillance: most recent asthma data.
2018
. Available at: www.cdc.gov/asthma/most_recent_data.htm. Accessed July 15, 2019
8
Talbot
TR
,
Hartert
TV
,
Mitchel
E
, et al
.
Asthma as a risk factor for invasive pneumococcal disease
.
N Engl J Med
.
2005
;
352
(
20
):
2082
2090
9
Boikos
C
,
Quach
C
.
Risk of invasive pneumococcal disease in children and adults with asthma: a systematic review
.
Vaccine
.
2013
;
31
(
42
):
4820
4826
10
Wells
GA
,
Shea
B
,
O’Connel
D
, et al
The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses.
2009
. Available at: www.ohri.ca/programs/clinical_epidemiology/oxford.htm. Accessed July 15, 2019
11
Cook
DA
,
Reed
DA
.
Appraising the quality of medical education research methods: the Medical Education Research Study Quality Instrument and the Newcastle-Ottawa Scale-Education
.
Acad Med
.
2015
;
90
(
8
):
1067
1076
12
Higgins
JP
,
Thompson
SG
,
Deeks
JJ
,
Altman
DG
.
Measuring inconsistency in meta-analyses
.
BMJ
.
2003
;
327
(
7414
):
557
560
13
Pilishvili
T
,
Zell
ER
,
Farley
MM
, et al
.
Risk factors for invasive pneumococcal disease in children in the era of conjugate vaccine use
.
Pediatrics
.
2010
;
126
(
1
).
14
Pelton
SI
,
Weycker
D
,
Farkouh
RA
,
Strutton
DR
,
Shea
KM
,
Edelsberg
J
.
Risk of pneumococcal disease in children with chronic medical conditions in the era of pneumococcal conjugate vaccine
.
Clin Infect Dis
.
2014
;
59
(
5
):
615
623
15
Kwak
BO
,
Choung
JT
,
Park
YM
.
The association between asthma and invasive pneumococcal disease: a nationwide study in Korea
.
J Korean Med Sci
.
2015
;
30
(
1
):
60
65
16
Weycker
D
,
Farkouh
RA
,
Strutton
DR
,
Edelsberg
J
,
Shea
KM
,
Pelton
SI
.
Rates and costs of invasive pneumococcal disease and pneumonia in persons with underlying medical conditions
.
BMC Health Serv Res
.
2016
;
16
:
182
17
Hsu
KK
,
Shea
KM
,
Stevenson
AE
,
Pelton
SI
;
Members of the Massachusetts Department of Public Health
.
Underlying conditions in children with invasive pneumococcal disease in the conjugate vaccine era
.
Pediatr Infect Dis J
.
2011
;
30
(
3
):
251
253
18
Shea
KM
,
Lash
TL
,
Antonsen
S
,
Jick
SS
,
Sørensen
HT
.
Population-based study of the association between asthma and pneumococcal disease in children
.
Clin Epidemiol
.
2015
;
7
:
325
334
19
Backhaus
E
,
Berg
S
,
Andersson
R
, et al
.
Epidemiology of invasive pneumococcal infections: manifestations, incidence and case fatality rate correlated to age, gender and risk factors
.
BMC Infect Dis
.
2016
;
16
:
367
20
Makwana
A
,
Sheppard
C
,
Borrow
R
,
Fry
N
,
Andrews
NJ
,
Ladhani
SN
.
Characteristics of children with invasive pneumococcal disease after the introduction of the 13-valent pneumococcal conjugate vaccine in England and Wales, 2010-2016
.
Pediatr Infect Dis J
.
2018
;
37
(
7
):
697
703
21
Klemets
P
,
Lyytikäinen
O
,
Ruutu
P
, et al
.
Risk of invasive pneumococcal infections among working age adults with asthma
.
Thorax
.
2010
;
65
(
8
):
698
702
22
Pitts
SI
,
Apostolou
A
,
DasGupta
S
, et al
.
Serotype 10A in case patients with invasive pneumococcal disease: a pilot study of PCR-based serotyping in New Jersey
.
Public Health Rep
.
2015
;
130
(
1
):
54
59
23
Zhang
L
,
Prietsch
SO
,
Mendes
AP
, et al
.
Inhaled corticosteroids increase the risk of oropharyngeal colonization by Streptococcus pneumoniae in children with asthma
.
Respirology
.
2013
;
18
(
2
):
272
277
24
Fukushima
C
,
Matsuse
H
,
Saeki
S
, et al
.
Salivary IgA and oral candidiasis in asthmatic patients treated with inhaled corticosteroid
.
J Asthma
.
2005
;
42
(
7
):
601
604
25
Esposito
S
,
Terranova
L
,
Patria
MF
, et al
.
Streptococcus pneumoniae colonisation in children and adolescents with asthma: impact of the heptavalent pneumococcal conjugate vaccine and evaluation of potential effect of thirteen-valent pneumococcal conjugate vaccine
.
BMC Infect Dis
.
2016
;
16
:
12
26
Qian
CJ
,
Coulombe
J
,
Suissa
S
,
Ernst
P
.
Pneumonia risk in asthma patients using inhaled corticosteroids: a quasi-cohort study
.
Br J Clin Pharmacol
.
2017
;
83
(
9
):
2077
2086
27
Arkwright
PD
,
Patel
L
,
Moran
A
,
Haeney
MR
,
Ewing
CI
,
David
TJ
.
Atopic eczema is associated with delayed maturation of the antibody response to pneumococcal vaccine
.
Clin Exp Immunol
.
2000
;
122
(
1
):
16
19
28
Quezada
A
,
Maggi
L
,
Norambuena
X
,
Inostroza
J
,
Quevedo
F
.
Response to pneumococcal polysaccharide vaccine in children with asthma, and children with recurrent respiratory infections, and healthy children
.
Allergol Immunopathol (Madr)
.
2016
;
44
(
4
):
376
381
29
Rose
MA
,
Gruendler
M
,
Schubert
R
,
Kitz
R
,
Schulze
J
,
Zielen
S
.
Safety and immunogenicity of sequential pneumococcal immunization in preschool asthmatics
.
Vaccine
.
2009
;
27
(
38
):
5259
5264
30
Okapuu
JM
,
Chétrit
E
,
Lefebvre
B
,
Quach
C
.
How many individuals with asthma need to be vaccinated to prevent one case of invasive pneumococcal disease?
Can J Infect Dis Med Microbiol
.
2014
;
25
(
3
):
147
150

Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.