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Keywords:

  • asthma;
  • cross-sectional study;
  • inhaled corticosteroid;
  • oropharyngeal colonization;
  • Streptococcus pneumoniae

ABSTRACT

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgement
  8. REFERENCES

Background and objective:  Recent studies have raised concerns about the link between use of inhaled corticosteroids (ICS) and risk of pneumonia in patients with chronic obstructive pulmonary disease. This cross-sectional study aimed to investigate the association between ICS and oropharyngeal colonization by Streptococcus pneumoniae (S. pneumoniae) among children (up to 18 years old) with asthma.

Methods:  Two age-matched groups of patients were consecutively recruited: (i) exposed group: children who had persistent asthma and were being treated with daily ICS for at least 30 days and (ii) non-exposed group: children who had asthma and were not being treated with ICS at study entry. Oropharyngeal specimens from the tonsillar area and posterior pharyngeal wall were collected. S. pneumoniae was identified according to National Committee for Clinical Laboratory Standards recommendations.

Results:  A total of 200 consecutive patients were recruited and 192 (96 in each group) were included in the analysis. In the exposed group, the mean daily dose of ICS was 400 µg of beclomethasone or equivalent and the mean duration of treatment was 8.6 months. The prevalence of oropharyngeal colonization by S. pneumoniae was higher in the exposed group compared with the non-exposed group (27.1% vs 8.3%, P = 0.001). After adjusting for potential confounders, use of ICS was an independent risk factor for oropharyngeal carriage of S. pneumoniae, with an adjusted prevalence ratio of 3.75 (95% confidence interval: 1.72–8.18, P = 0.001).

Conclusions:  Regular use of ICS is associated with an increased risk of having oropharyngeal colonization by S. pneumoniae in children with asthma.


Abbreviations:
ICS

inhaled corticosteroid

S. pneumoniae

Streptococcus pneumoniae

INTRODUCTION

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgement
  8. REFERENCES

Inhaled corticosteroids (ICS) are widely used in the treatment of persistent adult and childhood asthma and chronic obstructive pulmonary disease in adults.1–3 They are generally recognized as safe and well tolerated in both adults and children;4,5 however, recent studies have demonstrated a link between use of ICS and increased risk of pneumonia in patients with chronic obstructive pulmonary disease.6,7 So far, little is know about whether such association may also be observed among patients with asthma. A retrospective analysis of 60 randomized controlled trials showed that there was no increased risk of pneumonia in patients with asthma using budesinide.8 Moreover, the analysis of the primary dataset of 26 placebo-controlled, randomized trials (n = 9067 for budesonide; n = 5926 for placebo) found a reduced risk of pneumonia in patients with asthma receiving budesonide (hazard ratio: 0.52; 95% confidence interval (CI): 0.36–0.76; P < 0.001). However, caution should be taken in interpreting the results of this study. Firstly, the datasets were collated by the manufacturer of budesonide (AstraZeneca, London, UK), and all 60 trials included in the analysis were conducted or sponsored by AstraZeneca. Secondly, most of the trials were designed to assess the efficacy of budesonide, and occurrence of pneumonia as an adverse event was reported as secondary outcome. The lack of predefined criteria for diagnosis of pneumonia may have led to misclassification between pneumonia and acute asthma exacerbation, and frequency of the latter can be reduced by use of ICS. Therefore, more evidence from independent prospective studies is still needed regarding the possible link between use of ICS and risk of pneumonia in patients with asthma, especially in paediatric population.

ICS deposited in the oropharynx may inhibit mucosal immune response through their immunosuppressive effects which has been considered responsible for oropharyngeal candidiasis, a well-known local adverse event of ICS in patients with asthma.9 It may be expected that impaired local immune response caused by ICS could also favour oropharyngeal colonization by other microorganisms, including potential respiratory pathogens. We conducted this study to test the hypothesis that daily use of ICS in children with asthma may increase oropharyngeal carriage rate of Streptococcus pneumoniae (S. pneumoniae), one of the most important pathogen for community-acquired respiratory infections. The confirmation of the hypothesis may provide clues for the possible link between use of ICS and risk of pneumococcal respiratory infections in children with asthma.

METHODS

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgement
  8. REFERENCES

Study design and setting

This cross-sectional study has been conducted, between January 2009 and March 2011, at the Pediatric Pulmonary Clinic of a teaching hospital in the municipality of Rio Grande, located in the extreme south of Brazil and with a population of approximately 200 000. This is the only public health facility in the municipality providing subspecialist care for paediatric asthma patients. The research project has been approved by the Health Research Ethics Committee of the university (No.23116.004200/2008-2003) and written informed consent was obtained from parents/guardians of all participants before the recruitment.

Study subjects

Children up to 18 years old with diagnosis of asthma were eligible for the study. The clinical diagnosis of asthma was made by two senior paediatric pulmonologists based on the criteria of the Global Initiative for Asthma:10 (i) recurrent episodes (≥3) of wheezing, coughing or difficulty breathing; (ii) symptoms relieved by short-acting bronchodilators associated or not with corticosteroids; (iii) presence of precipitating or aggravating factors such as exposure to allergens or irritants, physical activities, emotional stress or climate change; and (iv) history of asthma, allergic rhinitis or atopic eczema among first-degree relatives and/or personal history of atopic eczema or allergic rhinitis.

Two groups of participants were consecutively recruited: (i) exposed group: children who had persistent asthma and were being treated with daily ICS, alone or in combination with long-acting β2-agonists, for at least 30 days and (ii) non-exposed group: children who had asthma and were not being treated with ICS at study entry. This group consisted of two subgroups: (i) patients with intermittent asthma and (ii) patients with persistent asthma, either before starting ICS therapy or ICS has been discontinued for at least 3 months due to good control of the disease. The classification of asthma severity and treatment regimes were based on the Global Initiative for Asthma guidelines.10

Children were excluded from the study if they had a history of any significant comorbid disease, such as neonatal chronic lung disease, cystic fibrosis, congenital cardiopulmonary diseases, chronic encephalopathy or immune deficiency syndrome; or if they had acute respiratory infections or acute asthma exacerbation requiring use of systemic corticosteroids within the past 2 weeks.

Data collection and laboratory procedures

Data collection was performed through an interview with child's parent or caretaker using a standard questionnaire. The following data of the child were obtained: age, gender, race, household size, number of siblings, exposure to tobacco smoke, attending day-care facilities or school, vaccination against S. pneumoniae, antibiotic use in the last 3 months and hospitalization in the last 6 months. Data regarding use of ICS and other medications such as intranasal corticosteroids were obtained from patient's medical record. Clinical evaluation and use of medications were recorded by two senior paediatric pulmonologists during regular clinic visits.

Oropharyngeal specimens from the tonsillar area and posterior pharyngeal wall were collected by one of the two investigators using a sterile cotton-tipped swab. The swabs were streaked onto 5% sheep blood agar and incubated aerobically at 37°C for 24 h. S. pneumoniae was identified by using standard microbiologic methods, which included colony morphology, Gram stain and optochin susceptibility. Antibiotic susceptibility was performed by the disk-diffusion method. All laboratory procedures were performed according to National Committee for Clinical Laboratory Standards recommendations.11 Both laboratory investigators and interviewers were blind to patient groups.

Statistical analysis

Sample size calculation was based on the preliminary results of 60 patients in which the prevalence of oropharyngeal colonization by S. pneumoniae was 6.7% (2/30) in the non-exposed group and 23.3% (7/30) in the exposed group. We recruited one age-matched non-exposed participant for each exposed participant, and our sample size calculation (power = 80%, α level = 0.05) determined that we would need to include at least 84 children in each group. For non-exposed group, we recruited two subgroups as previously defined with equal number of patients and matched for age.

Data were entered into the Epi-Info version 6.4 (Centers for Disease Control and Prevention, Atlanta, GA, USA) database. Statistical analysis was performed using the Stata version 11.0 program (Stata Corporation, College Station, TX, USA). The chi-square test or Fisher's exact test were used for categorical data as appropriate, and the two-tailed unpaired Student's t-test was used for normally-distributed continuous data when comparing the two groups. If normality assumption was not met, the Mann–Whitney test was performed. Association between use of ICS and S. pneumoniae colonization was estimated by prevalence ratio, that is, prevalence of oropharyngeal colonization in the exposed group divided by prevalence of oropharyngeal colonization in the non-exposed group. Poisson regression was used to calculate crude prevalence ratio and multivariate Poisson regression with robust variance was used to derive adjusted prevalence ratio, controlling for the effects of potential confounders. A Wald test was used to assess statistical significance. Two sensitivity analyses were performed to investigate the robustness of the findings: (i) excluding patients younger than 2 years old because diagnosis of asthma in that age group is less accurate2,10 and (ii) excluding patients with intermittent asthma from non-exposed group to assess the influence of asthma severity on the association between use of ICS and oropharyngeal colonization. Subgroup analyses were conducted to explore the effects of daily dose and treatment duration of ICS. For statistical analysis, the cut-off probability for rejecting the null hypothesis was defined as less than 5% (P < 0.05).

RESULTS

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgement
  8. REFERENCES

A total of 200 consecutive patients were recruited for the study. Eight patients, four from each group, were not included in the analysis because of failure in matching for age. There were no significant differences between the exposed and non-exposed groups in terms of patient characteristics (Table 1). Of the 96 patients in the exposed group, 66 used ICS alone (64 beclomethasone and 2 fluticasone) and 30 used ICS combined with long-acting β2-agonists (28 fluticasone/salmeterol and 2 budesonide/formeterol). Ninety-two patients used metered dose inhalers with spacer and four used dry powder inhalers. The mean daily dose of ICS at study entry was 400 µg of beclomethasone or equivalent (95% CI: 373–425 µg; 100–200 µg: n = 17, 300–400 µg: n = 29, 500 µg: n = 49, 800 µg: n = 1). The mean duration of treatment was 8.6 months (95% CI: 6.6–10.6 months; <6 months: n = 55, 6–12 months: n = 27, > 12 months: n = 14).

Table 1. Characteristics of the study sample
CharacteristicsExposed group (n = 96)Non-exposed group (n = 96) P-value
  •  

    Student's t-test.

  •  

    Chi-square test.

  • § 

    Mann–Whitney test.

  •  

    Fisher's exact test.

  • CI, confidence interval.

Age (year), mean (95% CI)6.0 (5.2–6.8)5.9 (5.1–6.8)0.90
Age groups, n (%)   
 <2 years19 (19.9%)19 (19.9%)1.00
 2–6 years32 (33.3%)32 (33.3%)
 >6–18 years45 (46.8%)45 (46.8%)
Gender, male, n (%)53 (55.2%)48 (50.0%)0.47
Race, white, n (%)77 (80.2%)68 (70.8%)0.18
Household size, mean (95% CI)4.3 (3.9–4.6)4.1 (3.8–4.4)0.35§
Number of siblings, mean (95% CI)1.4 (1.1–1.6)1.1 (0.8–1.3)0.11§
Attending day-care facilities/school, n (%)59 (61.5%)70 (72.9%)0.09
Maternal smoking, n (%)14 (15.7%)20 (21.7%)0.30
Concomitant use of intranasal corticosteroids, n (%)30 (31.3%)24 (25.0%)0.34
Vaccination against Streptococcus pneumoniae, n (%)19 (19.8%)21 (21.9%)0.72
Antibiotic use in the last 3 months, n (%)35 (36.5%)37 (38.5%)0.77
Hospitalization in the last 6 months, n (%)8 (8.3%)4 (4.2%)0.37

The prevalence of oropharyngeal colonization by S. pneumoniae was higher among patients exposed to regular use of ICS than among those not exposed to ICS (27.1% vs 8.3%, P = 0.001) (Table 2). After adjusting for gender, race, household size, number of siblings, attending day-care facilities/school, maternal smoking, concomitant use of intranasal steroids, vaccination against S. pneumoniae, antibiotic use in the last 3 months and hospitalization in the last 6 months, regular use of ICS was an independent risk factor for oropharyngeal carriage of S. pneumoniae, with an adjusted prevalence ratio of 3.75 (95% CI: 1.72–8.18, P = 0.001). Similar results were found in both sensitivity analyses by either excluding patients younger than 2 years old or excluding patients with intermittent asthma from non-exposed group (Table 2). Subgroup analyses showed a significant dose–response trend of ICS (P for trend = 0.005) (Fig. 1a) and a positive relationship between prevalence of S. pneumoniae colonization and treatment duration (P for trend = 0.0002) (Fig. 1b).

Table 2. Association between daily use of inhaled corticosteroids and risk of oropharyngeal colonization by Streptococcus pneumoniae (S. pneumoniae) among children with asthma
Type of analysisPrevalence of colonization by S. pneumoniae, n/N (%) P-valuePR for colonization (95% CI, P-value)
Exposed groupNon-exposed groupCrudeAdjusted
  •  

    Chi-square test.

  •  

    Fisher's exact test.

  • § 

    Model 1—PR adjusted for gender, race, household size, number of siblings, attending day-care facilities/school, maternal smoking, concomitant use of intranasal steroids, vaccination against S. pneumoniae, antibiotic use in the last 3 months and hospitalization in the last 6 months.

  •  

    Model 2—model 1 plus adjustment for age.

  • CI, confidence interval; PR, prevalence ratio.

All patients (n = 192)26/96 (27.1%)8/96 (8.3%)0.0013.25 (1.47–7.18, P = 0.004)3.75 (1.72–8.18, P = 0.001)§
Sensitivity analyses     
 Excluding patients younger than 2 years (n = 154)22/77 (28.6%)7/77 (9.1%)0.0023.14 (1.34–7.36, P = 0.008)3.43 (1.50–7.81, P = 0.003)
 Excluding patients with intermittent asthma (n = 143)26/96 (27.1%)3/47 (6.4%)0.0044.24 (1.28–14.02, P = 0.018)6.23 (1.50–25.92, P = 0.012)
image

Figure 1. (a) Prevalence of Streptococcus pneumoniae (S. pneumoniae) colonization and daily inhaled corticosteroids (ICS) dose. (inline image) Non-exposed; (□) <100–300 µg; (inline image) 400–800 µg. (b) Prevalence of S. pneumoniae colonization and treatment duration of ICS. (inline image) Non-exposed; (□) <6 months; (inline image) ≥6 months.

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Seven out of 26 (26.9%) strains of S. pneumoniae in the exposed group and one of eight (12.5%) strains of S. pneumoniae in the non-exposed group were resistant to penicillin (P = 0.65). All strains of S. pneumoniae were sensitive to chloramphenicol, macrolides and quinolones, except one from the exposed group, who was resistant to quinolones, and another from the non-exposed group, who was resistant to macrolides.

DISCUSSION

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgement
  8. REFERENCES

This is the first study showing that children with persistent asthma taking daily ICS are nearly four times as likely to have oropharyngeal colonization by S. pneumoniae as children with asthma not receiving ICS. Given that naso-oropharyngeal colonization is an obligatory first step for S. pneumoniae infections,12,13 the findings of this study may provide some clues about a possible link between use of ICS and risk of pneumococcal respiratory infections in children with persistent asthma.

Asymptomatic naso-oropharyngeal colonization by S. pneumoniae is common in childhood, but prevalence varies substantially between different regions, age groups and socioeconomic and environmental conditions.12,14 After colonization, microorganisms may gain access to other parts of the upper and lower respiratory tract by direct extension. In a health host, airway clearance mechanism can prevent clinical infection. However, airway clearance may be impaired by many clinical situations such as viral infections, asthma, chronic obstructive pulmonary disease and smoking, and consequently, naso-oropharyngeal colonization may progress to respiratory infection.12,14–17 Taken together, we postulate that a higher carriage rate of S. pneumoniae in the oropharynx along with impaired airway clearance may increase the risk of having pneumococcal respiratory infections in children with persistent asthma receiving regular ICS. Further larger prospective studies are needed to better define the relationship between ICS therapy, oropharyngeal colonization by potential respiratory pathogens and clinical outcomes of these patients. The influence of doses of ICS, duration of treatment, type of ICS and type of delivery device is also needed to be investigated.

The rate of penicillin resistance among isolates of S. pneumoniae in the exposed group was twice that of the non-exposed group, although the difference was not statistically significant. This non-significant trend may suggest different antibiotic susceptibility profiles of S. pneumoniae isolated from two groups. It is generally believed that penicillin resistance in S. pneumoniae is linked to antibiotic selection pressure.18,19 However, the prevalence of antibiotic use in the last 3 months was similar between the exposed and the non-exposed groups. These findings may raise an interesting question for further research: does continuous exposure to ICS affect antibiotic susceptibility of S. pneumoniae?

Several methodological issues of this study deserve mention. Firstly, cross-sectional design cannot confirm a causal relationship between exposure and outcome, but a significant dose–response trend of ICS shown by subgroup analysis may suggest such relationship. Cross-sectional design is also susceptible to bias and confounding. In this study, most of the potential confounders were adequately controlled by either matching or statistical adjustment. However, the concern is that ICS use may be simply a surrogate for persistent asthma, and in this case, different rates of S. pneumoniae colonization may be due to differences in asthma severity between exposed and non-exposed groups rather than differences in use of ICS per se. To assess the influence of asthma severity on the association between ICS use and S. pneumoniae colonization, we performed a sensitivity analysis excluding patients with intermittent asthma from non-exposed group. This analysis increased the adjusted prevalence ratio from 4.24 (95% CI: 1.28–14.02) to 6.23 (95% CI: 1.50–25.9). However, the increase was not statistically significant because the two CI overlapped. Moreover, the analysis indicates that, even if the effects of asthma severity really exist, their potential impact is expected to reduce the effect size of ICS on the risk of having S. pneumoniae colonization and it does not confound the study's conclusions. Secondly, the diagnosis and classification of asthma were based on only clinical history without lung function measures because a considerable proportion of patients were younger than 6 years old. To assess the potential impact of diagnosis accuracy on the results of the study, we performed another sensitivity analysis in which children younger than 2 years of age were excluded because diagnosis of asthma in this age group is less accurate. However, no significant changes in the results were observed. Thirdly, treatment adherence was not evaluated in this study. Poor treatment adherence is common among patients taking daily ICS and it can potentially reduce effect size of ICS on rate of S. pneumoniae colonization. Fourthly, oropharyngeal sampling usually has a lower yield than nasopharyngeal sampling,20 and this may be the main cause for a relatively low rate of S. pneumoniae colonization (8.3%) in the comparator group of this study. However, the effects of sampling may be expected to occur in the same way in both groups. Moreover, a comparable nasopharyngeal carriage rate of S. pneumoniae (11.3%) was reported in a group of healthy Brazilian children with similar demographic and socioeconomic characteristics.21 Finally, this is a teaching hospital-based study and the study sample may not be representative of whole population of children with asthma.

Acknowledgement

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgement
  8. REFERENCES

The authors thank Raúl Mendoza-Sassi, MD, PhD, Division of Epidemiology, Faculty of Medicine, Federal University of Rio Grande, for his supervision of statistical analyses and critical review of the manuscript.

REFERENCES

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgement
  8. REFERENCES
  • 1
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    Talbot TR, Hartert TV, Mitchel E et al. Asthma as a risk factor for invasive pneumococcal disease. N. Engl. J. Med. 2005; 352: 208290.
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    Marrie TJ. Pneumococcal pneumonia: epidemiology and clinical features. Semin. Respir. Infect. 1999; 14: 22736.
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    Baquero F, Baquero-Artigao G, Cantón R et al. Antibiotic consumption and resistance selection in Streptococcus pneumoniae. J. Antimicrob. Chemother. 2002; 50(Suppl. S2): 27 37 .
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    Lieberman D, Shleyfer E, Castel H et al. Nasopharyngeal versus oropharyngeal sampling for isolation of potential respiratory pathogens in adults. J. Clin. Microbiol. 2006; 44: 52558.
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    D'Avila NE, Zhang L, Miller RG et al. High prevalence of nasopharyngeal colonization by Staphylococcus aureus among children with HIV-1 infection in extreme southern Brazil. J. Trop. Pediatr. 2008; 54: 4102.