Increased risk of serious pneumococcal disease in patients with atopic conditions other than asthma

Article Outline

• Abstract
• Methods
  • Study setting and population
  • Ascertainment of SPD cases
  • Selection of controls
  • Exposure ascertainment (ie, atopy conditions other than asthma)
  • Other variables
  • Data analysis
• Results
  • Study subjects
  • Atopic conditions and SPD
  • The role of asthma and other atopic conditions in SPD
• Discussion
• Acknowledgment
• References
• Copyright

Background

We reported an increased risk of serious pneumococcal disease (SPD) among patients with asthma. It is not known whether this is true for patients with other atopic conditions.

Objective

To determine the relationship between atopic conditions other than asthma and SPD.

Methods

The study subjects were residents of Rochester, Minn, who developed SPD between 1964 and 1983 and their 2 sex-matched and age-matched controls. We used a population-based computer-linked medical diagnosis system to identify all individuals with potential SPD. All records were reviewed by using explicit predetermined criteria for SPD. All individuals with atopic conditions were identified by the physician diagnoses including atopic dermatitis or eczema, allergic rhinitis, and hay fever documented in medical records. The associations between these atopic conditions and SPD were assessed by using conditional logistic regression.

Results

A total of 3941 records were reviewed, and we identified 174 SPD cases. Of these 174 cases, 50.6% were male, and 94.3% were Caucasian. Twenty-six (14.9%) of the SPD cases and 29 (8.3%) of the controls had atopy. Atopic conditions other than asthma were associated with an increased risk of SPD (odds ratio, 2.13; 95% CI, 1.04-4.35; P = .04) after adjusting for smoking status, previous high-risk conditions for SPD, educational status, and ethnicity.

Conclusion

Like asthma, other atopic conditions, particularly atopic dermatitis, are associated with an increased risk of SPD. There may be a common immunogenetic mechanism underlying increased risk of SPD among individuals with either asthma or other atopic conditions. Our study findings need to be studied further.

Key words: Atopic dermatitis, allergic rhinitis, serious pneumococcal disease, epidemiology, risk, pneumococcal pneumonia, Rochester Epidemiology Project

Abbreviations used: ACIP, Advisory Committee on Immunization Practices, IPD, Invasive pneumococcal disease, OR, Odds ratio, PPV-23, 23-Valent pneumococcal polysaccharide vaccine, SPD, Serious pneumococcal disease

Streptococcus pneumoniae presents a global threat of morbidity and mortality among children and adults. One million children younger than 5 years of age die from pneumonia and invasive pneumococcal disease (IPD) globally each year.¹ In the United States, the annual number of fatal pneumococcal infections is 40,000.² S pneumoniae is responsible for 6 million cases of otitis media per year; nasopharyngeal colonization among 20% to 50% of the population as a prelude to IPD; 100,000 cases of pneumonia; 60,000 cases of sepsis per year; and 3300 cases of meningitis per year in the United States. The case-fatality rate was 10% for all reported cases (1556 deaths/15,544 cases). Case-fatality rates increased from 1.4% among persons younger than 2 years to 20.6% among persons age 80 years or older.³

For the causes of IPD, the Advisory Committee on Immunization Practices (ACIP)–recommended pneumococcal vaccine–eligible conditions accounted for only 50.6% of IPD, but a large proportion of IPD cases occur among people without high-risk conditions for IPD.³ Talbot et al⁴ and Juhn et al⁵ independently reported that patients with asthma were at a significantly increased risk of IPD. According to the results of these studies, the population-attributable risk percentage for asthma was 11% to 17%. The ACIP has recently issued a new recommendation that all adults with asthma (19-64 years) receive a single dose of 23-valent pneumococcal polysaccharide vaccine (PPV-23) to prevent IPD.⁶

Atopic conditions other than asthma such as atopic dermatitis or eczema, allergic rhinitis, or hay fever share the similar underlying immunologic mechanisms with asthma—that is, T_H2-predominant immune milieu⁷, ⁸, ⁹, ¹⁰—and individuals with atopic dermatitis have been reported to have poor humoral and cell-mediated immune responses as well as innate immunity.¹¹, ¹², ¹³, ¹⁴, ¹⁵ Currently, despite the shared immunologic mechanism among asthma and other atopic conditions, little is known about whether patients with atopic conditions other than asthma are associated with the risk of serious pneumococcal disease (SPD). No population-based study has been conducted to examine the relationship between atopic conditions other than asthma and SPD. To determine whether individuals with atopic dermatitis and/or allergic rhinitis have an increased risk of developing SPD, defined as IPD and/or pneumococcal pneumonia, we conducted a population-based case-control study among the residents of Rochester, Minn, between 1964 and 1983.

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Methods 

The study was approved by the Institutional Review Boards at both the Mayo Clinic and Olmsted Medical Center. This is a population-based retrospective case-control study designed to assess whether there was a higher prevalence of atopic conditions other than asthma before January 1, 1984, among the Rochester residents who developed SPD between 1964 and 1983, a primarily prepneumococcal vaccine era, compared with controls. SPD cases were identified through reviewing 3941 medical records, and atopic dermatitis and/or allergic rhinitis were ascertained by using documentation of the physician diagnosis of atopic dermatitis or eczema, allergic rhinitis, and/or hay fever in medical records.

Study setting and population 

The study setting and population were previously described.⁵ Rochester, Minn, is an excellent setting to conduct a retrospective case-control study such as this because medical care is virtually self-contained within the community, and the Rochester Epidemiology Project provides information on all Rochester residents who had received medical care from 2 primary medical centers in Rochester. The medical records for each site contain all inpatient and outpatient data. All diagnostic information has been indexed since 1935 by using Berkson codes even before International Classification of Diseases codes were available.¹⁶ The incidence rate of asthma in Rochester was 238 per 100,000, which is comparable to those in other communities such as Tecumseh, Mich (250/100,000).¹⁷

Ascertainment of SPD cases 

We reported the details for ascertainment of SPD cases previously.⁵ Briefly, a total of 85 different medical index search codes (Berkson codes and International Classification of Diseases codes) were used to identify potential SPD cases, and each potential case was then confirmed by medical records review. We reviewed medical records of all 3941 persons and identified 174 SPD cases between 1964 and 1983. Case definition of SPD included isolation of S pneumoniae from a normally sterile site (such as blood or cerebrospinal fluid), and/or pneumococcal pneumonia requiring all 3 of the following criteria: (1) a physician diagnosis of pneumonia, (2) the isolation of pneumococcus from sputum gram-stain or culture, and (3) the documented pneumonia by chest radiograph. We defined the index date of onset of the SPD as the date of documented isolation of S pneumoniae.

Selection of controls 

Selection of controls was previously described.⁵ A list of potential controls was generated from the Rochester Epidemiology Project computerized database (almost 95% of community members), and the index date for controls was defined as the index date of SPD for the corresponding matched case. Two sex-matched and age-matched control individuals who had never developed SPD were randomly selected from the community. We applied the same eligibility and exclusion criteria of SPD cases to controls.

Exposure ascertainment (ie, atopy conditions other than asthma) 

After we identified SPD cases and their age-matched and sex-matched controls, atopic conditions were ascertained by the presence of physician diagnoses of atopic dermatitis or eczema, allergic rhinitis, and/or hay fever in medical records. To identify the physician diagnoses of these atopic conditions, we conducted a comprehensive medical record review. The category of the physician diagnoses of atopic conditions in verbatim included atopic dermatitis, eczema, allergic rhinitis, or hay fever documented in the entire medical records of individual subjects (ie, prevalent cases of atopic conditions before 1964 and the incident cases of atopic dermatitis between 1964 and 1983).

Other variables 

During data abstraction from medical records, we collected information including sociodemographic variables (age, sex, ethnicity, and educational status), high-risk conditions for SPD (on the basis of ACIP-recommended pneumococcal vaccine–eligible conditions) before the index date of SPD, smoking status at the time of index, pneumococcal vaccination status on the basis of medical records during the study period, and antibiotics use within 7 days before the index date of SPD.

Data analysis 

Data analysis for the association between atopic conditions other than asthma and SPD followed that for the association between asthma and SPD as previously reported.⁵ Briefly, conditional logistic regression for matched analysis was used to determine whether atopic conditions other than asthma were associated with the risk of SPD, adjusting for pertinent covariates or confounders. Associations were summarized using the odds ratios (ORs) and corresponding 95% CIs derived from the estimated parameters in the conditional logistic models. All calculated P values were 2-sided, and P values less than .05 were considered statistically significant. The analysis was conducted using the entire study cohort, and separately by age group (<18, ≥18 years of age). Analyses were performed by using the SAS version 9.1 software package (SAS Institute, Inc, Cary, NC).

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Results 

Study subjects 

The details of sociodemographic and clinical characteristics of study subjects are summarized in Table I. We reviewed a total of 3941 records and identified 174 SPD cases. Of these confirmed 174 SPD cases, 16% (n = 28), 22% (n = 38), and 62% (n = 108) had SPD, SPD with pneumococcal pneumonia, and pneumococcal pneumonia, respectively. Of the SPD cases, the age at index date was 57.0 (mean) ± 26.5 (SD) years old, 50.6% were male, and 94.3% were Caucasian. Only 21 cases (12%) were younger than 18 years. Fifty-one SPD cases (29.3%) and 18 controls (5.2%) had at least 1 high-risk condition for SPD before the index date of SPD. Twelve SPD cases (11 for 14-valent pneumococcal vaccine and 1 for 23-valent pneumococcal vaccines) had received a pneumococcal vaccine before the index date, whereas none of the controls had received a pneumococcal vaccine. Of these 12 SPD cases, 1 (58%) had pneumococcal vaccine–eligible conditions before the index date, whereas 5 (42%) did not have any pneumococcal vaccine–eligible conditions before the index date.

Table I. Demographic and clinical characteristics of cases with serious pneumococcal diseases and their age-matched and sex-matched corresponding controls

	Case (N = 174)	Control (N = 348)
Age at index date (y)
Mean (SD)	57.0 (26.5)	57.0 (26.4)
Median	65.1	65.1
Atopic conditions, no. (%)
Allergic rhinitis (or hay fever)	6 (3.5)	13 (3.7)
Atopic dermatitis	16 (9.2)	13 (3.7)
Both	4 (2.3)	3 (0.9)
No	148 (85.1)	319 (91.7)
Asthma, no. (%)
Yes	11 (6.3)	13 (3.7)
No	163 (93.7)	335 (96.3)
Sex, no. (%)
Male	88 (50.6)	176 (50.6)
Female	86 (49.4)	172 (49.4)
Ethnicity, no. (%)
Caucasian	164 (94.3)	340 (97.7)
Asian	2 (1.1)	0 (0.0)
Hispanic/Latino	1 (0.6)	1 (0.3)
African American	0 (0)	1 (0.3)
Unknown	7 (4.0)	6 (1.7)
Educational status,∗ no. (%)
<High school education	35 (20.1)	61 (17.5)
High school graduate	32 (18.4)	79 (22.7)
Some college education	11 (6.3)	49 (14.1)
College graduate	20 (11.5)	44 (12.6)
Unknown	76 (43.7)	115 (33.0)
Tobacco smoke exposure at index date, no. (%)
No	54 (31.0)	181 (52.0)
Active	54 (31.0)	62 (17.8)
Passive	15 (8.6)	15 (4.3)
Unknown	51 (29.3)	90 (25.9)
Vaccination before index date, no. (%)
No vaccination	162 (93.1)	348 (100)
14 valent only	11 (6.3)	0 (0.0)
23 valent only	1 (0.6)	0 (0.0)
Antibiotic use within 7 d of index date, no. (%)
No	164 (94.3)	346 (99.4)
Yes	9 (5.2)	2 (0.6)
Unknown	1 (0.6)	0 (0.0)
High-risk conditions† for SPD before the index date of SPD, no. (%)
Any condition	51 (29.3)	18 (5.2)
Cardiac disease	12 (15.6)	5 (20.8)
Chronic pulmonary disease	1 (1.3)	0
Neurosurgical trauma/procedure	1 (1.3)	0
Chronic renal insufficiency	5 (6.5)	1 (4.2)
Immunosuppressive therapy‡	9 (11.7)	0
Diabetes mellitus type I	8 (10.4)	7 (29.2)
Diabetes mellitus type II	3 (3.9)	3 (12.5)
Alcohol abuse	4 (5.2)	1 (4.2)
Chronic obstructive pulmonary disease in absence of asthma	24 (31)	4 (16.6)
Rheumatoid arthritis	3 (3.9)	3 (12.5)
Hepatic disease	3 (3.9)	0
Long-term corticosteroid use/high-dose steroid use at index date§	4 (5.2)	0

Atopic conditions and SPD 

The results are summarized in Table II. Twenty-six (14.9%) of the SPD cases and 29 (8.3%) of the controls had atopic conditions other than asthma. In analysis with all subjects, the unadjusted OR for SPD in association with atopic dermatitis, eczema, allergic rhinitis, and/or hay fever was 1.98 (95% CI, 1.11-3.55; P = .02)—that is, patients with these atopic conditions had almost 2 times higher odds of SPD compared with controls. In adult subjects, SPD was associated with atopic conditions (unadjusted OR, 1.89; 95% CI, 1.02-3.49; P = .04). Other than atopic conditions, ethnicity, smoking exposure, previous high-risk conditions for SPD, and educational status were significantly associated with the risk of SPD in univariate analyses based on the entire cohort. We adjusted the association between atopic conditions and SPD for these variables. In analysis with all subjects, atopic conditions were still associated with the risk of SPD (adjusted OR, 2.13; 95% CI, 1.04-4.35; P = .04), adjusting for smoking status, previous high-risk conditions for SPD, educational status, and ethnicity. However, in analysis with only adult subjects, the adjusted OR for atopic conditions was not significant (adjusted OR, 1.83; 95% CI, 0.85-3.92; P = .12), adjusting for the same covariates. We performed both matched conditional logistic and unmatched logistic regression, and we found similar results. We assessed the association between individual atopic condition (atopic dermatitis vs allergic rhinitis) and SPD in all subjects. Adjusting for ethnicity, smoking exposure, previous high-risk conditions for SPD, and educational status, atopic dermatitis was associated with the risk of SPD (adjusted OR, 2.45; 95% CI, 1.07-5.65; P = .04), whereas allergic rhinitis or hay fever did not reach statistical significance despite a similarly increased risk for SPD (adjusted OR, 1.99; 95% CI, 0.71-5.58; P = .19) because of a small sample size. Thus, each individual atopic condition, particularly atopic dermatitis, may be a risk factor for SPD.

Table II. The association between atopic conditions other than asthma and serious pneumococcal disease

	All subjects
SubjectsVariables	Unadjusted OR for SPD (95% CI), P value	Adjusted OR for SPD (95% CI), P value
Atopic conditions
No	Referent	Referent
Yes	1.98 (1.11-3.55), P = .02	2.13 (1.04- 4.35), P = .04
Ethnicity
Caucasian	Referent	Referent
Non-Caucasian	2.50 (0.99-6.33), P = .05	3.88 (1.34-11.27), P = .01
Tobacco smoke exposure at index date
Active	Referent	Referent
Passive	1.76 (0.60-5.13), P = .30	1.80 (0.52-6.19), P = .35
Nonsmokers	0.31 (0.18-0.52), P < .001	0.28 (0.15-0.51), P < .001
High-risk conditions (before index date)
No	Referent	Referent
Yes	7.31 (3.96-13.47), P < .001	8.27 (4.19-16.31), P < .001
Educational status∗
<High school education	Referent	Referent
High school graduate	0.69 (0.38-1.25), P = .22	0.85 (0.42-1.75), P = .66
Some college education	0.33 (0.14-0.76), P = .01	0.31 (0.12-0.78), P = .01
College graduate	0.70 (0.35-1.41), P = .32	0.85 (0.37-1.96), P = .70

The role of asthma and other atopic conditions in SPD 

As previously reported, asthma was associated with the risk of SPD and is associated with atopic conditions. In our study, 6 of 55 patients (11%) with a history of atopic conditions had asthma, compared with 18 subjects with asthma among 467 subjects (4%) without atopic conditions (P = .031). Thus, we adjusted the association between atopic conditions and SPD for asthma status in addition to the aforementioned covariates (ie, ethnicity, educational status, smoking exposure, and previous high-risk condition for SPD). Atopic conditions were still associated with the risk of SPD (adjusted OR, 2.07; 95% CI, 1.01-4.25; P = .048) among all subjects. However, in analysis with only adult subjects, atopy was not significantly associated with SPD after adjusting for ethnicity, educational status, smoking exposure, previous high-risk condition for SPD, and asthma status (adjusted OR, 1.82; 95% CI, 0.83-3.99; P = .14). On the other hand, in the same model with only adult subjects, asthma was strongly associated with the risk of SPD (adjusted OR, 6.79; 95% CI, 1.47-31.30; P = .01), adjusting for ethnicity, educational status, smoking exposure, previous high-risk condition for SPD, and atopic dermatitis and/or allergic rhinitis, which is virtually the same as the effect size for asthma in association with the risk of SPD we previously reported.

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Discussion 

In all subjects of our study, individuals with atopic conditions other than asthma were at an increased risk of developing SPD (adjusted OR, 2.13; 95% CI, 1.04-4.35; P = .04) compared with those without such conditions, adjusting for smoking status, previous high-risk conditions for SPD, educational status, and ethnicity. These findings were still significant after adjusting for asthma status (OR, 2.07; 95% CI, 1.01-4.25; P = .048), and thus, the impact of atopic dermatitis/allergic rhinitis on the risk of SPD in all subjects is likely to be independent of asthma status. The population-attributable risk percent for atopic conditions in all subjects was as much as 10%, suggesting that 10% of the disease burden of SPD can be attributable to atopic conditions at a population level. The results on adult subjects only showed that the direction of the association between the risk of SPD and atopic conditions was consistent, but they did not reach statistical significance, primarily because of a smaller sample size. Overall, our study results suggest that atopic conditions other than asthma may contribute to a risk of SPD independent of asthma, but in adult subjects, asthma status is still a major risk factor for SPD independent of atopic conditions. Currently, no previous studies on the relationship between atopic conditions other than asthma and SPD are available to compare with our study results; thus, our study results are subject to be studied further. However, we believe our study findings are noteworthy given the significant burden of pneumococcal disease and the high prevalence of atopic conditions other than asthma—for example, 10% to 19% of atopic dermatitis prevalence and 26% to 33% of allergic rhinitis prevalence in the United States.¹⁸, ¹⁹, ²⁰

The potential mechanisms underlying the increased risk of SPD among patients with asthma or other atopic conditions remain to be determined. The study results may imply that atopic conditions other than asthma themselves may potentially pose a risk for SPD. Although asthma is still a major risk factor for SPD, the results suggest a possibility that certain immunologic factors shared by atopic conditions in general may contribute to the risks of SPD in addition to factors unique to bronchial asthma at either the airway structure or the immunogenetic level. Patients with allergic rhinitis or atopic dermatitis may have certain features observed in asthma such as airway hyperresponsiveness,²¹, ²² but significant airway inflammation or airway remodeling observed in bronchial asthma is unlikely in those with atopic conditions without asthma.²³ Thus, immunogenetic mechanisms instead of alteration in airway architecture may play a more important role for increased risk of SPD in patients with atopic conditions without asthma. As a pneumococcal infection–specific mechanism, polymeric immunoglobulin receptor,²⁴ a receptor for pneumococcal cholin binding protein A that causes transcytosis of pneumococci across epithelial cells, has been suggested given the increased expression of this receptor by IL-4, a T_H2-cell cytokine²⁵ that is often upregulated in patients with atopic conditions. A previous study based on a mouse model reported that mice with allergic sensitization through intranasal challenge with ovalbumin increased the risk of pneumococcal colonization and the colony count of pneumococci in the sinus cavity.²⁶ As an alternative mechanism, Arkwright et al²⁷ compared the antibody response to PPV-23 between children with and without eczema age 3 to 8 years. They found that 17% of children with eczema responded to PPV-23, compared with 57% of children without eczema (OR, 0.2; 95% CI, 0.05-0.84; P = .03). The literature suggests that individuals with atopic dermatitis may have impaired innate and adaptive immunity against various microbial organisms.¹¹, ¹³, ¹⁴, ¹⁵, ²⁸, ²⁹, ³⁰

The main strength of this study was a population-based study design, which was conducted in a study setting with a self-contained health care environment and unified medical record system for research. Another strength of this study was a study population during a primarily prepneumococcal vaccine era. Also, our study has the inherent limitations of retrospective studies. A broad category of codes to identify SPD was applied in this study, but it is still possible to miss SPD cases. The physician diagnoses of atopic conditions ascertained by medical record review might not be entirely accurate, but this limitation is subject to a nondifferential misclassification bias. If it occurred, it is likely to support the null hypothesis. Also, we had limited statistical power in assessing the impact of atopic conditions on SPD in adult subjects. Although data abstractors were not blind to case and control status, they were not aware of the study hypothesis during the data collection and ascertained exposure status by using the specific physician diagnosis of atopic conditions. Also, we did not include socioeconomic measures other than educational status and clinical variables reflecting nutritional status. We included educational levels of parents for measuring socioeconomic status of children, whereas adults had their own educational levels. However, there was no a significant interaction between age and educational levels. Finally, given the predominantly Caucasian population of the study, one needs to be cautious when generalize the findings to other study settings.

In conclusion, individuals with atopic conditions, particularly atopic dermatitis, are at an increased risk of SPD. Our study findings need to be confirmed at other study settings. There may be a common immunogenetic mechanism underlying increased risk of SPD among individuals with either asthma or other atopic conditions, which deserves further investigation.

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We thank Kathy Inabnit and Chun Shan as well as other staff of the Pediatric Asthma Epidemiology Unit who made this study possible. We thank John Yunginger, MD, for his comments and support to use the database for the Rochester Asthma Epidemiology Project.

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