Chlamydia pneumoniae-Specific IgE Is Prevalent in Asthma and Is Associated with Disease Severity
PLoS One. 2012;7(4):e35945. doi: 10.1371/journal.pone.0035945.
Hahn DL1, Schure A2, Patel K2, Childs T2, Drizik E2, Webley W2.
1 Departments of Family Medicine, University of Wisconsin School of Medicine and Public Health, and Dean Clinic, Madison, Wisconsin, United States of America.
2 Department of Microbiology, University of Massachusetts, Amherst, Massachusetts, United States of America
Background: Several Chlamydia pneumoniae (Cp) biomarkers have been associated with asthma but Cp-specific IgE (Cp IgE) has not been investigated extensively. Our objective was to investigate Cp IgE in community adult asthma patients.
Methods: (1) Prevalence of Cp IgE (measured by immunoblotting) and Cp DNA (by polymerase chain reaction) in peripheral blood, and biomarker associations with asthma severity. (2) Case-control studies of Cp IgE association with asthma using healthy blood donor (study 1) and non-asthmatic clinic patient (study 2) controls.
Results: Of 66 asthma subjects (mean age 40.9 years, range 5-75, 59% male, 45% ever-smokers) 33 (50%) were Cp IgE positive and 16 (24%) were Cp DNA positive (P = 0.001 for association of Cp IgE and DNA). Cp IgE was detected in 21% of mild intermittent asthma v 79% of severe persistent asthma (test for trend over severity categories, P = 0.002). Cp IgE detection was significantly (P = 0.001) associated with asthma when compared to healthy blood donor controls but not when compared to clinic controls.
Conclusions: Half of this sample of community asthma patients had detectable IgE against C. pneumoniae. Cp IgE was strongly and positively associated with asthma severity and with asthma when healthy blood donor controls were used. These results support the inclusion of Cp IgE as a biomarker in future studies of infectious contributions to asthma pathogenesis.
The scope of the asthma problem
Asthma remains a major public health problem with increasing health care costs and prevalence rates, affecting over 300 million children and adults worldwide . Asthma prevalence has increased considerably over the past three decades, particularly in Western countries. According to the Centers for Disease Control and Prevention, over 25 million Americans are currently living with asthma (both children and adults), and the disease results in approximately half a million hospitalizations and two million emergency department visits per year. In addition, asthma results in an annual cost of over $56 billion in medical costs, lost work/school days, and early deaths. Most agree that there are few chronic illnesses which present such a therapeutic challenge to physicians as chronic asthma.
The growing refractory asthma population
A recent study concluded that 86% of asthma patients on controllers were inadequately treated as their asthma was not well or very poorly controlled . It was also determined that almost 50% of all asthma patients are characterized by non-atopic, non-IgE-dependent, and non-eosinophilic inﬂammation . These patients fail to satisfactorily respond to standard inhaled corticosteroid (ICS) therapy, and this type of steroid-resistant, severe asthma has been linked to the presence of neutrophilic lung inflammation and the affected patients are at greater risk for debilitating asthma pathology. This subset of refractory asthmatics is phenotypically different and might have a different etiology from atopic asthma patients whose airways are characterized by eosinophilic infiltration and who typically respond well to ICS treatment. While eosinophilic inflammation may still be important in these severe refractory asthma patients, the lack of control of inflammation and airway hyperresponsiveness, even after prolonged high dose steroid therapy, suggests that fundamental mediators in the expression of disease pathology are either not well controlled by glucocorticoid or are acting as suppressors of this pathway. While it is true that this is not the case for the majority of asthma patients, the significant subset of affected patients might be at greatest risk for asthma morbidity and mortality due to lack of effective disease control.
Previous work and rationale
We previously confirmed that there is a high prevalence of Chlamydia pneumoniae (Cp) organisms in the lungs of children with hard-to-control asthma  and demonstrated that these patients displayed an overwhelming neutrophilic airway inflammatory phenotype, which correlated with the presence of the live organisms . We have also demonstrated that pediatric patients with asthma produced IgE antibodies against Cp-specific antigens and that these antibodies could be found both in the serum and bronchoalveolar lavage fluid of pediatric patients . Importantly, our own research and work published by Horvat, et al [8,9], utilized a neonatal mouse model to demonstrate that chlamydial organisms can induce airway hyperresponsiveness with a neutrophilic inflammatory phenotype, closely reflecting our observations in the pediatric asthma patient cohort. Over 93% of our pediatric cohort with Cp-specific IgE displayed a neutrophilic asthma phenotype . This is an important observation since neutrophilic airway inflammation may lead to increased steroid resistance and an accelerated loss of lung function owing to tissue destruction in affected patients.
Cp-specific IgE biomarker for severe asthma and positive azithromycin treatment outcome
In the current study  we sought to determine the prevalence of Cp-specific serum IgE antibodies in a group of community asthma patients and to determine the outcome of antibiotic treatment in a subset of these chronic, severe asthma patients. Our evaluation of the patient population revealed that the average age of asthma onset was 22.4 years and the average of diagnosis was 24.2 years (Table 1). Approximately 28% of patients initially had a broader diagnosis of chronic airflow obstruction, defined as asthma, chronic bronchitis, or emphysema. The patient population included patients from 17 states and British Columbia, Canada. Our results demonstrated that the presence of Cp-specific IgE strongly correlated with asthma severity, with most IgE-positive patients having chronic severe asthma. Most physicians in the field of pulmonology now agree that transformative therapies for asthma must be more targeted than inhaled corticosteroids. We therefore wanted to determine if patients who were positive for Cp would benefit from treatment with a macrolide antibiotic. Patients in this cohort of severe adult asthmatics were therefore treated with azithromycin, a macrolide antibiotic with proven efficacy against the obligate intracellular chlamydial pathogens. Over the study period of two years, patients were reevaluated for asthma symptoms and a subset for the presence of Cp-specific DNA as well as IgE antibodies. A total of 85% of all patients treated reported significant symptom reduction and this was often accompanied by the disappearance of the Cp DNA from their peripheral blood, although Cp-specific IgE persisted in most patients who had repeat testing.
Table 1: Characteristics of asthma patients
Select Characteristics Asthma Patients (N=66) Mean age in years (SD) 40.9 (17.8) Mean age at asthma onset (SD) 22.4 (18.1) Mean age at asthma diagnosis (SD) 24.4 (19.8) Gender, male (% male) 39 (59%) Chronic Airflow Obstruction (% of total) 19 (28%) Allergic Asthma (% of total) 14 (21%) Skin Test Positive (% of all allergic asthmatics) 13 (93%) Allergic rhinitis (% of all allergic asthmatics) 12 (86%) Asthma diagnosis following airway infection 11 (17%) MIF IgG for C. pneumoniae 28 MIF IgM for C. pneumoniae 11 Cigarette smoking, no (%) 23 (35%), [14, were ex-smokers and 9 were current]
Our data suggests that Cp-specific IgE antibodies and the presence of Cp DNA by PCR might be important biomarkers of severe, ICS-resistant asthma that would benefit from macrolide antibiotic treatment. Since the patients who are at the highest risk for fatal asthma often have airways characterized by neutrophilic infiltration, most likely lured there by bacterial infections, there is a real possibility to also significantly impact asthma pathology, morbidity and mortality rates. We conclude that asthma phenotypes characterized by neutrophilic airway infiltration often have a microbial involvement and therefore require alternative treatment guidelines which include macrolide antibiotics (figure 1). We believe that C. pneumoniae is a frequent colonizer and has the ability to initiate, perpetuate and exacerbate airway pathology, since Cp DNA was found more frequently in the lungs of severe asthmatics compared to those diagnosed with a mild or moderate form of the disease.
Figure 1: Treatment outcomes and alternatives for different asthma phenotypes. The diagram illustrates the typical cellular and cytokine immune responses, treatment and treatment outcomes for two broad phenotypes of asthma (allergic asthma and non-allergic asthma). While inhaled corticosteroids is an effective treatment for most patients with allergic asthma, non-allergic asthmatics respond poorly, and their disease remain largely uncontrolled, even at the maximum allowable dose. A significant subset of non-allergic, neutrophilic airway patients are refractor to ICS treatment even in the presence of added Leukotriene Receptor Antagonist (LTRA) and Long-acting beta2-adrenergic agonist (LABA). In a subset of these patients with C. pneumoniae involvement as determined by PCR and Cp-specific IgE, the addition of azithromycin resulted in improved symptoms.
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