Original article
Asthma, lower airway diseases
Correlation of plasma complement split product levels with allergic respiratory disease activity and relation to allergen immunotherapy

https://doi.org/10.1016/j.anai.2009.11.021Get rights and content

Background

Allergens, including dust mite and grass pollen, and mast cell tryptase are known to generate the complement split products (CSPs) C5a and C3a, which can then trigger allergic inflammation. The relation of these anaphylatoxin levels to clinical allergic disease responses is not known.

Objective

To evaluate the relationship of plasma CSP levels to allergic respiratory disease variables in an adult cohort.

Methods

A cross-sectional survey was used to assess the association of plasma C5a desArg and C3a desArg levels with clinical allergic respiratory disease variables. Furthermore, a time course of the effect of routine allergen immunotherapy on plasma CSP levels and cutaneous and pulmonary responses was determined.

Results

Adult plasma C5a desArg levels correlate with asthma severity as determined by a physician (P = .01) and by Asthma Quality of Life Questionnaire scores (P < .01). Change in plasma C5a desArg levels 1 hour after immunotherapy is associated with baseline rhinoconjunctivitis symptom severity (P = .03), change in total mean wheal diameter (P = .05), and total dust mite dosage (P = .04). Change in plasma C3a desArg levels 3 hours after immunotherapy correlates with change in total mean wheal diameter induced by dust mite (P = .01). Change in plasma CSP levels after immunotherapy did not correlate with change in spirometric outcome.

Conclusions

Plasma C5a desArg levels reflect allergic respiratory disease severity as assessed by physicians and correlate with Asthma Quality of Life Questionnaire scores. Changes in CSP levels after immunotherapy reflect cutaneous allergic responses, especially to dust mite allergen.

Introduction

The role of innate immune responses to allergen involving complement in the pathogenesis of allergic disease has yet to be fully determined. The complement split product (CSP) proteins C5a and C3a, long recognized as anaphylatoxins, are cleaved from C5 and C3, respectively, by allergens,1 tissue-based phagocyte-derived proteases,2 and human mast cell β-tryptase.3 Levels of these CSPs are increased in bronchoalveolar lavage fluid after segmental allergen provocation.4 Elevated levels of C5a/C5a desArg have been detected in induced sputum from asthmatic patients and patients with chronic obstructive pulmonary disease.5 Airway activation of complement by allergens may potentiate airway responses in asthma and may contribute to clinical disease. Studies by Fregonese and colleagues6 have shown increased expression of anaphylatoxin receptor levels in the lung tissue of individuals with fatal asthma. There is a paradoxical protective effect demonstrated in murine models in which C5a also protects against allergen sensitization through its effects on dendritic cells.7, 8, 9 Once generated, C5a and C3a are rapidly cleaved by a C-terminal carboxypeptidase to C5a desArg and C3a desArg,10 respectively, the more stable and measurable end products.

There has been limited investigation of the association of complement levels with clinical allergic disease. Nakano et al11 determined that asthmatic patients admitted to the hospital for exacerbation of their lung disease have elevated C3a levels that subsequently decrease after inpatient treatment. Recent studies by Khodoun et al12 demonstrated that C3a is generated by peanut and cashew extract and may contribute to anaphylactic shock.

In a cross-sectional survey performed in an outpatient setting, we determined in this pilot study whether plasma levels of C5a/C5a desArg and C3a/C3a desArg correlate with clinical allergy variables. We further determined whether cutaneous allergic inflammation resulting from allergen immunotherapy correlates with changes in CSP levels and how these changes relate to changes in spirometric measures.

Section snippets

Methods

This protocol was approved by the institutional review board at State University of New York (SUNY) Downstate Medical Center. Patients signed informed consent or assent forms. Adults with asthma, allergic rhinoconjunctivitis, or both receiving care at SUNY were evaluated in 2 stages. The first stage was a cross-sectional survey of the relation of plasma CSP levels with parameters of allergic/asthma disease activity. The second stage evaluated change in plasma CSP levels after allergen

Survey

Plasma C5a desArg and C3a desArg levels were determined for outpatient allergic adults (n = 29 and 23, respectively). The demographics of the study patients and their CSP and IgE levels are given in Table 1, Table 2, respectively. Whereas C5a desArg levels were within the reference range, levels of C3a desArg and serum IgE were elevated. Table 3 indicates that plasma C5a desArg levels correlated with physician-determined asthma severity (r = 0.49, P = .02) and AQLQ scores (r = 0.73, P < .01)

Discussion

We found that plasma C5a desArg levels correlate with allergic respiratory disease severity as evaluated by physicians and patients via AQLQ scores. Whereas plasma levels of C5a desArg and C3a desArg do not increase after allergen injections of immunotherapy, changes in CSP levels after immunotherapy correlate with the associated cutaneous allergic inflammation, especially in association with dust mite allergen, and with eye and nasal allergic symptoms.

This pilot study of complement levels in

Acknowledgments

We thank Jeremy Weedon, PhD, Scientific/Academic Computing Center at SUNY Downstate Medical Center, for his statistical support.

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  • Disclosures: Authors have nothing to disclose.

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