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St. Louis, MO
Dr. Choo-Kang is Director, Division of Pediatric Pulmonary and Sleep Medicine, St. John’s Mercy Medical Center, and a member of the Speakers’ Bureau for Pharmacia Diagnostics.
Correspondence to: Lee R. Choo-Kang, MD, Pediatric Pulmonary and Sleep Medicine, St. John’s Mercy Medical Center, 621 S. New Ballas Rd, Suite 382A, St. Louis, MO 63141; e-mail: choolr{at}stlo.mercy.net
Perhaps because allergic sensitization is seen in as many as 75% of children and 50% of adults with asthma,1 pulmonologists have long shared the role of "asthma specialist" with our allergy colleagues. Important contributions to the understanding and treatment of asthma have undoubtedly been made by both disciplines, but allergy testing and immunotherapy have more traditionally been a part of the clinical allergist’s tools. In fact, several pulmonary fellowship training programs, both pediatric and adult, do not include formal allergy testing in their curricula. There may be several reasons for the difference in approach, but expertise in managing obstructive airway disease processes has likely contributed to the pulmonologist’s focus on lung function assessment and pharmaceutical therapies. In addition, the commonly used in vivo allergy tests, such as skin-prick testing (SPT) and intradermal testing (IDT), are time consuming, while radioallergosorbent testing, introduced clinically in the 1970s, lacked adequate credibility due to poor sensitivity. However, several changes in our understanding of the pathophysiology and role of allergy in asthma indicate that allergy testing should be part of a comprehensive asthma evaluation. From a patient’s or referring physician’s perspective, one-stop shopping is also preferred. Fortunately, significant improvements in the reliability of newer-generation in vitro testing can level the playing field with regard to allergy evaluation and permit the average pulmonologist an opportunity to be a more complete "asthmologist."
Longitudinal studies2345 over the past 2 decades have furthered our concepts of the natural history of infantile wheezing. Although as many as 50% of children will have at least one episode of wheezing by 3 years of age, only a third of them seem to be at risk for recurrent wheezing later in life.6 A genetic predisposition for atopic diseases, seen by a positive family history among first-degree relatives and a personal history of infantile eczema and allergic rhinitis, is the most significant risk factor for asthma.457 In fact, the National Heart Lung Blood Institute, in updating the Guidelines for the Diagnosis and Management of Asthma, incorporated the asthma predictive index7 in its recommendations for which preschool children should be started on daily antiinflammatory therapy.8 An infant or young child with recurrent wheezing and either one major criteria (parental history of asthma or a personal history of eczema), or two minor criteria (allergic rhinitis, wheezing apart from colds and peripheral eosinophilia > 4%), has approximately an 80% chance of persistent wheezing. Although such algorithms do not yet provide a dichotomous answer to the age-old question of whether a young child or infant has asthma, they identify those at risk, not only for recurrent wheezing, but also for potentially progressive failure to attain normal lung function. Whether daily inhaled corticosteroids started in preschool children can prevent the loss of lung function, which is still seen in 5- to 12-year-olds treated with nebulized budesonide,910 is not yet known. Alternatively, the abnormal lung function seen in some, regardless of therapy, may not be the result of inadequately treated asthma but rather its cause. Therefore, even earlier identification and proof of atopy in a child might offer a better chance for successful therapeutic intervention.
Infantile wheezing does not seem to exist in isolation but rather as part of a clinical progression commonly called the "atopic or allergy march." Although asthma may be the final event, and certainly the most clinically significant, the atopic child may experience a series of medical conditions including eczema, GI disorders (such as colic, constipation, diarrhea, and stomachaches), recurrent middle ear disease, and allergic rhinitis before ultimately receiving a diagnosis of asthma. Whether interruption of the atopic march can prevent asthma before a child starts to wheeze is an intriguing possibility suggested by the Early Treatment of the Atopic Child study.11 Children 2 years of age and younger with atopic dermatitis and sensitization to grass pollen (documented by elevated specific IgE levels) were treated with either cetirizine or placebo for 18 months. Those in the cetirizine-treated group demonstrated a decreased probability for subsequent wheezing compared to the placebo group that was maintained through 18 months of follow-up, even after active treatment was discontinued.
Newer-generation in vitro allergy tests that measure specific IgE levels have shown the ability to predict later childhood asthma among infants hospitalized for wheezing, and offer a more specific alternative to peripheral eosinophilia determinations in diagnostic algorithms.12 While diagnostic screening, including genetic tests for certain diseases such as cystic fibrosis, is acceptable among high-risk individuals even before signs and symptoms are present, and several genes potentially implicated in asthma have been identified, genetic testing for asthma is likely several years away. Allergy testing in the appropriately selected infant or young child should be viewed as "phenotype testing," in which a positive result is an indication for therapeutic intervention, including allergen avoidance, environmental modifications, and medications. The widespread availability of in vitro allergy tests should also permit the primary care physicians to test children as young as 3 months of age suspected to be at risk for asthma, and to confidently institute long-term inhaled corticosteroid therapy. However, it is certainly necessary for asthma specialists to educate the primary providers regarding proper utilization and interpretation of specific IgE test results, as with most objective diagnostic tools.
The diagnosis of asthma in the older child or adult is often facilitated by lung function tests, such as spirometry before and after bronchodilator treatment and bronchoprovocation studies. Spirometry also offers a way to monitor a patient’s response to therapy objectively. The presence of allergy, however, is often implied from history and physical examination. Yet, without specific diagnostic testing, even our allergy colleagues’ abilities to predict allergic sensitization rarely exceeded 50%.13 Left to rely on the same data, including our patients’ self-reports, we are likely to fare no better. Szeinbach et al14 found that only a third of the individuals receiving prescribed oral antihistamines, allegedly for allergic rhinitis, tested positive on a multiallergen-specific IgE test. A discussion regarding the limits of benefits from environmental modifications and other burdensome avoidance lifestyle changes is beyond the scope of this editorial. However, it is well recognized that asthma control is more difficult, if not impossible, to achieve in the presence of upper airway disease. Therefore, establishing the exact etiology of a patient’s upper airway disease—whether it be allergic rhinitis, a form of nonallergic rhinitis, or infectious in nature—permits a targeted approach to intervention. Perhaps in this regard the benefits of a negative allergy evaluation in an older child or an adult with asthma are readily seen. Unnecessary demands for environmental modifications are avoided, expense and potential side effects of antihistamines and intranasal steroids are spared, and investigation for nonallergic asthma triggers can be pursued without waiting for empiric allergy treatment to fail. As an aside, elevated total IgE and specific IgE levels may identify adults with COPD who would benefit from inhaled corticosteroids.1516
The financial benefits of specific IgE testing are also important to consider. The cost of blood testing for 12 to 15 allergens ($90 to $120) is generally less than a year’s worth of a prescription nonsedating antihistamine (approximately $75/month). Clearly, for patients who are IgE negative, the cost of blood testing is offset by the money saved on ineffective antihistamines. Compared to in vivo tests, on a per-allergen basis, blood testing can cost more, but skin testing typically utilizes many more allergens per patient. The 1996 Medicare Standard Analytical File showed that the median number of SPTs was 50 per patient (median charge, $255). The cost of another specialist consultation for in vivo evaluation is also avoided. The lack of any effect on in vitro test results by concurrent use of antihistamines, tricyclic antidepressants, and H2 antagonists or the presence of comorbid skin conditions, such as eczema and dermatographism, further enhances the appeal of in vitro testing over SPT. In addition, physicians avoid the rare but potential risk of anaphylaxis that can occur with in vivo tests.
The final and perhaps most important considerations are the accuracy and reliability of newer-generation in vitro tests that detect allergen-specific IgE in a patient’s blood. The first step requires incubation of a patient’s serum with allergens bound to a solid support. The nonpaper technology, such as the hydrophilic cellulose polymer of the ImmunoCAP (Pharmacia Diagnostics; Uppsala, Sweden) or matrices of soluble polymers as in the AlaSTAT (Diagnostic Products Corporation; Los Angeles, CA), have increased the amount of allergen available for binding several-fold over the previous radioallergosorbent technology. If allergen-specific IgE is in the serum, the IgE will complex with the solid-phase bound allergen. All other nonspecific IgE is washed away. Blood testing is calibrated to World Health Organization reference preparations to give reproducible results and must be performed in compliance with the Clinical Laboratory Improvement Act of 1988. At least 15 blood tests have received approval from the US Food and Drug Administration, and the number is likely to increase.17
Unfortunately, not all blood tests are equal. Williams et al18 analyzed the accuracy and precision of specific IgE testing on 26 masked serum samples sent to six different laboratories that used five different assays to detect 17 aeroallergens. Analysis of 12,708 test results showed considerable variation among laboratories, testing technologies, and allergens. A third-generation blood test (ImmunoCAP) used in two different laboratories performed closest to an ideal statistical standard and proved consistently superior to other assays. The study18 found that only the third-generation blood test was capable of measuring specific IgE over a large range with precision and accuracy, and the investigators supported its use, for the time being, as a standard for quantitative measurements of specific IgE.
An inherent limitation in comparing the relative diagnostic accuracy of skin testing vs in vitro allergy testing for inhalant allergy is the lack of a true diagnostic "gold standard." Such a standard would demonstrate conclusively whether a patient has a given condition. For example, a definitive diagnosis of a particular cancer might be based on results of a biopsy. There is no similar standard for the diagnosis of inhalant allergy. Typically a diagnosis of allergy is based on a combination of the case history and physical examination with a diagnostic test, such as in vitro test, skin test, or nasal/bronchial provocation test. None of these methods are adequate for diagnosis when used alone, and the detection of specific IgE does not necessarily indicate the presence of clinically relevant atopy. It is generally recognized that SPT and IDT lack the sensitivity and specificity, respectively, to be "gold standards." Nasal or bronchial provocation tests can be difficult to interpret, giving false-positive results because allergens are introduced into the nasal passages at higher concentrations and in a different form than would occur naturally. Despite the weakness inherent in comparing skin testing and in vitro testing without an external "gold standard," many studies do so, typically using skin testing as the diagnostic standard. This has contributed to the widely held perception that in vitro tests are not as diagnostically useful as skin testing.
More recently, an evidence-based analysis19 of comparative studies stated that skin and blood tests "have similar diagnostic performance" in evaluating suspected allergic rhinitis. Positive likelihood ratios (PLRs) for SPTs ranged from 3.23 to 16.17 and negative likelihood ratios (NLRs) ranged from 0.03 to 0.51. IDTs had PLRs of 0.89 to 8.80 and NLRs of 0.05 to 1.24. Blood tests had PLRs of 3.39 to 80.0 and NLRs of 0.09 to 0.84. The studies tested selected groups of allergens and used different "gold standards." The investigators19 concluded that either skin tests or well-performed blood tests were reasonable choices for diagnosis, counseling, and follow-up. The 2003 edition of Pediatric Allergy concludes that skin tests and quantitative IgE testing can be considered as interchangeable.20
Based on a review of literature, Poon et al21 also found a high degree of correlation between the results of skin and blood tests that improved from 68 to 95% of cases to 87 to 95% when comparison was limited to later-generation tests. These results are consistent with the finding that a regional profile, containing one member of each major inhalant allergen group, can detect > 95% of patients with allergy.22 Wood et al23 compared skin tests (SPT and IDT) with a third-generation blood test, evaluating their relative sensitivity, specificity, and positive and negative predictive values. The blood tests and SPTs were comparable, exhibiting high levels of sensitivity (87.2 ± 6.9% vs 93.6 ± 4.3%, respectively, for cat dander); specificity (90.5 ± 6.1% vs 80.1 ± 7.1%); positive predictive value (91.1 ± 5.9% vs 90.1 ± 5.3%); and negative predictive value (86.4 ± 7.1% vs 87.1 ± 6.0%). However, the positive predictive value of IDT was very low (60 ± 15.3%) and added little to diagnostic evaluation.
Almost certainly, a renewed interested in serum IgE levels has been sparked by the introduction of anti-IgE monoclonal antibody (omalizumab) therapy for asthma. However, rather than merely calculating the necessary dose of omalizumab needed to neutralize circulating IgE sufficiently in patients with poorly controlled asthma, perhaps pulmonologists will consider the roots and effects of allergen sensitization in all their patients, from the atopic infant to the adult with COPD and a questionable asthma component. Doing so would undoubtedly make us more complete "asthmologists."
References
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