(Chest. 2002;122:821-825.)
© 2002
American College of Chest Physicians
Value of a Negative Aeroallergen Skin-Prick Test Result in the Diagnosis of Asthma in Young Adults*
Correlative Study With Methacholine Challenge Testing
Yael Graif, MD;
Mordechai Yigla, MD;
Naveh Tov, MD and
Mordechai R. Kramer, MD, FCCP
* From the Allergy and Pulmonary Clinic (Dr. Graif), Israel Defense Forces, Tel Aviv; Division of Pulmonary Medicine (Drs. Tov and Yigla), Rambam Medical Center, Haifa; and Pulmonary Institute (Dr. Kramer), Rabin Medical Center, Petah-Tiqva, Israel.
Correspondence to: Yael Graif, MD, Allergy and Clinical Immunology Unit, Rabin Medical Center, 100 Jabotinsky St, Petach Tikva 49100, Israel; e-mail: graif{at}post.tau.ac.il
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Abstract
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Background: None of the existing tests for the diagnosis of asthma are considered to be definitive. Certain circumstances require prompt diagnosis, and a test able to predict the absence of asthma would be very useful.
Objective: To evaluate the contribution of a skin-prick test (SPT) to the diagnostic workup of subjects with suspected asthma.
Patients and methods: The study included three groups of subjects aged 18 to 24 years: group A, asthmatic patients (n = 175); group B, control subjects (n = 100); and group C, subjects with suspected asthma (n = 150) with normal spirometry findings and a negative exercise challenge test result. All underwent an SPT to a battery of common aeroallergens, and group C underwent a methacholine challenge test (MCT) in addition. The sensitivity, specificity, positive predictive value, and negative predictive values (NPV) of the SPT were calculated using provocative concentrations of methacholine causing a 20% fall in FEV1 (PC20) of < 4 mg/mL and < 8 mg/mL as diagnostic cutoff values for asthma in the MCT. Bayes’ formula was used to determine posttest probabilities of having asthma, both for positive and negative SPT results.
Results: A positive SPT result to at least one allergen was found in 95.5%, 54%, and 69% of patients in the three groups, respectively. The sensitivity, specificity, and NPV of the SPT were 90.7%, 52.0%, and 84.8%, respectively, with a cutoff value of PC20 < 8 mg/mL. The lower cutoff, PC20 < 4 mg/mL, increased the sensitivity and NPV to 98.2% and 97.8%, respectively. A negative SPT result decreased the probability of having asthma by 10-fold to 20-fold in subjects whose pretest probability was low to moderate.
Conclusions: Incorporating an SPT into the workup of subjects with suspected asthma can reduce the cost of this process significantly. The SPT may be used as a simple, fast, safe, inexpensive, and reliable method to predict the absence of asthma in young adults.
Key Words: bronchial asthma • bronchial hyperresponsiveness • skin-prick test
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Introduction
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The diagnosis of bronchial asthma arises among patients with characteristic symptoms, such as coughing, wheezing and unexplained episodes of dyspnea. Airflow obstruction, either variable over the course of time or reversible in response to the administration of bronchodilating agents, is required for a definitive diagnosis.1
Demonstration of bronchial hyperresponsiveness (BHR) to nonspecific stimuli is required for the diagnosis of asthma in subjects with characteristic symptoms having normal spirometry findings.2
Standard exercise and a variety of pharmacologic agents, such as methacholine, adenosine, and histamine, are widely used for this purpose.3
A link between allergy and asthma has long been recognized.4
5
Most patients with asthma, especially children, manifest clinical features of atopy, such as eczema, rhinitis, and a positive skin-prick test (SPT) result to aeroallergens, along with elevated IgE levels.6
7
Atopy is also common among adults with asthma.8
9
10
An SPT to a battery of commonly inhaled allergens is a simple, safe, inexpensive, rapid, and most common way of assessing the contribution of atopy.11
The incidence of a positive SPT result, at least to one aeroallergen in asthmatic adults residing in the United Kingdom (age range, 18 to 50 years) was 90%.7
However, a positive SPT result has been found in 15 to 40% of normal individuals.4
5
6
While a positive SPT result has been correlated both to the presence of asthma and even to the degree of BHR,12
13
the clinical significance of a negative SPT result in subjects with suspected asthma is unknown. This study examined the predictive value of SPT in the diagnosis of asthma among young adults presenting with dyspnea and/or chronic cough and compared it to the methacholine challenge test (MCT).
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Materials and Methods
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The study was carried out in an Allergy and Pulmonary Outpatient Clinic of the Israel Defense Forces (IDF). The study population was composed of three groups of patients (age range, 18 to 24 years), all of whom signed an informed consent.
Asthma Patients (Group A)
Group A included 175 consecutive patients, 54 women and 121 men, with active asthma according to American Thoracic Society guidelines1
2
followed by asthma specialists.
Control Group (Group B)
Group B included 100 volunteers (of 112 subjects who were asked to participate in the study), 39 women and 61 men, who attended an IDF Orthopedic Clinic. These subjects were asked to divulge if they were known to suffer from asthma or allergic rhinitis.
Study Group of Subjects With Suspected Asthma (Group C)
Group C included 150 patients, 36 women and 114 men, who were referred to the IDF Allergy and Pulmonary Outpatient Clinic by their primary physicians for evaluation of persistent cough and/or unexplained episodes of dyspnea. None gave a history of childhood asthma. All these patients exhibited a normal pulmonary function test result at rest, and lack of response to bronchodilators (defined as < 12% improvement) and a normal exercise challenge test result as previously described.3
SPT
All of the patients in the three groups underwent SPTs to a battery of common allergens, including indoor (mixed mites, feathers, cat, dogs, cockroaches) and outdoor (molds, trees, grasses, weeds) aeroallergens (Center Pharmaceutical; Port Washington, NY).11
A test was considered positive when the wheal diameter was greater than the diluent control by 
3 mm.
MCT
After inhaling an initial control solution of isotonic saline solution, patients were administered doubling concentrations of methacholine, starting from 0.0625 mg/mL, up to 16 mg/mL (if no response), by dosimeter.3
FEV1 was measured 1 min after the end of the corresponding inhalation. Each FEV1 measurement was expressed as a percentage from the baseline record. The provocation concentration of methacholine causing a fall of 20% in FEV1 (PC20) was recorded.
Data analysis
The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the SPT was calculated separately for PC20 < 4 mg/mL and PC20 < 8 mg/mL, respectively. The NPV of the SPT was calculated by Bayes’ formula.14
We also used Bayes’ formula to determine posttest probabilities for having asthma for positive (equation 1)
and negative (equation 2) SPT results.15
 | (1) |
and
 | (2) |
where PP = posttest probabilities, P = pretest probability, SE = sensitivity, and SP = specificity.
The pretest probability is the clinical estimate of having asthma expressed in percentage prior to the SPT, which in the setup described is approximately 60%.14
15
The difference between the pretest and posttest probabilities is the diagnostic gain of the test. The 
2 test was used to assess the correlation between the SPT and the MCT.
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Results
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The prevalence of a positive SPT result to at least one aeroallergen among group A (asthma patients) was 95.4% (167 of 175 patients). The vast majority (160 of 167 patients; 95.8%) of the patients with a positive SPT result responded to house dust mites.
The prevalence of positive SPT result to at least one allergen in group B (control subjects) was 54%, of which 47 of 54 subjects (87%) tested positive to house dust mites. A total of 7% had active asthma, in agreement with the reported prevalence of asthma in Israel in this age group.16
The calculated NPV was 0.985, indicating that the probability of a subject in this group with negative SPT result to be asthmatic is < 1.5%. In group C, 69% (104 of 150 subjects) with suspected asthma had a positive SPT result to at least one allergen; 93% (97 of 104 subjects) responded to house dust mites.
SPT and MCT results were correlated statistically significantly (2 = 32.1, p < 0.00001). Table 1
shows the results of SPTs and MCTs (diagnostic cutoff, PC20 
8 mg/mL) in the study group, demonstrating BHR in 50% (75 of 150 patients). Sixty-five percent (68 of 104 patients) with a positive SPT result and 15% (7 of 46 patients) with a negative SPT result had BHR, demonstrating sensitivity, specificity, and NPV of 90.7%, 52.0%, and 84.8%, respectively. Establishing the diagnostic cutoff for the diagnosis of asthma on PC20 as 4 mg/mL improved the diagnostic value of the SPT by increasing the sensitivity and NPV to 98.2% and 97.8%, respectively (Table 2
). Only 1 of 46 subjects with a negative SPT result had a positive MCT result (PC20 = 1 mg/mL). Fifty-four percent of the control group had a positive SPT result, and 46% had a negative SPT result, yielding NPVs in this group of 95.7% and 97.8%, respectively (Table 3
), similar to the data found among the subjects included in the study group.
Posttest probabilities of having asthma for both positive and negative SPT results are presented in Figure 1
. In a lower pretest probability, a negative SPT result will decrease the posttest probability by almost 10-fold, while in a moderate pretest probability it will yield a decrease of approximately 20-fold. No significant differences according to gender or to number of positive allergens were found.
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Discussion
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The diagnosis of asthma is based on clinical history, pulmonary function testing, and provocation testing.1
2
There is no "gold standard" for the diagnosis of asthma at present, and a test that would contribute to the exclusion of this diagnosis would be very useful. MCT, the established procedure for evaluating the state of airway responsiveness, is costly and requires time and cooperation. Factors that alter BHR, such as respiratory infection, cigarette smoking, and exposure to chemical irritants and several medications, may influence the results of the MCT.3
This test is more useful in excluding the diagnosis of asthma because its NPV is greater than its PPV.12
13
In testing the general population, patients with allergic rhinitis and active smokers with COPD produce MCT results with relatively high false-positive rates.17
18
When the presence of asthma would impair the ability of a person to perform demanding or life-saving work (eg, military, police), the diagnosis should be made promptly so that occupational and therapeutic decisions can be made as soon as possible.3
According to recent American Thoracic Society recommendations3
regarding interpretation of the MCT, a PC20 of < 1 mg/mL is considered as moderate-to-severe BHR, PC20 of 1 to 4 mg/mL is mild, PC20 of 4 to 16 mg/mL is borderline, and PC20 > 16 mg/mL is a normal response. These guidelines raise questions concerning the diagnosis of asthma among subjects whose PC20 values vary between 1 mg/mL and 16 mg/mL, and recommend follow-up to ensure or exclude the diagnosis. The limitations of the MCT raise the need for further diagnostic tools intended to exclude the possibility of asthma, especially where a prompt diagnosis is required.
Our study evaluated the applicability of an SPT to the workup of subjects with symptoms suggesting the diagnosis of asthma with a negative exercise challenge test result (group C). An SPT to aeroallergen is a simple, fast, reliable, and highly safe procedure.11
There was high correlation between the results of the SPT and the MCT (with the two cutoff levels used). The SPT gave an NPV of 84.8% for the diagnosis of BHR, using a cutoff of PC20 8 mg/mL (Table 1)
. Lowering this cutoff to PC20 < 4 mg/mL increased the NPV of the SPT to 97.8% (Table 2)
. Only 1 of 46 patients with a negative SPT result had BHR defined as PC20 4 mg/mL. This high NPV at both cutoff levels was in agreement with the NPV calculated by Bayes’ formula in the asthmatic patients (group A).
Sensitivity and specificity are good determinants of the diagnostic quality of a given test. However, proper use in clinical settings requires recognition of the prior probability of having the disease. Using Bayes’ formula, we calculated the posttest probability of having asthma in two populations of patients, those with negative or positive SPT results.14
15
We found that a positive SPT result had a minimal contribution to the diagnosis of asthma. A negative SPT result, however, decreased the probability of having asthma by 10-fold to 20-fold (Fig 1) in patients whose their pretest probability of having asthma is low to medium. As the estimated pretest probability of the subjects in the study group (with coughing and unexplained dyspnea) to have asthma is 50 to 70%,14
a negative SPT result significantly decreases their probability of having asthma.
Cost Benefit
In Israel, simple spirometry costs $25 and the cost of an SPT is $20. Exercise challenge costs $25, and an MCT costs $125. Normal spirometry and negative SPT findings can exclude asthma in 98% of cases at a cost of $45. While most physicians will perform spirometry, exercise challenge test, and an MCT, which will raise the cost of the diagnostic workup to $175 per patient.
We suggest an algorithm (Fig 2
) for the diagnosis of asthma in young adults, as follows: subjects with characteristic symptoms and normal spirometry findings not demonstrating BHR after administration of bronchodilating agents would undergo SPT. Proceeding to an exercise challenge test and/or to an MCT is recommended only for subjects whose SPT results are positive. Incorporating the SPT to the diagnostic workup of young adults with suspected asthma is expected to reduce to cost of this process significantly.
In summary, our results demonstrate that a negative SPT result is highly correlated with a negative MCT result in young adults, and may be used as a simple, fast, inexpensive, and reliable method to predict the absence of asthma in this age group. When the SPT result is positive, further investigation is needed. This approach is expected to reduce the cost of the workup significantly. As the prevalence of atopy varies with age, similar studies should be undertaken to evaluate the applicability of the SPT in other age groups with suspected asthma.
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Acknowledgements
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The authors thank Mrs. M. Perlmutter for her assistance in the preparation of this article.
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Footnotes
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Abbreviations: BHR = bronchial hyperresponsiveness; IDF = Israel Defense Forces; MCT = methacholine challenge test; NPV = negative predictive value; PC20 = provocation concentration of methacholine causing a fall of 20% in FEV1; PPV = positive predictive value; SPT = skin-prick test
Received for publication July 26, 2001.
Accepted for publication March 26, 2002.
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References
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Abstract
Introduction
