Correspondence

Self-reported, doctor-diagnosed ‘‘asthma’’ isnot necessarily asthma: 78.9% of these‘‘asthma’’ cases were atopic

To the Editor:I commend Dr Arbes et al1 for the work put into their recent arti-

cle. Although the authors mention several possible study limitations,I believe that there is another: self-reported, doctor-diagnosed‘‘asthma,’’ is not the same as asthma diagnosed with reversible ob-struction on spirometry. I think that the reader should be reminded ofthis, especially in the Journal, where asthma diagnosed by spirom-etry is the norm. It’s likely that many of the ‘‘asthma’’ diagnoses inthe study were made by physicians not specializing in asthma, andwithout the benefit of spirometry.

Cough, wheezing, shortness of breath, and/or chest tightness mayindicate asthma, but the differential diagnosis in these patients alsoincludes allergic rhinitis, rhinosinusitis, acid reflux, vocal corddysfunction, anxiety, bronchiectasis, cystic fibrosis, sarcoidosis,and others.2,3 These conditions may be misdiagnosed as asthma byphysicians who are not asthma specialists, especially when spirom-etry is not done. In addition, patients with a long smoking historyand airway obstruction may be given the euphemistic diagnosis ofasthma, where emphysema or chronic bronchitis might be morecorrect.

At least with regard to smoking, one could argue that the data inTable I are consistent with this theory; ‘‘asthma’’ subjects with thelowest serum cotinine levels had the highest percentage of atopy(84.5%) and population attributable risk (PAR%) (66.3%),whereas those with the highest cotinine levels had a lower per-centage of atopy (75.2%.) and PAR% (51.9%.) If one were to re-strict the diagnosis of asthma to subjects with a consistent historyand examination and reversible obstruction on spirometry andeliminate those who might more correctly have a diagnosis of em-physema or chronic bronchitis, the percentage of asthma caseswith atopy and the PAR% might be even higher than that reportedin this study.

In addition, in Table II, 78.9% of ‘‘asthma’’ cases had at least1 positive skin test result and were considered atopic. I think thatthis gives an equally valid assessment of the data and would be inline with what most allergists would expect.

Bernard A. Feigenbaum, MD

From the Division of General Internal Medicine, Department of Medicine and Division

of Head and Neck Allergy, Department of Otolaryngology, New York University

School of Medicine, New York, NY; and the Department of Medicine, Yale Univer-

sity, New Haven, Conn. E-mail: bernard.feigenbaum@med.nyu.edu.

Disclosure of potential conflict of interest: B. Feigenbaum owns stock in Sepracor.

REFERENCES

1. Arbes SJ Jr, Gergen PJ, Vaughn B, Zeldin DC. Asthma cases attributable to atopy:

results from the Third National Health and Nutrition Examination Survey. J Allergy

Clin Immunol 2007;120:1139-45.

2. Strek ME. Difficult asthma. Proc Am Thorac Soc 2006;3:116-23.

3. Busse WW. NAEPP Expert Panel Report 3: guidelines for the diagnosis and man-

agement of asthma. J Allergy Clin Immunol 2007;120:S94-138.

Available online March 28, 2008.

doi:10.1016/j.jaci.2008.02.021

Reply

To the Editor:We would like to respond to Dr Feigenbaum’s1 comments

by clarifying some of the issues he raised with respect to ourarticle,2 which was published in the November 2007 issue ofthe Journal.

Although we agree with Dr Feigenbaum’s general assertionthat self-reported, doctor-diagnosed asthma is not the same thingas asthma diagnosed by specialists with the aid of spirometry,many large, cross-sectional studies, such as the National Healthand Nutrition Examination Survey, use the former outcomemeasure for several reasons. First, information on self-report ofdiagnosis of asthma can be easily collected in population-basedstudies. It would be difficult, if not impossible, to perform certaindiagnostic tests such as bronchial challenge or bronchodilatoryresponsiveness in large surveys. Second, self-report of asthmawith or without a physician has been shown to have a highspecificity (low number of false-positives) with a lower sensi-tivity (higher false-negative rate).3,4 Thus, self-reported asthmamay undercount the number of patients with asthma in the pop-ulation, but the patients with asthma identified will have a highprobability of truly having asthma. High specificity is importantin studies looking at correlates or risk factors such as ours. Third,self-report of diagnosis and/or symptoms of asthma without theuse of spirometry to confirm the diagnosis is widely used inthe literature, even in articles published in the Journal.5-7 Fourth,spirometry with bronchodilator responsiveness has some limita-tions. For example, in a recent study on the diagnostic accuracyof bronchodilator responsiveness in children, the value of bron-chodilator responsiveness testing depended on the prevalenceof wheeze in the population. With an estimated pretest probabil-ity of wheeze of 10% in the community and 50% in a specialistclinic, the positive predictive values were 29% and 78%, respec-tively, for a 9% change in FEV1.8 Finally, it is generally thoughtthat demonstrated reversibility may be of less value in diagnosisof asthma among individuals who receive inhaled corticosteroidtreatment.

Dr Feigenbaum also argues that the data in Table I of our articleare consistent with his theory, at least with regard to smoking,because subjects with asthma with the lowest serum cotininelevels had the highest percentage of atopy and population attrib-utable risk, whereas those with the highest cotinine levels had alower percentage of atopy and population attributable risk. Itshould be pointed out, however, that higher prevalences of asthmaand atopy with lower levels of cotinine most likely reflect smokingavoidance by atopic subjects with asthma rather than the misdi-agnosis of patients with smoking history and airway obstruction ashaving asthma.

In summary, although we acknowledge that misdiagnosis andunderdiagnosis of asthma are potential limitations of our study, webelieve that self-reported, doctor-diagnosed asthma is a reason-able outcome measure to use in large, population-based studiessuch as the National Health and Nutrition Examination Surveyin which spirometric confirmation of the diagnosis by asthmaspecialists is neither feasible nor practical.

1291

melon nor kiwi allergy has been associated with sensitization toLTP. In particular, melon is frequently associated with profilinsensitization.5 Is there any possibility that profilin, a plant panal-lergen, played a role in inducing baker’s asthma, at least in someof these patients?

Riccardo Asero, MDa

Leonardo Antonicelli, MDb

From aAmbulatorio di Allergologia, Clinica San Carlo, Paderno Dugnano, and bServizio

di Allergologia, Ospedali Riuniti, Ancona, Italy. E-mail: r.asero@libero.it.

Disclosure of potential conflict of interest: The authors have declared that they have no

conflict of interest.

REFERENCES

1. Palacin A, Quirce S, Armentia A, Fernandez-Nieto M, Pacios LF, Asensio T, et al.

Wheat lipid transfer protein is a major allergen associated with baker’s asthma.

J Allergy Clin Immunol 2007;120:1132-8.

2. Pastorello EA, Farioli L, Pravettoni V, Ispano M, Scibola E, Trambaioli C, et al. The

maize major allergen, which is responsible for food-induced allergic reactions, is a

lipid transfer protein. J Allergy Clin Immunol 2000;106:744-51.

3. Curioni A, Santucci B, Cristaudo A, Canistraci C, Pietravalle M, Simonato B, et al.

Urticaria from beer: an immediate hypersensitivity reaction due to a 10-kDa protein

derived from barley. Clin Exp Allergy 1999;29:407-13.

4. Asero R, Mistrello G, Roncarolo D, Amato S, van Ree R. A case of allergy to beer

showing cross-reactivity between lipid transfer proteins. Ann Allergy Asthma

Immunol 2001;87:65-7.

5. Asero R, Mistrello G, Roncarolo D, Amato S, Zanoni D, Barocci F, et al. Detection

of clinical markers of sensitization to profilin in patients allergic to plant-derived

foods. J Allergy Clin Immunol 2003;112:427-32.

Available online April 7, 2008.

doi:10.1016/j.jaci.2008.02.034

Reply

To the Editor:1

J ALLERGY CLIN IMMUNOL

MAY 2008

1292 CORRESPONDENCE

Peter J. Gergen, MD, MPHa

Samuel J. Arbes, Jr, DDS, MPH, PhDb

Ben Vaughn, MSb

Darryl C. Zeldin, MDc

From athe Division of Allergy, Immunology and Transplantation, National Institute of

Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md; bRho,

Inc, Chapel Hill, NC; and cthe Laboratory of Respiratory Biology, National Institute

of Environmental Health Sciences, National Institutes of Health, Research Triangle

Park, NC. E-mail: zeldin@niehs.nih.gov.

Disclosure of potential conflict of interest: The authors have declared that they have no

conflict of interest.

REFERENCES

1. Feigenbaum BA. Self-reported, doctor-diagnosed ‘‘asthma’’ is not necessarily

asthma: 78.9% of these ‘‘asthma’’ cases were atopic. J Allergy Clin Immunol

2008;121:1291.

2. Arbes SJ Jr, Gergen PJ, Vaughn B, Zeldin DC. Asthma cases attributable to atopy:

results from the Third National Health and Nutrition Examination Survey. J Allergy

Clin Immunol 2007;120:1139-45.

3. Kilpelainen M, Terho EO, Helenius H, Koskenvuo M. Validation of a new questionnaire

on asthma, allergic rhinitis, and conjunctivitis in young adults. Allergy 2001;56:377-84.

4. Toren K, Brisman J, Jarvholm B. Asthma and asthma-like symptoms in adults as-

sessed by questionnaires: a literature review. Chest 1993;104:600-8.

5. Cazzoletti L, Marcon A, Janson C, Corsico A, Jarvis D, Pin I, et al. Asthma control

in Europe: a real-world evaluation based on an international population-based study.

J Allergy Clin Immunol 2007;120:1360-7.

6. Matheson MC, Erbas B, Balasuriya A, Jenkins MA, Wharton CL, Tang ML, et al.

Breast-feeding and atopic disease: a cohort study from childhood to middle age.

J Allergy Clin Immunol 2007;120:1051-7.

7. Arshad SH, Bateman B, Sadeghnejad A, Gant C, Matthews SM. Prevention of aller-

gic disease during childhood by allergen avoidance: the Isle of Wight prevention

study. J Allergy Clin Immunol 2007;119:307-13.

8. Dundas I, Chan EY, Bridge PD, McKenzie SA. Diagnostic accuracy of bronchodi-

lator responsiveness in wheezy children. Thorax 2005;60:13-6.

Available online April 14, 2008.

doi:10.1016/j.jaci.2008.02.022

Airborne allergy to wheat lipid transfer proteinwithout food allergy?

To the Editor:In their recent article, Palacin et al1 conclude that wheat lipid

transfer protein (LTP) is significantly associated with baker’sasthma. Although this finding is very interesting, we think thatsome clinical aspects are worth discussing further. As the authorscorrectly note, LTPs are major cross-reacting allergens in plant-derived foods. Notably, along with many cases of allergy to fruits(particularly peach and other Rosaceae), tree nuts, and vegetables,several cases of severe allergy to cereals, namely maize2 and bar-ley,3,4 have been reported in patients allergic to LTPs. Palacin etal1 report that all patients in their series tolerated the ingestionof wheat-based foods, although a history of peach allergy was pre-sent in several cases and despite the fact that cross-reactivity be-tween peach and wheat LTPs was clearly demonstrated in some ofthem. This fact is rather surprising. Because LTPs are extremelyheat and pepsin stable, one could expect some sort of wheat-induced food allergy, at least in a minority of cases. Do the authorshave an explanation for the absence of allergy to ingested wheat-based products? Should we consider patients with LTP-inducedbaker’s asthma at risk for severe allergic reactions on ingestionof bread or pasta?

Another interesting aspect is sensitization to plant foods otherthan cereals. Table I1 shows that 5 patients reported oral allergysyndrome from peach and showed sensitization (Oral allergy syn-drome as well?) to melon and kiwi. As far as we know, neither

Asero and Antonicelli raise 2 questions regarding our recentreport2 on wheat lipid transfer protein (LTP; Tri a 14) as a majorallergen associated with baker’s asthma.

First, do patients with baker’s asthma who are sensitized towheat LTP tolerate the ingestion of wheat-based foods? Mostpatients with baker’s asthma are able to ingest wheat productswithout symptoms, as reviewed by Palosuo.3 Moreover, subjectswith asthma induced by rice powder inhalation and sensitized torice LTP tolerate the ingestion of cooked rice without any adverseeffects.4 In the case of Tri a 14 and besides putative differences inthe immunologic responses triggered by inhalation versus inges-tion of the allergen, its allergenic potency can be drastically dif-ferent in raw flour and cooked, wheat-derived foodstuffs. TheIgE recognition of Tri a 14 in raw flour, but not in cooked flour,by some sera from patients with allergic reactions after the inges-tion of wheat products5 and preliminary results suggesting itsinactivation in bread and pasta treated with high heat (Sanchez-Monge et al, unpublished data) support this hypothesis.

The second question regards the allergens responsible forwheat flour/fruit (melon and kiwi) cross-reactivity. All patientssensitized to melon (5/40), kiwi (7/40), or both showed only oralallergy syndrome (except 1 subject sensitized to kiwi who alsohad contact urticaria). Profilin is a major melon allergen suscep-tible to pepsin digestion,6 but to the best of our knowledge, it hasbeen associated neither with baker’s asthma nor with wheat/melon cross-reactivity. Regarding kiwi, our available data(Palacin et al, unpublished data) indicate that cross-reactivecarbohydrate determinants and thiol proteases homologous toAct d 1 are responsible for wheat/kiwi cross-reactivity in somepatients with baker’s asthma.