Correspondence

Asthma

N Engl J Med 1993; 328:1639-1641June 3, 1993

Article

To the Editor:

In their comprehensive review of asthma, McFadden and Gilbert (Dec. 31 issue)1 appropriately question published epidemiologic data suggesting that all asthma is related to atopy. There is increasing evidence of immunologic differences between allergic and intrinsic, or nonatopic, asthma. Apart from higher eosinophil counts in peripheral blood,2 comparisons of persons with allergic and intrinsic asthma have found differences in the expression of activation markers on T-lymphocyte subgroups and in the profiles of cytokines in bronchoalveolar-lavage fluid3.

We question the authors' statements about the role of interleukin-2 in allergic asthma. None of the cited papers have in fact reported that interleukin-2 prolongs the survival of eosinophils. Furthermore, interleukin-2 is not a feature of allergic asthma4. Activated, interleukin-2 receptor-positive T lymphocytes have been observed in allergic as well as in intrinsic asthma. Persons with intrinsic asthma were the only group with asthma that had increased levels of interleukin-2 in bronchoalveolar-lavage fluid3. Although fluid from both persons with extrinsic asthma and those with intrinsic asthma has been shown to contain interleukin-5 (the most specific cytokine to prolong eosinophil survival), interleukin-4 was elevated only in those with allergic asthma3.

These data suggest that the clinically defined syndrome of asthma includes two independent pathogenetic pathways with different profiles of cytokines. Allergic asthma involves an acute immunologic activation with the classic IgE-dependent and mast-cell-mediated response. Nonatopic asthma has many features of a chronic cell-mediated disease that may occur independently of antibody(IgE)-mediated immune mechanisms. Hence, intrinsic asthma may be related to an as yet unidentified antigen (or autoantigen)-mediated T-lymphocyte activation, possibly triggered by a respiratory tract infection. Both immunologic mechanisms, however, may have a common final pathway -- an eosinophil-dominated reaction of the bronchial tissue that results in the clinical expression of asthma.

Claus Kroegel, M.D., Ph.D.
J.-Christian Virchow, Jr., M.D.
University Medical Clinic, D-7800 Freiburg, Germany

Christoph Walker
Swiss Institute of Allergy and Asthma Research, CH-7270 Davos, Switzerland

4 References

1. 1

   McFadden ER Jr, Gilbert IA. Asthma. N Engl J Med 1992;327:1928-1937
   Full Text | Web of Science | Medline

2. 2

   Weller PF, Goetzl EJ. The regulatory and effector roles of eosinophils. Adv Immunol 1979;27:339-371
   CrossRef | Medline

3. 3

   Walker C, Bode E, Boer L, Hansel TT, Blaser K, Virchow J-C Jr. Allergic and nonallergic asthmatics have distinct patterns of T-cell activation and cytokine production in peripheral blood and bronchoalveolar lavage. Am Rev Respir Dis 1992;146:109-115
   Web of Science | Medline

4. 4

   Robinson DS, Hamid Q, Ying S, et al. Predominant T_H2-like bronchoalveolar T-lymphocyte population in atopic asthma. N Engl J Med 1992;326:298-304
   Full Text | Web of Science | Medline

To the Editor:

In discussing the management of asthma, McFadden and Gilbert advocate the use of “cromolyn, inhaled glucocorticoids, or both” for “patients with active disease who have unstable lung function.” There are considerable data regarding the use of either cromolyn or inhaled steroids in the treatment of asthma, but no comparison studies have indicated an advantage of the combination of these agents over inhaled steroids alone1-5. I believe that it is inappropriate to suggest this combination unless there are clinical subgroups or dose regimens that can be defined that merit such an approach. Also, cromolyn is relatively expensive.

Albin Leong, M.D.
6600 Bruceville Rd., Sacramento, CA 95823

5 References

1. 1

   Hiller EJ, Milner AD. Betamethasone 17 valerate aerosol and disodium chromoglycate in severe childhood asthma. Br J Dis Chest 1975;69:103-106
   CrossRef | Medline

2. 2

   Mitchell I, Paterson IC, Cameron SJ, Grant IWB. Treatment of childhood asthma with sodium cromoglycate and beclomethasone dipropionate aerosol singly and in combination. BMJ 1976;2:457-458
   CrossRef | Web of Science | Medline

3. 3

   Dawood AG, Hendry AT, Walker SR. The combined use of betamethasone valerate and sodium cromoglycate in the treatment of asthma. Clin Allergy 1977;7:161-165
   CrossRef | Medline

4. 4

   Toogood JH, Jennings B, Lefcoe NM. A clinical trial of combined cromolyn/ beclomethasone treatment for chronic asthma. J Allergy Clin Immunol 1981;67:317-324
   CrossRef | Web of Science | Medline

5. 5

   Francis RS, McEnery G. Disodium cromoglycate compared with beclomethasone dipropionate in juvenile asthma. Clin Allergy 1984;14:537-540
   CrossRef | Medline

To the Editor:

I noted a number of apparent errors in the review by McFadden and Gilbert.

In Table 2 of the article, if the percentage predicted for the forced vital capacity (FVC) before bronchodilation is correct, the corresponding figure for an FVC of 100 percent after bronchodilation should be 5.18 rather than 5.78. Is this a transcriptional error?

None of the values for the FVC or the maximal forced expiratory flow (FEF_max) in Table 2 correspond to those in Figure 1 according to visual inspection. Were data for another patient inadvertently substituted?

The values for the FVC and vital capacity (VC), after correction for the (presumed) transcriptional error noted above, are identical. Although not stated, the FVC rather than the VC thus appears to have been used to compute the total lung capacity (TLC)1,2.

Jerome Reich, M.D.
Bess Kaiser Medical Center, Portland, OR 97227

2 References

1. 1

   Conrad SA. Lung volumes. In: Conrad SA, Kinasewitz GT, George RB, eds. Pulmonary function testing: principles and practice. New York: Churchill Livingstone, 1984:108.
   

2. 2

   Assessment of mechanical and bellows attributes of the lung. In: Cotes JE. Lung function: assessment and application in medicine. 4th ed. Oxford, England: Blackwell Scientific, 1979:103.
   

Author/Editor Response

The authors reply:

To the Editor: We are grateful to Dr. Reich for bringing to our attention the inconsistencies between Figure 1 and Table 2. These data were obtained in the same patient but at different times. Instead of providing the spirographic and lung-volume measurements associated with the flow-volume curves in Figure 1, as we intended, we inadvertently substituted a set of observations in Table 2 that were obtained after a period of treatment. The typographic error was introduced when the data were transcribed (i.e., 5.18 was miswritten as 5.78). We regret the confusion that our oversight caused. Fortunately, the patterns of physiologic derangements that we wished to demonstrate were not affected. In Table 2, the TLC was calculated according to standard procedures that incorporate the slow VC. In this particular instance, the FVC and the VC were equal.

Dr. Leong appears to have placed far more weight on our statements concerning the use of combined therapy with cromolyn and inhaled steroids than we intended. We carefully summarized the relative advantages and disadvantages of both drugs and developed some theoretical considerations about possible positive interactions between cromolyn and steroids. If appropriately controlled trials show otherwise, so be it. Unfortunately, to our knowledge, such data are not yet available. Although the studies cited by Dr. Leong in support of his position are provocative, their impact is limited by such issues as study design, numbers of patients, and the end points chosen to demonstrate efficacy.

We agree with Dr. Kroegel and associates that not all asthma is related to atopy. However, before addressing their concern, we wish to point out that we incorrectly cited the work of Sears et al.1 linking asthma with elevated serum IgE levels in children. The population in this study was not preselected, as we had indicated, and it appears that in children, asthma and elevated IgE levels are strongly associated. Kroegel et al. are correct in their statements that there are no data relating the presence of interleukin-2 to allergic asthma or to eosinophil survival in a direct fashion. Our discussion of interleukin-2 was colored by its capacity to influence other cytokine-producing systems that have profound effects on eosinophils. We should have been more specific. We also took the finding of the expression of messenger RNA for interleukin-2 in various cells or tissues in atopic asthma2,3 as evidence that interleukin-2 was physically present. Of course, this need not be the case. We did not become aware of the interesting and important observations of Walker and colleagues4 on the differences in cytokine production between allergic and nonallergic asthma in time to include them in our review.

E.R. McFadden, Jr., M.D.
Ileen A. Gilbert, M.D.
University Hospitals of Cleveland, Cleveland, OH 44106

4 References

1. 1

   Sears MR, Burrows B, Flannery EM, Herbison GP, Hewitt CJ, Holdaway MD. Relation between airway responsiveness and serum IgE in children with asthma and in apparently normal children. N Engl J Med 1991;325:1067-1071
   Full Text | Web of Science | Medline

2. 2

   Bentley AM, Meng Q, Robinson DS, Hamid Q, Kay AB, Durham SR. Increases in activated T lymphocytes, eosinophils, and cytokine mRNA expression for interleukin-5 and granulocyte/macrophage colony-stimulating factor in bronchial biopsies after allergen inhalation challenge in atopic asthmatics. Am J Respir Cell Mol Biol 1993;8:35-42
   Web of Science | Medline

3. 3

   Robinson DS, Hamid Q, Ying S, et al. Predominant T_H2-like bronchoalveolar T-lymphocyte population in atopic asthma. N Engl J Med 1992;326:298-304
   Full Text | Web of Science | Medline

4. 4

   Walker C, Boda E, Boer L, Hansel TT, Blaser K, Virchow JC Jr. Allergic and nonallergic asthmatics have distinct patterns of T-cell activation and cytokine production in peripheral blood and bronchoalveolar lavage. Am Rev Respir Dis 1992;146:109-115
   Web of Science | Medline

Citing Articles (4)

Citing Articles

1. 1

   MC Calixto, L Lintomen, A Schenka, MJ Saad, A Zanesco, E Antunes. (2010) Obesity enhances eosinophilic inflammation in a murine model of allergic asthma. British Journal of Pharmacology 159:3, 617-625
   CrossRef

2. 2

   Papi, Corbetta, Fabbri. (1998) What can we learn from late-onset and occupational asthma?. Clinical <html_ent glyph="@amp;" ascii="&"/> Experimental Allergy 28:Suppl. 5, 174-180
   CrossRef

3. 3

   M. I. C. GASPAR ELSAS, P. XAVIER ELSAS, D. JOSEPH, N. HAVET, L. A. ADELINO SILVA, D. R. SALGADO, B. SALIOU, B. B. VARGAFTIG. (1997) Stimulation of early eosinophil progenitors by a heat stable alveolar macrophage product from ovalbumin-sensitized and non-sensitized guinea pigs. Clinical <html_ent glyph="@amp;" ascii="&"/> Experimental Allergy 27:2, 208-217
   CrossRef

4. 4

   P. J. BARNES, S. T. HOLGATE, L. A. LAITINEN, R. PAUWELS. (1995) Asthma mechanisms, determinants of severity and treatment: the role of nedocromil sodium Report of a workshop held in Whistler, British Columbia, Canada, 18-19 May 1995. Clinical <html_ent glyph="@amp;" ascii="&"/> Experimental Allergy 25:8, 771-787
   CrossRef