Immunotherapy decreases skin sensitivity to ragweed extract: Demonstration by midpoint skin test titration

Brief report Immunotherapy decreases skin sensitivity to ragweed extract: Demonstration by midpoint skin test titration Thomas E, Van Metre, Jr., MD, N. Franklin Adkinson, Jr., MD, Anne Kagey-Sobotka, PhD, Arouna Khattignavong, MD, David G. Marsh, PhD, Philip S. Norman, MD, and Gary L. Rosenberg, MD Baltimore, Md. By use of midpoint skin test titration, we have recently demonstrated, in a controlled study, that immunotherapy with a specific cat extract decreased skin sensitivity to that cat extract. 1.2These positive findings agreed wtih findings of multiple other workers who, in controlled studies, demonstrated by various midpoint skin test titration methods that immunotherapy decreased skin sensitivity to cat, dog, dust mite, grass pollen, and Alternaria extracts, 3 but disagreed with the negative findings o f our controlled ragweedimmunotherapy studies.4, s We questioned whether our ragweed studies failed to demonstrate decrease in skin sensitivity to ragweed extract because we used an end point method (intradermal skin test end point dilution titration) instead of a midpoint method. 3 We recalculated the changes in skin sensitivity to ragweed by a midpoint method. We used tracings of the wheals produced by the intradermal skin tests done for determining the end point dilution in the 1980 ragweed study. 5 The largest and the orthogonal diameters of each wheal tracing were measured.l The arithmetic mean of these two values was plotted as a function of the log dose of ragweed extract (in micrograms of Amb aI equivalents) for the two successive dilutions of ragweed extract that produced wheal diameters of < 7 m m and > 7 mm, respectively. The dose that produced a wheal with a mean diameter of 7 m m (RW-ID7) was interpolated from the line connecting the two points. Data were analyzed as pre-

From The Johns Hopkins University School of Medicine, Department of Medicine, Division of Clinical Immunology, and The Johns Hopkins Asthma and Allergy Center, Baltimore, Md. Supported in part by the National Institutes of Health Gr~.nts AI 04866, AI 11936, 3 P50 AL 10304, AI 08270, and Outpatient Clinical Research Center Grant RR 00722. Computational assistance was obtained from CLINFO, sponsored by National Institutes of Health Grant 5MOIRR35-20. Reprint requests: Thomas E. Van Metre, Jr., MD, 11 E. Chase St., Baltimore, MD 21202. 1/1/23923

viously reported 1,z. 4.5 by means of the C L I N F O computer system. We used the Wilcoxin nonpaired ranksums test to measure the significance of increases in RW-ID7 and Spearman's rank-correlation coefficient (rs) to measure the significance of rank correlations. After 8 months of immunotherapy, the ragweedtreated patients, in comparison to the placebo-treated patients, had significant (p < 0.001) decreases in skin sensitivity to ragweed extract demonstrated by significant increases in RW-ID7 (Fig. 1). Direct comparison of the changes in skin sensitivity demonstrated by the midpoint method used in the present study to the changes demonstrated by the end point dilution method used in the original study 5 revealed that the midpoint method was the more sensitive of the two methods, since it detected significant changes in skin sensitivity, whereas the end point dilution method demonstrated no change or insignificant change. These findings are not surprising because the midpoint results were determined by a precise, easily measured point interpolated from the dose-response curve (wheal, 7 mm in diameter), whereas the end point results were determined by a broad end point (the first five-fold dilution of extract that initiated ->2 m m increase from baseline in wheal diameter). 3 Combining the new with the previously reported 5 data has demonstrated, for the first time, significant correlations in individual ragweed-treated patients between decreases in skin sensitivity to ragweed extract and (1) symptom-medication scores in the immunotherapy year (1980) ragweed season (rs = - 0 . 0 5 3 ; p < 0.001) and (2) ratio of symptommedication scores in the 1980 ragweed season to the same scores in the preimmunotherapy-year (1979) ragweed season (rs = - 0 . 4 7 ; p < 0.005). Like previous studies, 1' 2, 6 no significant correlations were found between decreases in skin sensitivity and (1) increases in ragweed IgG (postseason levels/pretreatment levels [rs = + 0 . 0 2 ; p > 0.25]) or (2) changes in ragweed IgE (preseason levels/pretreatment levels [rs = - 0.19; p = 0.15]) 587

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Van Metre et al.

J. ALLERGY CLIN. I M M U N O L . OCTOBER 1990

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FIG. 1. A comparison of the decreases in skin sensitivity demonstrated by the midpoint titration method and the end point dilution method. The increases in RW-ID7 (ratio of RW-ID7 after the ragweed season in October 1980 to RW-ID7 before treatment in January-February 1980) compared to the increases in the concentration of the end point dilution (ratio of end point dilution in October 1980 to end point dilution in January-February 1980) for each patient are indicated. Dashed lines indicate median values.

(postseason levels/preseason levels [rs--- +0.007; p > 0.25]). Therefore, immunotherapy significantly decreased skin sensitivity to ragweed extract. However, the changes were small (median, fivefold), and their demonstration required stable extracts and sensitive midpoint technique. The decreases in skin sensitivity in individual patients correlated significantly and inversely with the changes in the magnitudes of their ragweed hay fever symptom-medication scores after immunotherapy but not with their changes in ragweedIgG and ragweed-IgE antibodies. REFERENCES 1. Van Metre TE Jr, Marsh DG, Adkinson NF, et al. Immunotherapy for cat asthma. J ALLERGYCLIN IMMUNOL1988;82:105568.

2. Van Metre TE Jr, Marsh DG, Adkinson NF Jr, et al. Immunotherapy decreases skin sensitivity to cat extract. J ALLERGY CLIN IMMUNOL1989;83:888-99. 3. Van Metre TE Jr, Adkinson NF Jr, Kagey-Sobotka A, Marsh DG, Norman PS, Rosenberg GL. How should we use skin testing to quantify IgE sensitivy [Rostrum]? J ALLERGY CLrN IMMUNOL 1990;86:583-6. 4. Van Metre TE Jr, Adkinson NF Jr, Amodio FJ, et al. A comparative study of the effectiveness of the Rinkel method and the current standard method of immunotherapy for ragweed-pollen hay fever. J ALLERGYCLIN IMMUNOL1980;66:500-13. 5. Van Metre TE Jr, Adkinson NF Jr, Amodio FJ, et al. A comparison of immunotherapy schedules for injection treatment of ragweed-pollen hay fever. J ALLERGY CLIN IMMUNOL 1982; 69:181-3. 6. Hedlin G, Graff-Lonnevig V, Heilbom H, et al. Immunotherapy with cat- and dog-dander extracts. II. In vivo and in vitro immunologic effects observed in a 1-year double-blind study. J ALLERGYCLIN IMMUNOL1986;77:488-96.