Adverse drug reactions are important and frequent complications of medication therapy. Allergic drug reactions (involving immunologic mechanisms) account for approximately 5% to 10% of adverse reactions to help guide the selection and use of future medications and to properly manage the present reaction. Often the question of whether it is safe to readminister a medication in the future is an important clinical judgement that needs to be made. Along with certain in vivo and in vitro diagnostic tests, meticulous history taking by a motivated physician is often required to properly diagnose adverse drug reactions.

Measuring peak expiratory flow (PEF) variation has been suggested as a indicator of asthma disease severity and also of nonspecific bronchial hyperreactivity. To test these assumptions, we examined the relationships between PEF variation, methacholine reactivity, symptom scores, and medication requirements in 74 children with tightly controlled allergic asthma. The level of mean diurnal variation (MDV) for the group was 7.1%, which is generally regarded as normal. We found statistically significant correlations between MDV and both methacholine reactivity (r = 0.43, p = 0.0001) and symptom scores (r = 0.28, p = 0.016). These asthma variables were analyzed longitudinally in 33 children who were followed up at 6-month intervals for at least 36 months. Visit-to-visit changes in MDV were generally not reflective of changes in other variables. However, group levels of MDV gradually decreased over time, especially in children with initial MDV of more than 8%. This reduction in group MDV coincided with similar reductions in group medication requirements and methacholine reactivity. We conclude that children with moderately severe asthma that is tightly controlled may have normal levels of PEF variation. The correlation between PEF variation and other asthma variables is statistically significant but too weak to be useful in the treatment of individual patients. In contrast, measurement of MDV may be a useful indicator of disease severity in group studies of asthma.

To determine if four commercially available intravenous protamine preparations differed in their ability to bind to human antiprotamine antibody, the sera of seven protamine-insulin-dependent diabetics who had experienced life-threatening reactions to intravenous protamine and whose sera contained a mean of 67.4 micrograms/ml (range, 16-200 micrograms/ml) of antiprotamine IgG antibody were evaluated. Each serum was preincubated with buffer and 0.0014 to 1.4 mg/ml of the four protamine preparations before addition to an agarose-based solid-phase radioimmunoassay using 125I-radiolabeled staph protein A as the detection protein. In the seven sera, the concentration of soluble protamine inhibiting 50% of protamine antibody (IC50) was determined by interpolating from points above and below 50% inhibition for each protamine preparation. No significant difference was found in the IC50 among the four different protamine preparations (P greater than 0.25; Kruskal-Wallis). The authors concluded that there is no significant difference in the immunoreactivity of the four commercial protamine preparations with human antiprotamine IgG antibody. Thus, there appears to be no advantage in using a particular intravenous protamine preparation based on immunoreactivity with human antiprotamine antibody.

SummaryReactions to intravenous protamine include rash, urticaria, bronchospasm, hypotension. and/or pulmonary artery pressure elevation. We have previously shown that in diabetic patients receiving daily protamine insulin injeetions, the presence of anti‐protamine IgE or IgG antibodies are significant risk factors for acute, life‐threatening reactions when protamine is given intravenously. To study protamine reactions further, we measured serum anti‐protamine IgE and IgG antibody levels, in‐vitro basophil histamine release and intracutaneous skin testing to protamine serially in an NPH‐insulin dependent diabetic who had a severe, protracted anaphlactic reaction to protamine. At the time of his protamine reaction, his serum contained 8·5 ng/ml of anti‐protamine IgE and 1·3 μg/ml of anti‐protamine IgG antibody. One month following the reaction both anti‐protamine IgE and IgG increased to 16 ng/ml (twofold rise) and 90·5 μg/ml (70‐fold rise), respectively. With time, both anti‐protamine IgE and IgG antibody declined. Serial intradermal skin tests using protamine sulphate did not discriminate between the protamine reactor and nine normal control subjects who had no prior exposure nor any demonstrable serum IgE antibody to protamine. In‐vitro basophil histamine release to protamine sulphate was inconclusive in discriminating between the protamine reactor and normal control subjects. We postulate that protamine may be an incomplete or univalent antigen that must first combine with a tissue macromolecule or possibly heparin to become a complete multivalent antigen capable of eliciting IgE antibody‐dependent mediator release.

Life-threatening reactions to intravenous protamine, administered to reverse heparin anticoagulation, have been reported with increasing frequency as a consequence of the escalating use of cardiac catheterization and coronary bypass surgery. Retrospective studies have shown that such reactions are more common in diabetic patients receiving daily subcutaneous injections of protamine-insulin preparations. To determine whether anti-protamine IgE or IgG antibodies might explain the increased risk for protamine reactions among patients with protamine-insulin-dependent diabetes, we conducted a case-control study of 27 patients (diabetic and nondiabetic) who had acute reactions to intravenous protamine and 43 diabetic patients who tolerated protamine without a reaction during diagnostic or surgical procedures. Cases and controls were grouped according to previous exposure to protamine-insulin preparations. In diabetic patients who had received protamine-insulin injections, the presence of serum antiprotamine IgE antibody was a significant risk factor for acute protamine reactions (relative risk, 95; P = 1.0 X 10(-5), as was antiprotamine IgG (relative risk, 38; P = 1.2 X 10(-5). No patients without previous exposure to protamine-insulin injections had serum protamine IgE antibodies. In this group, anti-protamine IgG antibody was a risk factor for protamine reactions (relative risk, 25; P = 0.0062). We conclude that in protamine-insulin-dependent diabetics, the increased risk of serious reactions when intravenous protamine was given appeared to be caused largely by antibody-mediated mechanisms. In nondiabetic subjects, the presence of protamine IgG was significantly associated with an increased risk of acute protamine reactions, although many nondiabetic subjects who had reactions had no IgG antibodies.

Antihuman IgE is often used to study basophil- and mast cell-mediator release in vitro but is infrequently used in vivo. To evaluate in vivo skin reactivity to anti-IgE, an affinity-purified rabbit F(ab')2 fragment of antihuman IgE was injected intradermally in 22 nonallergic and 27 allergic subjects. All 49 subjects (including a subject with less than 1 ng/ml of total serum IgE) had positive immediate cutaneous reactions to anti-IgE. Although total serum IgE level was weakly correlated (r = -0.51; p less than 0.005) with in vivo skin reactivity to anti-IgE for the entire population, allergic subjects did not have significantly increased skin reactivity compared to nonallergic subjects (p = 0.18), despite having higher total serum IgE levels (p less than 0.002). A late-phase cutaneous response (LPR) to anti-IgE occurred in 60% of the allergic and in 50% of the nonallergic subjects. Subjects with an LPR required approximately tenfold higher concentrations of anti-IgE to produce an immediate wheal of 10 mm compared to subjects who did not develop an LPR (p = 0.02), suggesting that the concentration of the stimulus injected is more important for the development of a LPR than the size of the immediate cutaneous response. Skin reactivity to codeine phosphate (a non-IgE-dependent secretagogue) was correlated with skin reactivity to anti-IgE (r = 0.47; p less than 0.05), suggesting that in vivo skin mast cell degranulation is partially a function of mast cell releasability.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical & Experimental AllergyVolume 19, Issue 5 p. 557-557 Response to Blanca et al. M. E. Weiss, M. E. Weiss The Johns Hopkins University School of Medicine, The Good Samaritan Hospital Baltimore, MA 21239, U.S.ASearch for more papers by this authorN. F. Adkinson Jr, N. F. Adkinson Jr The Johns Hopkins University School of Medicine, The Good Samaritan Hospital Baltimore, MA 21239, U.S.ASearch for more papers by this author M. E. Weiss, M. E. Weiss The Johns Hopkins University School of Medicine, The Good Samaritan Hospital Baltimore, MA 21239, U.S.ASearch for more papers by this authorN. F. Adkinson Jr, N. F. Adkinson Jr The Johns Hopkins University School of Medicine, The Good Samaritan Hospital Baltimore, MA 21239, U.S.ASearch for more papers by this author First published: September 1989 https://doi.org/10.1111/j.1365-2222.1989.tb02435.xAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume19, Issue5September 1989Pages 557-557 RelatedInformation

Reproducibility of methacholine inhalation tests (MIT) over a 2-wk period has been established in adult populations, but similar studies demonstrating reproducibility in children are lacking. We set out to establish the reproducibility of MIT in children as a prerequisite for a study of the natural history of airway hyperreactivity in asthmatic children. Most inhalation testing is done in persons with mild asthma because the recommended time interval for the withholding of medications prior to bronchial challenge is poorly tolerated by more labile asthmatics. In order to evaluate asthmatics with more severe disease, we modified a standardized method of methacholine inhalation to include a three-tier pretest medication regimen and investigated the reproducibility of this MIT protocol in 11 children as young as 6 yr of age. The three tiers were designed to keep baseline FEV1 greater than or equal to 70% predicted since diminished baseline airway caliber may affect MIT results. Eight of the 11 children were bronchodilator-dependent, and two of the eight also required inhaled steroids. Eleven children (6 to 13 yr of age) underwent MIT, between December and March, 1 day, 1 wk, and 1 month after an initial test. The PD20FEV1 using cumulative breath units (BU) were compared. The range of PD20FEV1 in the 11 children was 0.27 to 14.4 BU, with nine subjects classified as severe (PD20FEV1 less than 2.5 BU). We found a high degree of reproducibility of MIT. The interest correlation coefficient (r) was 0.98 after 1 day, 0.95 after 1 wk, and 0.96 after 1 month.(ABSTRACT TRUNCATED AT 250 WORDS)