Allergen-specific IgE as a biomarker of exposure plus sensitization in inner-city adolescents with asthma.

BACKGROUND: Relationships among allergen-specific IgE levels, allergen exposure and asthma severity are poorly understood since sensitization has previously been evaluated as a dichotomous, rather than continuous characteristic. METHODS: Five hundred and forty-six inner-city adolescents enrolled in the Asthma Control Evaluation study underwent exhaled nitric oxide (FE(NO)) measurement, lung function testing, and completion of a questionnaire. Allergen-specific IgE levels and blood eosinophils were quantified. Dust samples were collected from the participants' bedrooms for quantification of allergen concentrations. Participants were followed for 12 months and clinical outcomes were tracked. RESULTS: Among sensitized participants, allergen-specific IgE levels were correlated with the corresponding settled dust allergen levels for cockroach, dust mite, and mouse (r = 0.38, 0.34, 0.19, respectively; P < 0.0001 for cockroach and dust mite and P = 0.03 for mouse), but not cat (r = -0.02, P = 0.71). Higher cockroach-, mite-, mouse-, and cat-specific IgE levels were associated with higher FE(NO) concentrations, poorer lung function, and higher blood eosinophils. Higher cat, dust mite, and mouse allergen-specific IgE levels were also associated with an increasing risk of exacerbations or hospitalization. CONCLUSIONS: Allergen-specific IgE levels were correlated with allergen exposure among sensitized participants, except for cat. Allergen-specific IgE levels were also associated with more severe asthma across a range of clinical and biologic markers. Adjusting for exposure did not provide additional predictive value, suggesting that higher allergen-specific IgE levels may be indicative of both higher exposure and a greater degree of sensitization, which in turn may result in greater asthma severity.

Drug metabolism, danger signals, and drug-induced hypersensitivity.

One of the most difficult challenges for the practicing allergist/immunologist today is that of evaluating and managing patients who present with histories of drug-induced reactions. Adverse drug reactions are heterogeneous, and a single drug can often cause a multitude of reactions. Because the mechanisms responsible for many of these reactions are not known, they can be, and often are, difficult to classify. Moreover, for those that have features consistent with immune-mediated mechanisms, our diagnostic tools remain limited, because little is known about the relevant immunogenic determinants of most drugs. Despite these challenges, management approaches must be devised for patients who present with histories of drug-induced disease. Simply telling such a patient to avoid all drugs that have been associated with previous adverse events leaves both the patient and the referring physician frustrated. The initial part of this review focuses on exciting current research that is furthering our understanding of the mechanisms responsible for drug-induced reactions. Because it will take time to translate this new information into clinical practice, the latter part of the review focuses on ways to evaluate and manage patients who present with drug-induced reactions using the tools and the knowledge that are currently available.

Clinical assessment of drug-induced disease.

Physicians are often confronted with patients who state that they are "allergic" to a drug or drugs. Knowing which medications can be prescribed safely is therefore difficult, and care of such patients frustrating. The goal of this review is to help physicians develop management plans for patients who present with drug-induced diseases. It provides information that allows physicians to differentiate between reactions that are truly allergic in nature and those that are not immunologically mediated. Relevant information on medical history, physical findings, and laboratory tests that may be helpful in the assessment are discussed, and guidance is provided on when and if a drug may be safely readministered. Unfortunately, however, until we are able to better understand the mechanisms responsible for drug-induced reactions, our management tools will remain limited.

Penicillin allergy: prevalence of vague history in skin test-positive patients.

OBJECTIVE: Penicillin (PCN) skin testing is a reliable tool for predicting which patients can safely receive the antibiotic. Depending on the study, 7% to 76% of patients who have a history of PCN allergy have positive PCN skin tests. Many physicians approach patients who have a vague history of PCN allergy less cautiously than they approach those who have a convincing history suggestive of an IgE-mediated reaction. We reviewed the published literature to determine how many patients who had a history of PCN allergy and who were skin test-positive had a vague history of allergy. DATA SOURCES: By cross-referencing the keywords "penicillin" and "skin test," an Ovid MEDLINE search for English language studies published from 1966 to 1998 was performed. STUDY SELECTION: Studies in which history positive/skin test-positive patients were identified, and which contained documentation of the type of previous reaction in these patients, were included in the analysis. The MEDLINE search revealed 295 English language articles, of which 27 fulfilled the inclusion criteria. Three additional studies published prior to 1966 (and therefore not available through MEDLINE) also were found, bringing the total to 30. A "convincing" history was defined to be one likely to be IgE-mediated (such as anaphylaxis, urticaria, angioedema or pruritic rash). A "vague" history was one unlikely to be IgE-mediated (such as maculopapular rash, GI symptoms, or an unknown reaction). RESULTS: Overall, 347/1063, or 33%, of history positive/skin test-positive patients had a vague PCN allergy history, with a range of 0% to 70% among the 30 studies. CONCLUSION: A large proportion of patients who have PCN-specific IgE antibodies, as determined by skin testing, have vague PCN allergy histories. These results therefore, indicate that, like patients with convincing histories, patients with vague allergic histories should undergo PCN skin testing prior to PCN administration.

Approach to the patient with multiple antibiotic sensitivities.

Allergists sometimes are asked to evaluate patients who have experienced multiple adverse drug reactions. By the time the patient reaches the allergist, the referring physician, as well as the patient, often are frustrated. Each seeks a quick and simple answer regarding the particular drugs the patient may safely receive. Unfortunately, however, in most instances, simple answers cannot be given. Currently we have limited knowledge of the mechanisms and of the clinically-relevant drug metabolites responsible for many of the reactions demonstrated and, for these reasons, we have few valid diagnostic tests that are able to provide clear-cut answers for our patients who present with multiple drug "allergies." Despite these limitations, using accurate and complete historical information along with limited diagnostic testing, logical and practical management approaches can be devised. In addition, due to new exciting data that are being generated from basic research studies in drug allergy, the mechanisms underlying the immunopathology of many drug reactions are becoming more clear. Through the acquisition of scientific information of this type, it is hoped that valid diagnostic tools soon will be developed so that definitive answers, desired by both the patient and the referring physician, can be provided.

Clinical approach to penicillin-allergic patients: a survey.

BACKGROUND: Approximately 10% of individuals report a history of penicillin allergy. OBJECTIVE: We chose to survey various physician groups to determine how they would manage penicillin-allergic patients who present with an infectious process for which penicillin is the drug of choice. METHODS: In situations where penicillin was the drug of choice, physicians were asked to choose the type of antibiotic treatment for patients who presented with diseases of varying severity and who had either vague or convincing penicillin-allergic histories. RESULTS: A total of 601 surveys were mailed and 93 (16%) were returned. For those patients who present with a vague history of penicillin allergy, 58% and 59% of the physicians surveyed stated that they would choose cephalosporins for individuals with mild and moderate diseases, respectively. In contrast, in the vague penicillin history/severe disease scenario, physicians were split between choosing cephalosporins (42% of responders) and vancomycin (40% of responders). For those patients who present with a convincing history of penicillin allergy, 55% of the physicians chose erythromycin for individuals with mild disease; 44% chose quinolones for individuals with moderate disease, and 63% chose vancomycin for individuals with severe disease. In each of the three disease severities, physicians were significantly more likely to choose cephalosporins for patients with a vague history of penicillin allergy than for patients with a convincing history (each P<10-5). CONCLUSION: The choice of antibiotics is influenced both by the type of penicillin allergic history and by the severity of the disease process to be treated. To decrease the use of broad-spectrum antibiotics in patients labeled "penicillin-allergic", an effort should be made to identify, by skin testing, those patients who lack penicillin-specific IgE antibodies.

Acute drug desensitization.

Evidence is accumulating that supports a role for acute desensitization for IgE-mediated drug allergy in those patients for whom no alternative drug exists. While most of the studies have been performed in penicillin-allergic patients, this procedure has been used safely in patients with IgE sensitivity to other agents. In addition, it has been shown that modified desensitization protocols may be effective in the prevention of other immune-mediated drug reactions, as well. Thus, while much research remains to be done in this area, drug desensitization will continue to be a powerful tool in the management of drug allergy.

Drug allergies.

Allergic drug reactions are a significant cause of morbidity and mortality. Because it is difficult to identify the culprit drug and the underlying pathophysiologic mechanisms involved in these reactions, a systematic approach should be adopted in the evaluation of drug-allergic patients. Initially, the type of reaction should be determined. It should be realized that not all adverse reactions are allergic in nature. Allergic drug reactions comprise only a small category of adverse reactions in general. Therefore, the physician must determine if the reaction demonstrates features common to immunologic reaction. Subsequently, a detailed history should be obtained and a physical should be performed. Important information includes medication usage, previous drug exposure, current illness, family history of drug allergy and personal history of drug allergy. In managing the drug-allergic patient, the physician may choose to: select an alternative, non-cross-reacting drug if future therapy is needed; premedicate prior to future drug exposure if such regimens have been shown to be effective; or consult an allergist regarding the potential graded challenge or desensitization.

Sulfonamide-induced reactions in desensitized patients with AIDS--the role of covalent protein haptenation by sulfamethoxazole.

BACKGROUND: Adverse reactions to sulfonamides cause significant morbidity in patients with AIDS. We have demonstrated previously a approximately 40 kd sulfamethoxazole (SMX)-substituted protein in the serum of some individuals treated with SMX. OBJECTIVE: The purpose of this study was to examine patients with AIDS who had undergone SMX desensitization because of a prior history of SMX allergy for the presence of SMX-haptenated serum proteins and to determine whether these proteins, SMX-specific IgG antibodies, or both predict the development of subsequent clinical reactivity. METHODS: Four patients with no history of allergy and in whom SMX prophylaxis was initiated and eight patients with AIDS who had undergone SMX desensitization because of prior allergy were evaluated. SMX-conjugated serum proteins were identified with an immunoblotting assay, and SMX-specific IgG antibodies were identified by ELISA inhibition. RESULTS: One of the four patients receiving SMX prophylactic treatment demonstrated SMX-protein haptenation, none had detectable SMX-specific IgG antibodies, and none developed an SMX-associated reaction during the time in which they were followed. Of the eight patients who underwent SMX desensitization, six (75%) demonstrated SMX-protein haptenation, and three of these six (50%) subsequently developed SMX-induced cutaneous reactions. Only one of these six patients had detectable SMX-specific IgG antibodies. The two individuals who did not demonstrate SMX-protein haptenation have not developed a clinical reaction. CONCLUSION: These preliminary data suggest that SMX haptenation, but not SMX-specific antibodies, may be important in the development of clinical sensitivity in patients with AIDS who have undergone SMX desensitization.

Southwestern Internal Medicine Conference: mastocytosis: developments during the past decade.

Mastocytosis is a spectrum of disorders characterized by an aberrant proliferation of tissue mast cells. Although this disease process often affects the skin, it may involve multiple organs. The clinical disorder varies according to patient age, the clinical manifestations demonstrated, and the extent of the mast cell proliferative process. A myriad of clinical symptoms occur, and these may be localized to the organ system involved or may be systemic, depending on whether there is local or generalized mast cell mediator release. Diagnosis includes the demonstration of increased tissue mast cells in involved organs as well as increased levels of biochemical mediators. Patients with cutaneous involvement only have the best prognosis. Treatment is directed toward stabilizing mast cell mediator release and blocking the effects of those mediators generated.

Immunochemical analysis of sulfonamide drug allergy: identification of sulfamethoxazole-substituted human serum proteins.

BACKGROUND: Sulfonamides undergo oxidative metabolism to yield reactive metabolites that haptenate proteins readily. Although it has been shown that sulfonamide metabolites bind covalently to murine microsomes, sulfonamide-conjugated serum proteins have not been analyzed in the peripheral blood of treated individuals. OBJECTIVE: We hypothesized that during treatment with sulfamethoxazole, intracellular proteins are haptenated by drug metabolites, and some of these are destined for secretion into the serum. METHODS: Using antibodies specific for sulfamethoxazole and an alkaline phosphatase immunoblotting technique, we attempted to demonstrate the presence of sulfamethoxazole-substituted proteins in the serum of individuals during a course of treatment. RESULTS: Five days into therapy, serum protein haptenation by sulfamethoxazole was demonstrated in two of the three individuals studied. In addition, Western blot analysis revealed that haptenation is not indiscriminate, but highly selective. A single 30 kd protein is the target of haptenation in all instances. A kinetic analysis revealed that substituted proteins can be detected early, within hours of administration. Moreover, haptenated proteins remain detectable in the serum 48 hours after discontinuation of the drug. CONCLUSION: The results presented here constitute the first direct evidence that sulfonamides, on being metabolized, covalently haptenate human serum proteins during a course of therapy.

Detection of human IgE to sulfamethoxazole by skin testing with sulfamethoxazoyl-poly-L-tyrosine.

Adverse reactions to sulfamethoxazole (SMX) occur in 4% to 6% of normal individuals. Many of these reactions resemble immunopathologic reactions, but skin test or in vitro evidence of a role for IgE is limited. Earlier RAST studies in our laboratory provided evidence that the N4-SMX hapten was a major determinant in immediate hypersensitivity reactions to SMX. We tested the hypothesis that IgE to this hapten is present on the mast cells of patients who have experienced immediate hypersensitivity reactions temporally related to exposure to SMX. A multivalent skin test reagent, SMX168-poly-L-tyrosine, and a univalent hapten, SMX-tyrosine, were synthesized. Forty-four patients with histories of allergic reactions to SMX and six subjects who had been exposed to the drug, but who had not reacted, were skin tested. Twenty-seven percent of the history-positive patients were skin test positive. None of the control individuals was positive. The immunologic responses to SMX in three patients who had experienced allergic reactions during SMX/trimethoprim therapy were analyzed in serial skin test and RAST assessments. One to three years after the clinical reactions, IgE to SMX could be demonstrated by skin testing in all three patients with a SMX-poly-L-tyrosine skin test reagent. Skin test reactions were inhibited by the monovalent reagent, SMX-tyrosine, in a dose-dependent manner. SMX-specific IgE antibodies could also be detected by RAST in serum obtained within days of the reactions from two of the three individuals.(ABSTRACT TRUNCATED AT 250 WORDS)

An indirect pathway of receptor-mediated 1,2-diacylglycerol formation in mast cells. I. IgE receptor-mediated activation of phospholipase D.

The current studies explore the role of phospholipase D (PLD) in mast cell activation. Although most investigators believe that receptor-mediated accumulation of 1,2-diacylglycerol (DAG) occurs by phospholipase C hydrolysis of phosphoinositides, our previous work indicated a modest role for these substrates and suggested that phosphatidylcholine (PC) is the more likely substrate. PLD cleaves the terminal phosphodiester bond of phospholipids to yield phosphatidic acid (PA), but in the presence of ethanol, it transfers the phosphatidyl moiety of the phospholipid substrate to ethanol producing phosphatidylethanol (PEt); a reaction termed transphosphatidylation. In purified rat mast cells prelabeled with [3H]arachidonic acid, [3H]palmitic acid, or 1-O-[3H]alkyl-lysoPC, a receptor-associated increase in PLD activity was initially suggested by the rapid accumulation of labeled PA, although other mechanisms might be involved. PLD activity was assessed more directly by the production of labeled PEt by PLD-mediated transphosphatidylation in the presence of ethanol. IgE receptor cross-linking resulted in a 3- to 10-fold increase in PLD activity during the 10 min after stimulation, approximately 50% of which occurred during the first two min. PEt formation was dependent on the concentration of ethanol and was maximal at 0.5%. At concentrations of ethanol greater than or equal to 0.2%, receptor-dependent formation of PA was reduced suggesting that the ethanol promoted transphosphatidylation at the expense of hydrolysis. The dose-related decline in PA accumulation seen in the presence of ethanol was similar to ethanol-mediated inhibition of exocytosis suggesting that receptor-mediated PA formation may be of regulatory importance. These observations indicate that PLD-mediated formation of PA occurs in stimulated mast cells and, in conjunction with separate findings of PA phosphohydrolase conversion of PA to DAG in mast cells, suggest that a major mechanism of DAG formation during mast cell activation is PC----PA----DAG.

Analysis of neonatally induced tolerance of H-2 alloantigens. III. Ease of abolition of tolerance of class I, but not class II, antigens with infusions of syngeneic, immunocompetent cells.

Neonatally-induced tolerance of class I H-2 alloantigens can be abolished in adult, long-term-tolerant mice by infusions of immunocompetent cells from donors syngeneic with the recipient. By contrast, neonatally-induced tolerance of Ia alloantigens can not be abolished easily, indicating that the Ia-specific tolerant state is maintained by an active process that can be impressed upon mature alloreactive lymphoid cells in the tolerant environment. This finding is concordant with previous observations that tolerance of Ia alloantigens can readily be transferred adoptively by inoculating lymphoid cells from tolerant mice into syngeneic, naive recipients. It is concluded that class II H-2 antigens induce a type of unresponsiveness that class I antigens fail to evoke, an unresponsiveness that is actively maintained among mature immunocompetent cells. It is proposed that, in addition to a central process of clonal deletion/inactivation that both class I and class II H-2 antigens induce in neonatal mice, Ia alloantigens also evoke a secondary, fail-safe mechanism that operates to prevent alloreactivity from emerging when cells with alloreactive potential escape the central mechanism, or mutate to alloreactivity at a later stage of maturation.

Analysis of neonatally induced tolerance of H-2 alloantigens. IV. Graft adaptation in long-term tolerated grafts.

Acceptance of orthotopic test skin grafts bearing putative tolerogenic H-2 determinants proves to be the most stringent criterion for the existence of neonatally induced transplantation tolerance. The large majority of long-standing grafts retain their original antigenicity--that is, they are rejected when tolerance is abolished by infusions of immunocompetent cells syngeneic with the tolerant host; and they remain immunogenic--that is, they induce their own rejection when excised and placed on naive recipients syngeneic with the tolerant animal. However, the ability of these long-standing grafts to reflect concordantly the alloreactive potential of peripheral lymphoid cells of tolerant mice deteriorates in time. A minority of tolerated grafts lose their ability to express their genetic endowment of H-2 alloantigens in an immunogenic form through a process of graft adaptation. Because the majority of long-standing Ia-disparate grafts remain immunogenic when transplanted to naive recipients, the adaptation process can not be ascribed exclusively to repopulation of original epidermal Langerhan's cells with similar cells of host origin.

Analysis of neonatally induced tolerance of H-2 alloantigens. II. Failure to detect alloantigen-specific T-lymphocyte precursors and suppressors.

There is a considerable amount of evidence, confirmed and extended by our studies, in favor of clonal deletion of alloantigen-reactive cells in neonatally induced transplantation tolerance. We have demonstrated in adult mice bearing long-standing skin allografts that lymphocytes specifically reactive with the tolerated H-2 alloantigens are undetectable by mixed lymphocyte and graft-versus-host reactions, and in cell-mediated lympholysis. In addition, lymphoid cells capable of suppressing the reactivity of syngeneic normal lymphocytes in these assays similarly escape detection. Moreover, putative precursors of T cells specific for the tolerated antigens cannot be activated polyclonally with concanavalin A (Con A), nor can they be identified among thymocytes of H-2-tolerant mice. Since the tolerant state can be adoptively transferred with lymphohematopoietic cells to adult, syngeneic mice, we infer that transplantation tolerance is maintained by an active process that achieves specific clonal deletion at an early stage in the ontogeny of alloreactive T lymphocytes.