International Consensus on drug allergy.

When drug reactions resembling allergy occur, they are called drug hypersensitivity reactions (DHRs) before showing the evidence of either drug-specific antibodies or T cells. DHRs may be allergic or nonallergic in nature, with drug allergies being immunologically mediated DHRs. These reactions are typically unpredictable. They can be life-threatening, may require or prolong hospitalization, and may necessitate changes in subsequent therapy. Both underdiagnosis (due to under-reporting) and overdiagnosis (due to an overuse of the term 'allergy') are common. A definitive diagnosis of such reactions is required in order to institute adequate treatment options and proper preventive measures. Misclassification based solely on the DHR history without further testing may affect treatment options, result in adverse consequences, and lead to the use of more-expensive or less-effective drugs, in contrast to patients who had undergone a complete drug allergy workup. Several guidelines and/or consensus documents on general or specific drug class-induced DHRs are available to support the medical decision process. The use of standardized systematic approaches for the diagnosis and management of DHRs carries the potential to improve outcomes and should thus be disseminated and implemented. Consequently, the International Collaboration in Asthma, Allergy and Immunology (iCAALL), formed by the European Academy of Allergy and Clinical Immunology (EAACI), the American Academy of Allergy, Asthma and Immunology (AAAAI), the American College of Allergy, Asthma and Immunology (ACAAI), and the World Allergy Organization (WAO), has decided to issue an International CONsensus (ICON) on drug allergy. The purpose of this document is to highlight the key messages that are common to many of the existing guidelines, while critically reviewing and commenting on any differences and deficiencies of evidence, thus providing a comprehensive reference document for the diagnosis and management of DHRs.

Ionophore and arachidonic acid stimulation of airway responses in rhesus monkeys.

Aerosolized doses of the ionophore, A23187, and arachidonic acid individually resulted in no airway response in rhesus monkeys. When these two agents were given simultaneously, by aerosol, an airway response occurred. The pulmonary function abnormalities that occurred qualitatively simulated those of an antigen-induced airway response. This is the first demonstration in our laboratory of two agents which singly will not produce a response but which are reactive when delivered in combination. Other fatty acids did not produce a similar response. The response to A23187 and arachidonic acid occurred only in rhesus monkeys from our colony which had been demonstrated to have airway responses to aerosolized antigen challenge, a response shown previously to be associated with hyperreactive airways to pharmacologic stimuli. The A23187 and arachidonic acid response was inhibited by aerosolized 5,8,11,14-eicosatetraynoic acid, an inhibitor of the cyclooxygenase and lipoxygenase pathways of arachidonic acid metabolism. Further, indomethacin, a prostaglandin synthetase inhibitor of the cyclooxygenase pathway, inhibited the response, although previous studies showed that this drug will potentiate an antigen-induced response in this animal model of asthma. The slow-reacting substance of anaphylaxis antagonist, FPL 55712, did not inhibit the A23187-arachidonic acid response under the conditions of these experiments. The mechanism of the A23187-arachidonic acid airway response in rhesus monkeys may or may not be the same as the antigen-induced response.

Lipid pneumonia with atypical mycobacterial colonization. Association with allergic bronchopulmonary aspergillosis.

Exogenous lipid pneumonia following bronchography occurred in a woman with allergic bronchopulmonary aspergillosis (ABPA) whose bronchi had been colonized with Mycobacterium chelonei chelonei for the previous year. The lung biopsy specimen disclosed organisms within lipid vacuoles in the areas of lipid pneumonia, while caseating granulomas, the usual tissue reaction to pathogenic mycobacteria, were absent. These pathologic findings suggested that the infection with M chelonei was noninvasive, and we were able to continue the corticosteroid therapy that was necessary for control of the underlying ABPA.

Clinical summary and course of idiopathic anaphylaxis in 73 patients.

Seventy-three patients with anaphylaxis of unknown cause were studied. Repeated histories and physical examinations were performed by the Northwestern University (Chicago) allergy service in an attempt to find a cause for the anaphylaxis. Documentation of abnormal physical findings during an episode of anaphylaxis was necessary in each patient. Prior to our initial consultation, these 73 patients had required 115 emergency room visits and 37 hospitalizations. No deaths have occurred in 224 patient years of follow-up from initial presentation. Thirty-eight (52%) patients have infrequent reactions (defined as one episode only or mild episodes less than six times per year) requiring acute treatment alone. Thirty-five (48%) patients have severe or frequent life-threatening reactions (defined as episodes that include syncope, documented hypotension, and airway compromise as major manifestations) requiring maintenance antihistamines and prednisone. Laboratory studies were not helpful in finding a cause of anaphylaxis in any of the 73 patients. Associated atopic conditions were present in 45 patients. Twenty-three patients had chronic idiopathic angioedema, urticaria, or both prior to developing idiopathic anaphylaxis. Sixteen patients only treated acutely for each episode of anaphylaxis and seven patients previously receiving maintenance medication are now asymptomatic without medication for longer than one year.

Spontaneous pneumothorax in allergic bronchopulmonary aspergillosis.

A new roentgenographic finding of spontaneous pneumothorax occurred in a patient with well-advanced (stage V) allergic bronchopulmonary aspergillosis (ABPA). The pneumothorax responded to chest tube evacuation. Patients with well-advanced ABPA and severe chest pain should be carefully examined and treated for pneumothorax, to maintain as much functioning lung as possible.

Prophylaxis against repeated radiocontrast media reactions in 857 cases. Adverse experience with cimetidine and safety of beta-adrenergic antagonists.

Eight hundred fifty-seven radiocontrast media (RCM) procedures were performed from 1974 to 1984 in 743 patients who previously had experienced an immediate generalized (anaphylactoid) reaction to RCM. During the 695 intravascular infusions of RCM, prednisone-diphenhydramine hydrochloride pretreatment of 415 essential repeated RCM procedures from 1974 to 1980 resulted in 45 (10.8%) reactions during which transient hypotension occurred in three (0.7%) patients. From 1980 to 1983, prednisone-diphenhydramine-ephedrine sulfate pretreatment of 180 procedures was associated with only nine reactions (5.0%) (chi 2 = 5.195). The addition of cimetidine hydrochloride in 1983 to 1984 was not useful in that 14 reactions occurred during 100 procedures (14.0%). The 21 patients who had been receiving beta-adrenergic antagonist therapy were protected as well as those who were not, in that none of 11 patients receiving the three-drug regimen had a repeated reaction and only one of ten patients receiving the four-drug regimen reacted.

An immediate generalized reaction to iopamidol.

Intravascularly administered lower-osmolality contrast media cause fewer adverse effects than do higher-osmolality media. Immediate generalized reactions such as acute urticaria or bronchospasm have been documented occasionally in patients receiving lower-osmolality contrast media. To our knowledge, this is the first reported case of an immediate generalized reaction to a lower-osmolality contrast medium in which significant hypotension also occurred. During cardiac catheterization, in a patient who had never been exposed to a contrast medium, a 69-year old man developed chest tightness, periorbital and facial edema, slight uvular edema, and a decline in blood pressure from 150/71 to 97/67 mm Hg. Epinephrine hydrochloride, diphenhydramine hydrochloride, and hydrocortisone were administered. The lack of absolute safety of lower-osmolality contrast media emphasizes the need for clinical awareness and availability of emergency therapy when these agents are utilized.

Outcomes of pregnancy in adolescents with severe asthma.

Asthma in adolescent pregnancies is not rare and may make patient management difficult, especially since mortality from asthma is of particular concern in the adolescent age group. We present a series of 21 pregnant adolescents with severe asthma. During 28 pregnancies, there were 56 exacerbations of asthma, including 22 hospitalizations and 20 emergency room visits. For 18 (64%) of the 28 pregnancies, outpatient systemic corticosteroids were administered, and inhaled corticosteroids were prescribed for 8 (29%). Factors associated with exacerbations included respiratory tract infections (59%) and noncompliance with medical regimens (27%). There were no maternal or fetal deaths or evidence for intrauterine growth retardation. Two infants were premature, with one experiencing acute respiratory distress syndrome. Aggressive treatment of asthma and associated respiratory tract infections, as well as careful ambulatory care, to encourage patient compliance are advisable to achieve a favorable maternal-fetal outcome.

Allergic bronchopulmonary aspergillosis.

Since 1968 the number of reported cases of allergic bronchopulmonary aspergillosis in the United States has risen secondary to increased awareness by physicians and to improved diagnostic criteria for identifying the disease. The eight diagnostic criteria, the five clinical stages of the disease, the common radiographic changes, the pathologic findings, the common laboratory findings, the possible pathogenetic mechanisms involved, the differential diagnosis, the acute and chronic pulmonary function changes, and the importance of corticosteroid therapy in treatment of exacerbations and prevention of further lung damage are reviewed.

Natural history of asthma in patients requiring long-term systemic corticosteroids.

To study the natural history of corticosteroid-dependent asthma, we evaluated 40 randomly selected adult patients with severe asthma who were refractory to management with inhaled corticosteroids and bronchodilators and who required long-term prednisone therapy (mean duration, 6.2 +/- 5.1 years). During long-term observation, 13 patients (32.5%) significantly improved; ten (25%) of these tolerated discontinuation of long-term prednisone use and three (7.5%) had decreased prednisone requirements. Three patients (7.5%) had increased requirements for prednisone. Twenty-four patients (60%) had generally unchanged, long-term prednisone requirements; of note, eight of these had significant, but temporary intervals (mean, 3.2 years) when they could be managed without prednisone. Patients with mixed asthma were more likely to tolerate discontinuation of long-term prednisone; no other factors studied were predictive of the course of asthma. Although prior to our care many patients had a history of numerous emergency room visits and hospitalizations (some for life-threatening episodes of status asthmaticus), there were few emergency room visits and hospitalizations while under strict management by our service. Variations observed in the natural history of corticosteroid requirements in asthma must be considered in designing studies seeking to evaluate efficacy of new experimental therapies for asthma.

Stage V (fibrotic) allergic bronchopulmonary aspergillosis. A review of 17 cases followed from diagnosis.

A review of the records of 17 patients with stage V (fibrotic stage) allergic bronchopulmonary aspergillosis observed since initial diagnosis (mean observation period, 4.9 years) demonstrated that, of the 11 surviving patients, four have very severe respiratory impairment. The other seven patients have mild or moderate functional impairment, but most of these have not shown clinical deterioration during the observation period. The occurrence of new roentgenographic infiltrates after the time of diagnosis was observed in only one patient in this series. Serum IgE and IgG levels against Aspergillus fumigatus, when compared with those of a control pool of serum samples from asthmatic patients with immediate cutaneous reactivity to Aspergillus, were the most useful immunologic studies diagnostically. Lung biopsy specimens obtained in five patients were of relatively little diagnostic value. All patients have required long-term prednisone therapy for control of asthma. Those patients whose forced expiratory volume in 1 s (FEV1) remained less than or equal to 0.8 L after initial corticosteroid treatment demonstrated a poor prognosis. When only moderate lung damage has occurred at the time of diagnosis, a stable subsequent course may be expected even in patients with stage V disease.

Allergic bronchopulmonary aspergillosis. Natural history and classification of early disease by serologic and roentgenographic studies.

Eighty-four patients with allergic bronchopulmonary aspergillosis (ABPA) were evaluated for a total of 294 patient-years with a mean observation period of 3.7 years and classified by the stage of ABPA. The largest percentage of patients were in the stage IV (corticosteroid-dependent asthma stage) group. The next largest percentage were in the stage V (fibrotic, end-stage lung disease) group. Of the latter 24 patients, eight had died. In addition, we describe 13 patients with all serologic characteristics of ABPA but without central bronchiectasis. We propose that these patients have seropositive ABPA and represent the earliest cases of it that can be diagnosed in contrast with ABPA with central bronchiectasis in which lung damage is already present.

The incidence of antimicrobial allergies in hospitalized patients: implications regarding prescribing patterns and emerging bacterial resistance.

BACKGROUND: The development of antimicrobial guidelines is one way in which institutions attempt to control emerging resistance, but the real challenge falls on promoting and ensuring adherence to these guidelines. Investigating reasons for the prescribing of alternative antimicrobial agents outside of these guidelines is crucial for modifying practices that may adversely impact institutional antimicrobial goals. METHODS: Retrospective cross-referencing of computerized pharmacy printouts and concurrent manual medical record review. RESULTS: Approximately 25% (470/1893) of the patients requiring antimicrobial therapy reported an allergy to at least 1 antimicrobial agent. The most commonly reported antimicrobial allergy was penicillin (295/1893 [15.6%]). Eighty-five patients (18.1%) reported having an allergy to 2 or more antimicrobial agents. Only 4% (27/601) of the reported antimicrobial allergies contained documentation as to the nature of the specific allergic reactions, while a manual medical record review revealed that 32% (23/73) of the antimicrobial allergies contained documentation of the specific allergic reaction. Ninety-eight (39. 7%) of 247 patients reporting an allergy only to penicillin and/or cephalosporin received vancomycin in comparison with 247 (17.4%) of 1423 patients without any antimicrobial allergies (P<.001). Similarly, 53 (21.5%) of 247 patients with reported penicillin and/or cephalosporin allergies received levofloxacin compared with 114 (8.0%) of 1423 patients without any antimicrobial allergy (P<. 001). CONCLUSION: The incidence of penicillin allergy at our institution exceeds population averages. This finding, in combination with limited documentation of drug allergies, appears to lead to the prescribing of alternative antimicrobial agents that do not fit into institutional antimicrobial guidelines and, in some instances, may put the patient at risk for infection and/or colonization with resistant organisms. Use of these alternative agents may adversely impact the ability to manage emerging antimicrobial resistance.

Results of the National Institute of Allergy and Infectious Diseases Collaborative Clinical Trial to test the predictive value of skin testing with major and minor penicillin derivatives in hospitalized adults.

BACKGROUND: A history (or lack thereof) of penicillin allergy is known to be unreliable in predicting reactions on subsequent administration of the drug. This study tests the usefulness of four penicillin allergen skin tests in the prediction of IgE-mediated reactions subsequent to administration of penicillin. METHODS: Eight centers cooperated in the National Institute of Allergy and Infectious Diseases trial of the predictive value of skin testing with major and minor penicillin derivatives. Hospitalized adults were tested with a major determinant (octa-benzylpenicilloyl-ocytalysine) and a minor determinant mixture and its components (potassium benzylpenicillin, benzylpenicilloate, and benzylpenicilloyl-N-propylamine). Patients then received a therapeutic course of penicillin and were observed, for 48 hours, for adverse reactions compatible with an IgE-mediated immediate or accelerated allergy. RESULTS: Among 726 history-positive patients, 566 with negative skin tests received penicillin and only seven (1.2%) had possibly IgE-mediated reactions. Among 600 history-negative patients, 568 with negative skin tests received penicillin and none had a reaction. Only nine of the 167 positive skin test reactors received a penicillin agent and then usually by cautious incremental dosing. Two (22%) of these nine patients had reactions compatible with IgE-mediated immediate or accelerated penicillin allergy; both were positive to the two determinants. CONCLUSIONS: These data corroborate previous data about the negative predictive value of negative skin tests to these materials. The reaction rate in skin test-positive patients was significantly higher than in those with negative skin tests, demonstrating the positive predictive value of positive tests to both major and minor determinants. The number of patients positive only to the major determinant or only to the minor determinant mix was too small to draw conclusions about the positive predictive value of either reagent alone.

Comparison of prednisolone kinetics in patients receiving daily or alternate-day prednisone for asthma.

Prednisolone pharmacokinetics were compared in seven patients with asthma managed by alternate-day prednisone therapy and in seven patients with asthma requiring daily doses of prednisone. Steroid requirements of these patients were carefully characterized and had been stable for at least 12 months. Prednisolone volume of distribution, elimination clearance, and elimination t1/2 averaged 0.606 +/- 0.061 and 0.553 +/- 0.162 L/kg, 2.28 +/- 0.43 and 1.93 +/- 0.54 ml/min/kg, and 204 +/- 44 and 214 +/- 19 minutes in patients receiving alternate-day or daily prednisone therapy, respectively. These results indicate that differences in these pharmacokinetic parameters do not account for the well-established clinical observation that some patients require daily prednisone doses and that their disease cannot be managed with alternate-day steroid therapy.

Pharmacokinetics of prednisolone transfer to breast milk.

Prednisolone transfer to breast milk was studied in three nursing women who required oral steroid therapy for asthma. Each patient received a 50 mg intravenous dose of prednisolone phosphate, and blood and breast milk were sampled for 6 hours. Concentrations of prednisolone in milk declined more rapidly than in serum but were similar to expected unbound serum concentrations, suggesting that exchange between unbound prednisolone in serum and breast milk is relatively rapid and bidirectional. Because an average of 0.025% (range, 0.010% to 0.049%) of the prednisolone dose was recovered in milk, prednisolone transfer to breast milk does not appear to pose a clinically significant risk to nursing infants.

Life-threatening idiopathic anaphylaxis associated with hyperimmunoglobulinemia E.

After five years of mild, intermittent urticaria, a man had life-threatening idiopathic anaphylactic reactions associated with transient myocardial ischemia, small bowel obstruction, and orthostatic hypotension. There was no evidence of causes for the anaphylactic reactions over a two and a half year period. The total serum IgE level was increased substantially, with sharp elevations occurring during three episodes of anaphylactic reactions. The elevation in total IgE levels, which was not associated with peripheral blood eosinophilia, is the first recognized serologic abnormality in this syndrome.

A prospective evaluation of elevated serum theophylline concentrations to determine if high concentrations are predictable.

PURPOSE: To evaluate prospectively whether serum theophylline concentrations of 25 mg/L and greater were predictable (and presumably preventable) by use of basic pharmacokinetic calculations. DESIGN: Prospective study. PATIENTS: Fifty-five patients with a serum theophylline concentration of at least 25.0 mg/L were evaluated initially and if subsequent elevated theophylline concentrations occurred. INTERVENTIONS: The predicted steady-state serum theophylline concentration was calculated from the dosage rate divided by the predicted clearance to determine how many elevated concentrations (greater than 20 mg/L) were predictable. Predicted clearances were 0.04 L/kg/hour for normal subjects less than 70 years of age and 0.02 L/kg/hour for patients with congestive heart failure, chronic obstructive pulmonary disease, or liver disease. Estimated clearances were determined and compared with predicted clearances. If patients did not have steady-state concentrations, additional calculations were made. MAIN RESULTS: From 6,368 consecutive theophylline determinations, 69 (1.08%) samples from 55 patients were 25 mg/L or higher. Predictably high concentrations occurred in 23 of 33 (69.7%) fully evaluable cases. These concentrations occurred because of a failure to consider decreased elimination clearance from congestive heart failure, chronic obstructive pulmonary disease, or hepatic disease. Five fatalities occurred, and in two cases, theophylline appeared to contribute to the patient's death. Three other patients experienced syncope. The predicted elimination clearance of theophylline of 0.02 L/kg/hour was too high in eight patients over 70 years old with cardiac or pulmonary disease. Nursing and pharmacy oversights were identified as three patients were given two theophylline products simultaneously. CONCLUSIONS: Most elevated theophylline concentrations are predictable (and preventable) by basic pharmacokinetic calculations. Patients experiencing elevated theophylline concentrations often had comorbid conditions and were greater than 60 years of age. The dosage rate of theophylline (mg/hour) can be estimated from predicted clearance (L/kg/hour) times desired steady-state serum concentration (mg/L).

Pathologic findings in allergic aspergillus sinusitis. A newly recognized form of sinusitis.

The pathologic findings are described in seven cases of allergic aspergillus sinusitis, a newly recognized form of sinusitis. Grossly, the sinuses are filled with firm, white-tan mucoid material. Microscopically this material consists of mucin-containing numerous eosinophils, sloughed respiratory epithelial cells, cellular debris, Charcot-Leyden crystals, and scattered fungal hyphae resembling aspergillus species. This histologic appearance is identical to mucoid impaction occurring in bronchi in allergic bronchopulmonary aspergillosis. Allergic aspergillus sinusitis and allergic bronchopulmonary aspergillosis may represent different manifestations of aspergillus hypersensitivity in the respiratory tract. Implications for treatment of allergic aspergillus sinusitis and a possible relationship between it and allergic bronchopulmonary aspergillosis are discussed.

Pathologic features of allergic bronchopulmonary aspergillosis.

We describe the pathologic features in surgically excised lung tissue specimens from 18 cases of allergic bronchopulmonary aspergillosis (ABPA). The main abnormalities involved bronchi and bronchioles. All cases showed bronchocentric granulomatosis (BCG), mucoid impaction of bronchi (MIB), or both. The impacted mucin of MIB contained large numbers of eosinophils and Charcot-Leyden crystals. A distinctive exudative bronchiolitis was present distal to areas of BCG in 13 cases. This lesion was characterized by filling of bronchiolar lumens with necrotic neutrophils and eosinophils in a basophilic mucinous exudate. A peribronchiolar chronic inflammatory infiltrate was seen in 15 cases; eosinophils were prominent in 10 of these cases. Foci of eosinophilic pneumonia were seen in 13 cases, and noninvasive fungal hyphae were identified in 14. We conclude that the finding of BCG or MIB, or a combination of both, especially in conjunction with tissue eosinophilia, should suggest the diagnosis of ABPA. When noninvasive fungal hyphae are also present, the changes are diagnostic of ABPA or a related allergic fungal reaction.