Serum sickness-like syndrome associated with minocycline therapy

A 19 year-old youth was taking oral minocycline and after 8 days he presented all four cardinal symptoms of serum sickness (urticaria, fever, lymphadenopathy and joint symptoms). C3, C4 and CH50 evolution imitate experimental serum sickness complement evolution. We exclude other causes of this syndrome. Although other hypersensitivity reactions have occurred with minocycline usage, to our knowledge serum sickness-like syndrome has not been previously reported with this drug.     

Characterization of an anaphylactoid reaction to omalizumab.

BACKGROUND: The novel humanized murine monoclonal antibody omalizumab prevents binding of human IgE to its high-affinity receptor. A contraindication to therapy with omalizumab is allergy to the medication or previous immediate-type hypersensitivity or anaphylaxis to omalizumab or similar medications. OBJECTIVE: To determine whether a 32-year-old woman with asthma, allergic rhinitis, and idiopathic chronic urticaria and angioedema with anaphylactoid reactions to omalizumab could tolerate the medication in a desensitization protocol. METHODS: Omalizumab was administered after pretreatment with nonsteroidal anti-inflammatory drugs (ibuprofen, 600 mg) while the patient was closely monitored in an intensive care unit. RESULTS: Omalizumab was well tolerated using this protocol, but a serum sickness-like reaction developed that required discontinuation of the medication after the seventh dose. CONCLUSIONS: Our experience suggests that some patients with anaphylactoid reactions to omalizumab can tolerate the medication when pretreated with nonsteroidal anti-inflammatory drugs but that a serum sickness-like illness may develop, requiring discontinued use of the medication.     

Concurrent cell-mediated immunity and immediate hypersensitivity in animal model

Drug induced allergic reactions in treated patients are sometimes accompanied by laboratory evidence of a simultaneous drug-specific humoral and cellular immunity. The relationship between the two types of immune response was studied in an experimental model. In the present studies ICR mice were sensitized with horse serum to induce an anaphylactic shock. Macrophage migration inhibition factor (MIF) test, which is an in vitro correlate for cell-mediated immunity (CMI), was performed with the animal's lymphocytes against horse serum. A significant inhibition in the macrophage migration was observed in the sensitized mice as compared to the control group. No significant difference was observed between the migration index of the mice that suffered fatal anaphylactic shock and those with milder symptoms that survived it. The demonstration of a positive MIF in an immediate type allergic reaction does not necessarily indicate a direct involvement of the CMI system in the production of clinical manifestations, although the MIF test may be clinically useful for diagnostic purposes, even in immediate hypersensitivity cases.     

Anisakis simplex allergy: a murine model of anaphylaxis induced by parasitic proteins displays a mixed Th1/Th2 pattern

The study of the singular hypersensitivity reactions to Anisakis simplex (A.s) proteins, may help us to undestand many of the unknown immune interactions between helmiths infections and allergy. We have developed a murine model of allergy to A. simplex, that mimics human A. simplex allergy to study the specific aspects of anaphylaxis induced by parasites. Male C3H/HeJ mice were intraperitoneally sensitized to A. simplex. Mice were then intravenous or orally challenged with A. simplex. Antigen-specific immunoglobulins, polyclonal IgE, anaphylactic symptoms, plasma histamine levels and cytokine profiles were determined. Comparative IgE immunoblot analyses were also performed. Specific IgE, IgG(1) and IgG(2a) were detected in sensitized mice since week 3. Polyclonal IgE raised and peaked with different kinetics. Intravenous A. simplex challenge produced anaphylaxis in mice, accompanied by plasma histamine release. Oral A. simplex challenge in similarly sensitized mice did not caused symptoms nor histamine release. Numerous A. simplex allergens were recognized by sensitized mouse sera, some of them similar to human serum. The A. simplex stimulated splenocytes released IL-10, IFN-gamma, IL-4, IL-13 and IL-5. We describe a new animal model of anaphylaxis. It exhibits characteristics of type I hypersensitivity reactions to Anisakis simplex similar to those observed in allergic humans. Different responses to i.v. or oral A. simplex challenges emerged, which did not reflect a window tolerization period. The cytokine profile developed (mixed Th(1)/Th(2) pattern) differed from the observed in classical models of anaphylaxis or allergy to food antigens. This model may permit to investigate the peculiar allergic reactions to parasitic proteins.     

A Case of Pranlukast-Induced Anaphylactic Shock

Leukotriene receptor antagonists, which are generally considered safe with a few adverse drug reactions, are increasingly used in the treatment of various allergic diseases, including asthma and allergic rhinitis. Although a few anaphylactic reactions to montelukast have been reported worldwide, there is still a lack of reports about severe adverse drug reactions associated with pranlukast. Here, we report a case of severe hypersensitivity reaction associated with pranlukast. A 65-year-old woman developed anaphylactic shock that presented as generalized urticaria, angioedema, collapse, and loss of consciousness after receiving pranlukast. A positive response to oral challenge and skin prick testing with pranlukast was observed in the patient. In this case, it was demonstrated that pranlukast can induce anaphylaxis, possibly mediated by the IgE-dependent pathway.     

Management of hypersensitivity reactions to anti‐D immunoglobulin preparations

RhD immunoglobulin G (anti‐D) administered to pregnant Rh(?) women prevents Rh isoimmunization. Its use has significantly reduced the incidence of haemolytic disease of the foetus and newborn previously responsible for one death in every 2200 births. In pregnancy, acute drug‐induced hypersensitivity reactions including anaphylaxis can have serious deleterious effects on the mother and foetus/neonate. Women can be erroneously labelled as drug allergic as the investigation of hypersensitivity reactions in pregnancy is complex and drug challenges are usually contraindicated. We present three cases of suspected anti‐D hypersensitivity clinically presenting as anaphylaxis and delayed transfusion‐related reaction. We also propose a new algorithm for the investigations of such reaction. It relies on detailed history, cautious interpretation of skin tests, foetal Rh genotyping from maternal blood and, in some cases, anti‐D challenges. This is not to deprive women of anti‐D which might put their future pregnancies at risk.     

Pretreatment with glycomacropeptide reduces allergen sensitization, alleviates immediate cutaneous hypersensitivity and protects from anaphylaxis

Allergic disorders are characterized by the involvement of allergen-specific immunoglobulin (Ig)E antibodies and T helper type 2 (Th2) cells. The search for new therapies for allergic diseases has been the primary focus of interest for many investigators in recent years. Glycomacropeptide (GMP) is a biologically active component of milk that exhibits a range of immunomodulatory functions. We examined whether oral administration of GMP could affect the development of allergic sensitization and the severity of immediate cutaneous hypersensitivity reactions and of anaphylaxis. Rats treated with or without GMP were ovalbumin (OVA)-sensitized and several indicators of allergy were evaluated. Pretreatment with GMP resulted in reduction of antigen-specific IgE titre in rats when sensitized with OVA. GMP administration also markedly suppressed the proliferative response of splenocytes to antigen and the production of interleukin (IL)-13 by splenocytes of sensitized animals. In addition, GMP pretreatment attenuated the intensity of the immediate cutaneous reaction induced by antigen and protected the sensitized rats from severe anaphylaxis. These data demonstrate, for the first time, that the administration of GMP prevents allergen sensitization and reduces the severity of the early-phase reaction induced by antigen in cutaneous hypersensitivity and in anaphylaxis. GMP may be used as a novel prophylactic agent for the control of allergic diseases.     

Hypersensitivity Reactions to Corticosteroids

Hypersensitivity reactions to corticosteroids (CS) are rare in the general population, but they are not uncommon in high-risk groups such as patients who receive repeated doses of CS. Hypersensitivity reactions to steroids are broadly divided into two categories: immediate reactions, typically occurring within 1 h of drug administration, and non-immediate reactions, which manifest more than an hour after drug administration. The latter group is more common. We reviewed the literature using the search terms “hypersensitivity to steroids, adverse effects of steroids, steroid allergy, allergic contact dermatitis, corticosteroid side effects, and type I hypersensitivity” to identify studies or clinical reports of steroid hypersensitivity. We discuss the prevalence, mechanism, presentation, evaluation, and therapeutic options in corticosteroid hypersensitivity reactions. There is a paucity of literature on corticosteroid allergy, with most reports being case reports. Most reports involve non-systemic application of corticosteroids. Steroid hypersensitivity has been associated with type I IgE-mediated allergy including anaphylaxis. The overall prevalence of type I steroid hypersensitivity is estimated to be 0.3–0.5 %. Allergic contact dermatitis (ACD) is the most commonly reported non-immediate hypersensitivity reaction and usually follows topical CS application. Atopic dermatitis and stasis dermatitis of the lower extremities are risk factors for the development of ACD from topical CS. Patients can also develop hypersensitivity reactions to nasal, inhaled, oral, and parenteral CS. A close and detailed evaluation is required for the clinician to confirm the presence of a true hypersensitivity reaction to the suspected drug and choose the safest alternative. Choosing an alternative CS is not only paramount to the patient’s safety but also ameliorates the worry of developing an allergic, and potentially fatal, steroid hypersensitivity reaction. This evaluation becomes especially important in high-risk groups where steroids are a life-saving treatment. The assessment should be done when the patient’s underlying condition is in a quiescent state.     

Hypersensitivity reactions to chemotherapeutic drugs

There is an ever-increasing number of therapeutics used to treat cancer. A recent publication listed 86 currently available antineoplastic medications. Despite this large number, hypersensitivity reactions are not common except with platinum compound (cisplatin, carboplatin), epipodophyllotoxins (teniposide, etoposide), asparaginase, taxanes (paclitaxel), and procarbazine. Doxorubicin and 6-mercaptopurine are occasionally associated with hypersensitivity reaction. Comparable reactions with other chemotherapeutic agents are. uncommon; many are only anecdotal reports. Reactions associated with individual drugs are discussed in detail. The mechanisms responsible for most of these reactions are not known, as they have generally not been evaluated. The term “hypersensitivity” is widely used in the chemotherapy literature without a common definition. Hypersensitivity is defined here as an unexpected reaction with signs and symptoms not consistent with known toxicity of the drug. Most reactions are coincident with or within hours of drug administration. Almost all are associated with parenteral administration. Symptoms include flushing, alterations in heart rate and blood pressure, dyspnea and bronchospasm, back pain, fever, pruritus, nausea and all types of rashes. Some cases may be due to non-immune mediated release of histamine or cytokines, as many patients can subsequently tolerate re-exposure after pretreatment with steroids and antihistamine, and slow readministration of the drug. This is more compatible with a graded challenge, than desensitization and is generally successful for taxanes less so for platinum compounds. In most cases hypersensitivity reactions are associated with the specific chemotherapeutic drug. Reaction rates may vary with different forms of the drugs, e.g. pegylated. Occasionally excipients such as Cremaphor EL may induce hypersensitivity reactions.     

Can we identify patients at risk of life‐threatening allergic reactions to food?

Anaphylaxis has been defined as a ‘severe, life‐threatening generalized or systemic hypersensitivity reaction’. However, data indicate that the vast majority of food‐triggered anaphylactic reactions are not life‐threatening. Nonetheless, severe life‐threatening reactions do occur and are unpredictable. We discuss the concepts surrounding perceptions of severe, life‐threatening allergic reactions to food by different stakeholders, with particular reference to the inclusion of clinical severity as a factor in allergy and allergen risk management. We review the evidence regarding factors that might be used to identify those at most risk of severe allergic reactions to food, and the consequences of misinformation in this regard. For example, a significant proportion of food‐allergic children also have asthma, yet almost none will experience a fatal food‐allergic reaction; asthma is not, in itself, a strong predictor for fatal anaphylaxis. The relationship between dose of allergen exposure and symptom severity is unclear. While dose appears to be a risk factor in at least a subgroup of patients, studies report that individuals with prior anaphylaxis do not have a lower eliciting dose than those reporting previous mild reactions. It is therefore important to consider severity and sensitivity as separate factors, as a highly sensitive individual will not necessarily experience severe symptoms during an allergic reaction. We identify the knowledge gaps that need to be addressed to improve our ability to better identify those most at risk of severe food‐induced allergic reactions.     

A Single Intraduodenal Administration of Human Adenovirus 40 Vaccine Effectively Prevents Anaphylactic Shock

Vaccine administration into the intestine is known to induce mucosal tolerance most efficiently. Therefore, developing a delivery system that targets the intestinal mucosa is expected to improve the efficiency of immunosuppression. Human enteric adenovirus serotype 40 (Ad40)-based vectors have the advantage of targeting intestinal mucosa, making them prime candidates as mucosal vaccine carriers for immunosuppression. Here, after both oral and intraduodenal administrations, the vector distribution of replication-defective recombinant Ad40 vectors (rAd40) was significantly higher than that of a conventional Ad vector based on human adenovirus 5 (Ad5) in ilea containing Peyer''s patches. Single intraduodenal administration of rAd40 induced antigen-specific mucosal immunoreaction mediated by intestinal mucosal and systemic immunity. In ovalbumin-induced allergy mouse models, this approach inhibited antigen-specific delayed-type hypersensitivity reactions, diarrhea occurrence, and systemic anaphylaxis. Thus, a single intraduodenal administration of rAd40 provides a potent method of inducing allergen-specific mucosal tolerance and a new allergen-specific immunotherapy for overcoming problems with current therapies against life-threatening allergic reactions, including anaphylaxis.     

Peanut-induced anaphylactic reactions.

Food allergies, particularly to peanuts, are a common cause of anaphylaxis. Approximately 125 people die each year in the USA secondary to food-induced anaphylaxis. Clinical anaphylaxis is a syndrome of diverse etiology and dramatic presentation of symptoms associated with the classic features of type I, IgE-mediated hypersensitivity [1]. Typically the term anaphylaxis connotes an immunologically-mediated event that occurs after exposure to certain foreign substances. This reaction results from the generation and release of a variety of potent biologically active mediators and their concerted effects on various target organs. Anaphylaxis is recognized by cutaneous, respiratory, cardiovascular, and gastrointestinal signs and symptoms occurring singly or in combination. This article focuses on allergic reactions to peanuts that manifest as signs and symptoms involving multiple target organs or the cardiovascular system alone.     

Clinical presentation and time course in hypersensitivity reactions to beta-lactams

Background:  β-lactam hypersensitivity reactions are classified as immediate or nonimmediate. Diagnosis is usually based upon skin tests and provocation challenges.
Objective:  The time course of the reactions in proven β-lactam hypersensitivities was studied and then correlated with the symptoms to determine the relationship between the clinical presentations and the time course.
Method:  All of the patients who consulted between 1996 and 2004 for a suspected β-lactam hypersensitivity reaction were studied. Two hundred and ten patients with a proven hypersensitivity reaction diagnosed according to the European Network on Drug Allergy were included in the present study.
Results:  Of the patients, 36.7% had urticaria as a single symptom, 19.1% anaphylaxis without shock, 17.6% anaphylactic shock and 19.1% maculopapular exanthema. Anaphylactic shock and anaphylaxis mostly occurred within 1 h after drug administration. Exanthema mainly occurred after 24 h. Urticaria as a single symptom occurred at any time. A firm diagnosis was determined using immediate-reading skin prick (10.0%) and intradermal tests (38.1%), late-reading skin tests (19.1%) or provocation tests (32.9%).
Conclusion and clinical implication:  Depending on the time course of the reaction, three clinical groups were identified: anaphylaxis and anaphylactic shock (immediate reaction); maculopapular exanthema (late reaction) as well as urticaria (immediate and late reaction).     

Typical antimicrobials induce mast cell degranulation and anaphylactoid reactions via MRGPRX2 and its murine homologue MRGPRB2

Mast cells are unique immune cells that function as sentinels in host defence reactions, including immediate hypersensitivity responses and allergic responses. The mast cell‐specific receptor named MAS‐related G protein‐coupled receptor X2 (MRGPRX2) triggers mast‐cell degranulation, a key process in anaphylactoid reactions. It is widely observed that antimicrobials can induce pseudo‐allergic reactions (i.e. IgE‐independent mechanism) with symptoms ranging from skin inflammation to life‐threatening systemic anaphylaxis. However, their direct involvement and the mechanisms underlying anaphylactoid reactions caused by antimicrobials have not been demonstrated. Structurally different antimicrobials were screened by Ca²⁺ imaging using MRGPRX2 overexpressing HEK293 cells. MRGPRX2 related anaphylactoid reactions induced by these components were investigated by body temperature drop and mast cell degranulation assays. We showed that MRGPRX2 is involved in allergic‐like reactions to three types of antimicrobials in a dose‐dependent manner. However, mast cells lacking the receptor show reduced degranulation. Furthermore, mice without MAS‐related G protein‐coupled receptor B2 (the orthologous gene of MRGPRX2) exhibited reduced substance‐induced inflammation. Interestingly, β‐lactam and antiviral nucleoside analogues did not induce anaphylactic reactions, which were also observed in vitro. These results should alarm many clinicians that such drugs might induce anaphylactoid reactions and provide guidance on safe dosage of these drugs.     

Severe serum sickness-like reaction to oral penicillin drugs: three case reports.

BACKGROUND: Because the use of heterologous sera has diminished, the incidence of serum sickness has declined. However, serum sickness-like reactions to nonprotein drugs continue to occur. METHODS: We report three cases of severe serum sickness-like reactions in adults to oral penicillin drugs. RESULTS: In each patient, significant symptom resolution occurred within 24 hours of starting therapy with oral corticosteroids. CONCLUSIONS: Serum sickness-like reactions to oral penicillin drugs may be more common than reported in the literature and can be very severe. No specific laboratory finding is universally present or definitively diagnostic. As with classic serum sickness, the diagnosis of serum sickness-like reaction is made clinically. In severe cases such as those presented here with debilitating joint symptoms or life-threatening angioedema, a diagnostic-therapeutic trial of prednisone, 40 to 60 mg at least once daily, is warranted.     

A case of anaphylaxis by ant (Ectomomyrmex spp.) venom and measurements of specific IgE and IgG subclasses.

Hypersensitivity to the stings of the Hymenoptera has been described since antiquity. The hypersensitive reactions to insect stings vary from minor skin reactions to severe and sometimes fatal anaphylaxis. Concerns about sting hypersensitivity have been increasing because of many incidents of allergic reactions of patients to the fire ant in the southern area of the United States as well as the harvester ant in some areas. We experienced one unique case with severe allergic reactions by ant of the Ectomomyrmex spp. of the subfamily Ponerinae, which is not a harvester ant. For three years the patient had been suffering from generalized allergic reactions such as anaphylaxis after the ant stings four-five attacks in a year. We determined that her reactions were due to specific IgE mediated type I hypersensitivity by the detection of a high level of specific IgE to the ant venom in her serum. The high level of specific IgG4 to the ant venom was also noted in her serum, however, the role of ant venom IgG4 was not clearly determined.     

Fatalities following allergen immunotherapy

Allergen immunotherapy has been in use for nearly 100 yr and has become an important method of reducing allergic symptoms in select patients with allergic rhinitis, asthma, and insect venom hypersensitivity. Unfortunately, immunotherapy has been associated with anaphylaxis and death. Although the relative risk of severe reactions to immunotherapy is low, the number of such reactions has increased since the introduction of standardized and more potent extracts. There are a number of risk factors associated with such severe anaphylactic reactions. Such risk factors include errors in dosage, failure to reduce the dosage after a longer than scheduled interval, administration of the wrong extract, inadvertent intravenous administration, failure to postpone injection because of infection or asthma exacerbation, failure to observe patients for appropriate length of time, failure to adhere to guidelines for established contraindications, concurrent use of beta-adrenergic blocking agents, uses of mixtures of allergens, immunotherapy during the active allergy season, and types of allergens. In this review, we focus on these and other risk factors in attempts to reduce the risk of anaphylaxis following allergen immunotherapy.     

Advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insect stings

This review highlights some of the research advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insect venom that were reported primarily in the Journal of Allergy and Clinical Immunology from 2002 through 2003. Among the topics highlighted are new insights into the pathogenesis of atopic dermatitis and potential strategies for more effective treatment of the atopic march. Patients should remain supine with raised legs during anaphylactic shock because upper body elevation could result in sudden death from loss of venous return to the heart. A major advance in food allergy was that humanized, monoclonal anti-IgE antibody showed protection against peanut-induced anaphylaxis. In addition to studies elucidating mechanisms of drug hypersensitivity, a clinical study showed patients with a history of prior penicillin allergy with negative penicillin allergy test results are unlikely to experience reactions or resensitization on subsequent oral courses of penicillin. Lastly, there are new recommendations for patients with convincing insect sting reaction histories but negative skin test responses to venom.     

Antiallergic activity of 6-(2-cyclohexylethyl)-[1,3,4]thiadiazolo- [3,2-a]-1,2,3-triazolo-[4,5-d]pyrimidin-9(3H)-one (DS-4574) in rats.

The antiallergic activity of DS-4574 was evaluated in several commonly used rat models for allergic diseases. In passive cutaneous anaphylaxis, DS-4574 given intravenously and orally induced dose-dependent inhibition with ID50 values of 0.55 and 2.8 mg/kg, respectively. In contrast, this compound had no antagonistic activity against the histamine- and serotonin-induced cutaneous vascular permeability. In lung anaphylaxis, DS-4574 inhibited pulmonary function changes induced by the antigen in a dose-dependent manner when it was given intravenously and orally, the ID50 values being 0.04 and 0.89 mg/kg, respectively. DS-4574 also inhibited antigen-induced histamine and leukotriene release in passive peritoneal anaphylaxis following oral administration. In addition, this compound prevented antigen-induced histamine release in passively sensitized mast cells in vitro. These potent activities of DS-4574 in in vivo and in vitro models of immediate-type hypersensitivity reactions suggest that this compound could be useful in the treatment of allergic diseases including asthma.     

Serum tryptase levels in adverse drug reactions

We evaluated the usefulness of individual tryptase levels and variations after adverse drug reactions in 64 patients. Our aim was to find a tool for the diagnosis of drug allergy. Thirty-seven subjects were confirmed to have drug allergy, 12 had nonsteroidal anti-inflammatory drug (NSAID) reactions, five had negative controlled drug challenges (NAAR), and 10 had symptoms after placebo intake (PLA). Serum tryptase levels greatly increased after anaphylactic shocks (2242%) and anaphylaxis (710.5%). Patients with allergic urticaria and those with idiosyncratic responses to acetylsalicylic acid (ASA) exhibited a small increase in serum tryptase (49.5% and 38.2%, respectively). In the other two groups (NAAR and PLA), no variation in this serum protease was observed. The time of appearance of the serum tryptase peak differed considerably among patients with similar clinical reactions (from 30 min to 6 h) and was independent of the latent period, severity of symptoms, or the amount of tryptase released. We conclude that serum tryptase determinations are helpful in the diagnosis of anaphylactic shock and anaphylaxis, but serial measurements may be needed to confirm mast-cell participation in milder reactions.