Grands principes du diagnostic étiologique des réactions d’hypersensibilité immédiate aux médicaments et substances biologiques

Suspected immediate-type allergic reactions are frequently reported in patients treated with drugs and biologic agents. The most frequently suspected drugs are anti-infectious drugs, betalactams especially, and analgesic-antipyretic-non steroidal antiinflammatory drugs, radiocontrast agents, and other biological substances such as latex and myorelaxants, enzymes and hormones, etc. Diagnosis is primarily based on clinical examination of the patients, detailed anamnesis and immediate-reading skin tests. The diagnostic and/or predictive value of immediate-reading skin tests is good with betalactams, latex and myorelaxants, and several other substances such as corticosteroids, dyes, antiseptics, vaccines, etc, but low or unknown with other substances such as quinolones, macrolides and sulphonamides, protamine and aprotinin, insulins, and pancreatic enzymes. The diagnostic value of in vitro tests (specific IgE determination, histamine and leukotriene-release tests, basophil activation tests) is highly variable from one substance to another one and, at present, is not validated. In patients with negative skin and/or in vitro tests, diagnosis is based on challenge tests. However, those tests are potentially harmful. Thus, challenge tests in patients with suspected immediate-type hypersensitivity reactions to drugs and biological substances should be performed in the hospital only, under careful monitoring, after a careful assessment of the ratio benefit/risk.     

Les réactions allergiques et pseudoallergiques aux antalgiques,antipyrétiques et anti-inflammatoires non stéroïdiens

Antalgics, antipyretics and non-steroidal anti-inflammatory drugs (NSAIDs) are widely used, but suspected allergic reactions to these drugs are rare, especially in children. Most frequent reactions are cutaneous (urticaria, angioedema) and respiratory (rhinitis, asthma). Other reactions (anaphylaxis or anaphylactoid reactions, potentially harmful toxidermias) are rare. In a few patients, reactions may result from a specific (allergic) hypersensitivity (HS), with positive responses in prick and intradermal tests (anaphylaxis, immediate urticaria and/or angioedema) and in intradermal and patch tests (non-immediate reactions). However, most reactions result from a non-specific (non-allergic) HS (intolerance), with a frequent cross-reactivity between the various families of antalgics, antipyretics and NSAIDs, including acetaminophen (paracetamol). Based on a convincing clinical history and/or positive responses in challenge tests, intolerance to antalgics, antipyretics and NSAIDs has been diagnosed in 13 to 50% of the patients with allergic-like reactions to these drugs. Risk factors for HS to antalgics, antipyretics and NSAIDs are a personal atopy and age. In our experience, 50% of the children with allergic-like reactions to antipyretics, antalgics and NSAIDs were diagnosed intolerant to these drugs. Risk was high in children reporting reactions to NSAIDs (aspirin, ibuprofen) and lower in children reporting reactions to paracetamol. All the children intolerant to paracetamol were also intolerant to NSAIDs. In contrast, most children with NSAID intolerance were tolerant to paracetamol. A personal history of atopy and a mean age ≥ 8 years were significant risk factors for intolerance to antalgics, antipyretics and NSAIDs.     

Quoi de neuf en allergologie pédiatrique en 2006-2007 ? Partie 3: Allergie cutanée, alimentaire, médicamenteuse et aux insectes (une revue de la littérature internationale d’octobre 2005 à septembre 2007)

Most sensitizations in children with atopic dermatitis are non pathogenic. Thus, responses in prick-tests, specific IgE determinations and patch-tests should be carefully evaluated based on the clinical history of the children or responses in challenge tests. Moreover, although atopy patch-tests are highly specific, they have a low sensitivity. Food eviction is indicated in a few children only, since they may be responsible for anaphylactic reactions induced by accidental ingestion of the food or oral challenge tests. The predictive value of serum specific IgE to foods depends on the food investigated, the age of the children, their allergic disease (atopic dermatitis, urticaria/angioedema, anaphylaxis) and, may be, on their ethnical origin. The prevention of food-induced severe reactions is based on eviction. However, several studies suggest that oral desensitization to foods may be efficient. Most frequent reactions in children hypersensitive to antalgics, antipyretics and nonsteroidal antiinflammatory drugs are oedema (facial oedema especially) and urticaria. Usually, the severity of the reactions increases from one treatment to another one and with the dose of drug administered to the children. Diagnosis is based on a convincing clinical history or on challenge tests. Skin tests with vaccines should be performed according to a standardized procedure because they may give false positive responses. Most latex sensitizations detected by skin prick-tests and, especially, specific IgE determinations are non pathogenic. The prevention of reactions to latex is based on eviction. However, preliminary results suggest that sublingual desensitization with a latex extract is efficient and well-tolerated.     

Excellente tolérance du prick-test dans l’exploration des allergies médicamenteuses en milieu de type hospitalier

Introduction

The diagnosis of drug allergy is based on clinical history and skin tests. Although medical literature reports a risk of allergic reactions during skin tests, our experience, based upon several thousands of patients since 1998, strongly suggests that skin tests with drugs are well tolerated.

Patients and methods

In this prospective study, we analysed the adverse effects observed during skin testing of 183 patients explored for suspected drug-induced immediate hypersensitivity, such as urticaria, angioedema, bronchospasm, and anaphylactic shock, between November 2004 and March 2005. Patients were first tested with prick-tests, and with intradermal tests (IDT) at 1/1000 and 1/100 dilutions of the prick solution only when the prick-tests were negative.

Results

One hundred and seventy-nine prick-tests and 169 IDT were realised with drugs diluted by the hospital's chemist. Nine of the 183 patients (5.0%) were diagnosed as having drug-induced immediate-type hypersensitivity, based on a severe suggestive initial reaction and immediate responses in prick or IDT. No reaction was observed during prick testing. IDT induced a non-severe reaction, with less severe symptoms than the initial accident, in one patient only.

Conclusion

Our results confirm the excellent tolerance of prick-tests. Also, they strongly suggest that it is important to investigate drug hypersensitivity with a well-defined protocol, in a hospital setting, starting with pricks and using low concentrations of drugs in IDT.     

Fièvre médicamenteuse : un diagnostic à ne pas oublier

Drug fever (DF) is a febrile reaction induced by a drug without additional clinical features like skin eruption. This adverse drug reaction is probably common but under diagnosed. While its outcome is generally favourable, DF generates unnecessary diagnostic procedures as well as hospitalisations or hospitalisation prolongations. Clinical presentation and biological findings are not specific. Fever is generally well tolerated but may be accompanied by general symptoms mimicking sepsis. Moderate biological disorders could be expected, including elevation or decrease in white blood cell count, eosinophilia, liver cytolysis, and increased C-reactive protein. An infection should be systematically ruled out. Clinical or biological signs of severity should question DF diagnosis. When DF is suspected, the involved drug(s) should be stopped after a reliable assessment of imputability. Antibiotics represent the most often implicated drugs. Fever disappearance after discontinuing the suspected drug is the cornerstone of DF diagnosis. Before stopping the administration of the suspected drug(s), a risk/benefit ratio assessment is necessary. Consistently, it may be complicated to stop an antimicrobial drug when treating an infection or an immunosuppressive drug if required.     

Sensibilisation aux médicaments topiques

The management of patients who have developed a contact dermatitis due to topical drugs requires to stop the suspected drug application, to declare, if severe, the adverse drug reaction to a center for drug safety, to treat the patient with corticosteroid ointments, to perform dermatoallergological investigations e.g. drug patch tests in case of contact eczema and diluted prick tests in case of contact urticaria in order to determine whether the adverse drug reaction was due to excipients or to the drug itself. It is also absolutely necessary to advise the patient concerning the avoidance of topical but also systemic readministration of the responsible molecule. An excipient responsible in inducing a contact sensitization to a topical drug can also be found in cosmetics, the name of the responsible excipient has to be given to the patient under the common name but also under the INCI and/or CFTA name. When the drug itself is responsible in inducing a contact allergy it is necessary to determine if cross reactions with other drugs can occur and if the responsible molecule can induce systemic cutaneous adverse drug reactions if the drug is systemically readministred. Among NSAID there is no cross reactions between bufexamac and diclofenac, between salicylamide, glycol salicylate, salicylic acid and acetylsalicylic acid. In case of photosensitization 1) to ketoprofen or 2) piroxicam the topical and/or systemic administration of the following molecules are contraindicated with respectively 1) ketoprofen, tiaprofenic acid, fenofibrate, oxybenzone or 2) piroxicam, thimerosal. A patient sensitized to corticosteroid ointment has to be tested in order to determine which corticosteroid classes are sensitizing. The topical and systemic administrations of molecules belonging to the sensitizing classes (A, B, C, D1 or D2) have to be forbidden. In general, a contact dermatitis due to an antimicrobial drug induces a contraindication in further topical or systemic uses of the drug and to all the molecules belonging to the same class. In most of the cases there is no risk in systemically administering iodine, sulfites or excipients in a sensitized patient who had developed a contact dermatitis to topical medications.     

Valeurs diagnostique et prédictive des tests cutanés aux médicaments et substances biologiques

Immediate-reading skin tests (pricks and intradermal tests) are indicated in patients reporting symtoms suggesting immediate-type hypersensitivity reactions. The diagnostic and/or predictive value of these tests is good with betalactams, latex and myorelaxants, and several other substances such as corticosteroids, dyes, antiseptics, vaccines, etc. Non irritant concentrations have been determined for several substances (betalactams, myorelaxants, etc.), but are unknown for numerous other substances. For other substances, non irritant concentrations in skin tests should be evaluated in control patients, in parralel with skin tests performed in patients. The diagnostic value of nonimmediate-reading skin tests is highly variable, and depends on the drug and the nature of the symptoms. Although the sensitivity and the specificity of nonimmediate-reading skin tests are not perfect, these tests are useful in the diagnosis of mild to moderately severe toxidermias, such as nonimmediate urticarias and angio-oedemas, fixed drug eruptions, maculopapular rashes, and acute generalized exanthematic pustulosis. In contrast, their diagnostic value is low in potentially severe toxidermias. The diagnostic value of responses in intradermal tests is usually higher than in patch-tests. However, patch-tests may be positive in few patients with negative intradermal tests. Ideally, skin tests should be performed between 6 weeks and 1 to 2 years after the clinical reaction. However, most nonimmediate drug sensitizations can be diagnosed several years later.     

La myasthénie du côté de l’interniste

Myasthenia gravis is an autoimmune disease due to specific antibodies inducing a neuromuscular transmission defect causing muscle fatigability. If onset of the disease may be at any age, myasthenia gravis concerns mostly young adults, in majority females. The disease characteristic features are the following: ocular symptoms (ptosis or diplopia) as main initial manifestation, extension to other muscles in 80 % of the cases, variability of the deficit, effort induced worsening, successive periods of exacerbation during the disease course, severity depending on respiratory and swallowing impairment (if rapid worsening, a myasthenic crisis is to be suspected), association with thymoma in 20 % of patients and with other various autoimmune diseases, most commonly hyperthyroidism and Hashimoto's disease. Diagnosis relies on the clinical features, improvement with cholinesterase inhibitors, detection of specific autoantibodies (anti-AChR or anti-MuSK), and significant decrement evidenced by electrophysiological tests. The points concerning specifically the internist have been highlighted in this article: diagnostic traps, associated autoimmune diseases, including inflammatory myopathies that may mimic myasthenia gravis, adverse effects of medications commonly used in internal medicine, some of them inducing myasthenic syndromes. The treatment is well codified: the treatment is well codified: (1) respect of adverse drugs contra-indications, systematically use of cholinesterase inhibitors, (2) thymectomy if thymoma completed with radiotherapy if malignant, (3) corticosteroids or immunosuppressive agent in severe or disabling form, (4) intensive care unit monitoring, plasmapheresis or intravenous immunoglobulins for patients with myasthenic crisis.     

Les urticaires au cours d'un traitement anti-infectieux : le médicament est-il vraiment souvent en cause ?

Hypersensitivity drug reactions, including immediate allergic reactions, are one of many types of adverse drug reactions. While urticaria is one of the most frequent clinical forms of drug allergy, other manifestations may also occur. To determine that the cause of an urticarial reaction is drug-induced is important, although in most cases this diagnosis is not established. Diagnosis is based on immediate skin test reactions and drug provocation testing. These tests are not without danger, which is why a complete clinical history and the patient's responses to the ENDA (European Network for Drug Allergy) questionnaire, as well as careful attention to necessary precautions, are important. The Drug Allergy and Hypersensitivity Database (DAHD) includes 1,267 reports of urticaria possibly due to drugs; β-lactams were the most frequently involved (35.6%). However, a drug allergy work-up demonstrated that only 15.4% of these reactions were actually due to a drug; 44.6% were diagnosed by means of skin tests, the rest by provocation tests. Of the positive tests, 41.2% were positive within the first hour and 16.6% only after 24 hours. Urticaria may be induced by drugs, especially antibiotics, but drugs are not the main cause of urticaria. The diagnosis of drug allergy requires confirmation by relevant tests.     

Histamine : le rôle du médiateur

Histamine is an essential mediator of the pathophysiology of many allergic diseases. It is synthesized in inflammatory and immunocompetent cells, in gastric parietal cells and in neurons (labile reserve). It can be liberated in the skin, intestines, liver and bronchi by antigen–antibody interactions as well as by drugs (for example, morphine), venoms, toxins, endogenous agents (for example, kinins), radiation, burns and inflammatory reactions. It is a potent vasodilator that can increase capillary permeability, induce bronchoconstriction, activate inflammatory cells, stimulate gastric secretion and, depending on the circumstances, inhibit or stimulate the central and peripheral nervous systems. The biological actions of histamine result from the activation of four types of receptors, H1, H2, H3 and H4. H1 receptors predominate in smooth muscle tissues (bronchi, intestines, etc.), nerve fibers and immuno-inflammatory cells. H2 receptors predominate in the stomach and heart, H3 receptors in central and peripheral nerve fibers, and H4 receptors are predominant on immuno-inflammatory cells.     

Vaccinations et allergie

In atopic patients, vaccine may induce allergic reactions to vaccine components and non specifically promote hyperreactivity to non related allergens. Several studies have also suggested that vaccinations may promote the development of allergic disease in atopy-prone subjects. Diagnostic and/or predictive value of skin tests with vaccines and specific antibody determinations is highly variable upon the type and chronology of the reaction, and the substances involved. In patients with proven or highly suspected allergy, withholding booster injections is advised if specific IgM/IgG levels are high. If the levels are low, sequential injections of vaccines containing a single vaccinating agent are usually tolerated. However, injections of the vaccine should be performed using a “desensitization” procedure in patients reporting anaphylaxis and immediate or accelerated urticaria and/or angioedema. Vaccines may also promote allergen-induced asthma and/or atopic dermatitis exacerbations in highly atopic patients. In patients with well-controlled asthma, influenza vaccines do not induce bronchial hyperreactivity and are usually well tolerated. In general practice, vaccine injections should be performed in patients with optimal control of their allergic disease only. Finally, most of the recent studies and meta-analyses strongly suggest that vaccines have no influence on the risk of atopic disease in children and adults.     

Sclérites et épisclérites : prise en charge diagnostique et thérapeutique

Episcleritis and scleritis are distinct entities with regard to visual prognosis, risk of associated systemic disease, and treatment. The pertinence of the clinical classification of episcleritis and scleritis established in 1976 still persists, with significant differences in terms of visual prognosis, associated general conditions, and therapeutic choices according to each scleritis subtype. Episcleritis requires rarely to be referred to a tertiary care centre, and if so it has to be monitored similarly to scleritis. In this paper, an analysis of 1358 scleritis cases from the main distinct large series published since 1976 shows a mean proportion of 8% of infectious aetiologies (mainly herpes viruses), and 28% of systemic diseases with two main subgroups: inflammatory rheumatisms 12.8%, and systemic vasculitis 7.8%. Overall, the risk for visual loss following scleritis is around 16%. However, the risks of associated systemic disease and visual loss are both highly variable according to the type of scleritis, and culminate at 80% and 50% in the necrotizing subtype respectively. As compared with older series, the proportion of necrotizing scleritis is lower in recent series which is likely due to the advances obtained over the past 20 years in immunomodulatory therapy, as well as its wide use in the treatment of the main systemic conditions associated with scleritis. The treatment of scleritis should be managed by physicians who are experts in the use of immunosuppressive drugs that may be required in one out of two affected patients.     

Aspects cliniques des allergies cutanées graves (toxidermies exclues)

Some skin diseases require emergency medical intervention when they are life-threatening or when the eruption is spectacular and brutal and the patient has an elevated temperature. We will discuss the clinical presentations of these conditions, excluding cutaneous drugs eruptions. Patients with severe atopic dermatitis may require brief hospitalisation if their eczema is generalized, refractory to classical therapy, or there are infectious complications, as in the Kaposi-Juliusberg syndrome when the condition is associated with a secondary herpetic infection. Acute urticaria and angioedema are frequent causes of emergency room-visits. They can be the result of drug allergy, food allergy, allergy to stinging insects or contact urticaria. However, the cause is not always identified, even after a complete allergy work-up. Some cases of contact eczema are spectacular, in particular when the face is severely oedematous. Paraphenylenediamine, topical corticosteroids and topical non-steroidal anti-inflammatory drugs are often the cause of severe delayed-type hypersensitivity reactions.     

Maladies auto-immunes et cancers. Première partie : cancers au cours des maladies auto-immunes et de leur traitement

The link between systemic disease and cancer is not fortuitous. An autoimmune disease can represent the starter for developing a non-Hodgkin lymphoma. This is particularly true for Sjögren's syndrome that is associated with the highest risk of lymphoma (odds ratio up to 44). Other systemic autoimmune diseases concerned are systemic lupus with an odds ratio of 4.5 and rheumatoid arthritis with an odds ratio of 2 to 3. It is now well established that high inflammatory activity, rather than immunosuppressive treatment, is the major risk determinant. The association between solid cancer and autoimmune systemic disease is uncommon and concerns in particular scleroderma and lung cancer. Concerning biotherapy-induced cancers, there is no demonstrated increased risk with anti-TNFα (except for cutaneous carcinoma and maybe melanoma) or with tocilizumab and abatacept even if studies with longer follow-up are needed at least for these two last drugs.     

Controverse : les tests de provocation médicamenteux assurent toujours le diagnostic d’allergie médicamenteuse

The diagnosis of drug allergy is important because most suspected cases are not confirmed. Diagnosis is based on immediate or delayed skin test reactions, done in the absence of contraindications. In vitro laboratory tests have not yet replaced skin testing. Skin tests are not without risk, which accentuates the very important place of the clinical history, and also the need for precaution in skin testing, but in the large majority of cases they are the only means of confirming or rejecting the diagnosis of drug allergy.     

Quoi de neuf en allergologie pédiatrique en 2005 ? Partie 1 : épidémiologie,diagnostic précoce et prévention (une revue de la littérature internationale d'octobre 2004 à octobre 2005)

The most important notions published in 2004–2005 concern a positive relationship between the risk of in utero sensitization and allergen levels in maternal blood, a neonatal deficiency of immune responses to microbial components in atopy-prone children, varying patterns of sensitization to aeroallergens, with frequent remittance of early sensitizations to seasonal allergens, in contrast with persistence of sensitizations to perennial allergens, an increased risk of sensitization to aeroallergens in children exposed to long-term background ambient air pollutants, an increased risk of polysensitization in siblings of polysensitized children, and a low efficacy of rigorous dietary egg exclusion during gestation and breastfeeding. The relations between the risk of childhood atopy and maternal parity, neonatal and perinatal conditions, vaccinations and infectious diseases in infancy, and early exposure to pets remain controversial. The predictive value of biological tests in newborns (total serum IgE determination and eosinophil count) is still disputed. Finally, several studies confirm the end of the allergy « epidemics » in Europe, although the prevalence of childhood allergic diseases is still increasing in Eastern European countries.     

Jusqu’où explorer une hyperéosinophilie associée à des manifestations pulmonaires ?

An eosinophilic inflammatory response is associated with various lung diseases. Progress in the pathophysiology of certain diseases with hypereosinophilia, called idiopathic, has led to their being clarified, for example, the so-called idiopathic hypereosinophilic syndromes. In children, after eliminating parasitic infection, the diagnosis is guided by the patient's clinical status (association with asthma, changes in the general state of health, extrarespiratory symptoms, drugs). Bronchoscopy with broncho-alveoalar lavage and biopsy that show alveolar and parenchymal eosinophilia and a thoracic CT can narrow the diagnosis and determine the subsequent laboratory studies to be done. Whatever the cause, prolonged hypereosinophilia carries with it a risk of systemic pathology, especially cardiac, especially if the eosinophils are activated.     

Anaphylactic reaction to drugs commonly used for gastrointestinal system diseases: 3 case reports and review of the literature.

Proton pump inhibitors and H2 receptor antagonists, which are commonly used to treat peptic ulcer and gastroesophageal reflux diseases, are associated with a low incidence of adverse reactions. We report 3 cases of anaphylactic reactions induced by lansoprazole or ranitidine diagnosed in a population of 8304 first-referral patients over a 13-year period. Cutaneous sensitivity to famotidine, ranitidine, omeprazole, pantoprazole, and lansoprazole was evaluated by skin prick tests with a concentration of 10 mg/mL (at 1:1000, 1:100, 1:10 and 1:1 dilutions), and if they were negative, intradermal skin tests were performed with the same dilutions of the extracts. Single-blind, placebo-controlled oral provocation tests were performed with lansoprazole, omeprazole, famotidine, and ranitidine in 2 cases. One case involved anaphylaxis during an oral provocation test with lansoprazole, and 2 cases were anaphylactic reactions to ranitidine. In both cases the skin test was positive for ranitidine and in 1 case an oral provocation test was also positive. The second patient refused that test. Cross reactivity to other H2 receptor antagonists was not demonstrated and a safe alternative drug was found for all 3 patients. Although incidences of anaphylactic reactions induced by proton pump inhibitors or H2 reactions are rare, they can be life threatening.     

Allergie aux corticostéroïdes

Corticosteroids are widely used for their anti-inflammatory and immunosuppressive properties in the treatment of respiratory, allergic and autoimmune diseases. Their adverse effects are well known, but allergic reactions to these drugs are relatively rare although they are sometimes severe. While the route of administration was different in the two cases reported here - one oral, the other by inhalation - the adverse reactions began soon after administration and presented the same symptoms, namely, cough, dyspnea and wheezing. Skin tests and/or provocation tests are essential to confirm the diagnosis. They require tests with different groups of molecules. For our young asthmatic patient, the results were positive for only one group of corticosteroids, which allowed us to prescribe an alternative treatment.     

Manifestations systémiques et auto-immunes des syndromes myélodysplasiques

Myelodysplastic syndromes (MDS) can be associated with systemic or autoimmune diseases. Vasculitides (leucocytoclastic, periarteritis nodosa, micropolyangeitis, Wegener's granulomatosis), relapsing polychondritis, and Sweet's syndrome are the most commonly reported. Refractory anemia with excess of blasts (RAEB), transformed RAEB evolving to an acute leukemia, and chronic myelomonocytic leukemia (CMML) are preferentially associated with these vasculitides or systemic diseases. Corticosteroids are generally effective. Immunosuppressive drugs expose these patients to infectious complications and increase the risk of transformation into acute leukemia. Occurrence of relapsing polychondritis in a patient older than 60 years is associated with a myelodysplastic syndrome in 40% of the cases. Sweet's syndrome is associated in 10% of the cases with acute myeloid leukemia and MDS. Polyarthritis or oligoarthritis with systemic manifestations that include fever, skin rash, and more rarely serositis or haemolytic anemia can occur contemporarily to a MDS. Behçet's disease with intestinal involvement has been reported in patients presenting with trisomy 8 associated MDS. Pathogenic mechanisms underlying the association between MDS and autoimmune or systemic disorders remain to be elucidated.