Low end-tidal CO2 as a real-time severity marker of intra-anaesthetic acute hypersensitivity reactions.

BACKGROUND: Prompt diagnosis of intra-anaesthetic acute hypersensitivity reactions (AHR) is challenging because of the possible absence and/or difficulty in detecting the usual clinical signs and because of the higher prevalence of alternative diagnoses. Delayed epinephrine administration during AHR, because of incorrect/delayed diagnosis, can be associated with poor prognosis. Low end-tidal CO2 (etCO2) is known to be linked to low cardiac output. Yet, its clinical utility during suspected intra-anaesthetic AHR is not well documented. METHODS: Clinical data from the 86 patients of the Neutrophil Activation in Systemic Anaphylaxis (NASA) multicentre study were analysed. Consenting patients with clinical signs consistent with intra-anaesthetic AHR to a neuromuscular blocking agent were included. Severe AHR was defined as a Grade 3-4 of the Ring and Messmer classification. Causes of AHR were explored following recommended guidelines. RESULTS: Among the 86 patients, 50% had severe AHR and 69% had a confirmed/suspected IgE-mediated event. Occurrence and minimum values of arterial hypotension, hypocapnia and hypoxaemia increased significantly with the severity of AHR. Low etCO2 was the only factor able to distinguish mild [median 3.5 (3.2;3.9) kPa] from severe AHR [median 2.4 (1.6;3.0) kPa], without overlap in inter-quartile range values, with an area under the receiver operator characteristic curve of 0.92 [95% confidence interval: 0.79-1.00]. Among the 41% of patients who received epinephrine, only half received it as first-line therapy despite international guidelines. CONCLUSIONS: An etCO2 value below 2.6 kPa (20 mm Hg) could be useful for prompt diagnosis of severe intra-anaesthetic AHR, and could facilitate early treatment with titrated doses of epinephrine. CLINICAL TRIAL REGISTRATION: NCT01637220.

A multicentre study to determine the value and safety of drug patch tests for the three main classes of severe cutaneous adverse drug reactions.

BACKGROUND: Drug patch tests (PTs) can reproduce delayed hypersensitivity to drugs and entail a moderate re-exposure of patients to offending drugs. OBJECTIVES: To determine the value of PTs for identifying the responsible drug in severe cutaneous adverse drug reactions (SCARs) such as acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS) and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). METHODS: In a multicentre study, PTs were conducted on patients referred for DRESS, AGEP or SJS/TEN within 1 year of their SCAR. All drugs administered in the 2 months prior to and the week following the onset of the SCAR were tested. RESULTS: Among the 134 patients included (48 male, 86 female; mean age 51·7 years), positive drug PTs were obtained for 24 different drugs. These included positive tests for 64% (46/72) of patients with DRESS, 58% (26/45) of those with AGEP and 24% (4/17) of those with SJS/TEN, with only one relapse of AGEP. The value of PTs depended on the type of drug and the type of SCAR (e.g. carbamazepine was positive in 11/13 DRESS cases but none of the five SJS/TEN cases). PTs were frequently positive for beta lactams (22 cases), pristinamycin (11 cases) and in DRESS with pump proton inhibitors (five cases), but were usually negative for allopurinol and salazopyrin. Of 18 patients with DRESS, eight had virus reactivation and positive PTs. In DRESS, multiple drug reactivity was frequent (18% of cases), with patients remaining sensitized many years later. CONCLUSIONS: PTs are useful and safe for identifying agents inducing SCAR.

[Management of drug reaction with eosinophilia and systemic symptoms (DRESS)]. / Prise en charge du drug reaction with eosinophilia and systemic symptoms (DRESS).

OBJECTIVE: The management of drug-induced hypersensitivity syndrome or drug reaction with eosinophilia and systemic symptoms (DRESS) is not codified. Demonstration of the reactivation of Herpesviruses illustrates the specific pathophysiology of this syndrome. Proposals for the management of DRESS were elaborated by the cutaneous adverse drug reaction working group of the French Society of Dermatology to help with its management. METHODS: From a review of literature and the experience of the members of this group, consensual proposals were written about diagnostic criteria, tests, treatment options, and follow-up. These proposals will need to be validated in prospective studies. RESULTS: A decisional tree of treatment options is proposed, based on the severity of visceral manifestations. The importance of a rapid withdrawal of the culprit drug and of a long-term follow-up is underlined. Treatment will be adapted to the clinicobiological status (topical corticosteroid, systemic corticosteroid, intravenous gammaglobulins, antivirals).

[Treatment of chronic urticaria resistant to H1 antihistamines]. / Traitements de l'urticaire chronique résistant aux antihistaminiques H1.

Urticaria is a syndrome. Several signalisation factors (cytokines and chemokines) are implicated in activation of mast cells receptors. Immunologic or non immunologic mechanisms elicit mediator releases and inflammatory activities inducing urticaria lesions. In chronic urticaria the removal of an hypothetical cause is not possible, and the therapeutic management is first oriented towards palliation of symptoms. H1 antagonists are the treatment of choice. Higher dosage than those recommended may be necessary. But severely affected patients are not enough improved. Triggering factors should be avoided. Addition of other mediator antagonists such as leukotriene receptor antagonists have improved some patients and need further evaluation. Several alternative pathogenic therapies have been proposed with conflicting results. Tolerance induction may be tried in a few cases of severe physical urticaria. Oral steroids are reserved if possible for systemic urticaria and in short course for severe exacerbation. Immunosuppressive agents are only appropriate for patients with refractory urticaria to classical treatment. Oral cyclosporine has been used with encouraging results. Its has a suspensive effect but relapses can be treated by H1 antagonists. Whichever the drug or association of drug individual variations in the course of the disease need periodic reevaluation. A spontaneous unexplained remission is not an exception. In this heterogeneous disease an individual approach is required, leading to reduction of symptoms with the least invasive therapy, carefully balancing risk and benefits.

[Treatment of chronic urticaria with astemizole: a multicenter pediatric study]. / Traitement de l'urticaire chronique par l'astémizole: étude multicentrique pédiatrique.

An open multicentric pediatric clinical trial has been performed to evaluate the safety and efficacy of astemizole (HISMANAL suspension) at a 1 ml (2 mg) dosage per 10 kg body weight once daily in children with chronic urticaria. A good and very good effect has been observed in 63.2% of the children at day 7, in 79.2% after 2 weeks and in 88.9% at the end of the treatment (4 weeks). A marked improvement of the symptoms was reported in 63.8% of children at day 7. There was no decrease of efficacy at the end of the treatment. Tolerance was good in 87.% of the cases. Astemizole seems to be a useful treatment for chronic urticaria in pediatrics.

[Seasonal changes in specific IgE: the acarid Dermatophagoides pteronyssinus]. / Variations saisonnières des IgE spécifiques: acariens Dermatophagoïdes pteronyssinus (D.P.).

The authors have studied monthly the titres of specific IgE to Dermatophagoides pteronyssinus, by Phadebas RAST, in 8435 measurements, spread over 4 years. Significant seasonal and monthly variations were seen every year with a maximum level in the autumn or the beginning of winter, with a second peak at the end of winter in 3 years of the 4. There was no close superposition of pattern form one year to another. The domestic relative humidity had a significant effect on the seasonal variation with a mean shift of 2 months that could be explained by the length of the biological cycle of the mites. These data compare with those of the literature (sampling of mites in bedding, longitudinal studies...).

[Anaphylactic shock from succinylcholine, complicated by a rhabdomyolysis]. / Choc anaphylactique dû à la succinylcholine compliqué de rhabdomyolyse.

A young woman, with a contact dermatitis to nickel, experienced a life threatening anaphylaxis after induction of general anaesthesia for an emergency curettage. Hypersensitivity reaction involving IgE antibodies against succinylcholine was proven by positive skin test and radioimmunoassay detection of antibodies against succinylcholine and quaternary ammonium. After restoration of haemodynamics in a few hours, the patient had rhabdomyolysis predominant at lower left leg, which required a fasciotomy. An haemodialysis session was necessary, renal function being normalized thereafter. Several months later, the patient suffers from dysesthesia on the leg and foot. Muscular ischaemia was the consequence of the shock, the external compression due to the compression stockings probably being an additional factor.

Rush venom immunotherapy: a 3-day programme for hymenoptera sting allergy.

In a series of 102 patients consulting for allergic reactions following hymenoptera sting, fifty-two of them, who had experienced one or more severe systemic adverse reactions were selected for rush immunotherapy. The method employed made it possible to attain the maintenance dose of 100 micrograms of venom in 3 days. Patient tolerance was excellent, no serious side-effect was observed; immunotherapy never had to be stopped. Clinical effectiveness seems to be very satisfactory, since no abnormal reaction was reported in seven patients who later were spontaneously stung, and in fourteen patients who received an induced insect sting. The level of IgG antivenom antibodies rose regularly from the first month onwards to remain at a stable level. Because of its safety and effectiveness, it appears that this method should be recommended for immunotherapy in patients who are allergic to hymenoptera stings.

[Preventive treatment of severe allergic complications caused by Hymenoptera venom. Our experience apropos of 250 cases]. / Traitement préventif des accidents allergiques graves au venin d'hyménoptères. Notre expérience à propos de 250 cas.

Out of a total of 350 referrals for allergy to hymenoptera venom over four years, 250 patients who had one or more severe systemic reactions were selected for a "rush course" of immunotherapy after confirmation of the responsible reagin (skin tests, specific IgE). The method used in the 245 patients who accepted the protocol enabled us to arrive at a maintenance dose of 100 micrograms of venom in three days. Tolerance was excellent; no serious side effects were observed; the course of immunotherapy did not have to be stopped in any of the patients. Clinical efficacy appeared to be satisfactory as no systemic reaction occurred in a fifth (50) of the patients treated who were bitten again, either spontaneously (24 cases), sometimes successfully and repeatedly (11 cases), or intentionally (26 cases). The IgG antivenom antibody was constantly raised from the first month and remained at a stable value. This harmless and effective method should be offered to patients allergic to hymenoptera venom.

Lymphocyte proliferative responses to the purified Dermatophagoides farinae major allergen in untreated and hyposensitized atopic patients.

We investigated the proliferative response of lymphocytes from mite-sensitive patients (RAST D.far greater than 3.5 PRU/ml) in the presence of the major allergen Der.f.I purified from Dermatophagoides farinae. Comparative studies were carried out with peripheral blood mononuclear cells from non-atopic donors (RAST = 0), and from patients undergoing hyposensitization treatment (5 to 24 months). According to Student's t-test, there was no significant difference in the Der.f.I-induced proliferation of peripheral blood mononuclear cells from normal donors, untreated atopic patients and hyposensitized patients. In conclusion, it was impossible to discriminate between normal donors, atopic patients and hyposensitized patients with regard to their circulating lymphocyte responses to the purified major allergen Der.f.I.

[Gonococcal endocarditis. A new case]. / Endocardite à gonocoque. Un nouveau cas.

The authors report the case of a 35 year old female hospitalised for gonococcal endocarditis with mitral valve vegetations infecting pre-existing asymptomatic rheumatic mitral incompetence. Apyrexia was rapidly obtained with antibiotic therapy; the valvulopathy was well tolerated from the hemodynamic viewpoint; the echocardiographic appearances of the vegetations were stable. However, the patient died during the third week of a cerebral haemorrhage, probably due to rupture of a mycotic arterial aneurysm. The authors suggest that the difficulties encountered in the fight against sexually transmitted diseases may result in a recrudescence of this type of disseminated gonococcal infection.

Comparison of conidial and mycelial allergens of Alternaria alternata.

Alternaria allergens, separated by SDS polyacrylamide gel electrophoresis and transferred onto a nitrocellulose membrane, were identified using sera from Alternaria-allergic patients. 30 Alternaria components of spore and mycelium, ranging in molecular weight from more than 150 to 12 kD, bound IgE antibodies. 15 were detected by more than 25% of the sera and only 4 (85, 56, 42, 31 kD) by more than 50% of the sera. Among these four major allergens, the 56-kD component was present mostly in the spore extract, the 85- and 42-kD fractions in the mycelium extract and the 31-kD in both extracts. The 31-kD component showed the highest IgE binding and the highest frequency of binding (95% with mycelium extract and 79% with spore extract). It was composed of two subunits.

Human auto-anti-idiotypic antibodies to mite-specific IgE can degranulate human basophils in vitro.

BACKGROUND: Anti-idiotypic antibodies (anti-Ids) to specific IgE antibodies are formed spontaneously during an anti-allergen immune response and can be induced by immunotherapy. Although anti-Ids can down-regulate the production of IgE antibodies, at least in experimental models, their possible role in the modulation of target cell reactivity remains ill-defined. OBJECTIVE: The capacity of human anti-Ids to modulate the release of histamine was examined in an in vitro system of human basophil degranulation. Anti-Ids were prepared from the serum of six Dermatophagoides pteronyssinus (Dp)-hypersensitive patients suffering from atopic dermatitis and who had never been desensitized. Basophils were obtained from the blood of atopic donors. The extent of histamine release was determined using a fluorometric assay. RESULTS: We show that: anti-Ids trigger the release of histamine in an allergen-specific, dose- and IgE-dependent manner; the release is not due to the presence of allergen and/or anti-IgE antibodies; and that the degranulating activity can be removed by absorption with affinity-purified anti-Dp antibodies of the corresponding patient. CONCLUSION: These results indicate that spontaneously produced human anti-Ids can modulate the reactivity of human basophils.

Exercise-induced anaphylaxis: useful screening of food sensitization.

BACKGROUND AND OBJECTIVES: Exercise-induced anaphylaxis is a well-defined entity as described by Sheffer and Austen. Exercise-induced anaphylaxis can be associated with ingestion of a specific food. We report our experience with a series of cases of exercise-induced anaphylaxis in which anaphylaxis was considered to be associated with food allergy. METHODS: We observed 19 patients in whom severe systemic signs of anaphylaxis occurred during or immediately after exercise, while the severity of reactions excluded challenge testing. The causal relationship with various foods was systematically investigated in all cases, even in the absence of any history of allergy. RESULTS: Sensitization to wheat flour was demonstrated in 12 patients, to peanut in seven, and to tree nuts in six cases with skin tests and/or RAST. Sensitivity to various other foods was found less often. Further, avoidance of specific foods according to results of skin tests and RAST was systematically observed during the five hours prior to exercise and no symptom occurred, suggesting a role of specific food intake in the pathogenesis of exercise-induced anaphylaxis. With such elimination diets, most of these young patients were able to engage in regular vigorous exercises (more than twice a week in some cases) without any clinical manifestation with a median followup of 2 years. In two patients, however, recurrence of exercise-induced anaphylaxis was subsequently explained by concomitant ingestion of other foods such as rice and peanut. Additional avoidance of these foods before exercise was then effective in 14 cases (median follow up: 2 years). CONCLUSIONS: Investigations to detect food sensitization, in particular to wheat, peanut and/or tree nuts, and specific avoidance of these foods five hours before exercise appear essential in cases of exercise-induced anaphylaxis.

Il-4 and IFN-gamma mRNA induction in human peripheral lymphocytes specific for beta-lactam antibiotics in immediate or delayed hypersensitivity reactions.

Beta-lactam antibiotics elicit CD4+ and CD8+ T-cell-mediated immune responses that play a central role in allergic reactions. However, the involvement of a type 1- (Th1 or Tc1) or a type 2-like (Th2 or Tc2) differentiation in drug allergy remains unclear. We investigated the expression of interleukin 4 (IL-4) and interferon gamma (IFN-gamma) mRNA by quantitative reverse transcription and polymerase chain reaction (RT-PCR) in patient-derived peripheral blood lymphocytes following specific in vitro stimulation. Samples were collected from a total of 19 patients who had developed immediate or delayed clinical manifestations of hypersensitivity to beta-lactam and from 11 control subjects. Peripheral blood mononuclear cells (PBMCs) were stimulated with either free antibiotics or antibiotic-human serum albumin (HSA) conjugates. Specific induction of IFN-gamma mRNA expression was observed in 11 of 11 allergic patients with immediate reactions, in 6 of 8 patients with delayed reactions, and in 4 of 11 control subjects. IL-4 mRNA expression was induced in 5 of 11 allergic individuals with immediate reactions but in none of the 8 patients with delayed responses and none of the 11 control subjects. IL-4 mRNA expression was only induced following activation with free drugs, while IFN-gamma mRNA expression was predominantly induced in CD4+ T cells following stimulation with HSA-conjugated drugs. Immediate-type hypersensitivity to beta-lactams was not associated with a pure type 2-like response when PBMCs were specifically stimulated in vitro: Some patients with well-documented history of beta-lactam-induced immediate allergic reaction showed a high IFN-gamma response. Contact dermatitis involved Tc1 and Th1 cells and other delayed hypersensitivity reactions to beta-lactams were restricted to Th1 responses.

Mechanisms of drug-induced allergic contact dermatitis.

Allergic contact dermatitis is induced by a wide variety of drugs that trigger specific immune responses following topical exposure. Identified chemical structures involved in such reactions include the mercuric and thiosalicylic acid groups of thimerosal, the diphenylketone group of the anti-inflammatory drug ketoprofen, the amide or ester structure of local anesthetics, and the side-chain and thiazolidine ring of beta-lactams. The T cell responses to such compounds involve CD4+ and CD8+ alphabeta+ T lymphocytes and also CD4 /CD8 gammadelta+ T cells. Although "T helper 2" cytokine production by drug-specific human T cells from patients with allergic contact dermatitis has been described, T helper 1-like and T cytotoxic 1-like responses clearly play key roles in this cutaneous reaction.