Dendritic cells inclusion and cell-subset assessment improve flow-cytometry-based proliferation test in non-immediate drug hypersensitivity reactions.

BACKGROUND: Lymphocyte transformation test (LTT) has been widely used to evaluate non-immediate drug hypersensitivity reactions (NIDHRs). However, the lack of standardization and the low sensitivity have limited its routine diagnostic use. The drug presentation by dendritic cells (DCs) and the assessment of proliferation on effector cells have shown promising results. Flow-cytometry-based methods can help apply these improvements. We aimed to assess the added value of using drug-primed-DCs and the determination of the proliferative response of different lymphocyte subpopulations in NIDHRs. METHODS: Patients with confirmed NIDHR were evaluated by both conventional (C-LTT) and with drug-primed-DCs LTT (dDC-LTT)analysing the proliferative response in T cells and other effector cell subpopulations by using the fluorescent molecule, carboxyfluorescein diacetate succinimidyl ester (CFSE). RESULTS: The C-LTT showed a significantly lower sensitivity (29.4%) compared with dDC-LTT (61.8%), which was confirmed analysing each particular clinical entity: SJS-TEN (62.5% vs 87.5%), MPE (15% vs 47.4%) and AGEP (33% vs 80%). When including the effector cell subpopulations involved in each clinical entity, CD3+ +CD4+ Th 1 or CD3+ +NK cells in SJS-TEN, CD3+ +CD4+ Th 1+NK cells in MPE and CD3+ +NK cells in AGEP, we could significantly increase the sensitivity of the in vitro test to 100%, 68.4% and 100%, respectively, with an overall sensitivity of 87% and 85% of specificity in NIDHR. CONCLUSIONS: The use of a flow-cytometry-based test, DCs as drug presenting cells, and focusing on effector cell subpopulations for each clinical entity significantly improved the drug-specific proliferative response in NIDHRs with a unique cellular in vitro test.

Advances and novel developments in drug hypersensitivity diagnosis.

A correct diagnosis of drug hypersensitivity reactions (DHRs) is very important for both the patient and health system. However, DHRs diagnosis is complex, time consuming, requires trained personnel, is not standardized for many drugs, involves procedures not exempt of risk, and in most cases lacks standardized in vivo and in vitro tests. Thus, there is an urgent need for improving the different approaches to diagnose patients with suspected DHRs. In this review, we have analyzed the advances performed in immediate and nonimmediate DHRs diagnosis during the last two years and obtained several conclusions: the significant heterogeneity in current practice among centers illustrates the need to re-evaluate, update, and standardize in vivo tests and protocols for the diagnosis and management of patients with suspected drug allergy. Regarding in vitro tests, the latest studies have focused on increasing their sensitivity or on establishing the sensitivity and specificity for the tests performed with new drugs. There seems to be a consensus about combining in vivo and in vitro tests as the best way to increase the diagnostic accuracy.

Combined endoscopic and laparoscopic surgery for the treatment of complex benign colonic polyps (CELS): Observational study.

PURPOSE: Combined endoscopic and laparoscopic surgery (CELS) has emerged as a promising method for managing complex benign lesions that would otherwise require major colonic resection. The aim of this study was to describe the different techniques and to evaluate the safety of CELS, assess its outcomes in a technique that is scarcely widespread in our environment. METHOD: Observational retrospective study, short-term outcomes of patients undergoing CELS for benign colon polyps from October 2018 to June 2020 were evaluated. Postoperative outcomes, length of hospital stay and pathological findings were evaluated. RESULTS: Seventeen consecutive patients underwent CELS during the study period. The median size of the lesion was 3.5 cm (range 2.5-6.5 cm), the most frequent location was the cecum (10 from 17). Most patients treated with CELS underwent an endoscopic-assisted laparoscopic wedge resection (11 from 17). In four patients this resection was combined with another CELS technique, and two patients underwent an endoscopic-assisted laparoscopic segment resection. The success rate of CELS in our series was in 14 from 17 (82.4%). The median operative time was 85 min (range 50-225 min). The median hospital stay was 2 days (range 1-15 days). One patient experienced an organ/space surgical site infection which did not require further intervention. Four lesions were shown to be malignant by postoperative pathology study. CONCLUSION: CELS is a safe and multidisciplinar technique that requires collaboration between gastroenterologists and surgeons. It can be considered as an alternative to colonic resection for complex benign colonic polyps.

Combined endoscopic and laparoscopic surgery for the treatment of complex benign colonic polyps (CELS): observational study. / Cirugía endoscópica y laparoscópica combinada para el tratamiento de pólipos de colon benignos complejos (CELS): estudio observacional.

PURPOSE: Combined endoscopic and laparoscopic surgery (CELS) has emerged as a promising method for managing complex benign lesions that would otherwise require major colonic resection. The aim of this study was to describe the different techniques and to evaluate the safety of CELS, assess its outcomes in a technique that is scarcely widespread in our environment. METHOD: Observational retrospective study, short-term outcomes of patients undergoing CELS for benign colon polyps from October 2018 to June 2020 were evaluated. Postoperative outcomes, length of hospital stay and pathological findings were evaluated. RESULTS: Seventeen consecutive patients underwent CELS during the study period. The median size of the lesion was 3.5 cm (range 2.5 - 6.5 cm), the most frequent location was the cecum (10 from 17). Most patients treated with CELS underwent an endoscopic-assisted laparoscopic wedge resection (11 from 17). In four patients this resection was combined with another CELS technique, and two patients underwent an endoscopic-assisted laparoscopic segment resection. The success rate of CELS in our series was in 14 from 17 (82,4%). The median operative time was 85 min (range 50-225 min). The median hospital stay was 2 days (range 1-15 days). One patient experienced an organ/space surgical site infection which did not require further intervention. Four lesions were shown to be malignant by postoperative pathology study. CONCLUSION: CELS is a safe and multidisciplinar technique that requires collaboration between gastroenterologists and surgeons. It can be considered as an alternative to colonic resection for complex benign colonic polyps.

Penicillin and cephalosporin cross-reactivity: role of side chain and synthetic cefadroxil epitopes.

BACKGROUND: Analysis of cross-reactivity is necessary for prescribing safe cephalosporins for penicillin allergic patients. Amoxicillin (AX) is the betalactam most often involved in immediate hypersensitivity reactions (IHRs), and cefadroxil (CX) the most likely cephalosporin to cross-react with AX, since they share the same R1 side chain, unlike cefuroxime (CO), with a structurally different R1. We aimed to analyse cross-reactivity with CX and CO in patients with confirmed IHRs to AX, including sIgE recognition to AX, CX, CO, and novel synthetic determinants of CX. METHODS: Fifty-four patients with confirmed IHRs to AX based on skin test (ST) and/or drug provocation test (DPT) were included. Serum sIgE to AX and benzylpenicillin was determined by Radioallergosorbent test (RAST). Two potential determinants of CX, involving intact or modified R1 structure, with open betalactam ring, were synthesised and sIgE evaluated by RAST inhibition assay. RESULTS: Tolerance to CX (Group A) was observed in 64.8% cases and cross-reactivity in 35.2% cases (Group B). Cross-reactivity with CO was only found in 1.8% cases from Group B. ST to CX showed a negative predictive value of 94.6%. RAST inhibition assays showed higher recognition to CX as well as to both synthetic determinants (66% of positive cases) in Group B. CONCLUSIONS: Cross-reactivity with CX in AX allergic patients is 35%, being ST not enough for prediction. R1, although critical for recognition, is not the unique factor. The synthetic determinants of CX, 1-(HOPhG-Ser-Bu) and 2-(pyrazinone) are promising tools for determining in vitro cross-reactivity to CX in AX allergic patients.

Clinical Characterization and Diagnostic Approaches for Patients Reporting Hypersensitivity Reactions to Quinolones.

BACKGROUND: Quinolones are the second most frequent cause of hypersensitivity reactions (HSRs) to antibiotics. A marked increase in the number of patients with HSRs to quinolones has been detected. OBJECTIVE: To describe the clinical characteristics of patients with HSRs to quinolones and present methods for their diagnosis. METHODS: Patients attending the allergy unit due to reactions suggestive of HSRs to quinolones were prospectively evaluated between 2005 and 2018. Diagnosis was achieved using clinical history, skin tests (STs), basophil activation tests (BATs), and drug provocation tests (DPTs) if ST and BAT results were negative. RESULTS: We included 128 subjects confirmed as having HSRs to quinolones and 42 found to be tolerant. Anaphylaxis was the most frequent entity in immediate HSRs and was most commonly induced by moxifloxacin. Patients were evaluated a median of 150 days (interquartile range, 60-365 days) after the reaction. Of patients who underwent ST and BAT, 40.7% and 70%, respectively, were positive. DPT with a quinolone was performed in 48 cases, giving results depending on the culprit drug: when moxifloxacin was involved, 62.5% of patients gave a positive DPT result to ciprofloxacin, whereas none reacted to levofloxacin. The risk of HSR was 96 times higher in subjects who reported moxifloxacin-induced anaphylaxis and 18 times higher in those reporting immediate reactions compared with clinical entities induced by quinolones other than moxifloxacin and nonimmediate reactions. CONCLUSIONS: The diagnosis of HSR to quinolones is complex. The use of clinical history is essential as a first step. BAT shows higher sensitivity than STs. DPTs can be useful for finding safe alternative quinolones.

Is obesity a factor of surgical difficulty in transanal endoscopic surgery?

BACKGROUND: The aim of this study is to assess the feasibility of transanal endoscopic surgery (TES) in obese patients. METHODS: Observational descriptive study evaluating the feasibility of TES in obese rectal tumors between June 2004 and January 2019. Patients were assigned to two groups: body mass index (BMI) < 30 kg/m2 and BMI ≥30 kg/m2, the latter defined as obese. RESULTS: From 775 patients, 681 were enrolled in the study, 145 (21.3%) of them obese. No statistically significant differences between groups were found with respect to overall morbidity (27, 18.6%).The obese patients presented trends towards shorter mean surgical time (65 min, IQR 48 min), less perforation in the peritoneal cavity (eight, 5.5%), and 133 (91.7%) presented a lower rate of lesion fragmentation. CONCLUSION: There were no significant differences in postoperative outcomes in obese patients (BMI ≥30 kg/m2). TES in those obese patients does not represent a factor of surgical difficulty.

NSAIDs-hypersensitivity often induces a blended reaction pattern involving multiple organs.

Non-steroidal anti-inflammatory drugs (NSAIDs)-induced hypersensitivity reactions are classified by the European Network on Drug Allergy (ENDA) as either cross-reactive or selective. The former is the most frequent type and includes patients with exclusively respiratory symptoms (NSAIDs-exacerbated respiratory disease, NERD) or exclusively cutaneous symptoms: NSAIDs-induced urticaria/angioedema (NIUA); and NSAIDs-exacerbated cutaneous disease (NECD). However, although not reflected in the current classification scheme (ENDA), in clinical practice a combination of both skin and respiratory symptoms or even other organs such as gastrointestinal tract symptoms (mixed or blended reactions) is frequently observed. This entity has not been sufficiently characterised. Our aim was to clinically characterize blended reactions to NSAIDs, comparing their clinical features with NERD and NIUA. We evaluated patients with symptoms suggestive of hypersensitivity to NSAIDs who attended the Allergy Unit of the Regional University Hospital of Malaga (Malaga, Spain) between 2008 and 2015. We included 880 patients confirmed as cross-reactive based on clinical history, positive nasal provocation test with lysine acetylsalicylate (NPT-LASA), and/or positive drug provocation test (DPT) with acetylsalicylic acid (ASA), who were classified as blended (261; 29.6%), NERD (108; 12.3%) or NIUA (511; 58.1%). We compared symptoms, drugs, underlying diseases and diagnostic methods within and between groups. Among blended patients the most common sub-group comprised those developing urticaria/angioedema plus rhinitis/asthma (n = 138), who had a higher percentage of underlying rhinitis (p < 0.0001) and asthma (p < 0.0001) than NIUA patients, showing similarities to NERD. These differences were not found in the sub-group of blended patients who developed such respiratory symptoms as glottis oedema; these were more similar to NIUA. The percentage of positive NPT-LASA was similar for blended (77%) and NERD groups (78.7%). We conclude that blended reactions are hypersensitivity reactions to NSAIDs affecting at least two organs. In addition to classical skin and respiratory involvement, in our population a number of patients also develop gastrointestinal symptoms. Given the high rate of positive responses to NPT-LASA in NERD as well as blended reactions, we suggest that all patients reporting respiratory symptoms, regardless of whether they have other associated symptoms, should be initially evaluated using NPT-LASA, which poses less risk than DPT.

Direct intranasal application of the solid phase of ImmunoCAP® increases nasal specific immunoglobulin E detection in local allergic rhinitis patients.

BACKGROUND: The measurement of nasal specific IgE (NsIgE) in local allergic rhinitis (LAR) patients is challenging and shows variability. The objective of this work was to evaluate a minimally-invasive method of direct detection of NsIgE in patients with LAR to Dermatophagoides pteronyssinus (DP) using an automated immunoassay. METHODS: Fifty patients participated (LAR, n = 14; allergic rhinitis (AR), n = 20; healthy controls [HC], n = 16). Detection of NsIgE was performed by direct application of the solid phase of a commercial DP ImmunoCAP® test 24 hours after DP nasal provocation. RESULTS: There was no difference in the median volume of secretion absorbed by the solid phase of the ImmunoCAP test in the 3 studied groups (p = 0.17). According to receiver operating characteristic (ROC) curve analysis, NsIgE ≥0.1450 was the optimal cutoff point, obtaining in LAR patients 42.86% sensitivity with the highest specificity (100%), and 75% sensitivity and 100% specificity for AR. CONCLUSION: This study demonstrates the detection of NsIgE to DP in LAR by using a simple, commercial device with high specificity.

Use of the Basophil Activation Test May Reduce the Need for Drug Provocation in Amoxicillin-Clavulanic Allergy.

BACKGROUND: Reports of selective reactions to clavulanic acid (CLV) have increased in recent decades because of its increased prescription in combination with amoxicillin (AX) as AX-CLV. Basophil activation test (BAT) is used for diagnosing beta-lactam immediate hypersensitivity and is the only available in vitro assay for diagnosing patients with immediate hypersensitivity to CLV. However, few studies, and with limited numbers of patients have been published. OBJECTIVE: The aim of this study was to establish the sensitivity, specificity, and negativization rates of BAT to AX and CLV. METHODS: We studied 115 patients with immediate allergic reactions after AX-CLV treatment, 57 with selective reactions to AX (group A), 58 with selective reactions to CLV (group B), and 28 tolerant subjects. BAT was performed with AX in group A and with CLV in group B. A 4-year follow-up study was performed in patients with an initial positive BAT result. RESULTS: The overall sensitivity of BAT was 55%, specificity 89%, and positive predictive value (PPV) 96%. For group A, sensitivity was 47%, specificity 93%, and PPV 93%; for group B, sensitivity was 62%, specificity 89%, and PPV 92%. Follow-up study showed a faster negativization rate of BAT for group A, with around 40% of patients becoming negative at 12 months in both groups. CONCLUSIONS: The high PPV of BAT to CLV shows its potential value as a complementary tool to the allergological workup of patients with immediate allergic reactions after AX-CLV treatment. Importantly, the assay should be done within the first 12 months after the reaction to reduce false-negative results.

Adrenergic cardiomyopathy and cardiogenic shock as initial presentation of pheochromocytoma. A case report and review of the literature.

INTRODUCTION: Pheochromocytomas are infrequent tumors arised from the chromaphine cells of the adrenal sympathetic system. The excess of circulating catecholamines may lead to different cardiovascular disorders from silent alterations of the myocardial conduction to different forms of cardiomyopathy. The onset as cardiogenic shock is exceptional. PRESENTATION OF CASE: A 35-year-old male, with a known history of acute myopericarditis of unknown origin which debuted as acute pulmonary edema, was admitted with dyspnea in the context of a new heart failure episode with pulmonary edema. An initial ECG showed segmentary repolarization changes, reversed in subsequent ECGs. The echocardiogram showed severe left ventricular dysfunction and lateral and apical hypokinesia. Subsequent echocardiograms showed partial recovery of alterations and preserved systolic function. A cardiac MRI showed a subepicardial minimum catchment focus and myocardial edema suggestive of adrenergic myocarditis. A solid nodular lesion was found in the left adrenal gland, suggesting a pheochromocytoma. Laparoscopic left adrenalectomy confirmed a 30 mm adrenal tumor without signs of locoregional invasion. The patient had normal catecholamine excretion and heart function a few weeks after surgery. Histopathology confirmed the diagnosis of pheochromocytoma. DISCUSSION AND CONCLUSIONS: Adrenergic cardiomyopathy is a rare entity with a variable clinical presentation. The onset as cardiogenic shock is exceptional. The differential diagnosis of a patient with cardiogenic shock of unknown origin should consider the presence of an underlying pheocromocytoma as well as other states of adrenergic hyperstimulation. The reversibility of the myocardial affection in pheocromocytoma-associated myocardiopathy is common after the tumor resection.

Epidemiology, Mechanisms, and Diagnosis of Drug-Induced Anaphylaxis.

Anaphylaxis is an acute, life-threatening, multisystem syndrome resulting from the sudden release of mediators by mast cells and basophils. Although anaphylaxis is often under-communicated and thus underestimated, its incidence appears to have risen over recent decades. Drugs are among the most common triggers in adults, being analgesics and antibiotics the most common causal agents. Anaphylaxis can be caused by immunologic or non-immunologic mechanisms. Immunologic anaphylaxis can be mediated by IgE-dependent or -independent pathways. The former involves activation of Th2 cells and the cross-linking of two or more specific IgE (sIgE) antibodies on the surface of mast cells or basophils. The IgE-independent mechanism can be mediated by IgG, involving the release of platelet-activating factor, and/or complement activation. Non-immunological anaphylaxis can occur through the direct stimulation of mast cell degranulation by some drugs, inducing histamine release and leading to anaphylactic symptoms. Work-up of a suspected drug-induced anaphylaxis should include clinical history; however, this can be unreliable, and skin tests should also be used if available and validated. Drug provocation testing is not recommended due to the risk of inducing a harmful reaction. In vitro testing can help to confirm anaphylaxis by analyzing the release of mediators such as tryptase or histamine by mast cells. When immunologic mechanisms are suspected, serum-sIgE quantification or the use of the basophil activation test can help confirm the culprit drug. In this review, we will discuss multiple aspects of drug-induced anaphylaxis, including epidemiology, mechanisms, and diagnosis.

Patients Taking Amoxicillin-Clavulanic Can Become Simultaneously Sensitized to Both Drugs.

BACKGROUND: Patients can react to amoxicillin (AX) and clavulanic acid (CLV) taken in combination because of selective reactions to either drug. However, scant information exists concerning patients who react simultaneously to both compounds. OBJECTIVE: To analyze the mechanisms involved in 4 patients who developed allergic reactions to AX-CLV administration (3 with immediate IgE-mediated reaction and 1 with nonimmediate T-cell-mediated reaction) and who responded specifically to both AX and CLV. METHODS: Skin tests with benzylpenicillin (BP), AX, and CLV were done and, if necessary, drug provocation tests with BP/penicillin V, AX, and AX-CLV were carried out. In immediate reactors, serum specific IgE to benzylpenicilloyl and amoxicilloyl was determined by using the CAP-FEIA system (Pharmacia Diagnostics, Uppsala, Sweden), and basophil activation test to BP, AX, CLV, and AX-CLV was done. In nonimmediate reactors, immunohistochemistry of skin biopsy and analysis of dendritic cell maturation and T-cell-specific response to BP, AX, CLV, and AX-CLV at both acute and resolution phases of the reaction were conducted. RESULTS: All patients with immediate reactions (N = 3) had good tolerance to BP and penicillin V. Two cases also had specific IgE to AX and all had a basophil activation test positive to AX, CLV, and AX-CLV. The patient with a nonimmediate reaction exhibited dendritic cell and T-lymphocyte responses specific to both AX and CLV. Finally, the analysis of the cells infiltrating the skin and peripheral blood during the acute phase indicated a TH1 pattern response. CONCLUSIONS: Our study provides evidence that reactions to both AX and CLV can appear in the same patient.

Evolution of diagnostic approaches in betalactam hypersensitivity.

INTRODUCTION: Betalactams are the most widely used drugs against infections and the primary cause of antibiotic hypersensitivity reactions. Reaction patterns for different betalactams have been changing in accordance with consumption trends, and vary among countries. As a consequence, in vivo and in vitro tests have had to change with to keep up with new tendencies. Areas covered: This review is focused on advances in betalactam hypersensitivity diagnosis. Changes in in vivo methods have been limited to the inclusion of new haptens. In contrast, major progress has been achieved for in vitro tests since the 1960s, from the first description of immunoassays, the basophil activation test and the lymphocyte transformation test, to the more sophisticated assays developed in last years. Expert commentary: Issues with diagnosis are related to test sensitivity. In vivo tests show higher sensitivity, however they can be risky, especially in severe and life-threatening reactions. Therefore, we believe that in vitro tests should be the preferred method. Current efforts are under way to enhance their sensitivity. Only multidisciplinary approaches involving immunology, proteomics, nanotechnology and chemistry can help us to fully understand conjugate structures and mechanisms involved in hypersensitivity reactions to betalactams, and consequently lead to advances in in vitro methods.

Hypersensitivity Reactions to Non-Steroidal Anti-Inflammatory Drugs.

Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the leading causes of hypersensitivity reactions to drugs, and they are classified in two groups: those induced by nonspecific immunological mechanisms (non-allergic or cross-intolerance (CI) reactions), or by specific immunological mechanisms (allergic or selective reactions (SR)). The pathogenesis of CI is associated with their pharmacological activity (COX-1 inhibition), with symptoms due to an imbalance in the arachidonic acid pathway, independently of their chemical structure. SRs are mediated by specific IgE- or by a T-cell response and can be induced by a single NSAID or a class of chemically related NSAIDs, with patients tolerating chemically unrelated compounds. NSAIDs hypersensitivity reactions have been classified in five main groups: i) NSAIDs-exacerbated respiratory disease (NERD); ii) NSAIDs-exacerbated cutaneous disease (NECD); iii) NSAIDs-induced urticaria/angioedema (NIUA); iv) Single NSAID-induced urticaria/angioedema or anaphylaxis (SNIUAA); v) Single NSAID-induced delayed reactions (SNIDRs). Although this classification described above is widely accepted by most authors some phenotypes such as blended reactions do not fit. Therefore more research is needed in this topic.

Hypersensitivity reactions to nonsteroidal anti-inflammatory drugs.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the drugs most commonly involved in hypersensitivity drug reactions. Such reactions can be due to the release of inflammatory mediators in the absence of specific immunologic recognition, or immunoglobulin E (IgE)- or T-cell-selective responses. The former include upper and lower airway symptoms in patients with chronic underlying respiratory disease, the exacerbation of chronic spontaneous urticaria, and the induction of cutaneous symptoms. The latter include selective responses to a single NSAID with good tolerance to strong cyclooxygenase-1 inhibitors, with a putative IgE or T-cell mechanism proposed. These reactions can be acute or delayed.