Case Report: Mast cell anergy: absence of symptoms after accidental re-exposure to amoxicillin/clavulanic acid 3 days after anaphylaxis.

Empty mast cell syndrome, also named post anaphylaxis mast cell anergy (PAMA), is a temporary state of loss of mast cell responsiveness after a severe immediate hypersensitivity reaction. In this study, we describe a case of PAMA after accidental re-exposure to amoxicillin in a patient who developed severe anaphylaxis to this drug three days earlier in the operating room. To our knowledge, this report is the second to document this phenomenon.

Comprehensive ophthalmological evaluation in atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD), a chronic Type 2 inflammatory skin disease, is frequently associated with ocular surface diseases (OSD) which may appear or worsen under anti-Type 2-targeted treatments. However, the exact prevalence of OSD and the ophthalmology referral criteria remain ill-defined in AD patients before initiating such biotherapies. OBJECTIVE: We aimed to characterize the prevalence, the nature and the factors related to OSD development in AD that may justify an ophthalmological management. METHODS: A total of 98 consecutive AD inpatients without biological treatment were retrospectively included. These were systematically evaluated by an ophthalmologist during their dermatological care. Clinical and laboratory data were analyzed to characterize OSD and their risk factors. RESULTS: OSD were found in 83/98 AD patients (85%); mainly dry eye syndrome (64%, 63/98), allergic conjunctivitis (42%, 41/98), posterior (33%, 32/98), and anterior blepharitis (27%, 26/98). In AD patients without ocular symptoms, OSD were also frequently found (63%, 12/19) and were mostly mild. Risk factors for OSD were history of allergic rhinitis, allergic sensitization, head and neck AD, ocular symptoms (foreign body sensation in the eye, burning, itching, photophobia), and total IgE level >3000kU/L. CONCLUSION: The prevalence of OSD was high, even in asymptomatic patients. The risk factors identified may indicate the need for ophthalmological examination for therapeutic management, especially when biological agents targeting Type 2 inflammation are considered.

Atopic Dermatitis and Self-Image Design: A Real-Life Study in Children Using Drawings.

Background: Atopic dermatitis (AD) induces alterations of external appearance and self-esteem, with impact on the personal development of the children. However, tools for estimating such suffering are lacking. We aimed to assess how children with AD represent themselves through their drawings. Methods: In this retrospective study, we included children (<18 years) suffering from AD who followed the instruction "draw yourself with and without eczema" at the end of a routine follow-up consultation. Drawings were interpreted with the child and then classified in different analysis groups by 5 independent evaluators. Results: A total of 64 children (41 [64.1%] girls and 23 [35.9%] boys, median [range] age 8 [3-7] years) made 64 drawings. Five groups of drawing were identified: "amputee" (n = 8, 12.5%), "identical" (n = 18, 28.1%), "sad" (n = 19, 29.7%), "complex" (n = 11, 17.2%), and "other" (n = 8, 12.5%). Univariate analysis found that age was differently distributed among the different drawing groups (P = 0.0047), as was the predominance of light colors (P = 0.038). The distribution of the other variables (gender, investigator global assessment score, active AD, and duration of activity) was not different among drawing groups. Conclusions: The drawing allows a majority of the AD children to express their self-image with and without eczema, as well as their feelings and their interactions with the environment and with their entourage. The visual tool proposed herein could be used during consultations, to (a) become aware of the need to treat AD, (b) better evaluate the impact of AD burden in childhood, and (c) adjust appropriately AD treatment.

Efficacy and safety of ligelizumab in adults and adolescents with chronic spontaneous urticaria: results of two phase 3 randomised controlled trials.

BACKGROUND: Many patients with chronic spontaneous urticaria (CSU) do not achieve complete control of their symptoms with current available treatments. In a dose-finding phase 2b study, ligelizumab improved urticaria symptoms in patients with H1-antihistamine (H1-AH) refractory CSU. Here, we report the efficacy and safety outcomes from two ligelizumab phase 3 studies. METHODS: PEARL-1 and PEARL-2 were identically designed randomised, double-blind, active-controlled and placebo-controlled parallel-group studies. Patients aged 12 years or older with moderate-to-severe H1-AH refractory CSU were recruited from 347 sites in 46 countries and randomly allocated in a 3:3:3:1 ratio via Interactive Response Technology to 72 mg ligelizumab, 120 mg ligelizumab, 300 mg omalizumab, or placebo, dosed every 4 weeks, for 52 weeks. Patients allocated to placebo received 120 mg ligelizumab from week 24. The primary endpoint was change-from-baseline (CFB) in weekly Urticaria Activity Score (UAS7) at week 12, and was analysed in all eligible adult patients according to the treatment assigned at random allocation. Safety was assessed throughout the study in all patients who received at least one dose of the study drug. The studies were registered with ClinicalTrials.gov, NCT03580369 (PEARL-1) and NCT03580356 (PEARL-2). Both trials are now complete. FINDINGS: Between Oct 17, 2018, and Oct 26, 2021, 2057 adult patients were randomly allocated across both studies (72 mg ligelizumab n=614; 120 mg ligelizumab n=616; 300 mg omalizumab n=618, and placebo n=209). A total of 1480 (72%) of 2057 were female, and 577 (28%) of 2057 were male. Mean UAS7 at baseline across study groups ranged from 29·37 to 31·10. At week 12, estimated treatment differences in mean CFB-UAS7 were as follows: for 72 mg ligelizumab versus placebo, -8·0 (95% CI -10·6 to -5·4; PEARL-1), -10·0 (-12·6 to -7·4; PEARL-2); 72 mg ligelizumab versus omalizumab 0·7 (-1·2 to 2·5; PEARL-1), 0·4 (-1·4 to 2·2; PEARL-2); 120 mg ligelizumab versus placebo -8·0 (-10·5 to -5·4; PEARL-1), -11·1 (-13·7 to -8·5; PEARL-2); 120 mg ligelizumab versus omalizumab 0·7 (-1·1 to 2·5; PEARL-1), -0·7 (-2·5 to 1·1; PEARL-2). Both doses of ligelizumab were superior to placebo (p<0·0001), but not to omalizumab, in both studies. No new safety signals were identified for ligelizumab or omalizumab. INTERPRETATION: In the phase 3 PEARL studies, ligelizumab demonstrated superior efficacy versus placebo but not versus omalizumab. The safety profile of ligelizumab was consistent with previous studies. FUNDING: Novartis Pharma.

Omalizumab in the treatment of bullous pemphigoid resistant to first-line therapy: a French national multicentre retrospective study of 100 patients.

BACKGROUND: Interest in the use of omalizumab to treat bullous pemphigoid (BP) in the event of resistance or contraindication to conventional therapies is currently based on limited evidence. OBJECTIVES: To assess the effectiveness and safety of omalizumab in BP and to identify predictive factors in response to treatment. METHODS: We conducted a French national multicentre retrospective study including patients with a confirmed diagnosis of BP treated with omalizumab after failure of one or several treatment lines. We excluded patients with clinically atypical BP, as per Vaillant's criteria. The criteria for clinical response to omalizumab were defined according to the 2012 international consensus conference. Anti-BP180-NC16A IgE enzyme-linked immunosorbent assay was performed on sera collected before initiating omalizumab, when available. RESULTS: Between 2014 and 2021, 100 patients treated in 18 expert departments were included. Median age at diagnosis was 77 years (range 20-98). Complete remission (CR) was achieved in 77% of patients, and partial remission in an additional 9%. CR was maintained 'off therapy' in 11.7%, 'on minimal therapy' in 57.1%, and 'on non-minimal therapy' in 31.2%. Median time to CR was 3 months (range 2.2-24.5). Relapse rate was 14%, with a median follow-up time of 12 months (range 6-73). Adverse events occurred in four patients. CR was more frequently observed in patients with an increased serum baseline level of anti-BP180-NC16A IgE (75% vs. 41%; P = 0.011). Conversely, urticarial lesions, blood total IgE concentration or eosinophil count were not predictive of CR. Patients with an omalizumab dosage > 300 mg every 4 weeks showed a similar final outcome to those with a dosage ≤ 300 mg every 4 weeks, but control of disease activity [median 10 days (range 5-30) vs. 15 days (range 10-60); P < 0.001] and CR [median 2.4 months (range 2.2-8.2) vs. 3.9 months (range 2.3-24.5); P < 0.001] were achieved significantly faster. CONCLUSIONS: We report the largest series to date of BP treated by omalizumab and confirm its effectiveness and safety in this indication. Serum baseline level of anti-BP180-NC16A IgE may predict response to treatment.

Hypersensitivity infusion-associated reactions induced by enzyme replacement therapy in a cohort of patients with late-onset Pompe disease: An experience from the French Pompe Registry.

BACKGROUND AND OBJECTIVES: Pompe disease is a rare hereditary glycogen storage disorder due to lysosomal acid alpha-glucosidase deficiency. Enzyme replacement therapy (ERT) is the only available treatment. Infusion-associated reactions (IAR) are challenging since there are no guidelines for ERT rechallenge after a drug hypersensitivity reaction (DHR) in Pompe disease. The objective of the present study was to describe IAR and their management in late-onset Pompe disease (LOPD) patients in France, and to discuss the various possibilities of ERT rechallenge. METHODS: An exhaustive screening of LOPD patients receiving ERT between 2006 and 2020 from the 31-participating hospital-based or reference centers was performed. The patients who had presented at least one hypersensitivity IAR (=DHR) episode were included. Demographic characteristics of the patients, IAR onset and timing, were retrospectively collected from the French Pompe Registry. RESULTS: Fifteen patients among 115 treated LOPD patients in France presented at least 1 IAR; 80.0% were women. Twenty-nine IAR were reported; 18 (62.1%) IAR were Grade I reactions, 10 (34.5%) IAR were Grade II, and 1 (3.4%) IAR was Grade III. IgE-mediated hypersensitivity was found in 2/15 patients (13.3%). The median [IQR] time from ERT introduction to the first IAR was 15.0 months [11.0-24.0]. ERT was safely and effectively re-introduced either with premedication alone, or in combination with either modified regimen or desensitization protocol, in all 9 rechallenged patients; including in patients with IgE-mediated hypersensitivity, in the patient with the Grade III reaction, as well as in patients with very high anti-GAA titer. DISCUSSION: Based on the results herein and previous reports, we discuss premedication and modified regimen for Grade I reactions, and desensitization in Grade II and III reactions. In conclusion, ERT-induced IAR can be safely and effectively managed with a modified regimen or desensitization protocol in LOPD patients.

The efficacy of therapeutic plasma exchange in COVID-19 patients on endothelial tightness in vitro is hindered by platelet activation.

Coronavirus disease (COVID)-19 is characterised in particular by vascular inflammation with platelet activation and endothelial dysfunction. During the pandemic, therapeutic plasma exchange (TPE) was used to reduce the cytokine storm in the circulation and delay or prevent ICU admissions. This procedure consists in replacing the inflammatory plasma by fresh frozen plasma from healthy donors and is often used to remove pathogenic molecules from plasma (autoantibodies, immune complexes, toxins, etc.). This study uses an in vitro model of platelet-endothelial cell interactions to assess changes in these interactions by plasma from COVID-19 patients and to determine the extent to which TPE reduces such changes. We noted that exposure of an endothelial monolayer to plasmas from COVID-19 patients post-TPE induced less endothelial permeability compared to COVID-19 control plasmas. Yet, when endothelial cells were co-cultured with healthy platelets and exposed to the plasma, the beneficial effect of TPE on endothelial permeability was somewhat reduced. This was linked to platelet and endothelial phenotypical activation but not with inflammatory molecule secretion. Our work shows that, in parallel to the beneficial removal of inflammatory factors from the circulation, TPE triggers cellular activation which may partly explain the reduction in efficacy in terms of endothelial dysfunction. These findings provide new insights for improving the efficacy of TPE using supporting treatments targeting platelet activation, for instance.

Preparations of exploration of immediate hypersensitivity to antineoplastic agents: An oncology pharmacy perspective.

BACKGROUND: Cancer patients are being exposed to antineoplastic drugs more frequently and for longer periods, resulting in a higher risk of hypersensitivity reactions. The aim of this study was to assess the pharmaceutical time and direct cost of drug allergy explorations following immediate hypersensitivity reactions to antineoplastic agents. METHODS: A micro-costing method was used to collect data on consumption of human and material resources for allergy exploration preparations. The monetisation was carried out on the basis of prices and hourly wage costs applied in 2018. The number and type of allergy explorations prepared by the pharmacy as well as nature of antineoplastic drugs tested, and the number of culprit drugs reintroductions were collected. RESULTS: Almost 1.5 h is required to realise allergy tests for one patient including pharmacist time for prescription analysis and pharmacy technician's time for tests preparation. The mean manufacturing cost of these tests is estimated at €62.87 (€57.82-65.49) per culprit drug for one patient. Programming patients according to culprit drugs tested allows rationalising healthcare provider time and increasing efficiency. From January 2010 to December 2018, 277 patients were tested and 490 allergy explorations were performed, corresponding to more than 5000 preparations. Mostly, the culprit drug could be reintroduced (n = 383, 78.2%) allowing patients to receive the best possible treatment. CONCLUSION: Management of hypersensitivity reactions is constantly progressing, as it contributes to improving patient care in oncology. This activity is time-consuming for the pharmacy team but allows patients with previous hypersensitivity reaction to continue effective treatment.

SARS-CoV-2 Vaccination and Anaphylaxis: Recommendations of the French Allergy Community and the Montpellier World Health Organization Collaborating Center.

Vaccines against COVID-19 (and its emerging variants) are an essential global intervention to control the current pandemic situation. Anaphylactic reactions have been reported after SARS-CoV2 RNA vaccines. Anaphylaxis is defined as a severe life-threatening generalized or systemic hypersensitivity reaction. This risk is estimated at 1/1,000,000 in the context of vaccine safety surveillance programs. The COVID-19 vaccination is rolling-out vastly in different courtiers and surveillance programs are key to monitor severe adverse reactions, such as anaphylaxis. Anaphylaxis due to vaccine is extremely rare and specific cases should receive individualized investigation and care. The here presented recommendations and follow-up from the French allergy community and the Montpellier WHO Collaborating Center in order to support the vaccination program and intends to support to healthcare professionals in their daily basis.

Improvement of patient outcomes following therapeutic optimization of chronic urticaria: two-year data from France as part of the international real-life AWARE study.

BACKGROUND: It is important to assess the burden of chronic urticaria (CU) with real-life studies. The AWARE study was performed in 36 countries over two years in CU patients resistant to H1-antihistamines. OBJECTIVES: To correlate patient-reported outcomes and available therapeutic options in CU patients. MATERIALS & METHODS: The AWARE study was a prospective, non-interventional, international study that included adult patients who have had H1-antihistamine-resistant CU for at least two months. The primary endpoints were the evolution of disease activity (UAS7), urticaria control (UCT), dermatological quality of life (DLQI) and treatment satisfaction (visual analogic scale) during a two-year follow-up. The data from French centres are reported. RESULTS: Ninety-two patients were included (mean age: 47.8 years; women: 70.7%; mean disease duration: 6.5 years; angioedema: 34.1%). The percentage of patients with CU treatment increased from 56.5% at inclusion to 86.0% after two years (for patients with non-sedative H1-antihistamines from 52.2% to 74.4%, and omalizumab from 2.2% to 25.6%). During the follow-up, the percentage of patients with UAS7 score <6 increased from 12.5% to 60.9%, and patients with well-controlled CU (UCT score >12) increased from 11.1% to 62.2%. The negative impact on quality of life (DLQI >10) decreased from 34.1% to 10.5%. The mean score of patient satisfaction for treatment increased from 4.6 to 7.6. CONCLUSION: The management of CU patients resistant to H1-antihistamines was not optimal at inclusion with uncontrolled disease, impaired quality of life and insufficient treatment. After a two-year follow-up, disease symptoms and quality of life improved, but the therapeutic management could be further optimized.

Priming With Red Blood Cells Allows Red Blood Cell Exchange for Sickle Cell Disease in Low-Weight Children.

Red blood cell exchanges are frequently used to treat and prevent cerebrovascular complications in patients with sickle cell anemia (SCA). However, the low weight of young children represents serious concerns for this procedure. The Spectra Optia device can perform automatic priming using red blood cells (RBCs) (RCE/RBC-primed) which could allow RBC exchanges (RCE) to be performed in young children without hypovolemic complications, but this method requires evaluation. We prospectively analyzed the clinical safety of the RCE/RBC-primed procedure in 12 SCA low-weight children under either a chronic RCE program or emergency treatment over 65 sessions. We monitored grade 2 adverse events (AEs) such as a decrease in blood pressure, increase in heart rate, fainting sensation, or transfusion reactions and identified the critical times during the sessions in which AEs could occur. Post-apheresis hematocrit (Hct) and a fraction of cell remaining (FCR) values were compared to the expected values. We also compared the impact of automatic RCE (n = 7) vs. RCE/RBC-primed (n = 8) on blood viscosity and RBC rheology. A low incidence of complications was observed in the 65 RCE sessions with only seven episodes of transient grade 2 AEs. Post-apheresis Hct and FCR reached expected values with the RCE/RBC-primed method. Both the automatic and priming procedures improved RBC deformability and decreased the sickling tendency during deoxygenation. Blood rheological features improved in both RCE/RBC-primed and automatic RCE without priming conditions. The RCE/RBC-primed procedure provides blood rheological benefits, and is safe and efficient to treat, notably in young children with SCA in prophylactic programs or curatively when a SCA complication occurs.

Hyperprogression and impact of tumor growth kinetics after PD1/PDL1 inhibition in head and neck squamous cell carcinoma.

Background: Hyperprogressive disease (HPD) rate in head and neck squamous cell carcinoma (HNSCC) patients treated with immune checkpoint inhibitors (ICI) was determined using tumor growth kinetics (TGK) and compared with rapidly progressive screen-failure (SF) patients. The impact of TGK on outcomes with salvage chemotherapy (SCT) was also evaluated. Results: HPD was found in 22/120 (18%) patients. Median TGK before the onset of immunotherapy (TGKpre) was 2.7 for SF patients and 4.8 for HPD patients, with no significant difference (p = 0.17). Disease control rate after initial progressive disease on ICI was 86% with SCT in case of tumor growth deceleration vs 39% in case of tumor growth acceleration. Conclusions: HPD was frequent, but TGK of HPD patients treated with ICI did not differ from SF patients, suggesting that there is no relevant causal relationship between HPD and ICI. After initial PD with ICI, tumor growth deceleration was associated with better outcomes, indicating that TGKR might be useful to detect late responders, meriting prospective investigations. Materials and Methods: TGK ratio (TGKR) was defined as the ratio of TGK on ICI (TGKpost) to TGKpre. HPD was defined as TGKR ≥ 2. TGKR >1 indicated tumor growth acceleration, while 0 < TGKR < 1 indicated tumor deceleration.

Glucocorticoids for acute urticaria: study protocol for a double-blind non-inferiority randomised controlled trial.

INTRODUCTION: This study protocol describes a trial designed to investigate whether antihistamine alone in patients with acute urticaria does not increase the 7-day Urticaria Activity Score (UAS7) in comparison with an association of antihistamine and glucocorticoids and reduces short-term relapses and chronic-induced urticaria. METHODS AND ANALYSIS: This is a prospective, double-blind, parallel-group, multicentre non-inferiority randomised controlled trial. Two-hundred and forty patients with acute urticaria admitted to emergency department will be randomised in a 1:1 ratio to receive levocetirizine or an association of levocetirizine and prednisone. Randomisation will be stratified by centre. The primary outcome will be the UAS7 at day 7. The secondary outcomes will encompass recurrence of hives and/or itch at day 7; occurrence of spontaneous hives or itch for >6 weeks; patients with angioedema at day 7, and 2, 6, 12 and 24 weeks; new emergency visits for acute urticaria recurrences at days 7 and 14, and 3 months; Dermatology Life Quality Index at days 7 and 14, and 3 and 6 months; and Chronic Urticaria Quality of Life Questionnaire at 6 weeks. ETHICS AND DISSEMINATION: The protocol has been approved by the Comité de Protection des PersonnesSud-Méditerranée II and will be carried out in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. A steering committee will oversee the progress of the study. Findings will be disseminated through national and international scientific conferences and publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03545464.

Severe hypersensitivity reactions to platinum compounds post-pressurized intraperitoneal aerosol chemotherapy (PIPAC): first literature report.

BACKGROUND: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) shows encouraging results for patients with unresectable peritoneal metastasis. Several reports demonstrated the safety of the procedure combined with systemic chemotherapy, with a low rate of complication. The aim of this study is to report severe hypersensitivity reactions to platinum compounds (SHRPC) during PIPAC procedures. METHODS: All patients who underwent PIPAC for non-resectable PC in Lyon Sud University hospital were included in a prospective institutional database. All patients who presented a SHRPC after PIPAC were included in our analysis. RESULTS: One hundred and thirty-two patients underwent 383 PIPAC procedures between December 2015 and December 2017. oxaliplatin's and cisplatin-doxorubicin's protocols were used in 71 and 312 PIPAC, respectively. Four patients (3%) developed SHRPC; two patients (2.8%) after oxaliplatin and two patients (0.6%) after cisplatin-doxorubicin protocols. SHRPC occurred during the 6th PIPAC with cisplatin-doxorubicin protocol and during 2nd and 3rd PIPAC of the oxaliplatin protocol. Three events appeared within 15 min and one event occurred 50 min following nebulization. All the SHRPC have been managed successfully without any complication. CONCLUSIONS: This is the first report of SHRPC after PIPAC. The physician must constantly keep this rare but life-threatening complication in mind, especially after repeated PIPAC administration or previous platinum-based systemic chemotherapy.

Therapeutic patient education improves knowledge and skills for patients with chronic spontaneous urticaria.

Therapeutic patient education (TPE) allows patients to better understand their disease and cope with treatment. TPE programmes have not yet been evaluated for chronic spontaneous urticaria (CSU). To investigate the cognitive and behavioural impact of TPE on CSU patients. CSU patients were selected who completed a TPE programme. A pre-post comparison was performed using a skill/knowledge questionnaire, based on six educational objectives, before and after the intervention. The course of CSU was also analysed, according to daily hive count and itch intensity. All of the 61 enrolled patients improved their knowledge and skills following TPE, with greatest improvement in itch management and use of alternatives to scratching. CSU activity was reduced at the end of the programme in 60% of patients. TPE improves knowledge and skills for CSU patients. Further research is needed to demonstrate the positive impact of TPE on CSU activity.

Efficacy and Safety of Infliximab Tolerance Induction in Patients with Inflammatory Bowel Diseases who Experienced Acute Infusion Reactions.

BACKGROUND AND AIMS: One of the reasons for the failure of infliximab (IFX) is immediate hypersensitivity reactions (IHR). We aimed to report the efficacy and safety of a tolerance induction protocol in inflammatory bowel diseases (IBD) patients who had previously experienced IHR during IFX infusions. PATIENTS AND METHODS: We reported all cases of IBD patients who had previously experienced IHR due to IFX and who were submitted to a standardized protocol of tolerance induction to IFX from 2010 to 2015. RESULTS: IHR occurred in a majority of patients (69%) during the first 3 infusions and for half of them after a period of IFX withdrawn. Skin prick tests were negative and only 2 intradermal tests were positive. Basophil activation tests and antidrug antibody measurements were performed in 8 out of 16 patients and were positive in 3 and 4 patients respectively. Induction of tolerance was successful in 69% of patients and IFX was pursued with clinical efficacy > 1 year in 7 patients (44%). Allergologic investigations were not predictive of tolerance induction success. CONCLUSION: A majority of IHR to IFX infusions occurred during the beginning or restarting of treatment and was related to a nonallergic hypersensitivity. Induction of tolerance to IFX is feasible and effective and may safely allow retreatment of IFX in almost 70% of IBD patients.