Jaime Sánchez-López

Lipid transfer protein syndrome: clinical pattern, cofactor effect and profile of molecular sensitization to plant‐foods and pollens

Multiple plant‐food sensitizations with a complex pattern of clinical manifestations are a common feature of lipid transfer protein (LTP)‐allergic patients. Component‐resolved diagnosis permits the diagnosis of the allergen sensitization profile.

Biological agents: new drugs, old problems.

REFERENCES 1. Engelhardt KR, McGhee S, Winkler S, Sassi A, Woellner C, Lopez-Herreraet G, et al. Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome. J Allergy Clin Immunol 2009;124:1289-302, e4. 2. Holland SM, DeLeo FR, Ellumi HZ, Hsu AP, Uzel G, Brodsky N, et al. STAT3 mutations in the hyper-IgE syndrome. N Engl J Med 2007;357:1608-19. 3. Minegishi YM, Saito M, Tsuchiya I, Tsuge I, Takada H, Hara T, et al. Dominant– negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature 2007;448:1058-62. 4. Woellner C, Gertz EM, Schäffer AA, Lagos M, Perro M, Glocker E-O, et al. Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome. J Allergy Clin Immunol 2010;125:424-32. 5. Milner JD, Brenchley JM, Laurence A, Freeman AF, Hill BJ, Elias KM, et al. Impaired TH17 cell differentiation in subjects with autosomal dominant hyperIgE syndrome. Nature 2008;452:773-7. 6. Nester TA, Wagnon AH, Reilly WF, Spitzer G, Kjeldsberg CR, Hill HR. Effects of allogeneic peripheral stem cell transplantation in a patient with Job syndrome of hyperimmunoglobulinemia E and recurrent infections. Am J Med 1998;108:162-4. 7. Gennery AR, Flood TJ, Abinun M, Cant AJ. Bone marrow transplantation does not correct the hyper IgE syndrome. Bone Marrow Transplant 2000;25:1303-5. 8. Freeman AF, Holland SM. The hyper IgE syndromes. Immunol Allergy Clin North Am 2008;28:277-91. 9. Freeman AF, Kleiner DE, Nadiminti H, Davis J, Quezado M, Anderson V, et al. Causes of death in hyper-IgE syndrome. J Allergy Clin Immunol 2007;119:1234-40.

Platelet-activating factor nasal challenge induces nasal congestion and reduces nasal volume in both healthy volunteers and allergic rhinitis patients.

Background Platelet-activating factor (PAF) is a lipid mediator produced by most inflammatory cells. Clinical and experimental findings suggest that PAF participates in allergic rhinitis (AR) pathogenesis. The aim was to assess the PAF ability to induce clinical response in nasal airway after local stimulation. Method Ten nonatopic healthy volunteers (HVs) and 10 AR patients out of pollen season were enrolled. PAF increasing concentrations (100, 200, and 400 nM) were instilled into both nasal cavities (0, 30, and 60 minutes, respectively). Nasal symptoms (congestion, rhinorrhea, sneezing, itching, and total 4 symptom score and nasal volume between the 2nd and 5th cm (Vol2–5) using acoustic rhinometry (AcR), were assessed at −30, 0, 30, 60, 90, 120, and 240 minutes. Result PAF increased individual and total nasal symptom score in both HVs and seasonal AR (SAR) patients from 30 to 120 minutes (maximum score at 120’, p < 0.05). Nasal obstruction was the most relevant and lasting nasal symptom. PAF also induced a significant reduction of Vol2–5 at 90’ (27%), 120’ (38.7%), and 240’ (36.4%). No differences in the response to PAF nasal challenge were observed between HVs and SAR subjects in either clinical symptoms or AcR. Conclusion This is the first description of PAF effects on human nasal mucosa using a cumulative dose schedule and evaluated by both nasal symptoms and AcR. Nasal provocation with PAF showed long-lasting effects on nasal symptoms and nasal obstruction in HVs and in patients with SAR. Nasal challenge may be a useful tool to investigate the role of PAF in AR and the potential role of anti-PAF drugs.

Acoustic rhinometry and aspirin nasal challenge in the diagnosis of aspirin-intolerant asthma: clinical finding and safety aspects.

Background: The safety and utility of nasal provocation tests with lysine-aspirin (l-ASA) in the diagnosis of aspirin-intolerant asthma (AIA) have previously been described in a short series of patients. Objectives: To describe the clinical features and safety of an l-ASA challenge test in patients with AIA. Methods: We evaluated 72 patients (79% women), with a mean ± SD age of 47.9 ± 14.5 years. All patients were submitted to an l-ASA nasal provocation test (29 mg in each nostril) under acoustic rhinometry (AcR) control. Symptom score (0–3), visual analogical scale and nitric oxide determinations were performed at baseline and at 15, 30, 60 and 90 min. A decrease in nasal volume of at least 25% was considered a positive test. Nasal nitric oxide (nNO) and forced expiratory volume in 1 s were measured. Results: Nasal congestion and rhinorrhea represented 51 and 32%, respectively, of total symptoms. According to AcR data, the l-ASA challenge test was positive in 20% of patients at 15 min, an additional 36% were positive at 30 min, 18% at 60 min, and the remaining 26% at 90 min. nNO nasal values decreased but did not reach statistical significance. No pulmonary or systemic reactions were observed. Conclusions: Symptoms of nasal congestion associated with the reduction in nasal volume measured by AcR are the most useful parameters for establishing the diagnosis of AIA using the l-ASA nasal challenge. The method is very well tolerated and can be safely used even in patients with severe asthma.

Nonsteroidal anti-inflammatory drugs enhance IgE-mediated activation of human basophils in patients with food anaphylaxis dependent on and independent of nonsteroidal anti-inflammatory drugs.

Nonsteroidal anti‐inflammatory drugs (NSAIDs) act as cofactors worsening the allergic reactions induced by food allergens.

Safety of Parecoxib in Asthmatic Patients with Aspirin-Exacerbated Respiratory Disease

Background: Aspirin-exacerbated respiratory disease (AERD) affects a subset of patients with asthma. Cyclooxygenase 2 inhibitors are a safe alternative in patients with AERD. Parecoxib is the first cyclooxygenase 2 selective drug for parenteral administration, especially useful after surgery thanks to its analgesic power. The aim of the study is to assess the tolerance of parecoxib (Dynastat®; Pfizer) given by intramuscular route in patients with AERD. Methods: Patients evaluated were referred to the Pneumology and Respiratory Allergy Department of the Hospital Clinic (Barcelona, Spain) for asthma exacerbations precipitated by 2 or more different non-steroidal anti-inflammatory drugs (NSAIDs). AERD was confirmed by a nasal challenge test with aspirin. Patients were challenged with parecoxib, and urine samples were collected to measure the leukotriene E4 concentration. Results: Ten patients were challenged with parecoxib. No symptoms were reported with any of the administered doses, and there were no signs of immediate or delayed hypersensitivity. There were no alterations in the forced expiratory volume in 1 s or in acoustic rhinometry measurements. No significant differences between leukotriene E4 levels were detected. Conclusion: The drug was well tolerated by all patients, with no adverse reactions. This lack of reactions found in our study supports the fact that parecoxib could be a safe alternative in postsurgery analgesia in NSAID-intolerant asthma patients.

Effects of Rupatadine on Platelet- Activating Factor-Induced Human Mast Cell Degranulation Compared With Desloratadine and Levocetirizine (The MASPAF Study).

BACKGROUND AND OBJECTIVE Platelet-activating factor (PAF) is a lipid mediator involved in the pathophysiology of several allergic diseases, for example, in the amplification of mast cell (MC) activation in anaphylaxis. Rupatadine is an antihistamine with a demonstrated anti-PAF effect, although its capacity to inhibit PAF-induced MC degranulation has not been fully evaluated. Objectives: To compare the ability of rupatadine to inhibit PAF-induced MC degranulation with that of desloratadine and levocetirizine and to confirm the dual anti-H1 and anti-PAF activity of rupatadine. METHODS The human MC line LAD2 and primary MCs (human lung tissue MCs [hLMCs]) were used. MC mediator release was evaluated using the b-hexosaminidase and histamine release assay. The effects of rupatadine (H1 antagonist + PAF receptor antagonist), desloratadine, and levocetirizine (H1 antagonists) on LAD2 and hLMCs were compared. The PAF receptor antagonists WEB2086, BN52021, and CV6209 were also tested. PAF receptor protein expression was evaluated in both LAD2 and hLMCs. RESULTS CV6209 and rupatadine inhibited PAF-induced MC degranulation in both LAD2 and hLMCs. In LAD2, rupatadine (5 and 10 µM) and levocetirizine (5 µM), but not desloratadine, inhibited PAF-induced b-hexosaminidase release. Rupatadine (1-10 µM), levocetirizine (1-10 µM), and desloratadine (10 µM) inhibited PAF-induced histamine release. Rupatadine at 10 µM had an inhibitory effect on hLMC degranulation, but levocetirizine and desloratadine did not. CONCLUSIONS This study shows that rupatadine and, to a lesser extent, levocetirizine, but not desloratadine, inhibit PAF-induced degranulation in both LAD2 and hLMCs. These findings support the dual antihistamine and anti-PAF effect of rupatadine in allergic disorders.BACKGROUND AND OBJECTIVE Platelet-activating factor (PAF) is a lipid mediator involved in the pathophysiology of several allergic diseases, for example, in the amplification of mast cell (MC) activation in anaphylaxis. Rupatadine is an antihistamine with a demonstrated anti-PAF effect, although its capacity to inhibit PAF-induced MC degranulation has not been fully evaluated. Objectives: To compare the ability of rupatadine to inhibit PAF-induced MC degranulation with that of desloratadine and levocetirizine and to confirm the dual anti-H1 and anti-PAF activity of rupatadine. METHODS The human MC line LAD2 and primary MCs (human lung tissue MCs [hLMCs]) were used. MC mediator release was evaluated using the b-hexosaminidase and histamine release assay. The effects of rupatadine (H1 antagonist + PAF receptor antagonist), desloratadine, and levocetirizine (H1 antagonists) on LAD2 and hLMCs were compared. The PAF receptor antagonists WEB2086, BN52021, and CV6209 were also tested. PAF receptor protein expression was evaluated in both LAD2 and hLMCs. RESULTS CV6209 and rupatadine inhibited PAF-induced MC degranulation in both LAD2 and hLMCs. In LAD2, rupatadine (5 and 10 µM) and levocetirizine (5 µM), but not desloratadine, inhibited PAF-induced b-hexosaminidase release. Rupatadine (1-10 µM), levocetirizine (1-10 µM), and desloratadine (10 µM) inhibited PAF-induced histamine release. Rupatadine at 10 µM had an inhibitory effect on hLMC degranulation, but levocetirizine and desloratadine did not. CONCLUSIONS This study shows that rupatadine and, to a lesser extent, levocetirizine, but not desloratadine, inhibit PAF-induced degranulation in both LAD2 and hLMCs. These findings support the dual antihistamine and anti-PAF effect of rupatadine in allergic disorders.

Follow-up of patients with uncontrolled asthma: clinical features of asthma patients according to the level of control achieved (the COAS study)

Our aim was to study the asthma control achieved in patients with uncontrolled asthma who had received appropriate treatment according to the Global Initiative for Asthma (GINA) 2010 (valid at the time the study was designed), and to analyse the factors associated with a lack of asthma control. This was a multicentre study in routine clinical practice performed in patients with uncontrolled asthma according to GINA 2010. At visit 1, we recorded demographics, asthma characteristics and spirometry. We assessed asthma control using GINA 2010 criteria and the Asthma Control Test (ACT). Treatment was optimised according to GINA 2010. At visit 2, 3 months later, we reassessed spirometry, asthma control and factors associated with failure to achieve control. We recruited 1299 patients with uncontrolled asthma (mean age 46.5±17.3 years, 60.7% women, 25.8% obese). The mean percentage of predicted forced expiratory volume in 1 s was 76.4±12.8% and the mean post-bronchodilator increase was 14.9±6.8%. We observed poor agreement between ACT and GINA 2010 when evaluating asthma control (kappa = −0.151). At visit 2, asthma in 71.2% of patients was still not fully controlled. Patients whose asthma remained uncontrolled were older, had a higher body mass index, greater disease severity, longer disease evolution and worse lung function. After treatment optimisation, most patients did not achieve optimal control according to GINA 2010. Risk factors for failure to achieve asthma control were time of disease evolution, severity, age, weight and lung function impairment (excluded in the GINA 2014). Asthma in most patients is not fully controlled despite adjusting their treatment using GINA 2010 strategy criteria http://ow.ly/C73c307fMOZ

Desensitization to rituximab in a multidisciplinary setting

Background The need to offer first-line therapy to the increasing number of patients who have suffered an hypersensitivity reaction has stimulated the use of rapid desensitization protocols. Objective To present our experience working as a multidisciplinary team using a rituximab rapid desensitization scheme. Method Patient demographics, allergic reaction, skin tests to rituximab, number of desensitizations, reactions during the desensitization protocol and actions taken, number of administered and completed cycles, were retrospectively collected in patients who received at least one desensitization to rituximab. Main outcomes Number of desensitizations successfully managed. Results Between 2012 and June 2013 five patients received a total of 19 desensitizations to rituximab using a 12 step rapid desensitization protocol. All patients received the scheduled chemotherapeutic cycles as inpatients, with no delay in administration dates. Three patients presented a hypersensitivity reaction during the first desensitization and in one patient the event occurred again during the second treatment cycle. All reactions occurred in the last step, when the infusion rate reached the maximum speed. Conclusion The developed protocol for rapid desensitization was successful in five patients receiving rituximab. Patients could receive the full intended dose.

Relevance of food allergy in the assessment of NSAID-involved reactions

Method We prospectively recruited all consecutive patients from June 2012 to May 2014 consulting for an NSAID adverse reaction in which a confirmation diagnosis was reached. The practical approach to the diagnosis of hypersensitivity to NSAIDs was performed according to the protocol from the EAACI Task Force on NSAIDs Hypersensitivity. SPTs were also performed to a standard panel of inhalant and food allergens. Food allergy was assessed by a consistent clinical history and a positive SPT to the foods involved. A subgroup of patients diagnosed as NSAIDenhanced food allergy was challenged with the responsible food in the presence and absence of the NSAID to demonstrate the enhanced effect.