Manuel Pereira Barbosa

Primary B-Cell Deficiencies Reveal a Link between Human IL-17-Producing CD4 T-Cell Homeostasis and B-Cell Differentiation

IL-17 is a pro-inflammatory cytokine implicated in autoimmune and inflammatory conditions. The development/survival of IL-17-producing CD4 T cells (Th17) share critical cues with B-cell differentiation and the circulating follicular T helper subset was recently shown to be enriched in Th17 cells able to help B-cell differentiation. We investigated a putative link between Th17-cell homeostasis and B cells by studying the Th17-cell compartment in primary B-cell immunodeficiencies. Common Variable Immunodeficiency Disorders (CVID), defined by defects in B-cell differentiation into plasma and memory B cells, are frequently associated with autoimmune and inflammatory manifestations but we found no relationship between these and Th17-cell frequency. In fact, CVID patients showed a decrease in Th17-cell frequency in parallel with the expansion of activated non-differentiated B cells (CD21lowCD38low). Moreover, Congenital Agammaglobulinemia patients, lacking B cells due to impaired early B-cell development, had a severe reduction of circulating Th17 cells. Finally, we found a direct correlation in healthy individuals between circulating Th17-cell frequency and both switched-memory B cells and serum BAFF levels, a crucial cytokine for B-cell survival. Overall, our data support a relationship between Th17-cell homeostasis and B-cell maturation, with implications for the understanding of the pathogenesis of inflammatory/autoimmune diseases and the physiology of B-cell depleting therapies.

Carboplatin-, Oxaliplatin-, and Cisplatin–specific IgE: Cross-reactivity and Value in the Diagnosis of Carboplatin and Oxaliplatin Allergy

BACKGROUND The diagnosis of hypersensitivity reactions (HSR) to platins is based on the characterization of the reaction and the results of skin testing. Platins can be irritants when used in skin testing; therefore, in vitro testing may offer an alternative diagnostic tool. OBJECTIVE To evaluate sensitivity and specificity of platin specific IgE (sIgE) in patients with HSRs and in controls. METHODS Twenty-four patients with immediate HSR to platins were included (carboplatin, 12; oxaliplatin, 12): 19 women and 5 men (mean age, 61 years). The control group included 17 patients exposed to platin and with no HSR. Skin testing was performed on 22 patients. Carboplatin sIgE and oxaliplatin sIgE were measured in 24 patients and 17 controls; carboplatin sIgE was measured in 21 patients. RESULTS Skin test results were positive in 22 patients (carboplatin, 12/12; oxaliplatin, 10/12). Seven of 12 patients sensitive to carboplatin (59%) had positive carboplatin sIgE, 2 also had positive cisplatin sIgE, and all had negative oxaliplatin sIgE; 9 of 12 patients sensitive to oxaliplatin (75%) had positive sIgE to oxaliplatin, 8 of 12 (67%) also had positive carboplatin and cisplatin sIgE, to which they had not been exposed. All 5 carboplatin controls had negative sIgE; 3 oxaliplatin controls (25%) had positive carboplatin sIgE, and 2 had positive oxaliplatin sIgE. CONCLUSION Carboplatin sIgE is very specific but less sensitive. In contrast, oxaliplatin sIgE had higher sensitivity but lower specificity. Analysis of our data suggests that oxaliplatin exposure was more immunogenic. This could be clinically relevant because patients sensitized to carboplatin may be able to tolerate oxaliplatin, but patients sensitized to oxaliplatin may be at risk when exposed to carboplatin and cisplatin.

Monocyte activation is a feature of common variable immunodeficiency irrespective of plasma lipopolysaccharide levels

Common variable immunodeficiency disorders (CVID), the most frequent cause of symptomatic primary immunodeficiency, are defined by impaired antibody production. Notwithstanding, T cell activation and granulomatous manifestations represent the main causes of CVID morbidity even in patients receiving immunoglobulin (Ig) G replacement therapy. Additionally, gut pathology is a frequent feature of CVID. In this study, we investigated monocyte imbalances and their possible relationship with increased microbial translocation in CVID patients. Monocyte subsets were defined according to CD14 and CD16 expression levels and evaluated in terms of human leucocyte antigen D‐related (HLA‐DR), CD86 and programmed death‐1 molecule ligand 1 (PD‐L1) expression by flow cytometry, in parallel with the quantification of plasma lipopolysaccharide (LPS) and serum levels of soluble CD14 (sCD14), LPS‐binding protein (LBP) and anti‐LPS antibodies. CVID patients (n = 31) featured significantly increased levels of serum sCD14 and an expansion of CD14brightCD16+ monocytes in direct correlation with T cell and B cell activation, the latter illustrated by the frequency of the CD21lowCD38low subset. Such alterations were not observed in patients lacking B cells due to congenital agammaglobulinaemia (n = 4). Moreover, we found no significant increase in circulating LPS or LBP levels in CVID patients, together with a relative preservation of serum anti‐LPS antibodies, in agreement with their presence in commercial IgG preparations. In conclusion, CVID was associated with monocyte imbalances that correlated directly with T cell activation markers and with B cell imbalances, without an association with plasma LPS levels. The heightened monocyte activated state observed in CVID may represent an important target for complementary therapeutic strategies.

Long-term efficacy of omalizumab in seven patients with treatment-resistant chronic spontaneous urticaria

BACKGROUND Monoclonal anti-IgE antibody omalizumab is a promising therapeutic option in patients with chronic urticaria (CU) resistant to non-sedating H1-antihistamines (nsAH). However, data about its long-term efficacy and safety are still scant. OBJECTIVE We retrospectively analysed the clinical course of patients with severe recalcitrant CU that were treated in our department with omalizumab for a period greater than 24 months. METHODS AND PATIENTS Seven patients (six females, median 43 years) treated for a median of 35 months have been evaluated. Before treatment, all suffered from persistent symptoms despite receiving high doses of nsAH [4×/day], leukotriene antagonists and prednisolone (10-30 mg/day for a median duration of 48 months). Response to treatment was assessed using urticaria activity score (UAS) and a combined symptom/medication score. RESULTS There was a complete remission of disease in four patients after the first dose of omalizumab. Before the 5th administration, all patients had a UAS of 0. We found a significant improvement in UAS between pre-treatment and first dose (p=0.017) and a gradual decrease in the symptom/medication score over the course of the first five administrations. Tapering of prednisolone was possible in all patients. Administration intervals were gradually increased, although all experienced resurgence of symptoms in cycles greater than six weeks. There were no reported adverse reactions attributable to the drug. CONCLUSION Omalizumab was a safe and effective corticosteroid alternative for maintaining long-term remission of symptoms in these patients. Treatment intervals required individual patient-by-patient determination. The drug did not seem to alter the natural history of the disease.

Anaphylaxis caused by honey: a case report

Honey allergy is a very rare, but serious health condition. In this study, we presented 1 patient who had anaphylaxis after the honey allergological investigation with skin prick-prick test with honey. Honey as a food has been associated to allergic reactions and as the increased consumption of honey in health food may increase the incidence of honey-related allergic reactions.

Perineal Groove: A Rare Congenital Anomaly

Perineal groove is a rare congenital anorectal malformation, with incidence yet undetermined. It is almost exclusive to the female newborn and its embryogenic origin remains uncertain. We present a case-report of a newborn girl that was discharged from the nursery without complications. At her first appointment at primary care we noted a wet sulcus connecting the posterior vaginal commissure and the anus. This case report emphasizes the rarity of the perineal groove and the importance of a good quality history and physical examination at primary care.

The Contribution of the Basophil Activation Test to the Diagnosis of Hypersensitivity Reactions to Oxaliplatin

Cytostatics, mainly oxaliplatin, are widely used to treat oncological diseases. There has been an increase in hypersensitivity reactions to these drugs, mostly IgE-mediated. Skin tests are the main diagnostic method used but they may induce irritant local reactions and contamination by health care professionals. The main goals of this work were to evaluate the contribution of the basophil activation test (BAT) as a diagnostic tool for hypersensitivity reactions to oxaliplatin, and to compare the expression of CD63 and CD203c molecules. BAT was performed with oxaliplatin in 6 oncological patients with previous documented hypersensitivity reactions to oxaliplatin and in 5 controls (4 oncological patients tolerant to oxaliplatin and 1 healthy control), assessing CD63 and CD203c expression on basophil population. We found higher values for the basophil activation percentage and mean stimulation index for CD203c expression with all oxaliplatin concentrations tested (most significant at 150 μg/mL: p = 0,0087; p = 0.0222) in the patients than in controls. The same did not occur, with statistical significance, for CD63 expression. When we compared the 2 activation markers in the patients, we observed a more enhanced expression of CD203c in both evaluations, with statistical significance at the 150-μg/mL concentration (p = 0,026; p = 0,0129). These data show a higher positivity of BAT with oxaliplatin in patients with previous hypersensitivity reactions, when compared to controls, suggesting that BAT may be a promising diagnostic method as an alternative to skin tests. CD203c appears to play a more prominent role than CD63, which is consistent with what is published in the literature.

The use of recombinant fish parvalbumin Gad c 1 in the characterisation of fish allergic patients

Material and methods We selected 55 pts (34M, 21F; average age:7.4 years). All had fish allergy, characterized by positive clinical history, skin-prick tests and serum specific IgE to several fish and Gad c 1 (UniCap, Thermo-Fisher). Oral food challenge was performed to evaluate fish tolerance acquisition. Statistical analysis was performed using GraphPad Prisma version 5.0 (GraphPad Software Inc, SD). Two groups were compared using a paired t test Wilcoxon. P values<0.05 were considered significant.

Poster 1012: Safety and efficacy of omalizumab in 10 children with asthma and other allergic comorbidities

Methods We retrospectively analyzed the clinical files of all pediatric pts treated with omalizumab from December 2009 to July 2013. The evaluated parameters included: adverse reactions to omalizumab, clinical evolution, Asthma Control Test (ACT) and Severity Scoring of Atopic Dermatitis (SCORAD) score evolution and medication decrease. Statistical significance was defined by a p value in the appropriate nonparametric test lower than 0.05.

Poster 1020: Efficacy and safety of sublingual specific immunotherapy with Pru p 3 in a portuguese population - clinical and immunological evaluation during 12 months

Background Peach allergy is prevalent, persistent and potentially severe. LTPs (Pru p 3) and profilins (Pru p 4) are the main allergens involved in this kind of allergy in patients(pts) of Mediterranean area. The hidden presence of LTPs in foodstuffs and in other food involved in LTP syndrome can trigger severe reactions, including anaphylaxis. Thus, this type of allergy can be considered an important target for specific immunotherapy(IT).