The molecular and functional characterization of clonally expanded CD8+ TCR BV T cells in eosinophilic granulomatosis with polyangiitis (EGPA).

In eosinophilic granulomatosis with polyangiitis (EGPA) clonally expanded T cells might concur in granuloma formation and vascular injury. The TCR ß-variable (BV) chain repertoire and third complementarity determining region (CDR3) of peripheral CD4+ and CD8+ cells in EGPA patients and age-matched controls and the expression of cytokines and chemokine receptors were investigated. The CD8+ lymphocytes of EGPA patients showed an increased frequency of BV expansions with a skewed profile of BV CDR3 lengths, increased CCR5 and CXCR3 expression and increased INFγ and TNFα production. In two patients, the TCR CDR3 cDNA sequences of the expanded BV family were identified. The CD4+ lymphocytes of EGPA patients revealed a higher expression of CRTH2 and increased production of IL-5. In conclusion, CD4+ T cells display a Th2 profile and CD8+ T cells are clonally expanded in EGPA and have a proinflammatory phenotype, suggesting their pathogenic role in vasculitic damage.

Safety and Tolerability of COVID-19 Vaccine in Mast Cell Disorders Real-Life Data from a Single Centre in Italy.

Background In the past three years, COVID-19 has had a significant impact on the healthcare systems and people's safety worldwide. Mass vaccinations dramatically improved the health and economic damage caused by SARS-CoV-2. However, the safety of COVID-19 vaccines in patients at high risk of allergic reactions still has many unmet needs that should be clarified. Material and methods A retrospective, single-centre study was performed by collecting demographic and clinical data of patients with Mast Cell Disorders (MCDs) to evaluate the safety and tolerability of COVID-19 vaccinations. Moreover, any changes in the natural history of the underlying disease following the vaccine have been evaluated. Results This study included 66 patients affected with MCDs. Out of them, 52 (78.8%) received a COVID-19 vaccination and 41 (78.8%) completed the vaccination course. Premedication came first in 86.6% of our patients. A total of seven (4.5%) patients complained about an immediate reaction and two (1.3%) had a late reaction. Worsening of MCD history was observed in a single patient. Conclusions Despite the overall high risk of allergic reactions, our study did not reveal any increased risk for SARS-CoV-2 allergic reactions in MCD patients, thus supporting the recommendation in favour of the SARS-CoV-2 vaccination. However, due to the potentially increased rate of anaphylactic reactions, MCD patients should receive vaccine premedication and should be treated in a hospital setting after an allergological specialistic evaluation.

Resolutive pulmonary endarterectomy in a non-compliant patient with systemic lupus erythematosus and antiphospholipid syndrome.

Patients with chronic thromboembolic pulmonary hypertension (CTEPH) have poor prognosis, and pulmonary endarterectomy (PEA) is considered the treatment of choice for this condition. We report a case and review the literature of successful PEA for CTEPH due to antiphospholipid syndrome associated with systemic lupus erythematosus. The definitive and decisive approach needed to treat this high-risk patient with a history of comorbidity, long-term illness and poor compliance was found with a therapy of PEA.

MAURIVAX: A Vaccination Campaign Project in a Hospital Environment for Patients Affected by Autoimmune Diseases and Adult Primary Immunodeficiencies.

Background: Patients with autoimmune diseases (ADs) and primary immunodeficiencies (PIDs) are characterized by an increased risk of noninvasive and widespread infections as they are considered frail patients. In addition, many flares of the underlying disease are reported after routine vaccinations. To date, the vaccination rate in these two populations is suboptimal. According to the latest guidelines, targeted interventions are needed, such as strengthening the network of vaccination activities. Our project aimed to propose a pilot network for carrying out the recommended vaccinations in frail patients. Methods: The Allergy and Immunology Center of the Mauriziano Hospital in Turin, Italy started the "Maurivax" project, a facilitated pathway for frail patients to administer the recommended vaccinations in the setting of a dedicated structure where they could be properly followed up. Results: From June 2022 to February 2023, 49 patients underwent a vaccination consultation: 45 of them (91.8%) were subsequently vaccinated. Among these, 36 subjects (80%) were affected by an active AD and were already in treatment with immunosuppressive therapy or about to start it. Seven patients (15.5%) had a confirmed diagnosis of PID or showed a clinical presentation that was highly suggestive of that condition. Overall, twenty-seven patients (60%) showed a high-grade immunosuppression and six (13.3%) had a low-grade immunosuppression. No patients had a disease flare within 30 days from vaccination and no severe reactions after vaccination was observed. Conclusions: Adherence and vaccination safety at our immunology hospital vaccine clinic dedicated to patients with ADs and PIDs were high. We propose an effective model for managing vaccinations in frail patients in a specialist hospital setting.

Innate and lymphocytic response of birch-allergic patients before and after sublingual immunotherapy.

Functional imbalance in Th1/Th2 cell response toward allergens is a recognized hallmark of allergic patients and a major role of dendritic cells (DCs) in redirecting T-cell phenotypes after specific immunotherapy has been suggested. This study investigates the proliferative and cytokine responses of T cells cocultured with monocyte-derived DCs (MoDCs) after allergen stimulation in birch-allergic patients compared with controls and investigates whether sublingual immunotherapy (SLIT) could change the DC-driven immune response. T cells were stimulated with the major birch pollen allergen (nBet v1) and MoDCs from eight birch-allergic patients with seasonal allergic rhinitis and eight nonallergic controls. Proliferation and cytokine production were measured before and after one course of SLIT with birch allergoid. Significantly lower levels of proinflammatory (IL-1beta, p = 0.027; IL-6, p = 0.030; TNF-alpha, p = 0.019) and Th1 (interferon gamma, p = 0.032; IL-12, p = 0.05) cytokines were measured in supernatants of T cells and MoDCs cultures from allergic patients compared with nonallergic controls. After SLIT, significant increase in IL-12 (p = 0.039), IL-1beta (p = 0.040), IL-6 (p = 0.041), TNF-α (p = 0.048), and IL-10 (p = 0.048) and significant decrease in IL-13 (p = 0.001) were observed. MoDCs/T-cell cocultures, pulsed with the specific allergen, produced lower quantities of proinflammatory and Th1 cytokines in allergic patients compared with healthy subjects, suggesting an allergen-specific impairment of natural immunity and Th1 immune response. A single course of SLIT was able to enhance allergen-specific innate immunity and to modify lymphocyte response, promoting Th1 and T-cell regulatory activity.

Cutaneous allergic reaction correlates with anti-erythropoietin antibodies in dialysis patient developing pure red cell aplasia.

We describe a case of concomitant erythropoietin allergy and resistance with a possible IgE and IgG-mediated immune response, in which the local allergic cutaneous symptoms preceded the antibody-mediated anemia.

The increase in exhaled NO following allergen challenge is not associated with airway acidification.

BACKGROUND: Exhaled nitric oxide (NO), commonly accepted marker of airways inflammation, may be generated both by specific enzymes, NO synthases, as well as by nonenzymatic reduction in its metabolites. During asthma exacerbations, owing to lower airways pH, it has been reported that nitrite reduction may contribute to the increase in exhaled NO. Allergen exposure, an important cause of asthma exacerbations, is also known to increase exhaled NO. DESIGN: To investigate whether cat allergen exposure of cat-sensitized asthmatics leads to airway acidification, which could explain the expected increase in exhaled NO. Twelve nonsmoking, cat-sensitized patients (nine women) aged 33·5 (22-54) years with mild intermittent asthma performed a cat allergen challenge. Exhaled NO at 50-200 mL s(-1), nasal NO, exhaled breath condensate (EBC) pH, nitrite and nitrate were measured before, 8 and 24 h after allergen challenge. RESULTS: A significant increase in FE(NO 50) was observed 24 h after allergen challenge compared to baseline: 110 ppb (34, 143) vs. 60 ppb (19, 122), P = 0·006. This was mainly explained by an increase in bronchial NO flux (P = 0·02), while no changes in EBC pH were observed (P = 0·35). CONCLUSIONS: Allergen exposure is not associated with airways acidification, implying that the observed increase in exhaled NO is probably because of enzymatic NO production.

Anxiety and Depression Effects During Drug Provocation Test.

BACKGROUND: Drug provocation test (DPT) represents the gold standard for the diagnosis of drug allergy. A DPT can be performed in a single-blind placebo-controlled manner. In anxiety and depressive disorders, patients need to be evaluated to understand the nature of placebo reactions. OBJECTIVE: The aim of this study was to evaluate the psychological profile of patients with reactions to placebo during a DPT. METHODS: We consecutively enrolled patients with suspected drug allergy undergoing a DPT preceded by the administration of the placebo. All patients underwent the Hospital Anxiety and Depression Scale (HADS), a questionnaire aimed to identify anxiety and depression, before the challenge test. RESULTS: A total of 196 patients were enrolled into this study: 8 (4%) patients resulted positive to the DPT, 60 (30.6%) demonstrated anxiety or depression based on the HADS, and 54 had at least 1 placebo reaction during drug provocation. There were statically significant correlations between the positivity of the HADS and the finding of a placebo reaction (Fisher's exact test: P < .001), and between the latter and a history of severe reactions to drug (Fisher's exact test: P < .001). CONCLUSIONS: There is a significant and strong correlation between the loss of psychic equilibrium and the development of a placebo reaction during a DPT. We suggest the use the HADS or other validated questionnaire in clinical practice before a DPT to evaluate the possible psychiatric components.

Diagnostic classification of persistent rhinitis and its relationship to exhaled nitric oxide and asthma: a clinical study of a consecutive series of patients.

BACKGROUND: Rhinitis and asthma represent the manifestation of one syndrome. Our hypothesis is that in patients with symptoms of persistent rhinitis, lower airway inflammation, lower respiratory symptoms, and lung function abnormalities compatible with asthma are more frequently associated with the diagnosis of allergic rhinitis (AR) and chronic rhinosinusitis (CRS) than with nonallergic rhinitis (NAR). METHODS: One hundred eight of 590 consecutive patients referred in 1 year for rhinitis were enrolled on the basis of nasal symptoms lasting > 4 weeks. Asthma was diagnosed on the basis of symptoms and a positive bronchodilation testing result and/or methacholine hyperresponsiveness. Exhaled nitric oxide (Feno) was measured with the single exhalation method at 50 mL/s. RESULTS: AR was diagnosed in 39%, NAR in 21%, and CRS in 40%. The prevalence of asthma was significantly higher in AR patients (33%) and CRS patients (42%) than in NAR patients (8.7%) [p = 0.036 and p = 0.005, respectively]. Feno was significantly higher in patients with AR and CRS compared to patients with NAR (44.3 parts per billion [ppb]; 95% confidence interval [CI], 34 to 54 ppb; and 53 ppb; 95% CI, 42 to 64 ppb; vs 22 ppb; 95% CI, 18 to 27 ppb; p = 0.002 and p = 0.001, respectively). Patients with asthma had Feno values significantly higher than patients without asthma (64 ppb; 95% CI, 51 to 77 ppb; vs 33.3 ppb; 95% CI, 28 to 39 ppb; p < 0.001). CONCLUSIONS: The diagnostic classification of persistent rhinitis helps to predict lower airway inflammation (increased Feno) and prevalence of asthma: AR and CRS are associated with higher mean Feno values and higher prevalence of asthma than NAR.

Itraconazole as 'bridge therapy' to anti-IgE in a patient with severe asthma with fungal sensitisation.

Sensitisation to fungi has been reported to play an important role in a particular phenotype of severe asthma, the so-called severe asthma with fungal sensitisation, characterised by high levels of total IgE, which may be an obstacle to anti-IgE therapy. We describe here the case of a polysensitised woman with refractory asthma, sensitised to Aspergillus fumigatus with high total IgE values (1793 kUA/l), but without the diagnostic criteria for allergic bronchopulmonary aspergillosis. Additional therapy with itraconazole leads to the decrease of total IgE to the limits recommended for proper omalizumab dosing (30-1500 kUA/l). Itraconazole, used as bridge therapy, provided us the opportunity to start anti-IgE treatment in a patient with high levels of total IgE, beyond the upper limits recommended for proper prescription of omalizumab.

Nasal nitric oxide is a marker of poor asthma control.

Asthma control, evaluated by symptoms, exacerbations rate and lung function may be greatly influenced by comorbidities, particularly chronic rhinosinusitis (CRS). Measurement of nasal nitric oxide (nNO) is a simple way to assess the severity of CRS. We aimed to analyze the relationship between asthma control and nasal NO. All patients with moderate-to-severe asthma on regular follow-up at our Outpatients' Clinic between November 2009 and April 2010 were included into the study. All patients were evaluated for asthma control by asthma control questionnaire (ACQ) and comorbidities (rhinitis, chronic rhinosinusitis with (CRSwNP) or without nasal polyps, obesity). Exhaled nitric oxide and nNO were obtained in all patients. Eighty-two patients were enrolled (mean age: 48 years, range: 21-80; 42 females). According to ACQ, 53 patients (64.6%) reported controlled asthma. Patients with uncontrolled asthma had lower nNO and higher prevalence of CRSwNP, with a significant correlation between nNO and ACQ. nNO is a biomarker negatively related to asthma control. As low nNO values were associated to CRSwNP, our results indicate that asthma control is highly influenced by this comorbidity.

Hypersensitivity reaction to human papillomavirus vaccine due to polysorbate 80.

A 17-year-old girl reported generalised urticaria, eyelid angioedema, rhino-conjunctivitis, dyspnoea and wheezing 1 h after third intramuscular administration of quadrivalent human papilloma virus vaccine (Gardasil). She was treated with antihistamine, and corticosteroids with prompt relief of rhinitis and dyspnoea, while urticaria and angioedema lasted 24 h. Intradermal test with Gardasil, which contains polysorbate 80 (PS80), resulted positive, while skin tests with the bivalent vaccine were negative. Prick test performed with PS80 resulted positive in the patient and negative in ten healthy controls. The CD203 basophil activation test result was negative for PS80 at all the tested dilutions and specific IgE was not found. As flu vaccine was recommended, the authors skin tested two flu vaccine, one containing PS80 (Fluarix, GSK), which resulted positive and another flu vaccine with no adjuvant or preservative (Vaxigrip, Sanofi Pasteur MSD), which gave negative results. The patient then received Vaxigrip without adverse reactions.

Exhaled breath condensate nitrates, but not nitrites or FENO, relate to asthma control.

BACKGROUND: Asthma is a chronic respiratory disease, characterised by airways inflammation, obstruction and hyperresponsiveness. Asthma control is the goal of asthma treatment, but many patients have sub-optimal control. Exhaled NO and exhaled breath condensate (EBC) NO metabolites (nitrites and nitrates) measurements are non-invasive tools to assess airways inflammation. Our aim was to investigate the relationships between asthma control and the above-named biomarkers of airways inflammation. METHODS: Thirty-nine non-smoking asthmatic patients (19 women) aged 50 (21-80) years performed measurements of exhaled NO (FENO), EBC nitrates, nitrites and pH, and answered Asthma Control Questionnaire (ACQ) and Asthma Control Test (ACT)-questionnaire. RESULTS: The ACT and ACQ score were strongly interrelated (ρ = -0.84, p < 0.001). No relationships between ACT or ACQ score and FENO were found (p > 0.05). EBC nitrates were negatively related to ACT score (ρ = -0.34, p = 0.03) and positively related to ACQ score (ρ = 0.41, p = 0.001) while no relation of EBC nitrites to either ACQ or ACT score was found (p>0.05). CONCLUSION: EBC nitrates were the only biomarker that was significantly related to asthma control. This suggests that nitrates, but not nitrites or FENO, reflect an aspect of airways inflammation that is closer related to asthma symptoms. Therefore there is a potential role for EBC nitrates in objective assessment of asthma control.

Increased oral nitric oxide in obstructive sleep apnoea.

BACKGROUND: Hypoxia and snoring-related mechanical trauma contribute to airway inflammation in obstructive sleep apnoea (OSA). Increased exhaled nitric oxide (FENO), an airway inflammation marker, has been reported in OSA patients. We propose the measure of NO in the oral cavity (oNO) as marker of oropharyngeal inflammation in OSA. METHODS: We compared oNO and FENO of 39 OSA patients with those of 26 mild asthmatics (ASTHMA), 15 patients with chronic rhinitis or rhinosinusitis (CRS) and 24 healthy subjects. A special device was used for oNO measurement. Apnoea/hypopnoea index (AHI), oxygen desaturation index, mean and nadir SaO2 were calculated from the polysomnography. RESULTS: oNO was significantly increased in OSA (104.2 95%CI 80.2-135.5ppb) as compared to ASTHMA (71.9 95%CI 56.3-91.9ppb; p=0.015), CRS (54.4 95%CI 40.2-73.7ppb; p=0.009) and healthy subjects (63.6 95%CI 59-73ppb; p<0.001). oNO was directly related to AHI (r=0.466, p=0.003) and to minutes slept with SaO2 <90% (r=0.471, p=0.011) and it was inversely related to nadirSaO2 (r=-0.393, p=0.018). FENO was highest in asthmatics (40.3 95%CI 32.5-50.1ppb) and only slightly elevated in OSA (23.1 95%CI 19,8-28.3ppb) and CRS (22.8 95%CI 16.8-32.5ppb). CONCLUSIONS: The finding that oral NO is increased in OSA and is related to upper airway obstructive episodes and to hypoxemia severity, strengthens the clinical and pathogenic role of oral inflammation in OSA.

Determinants of exhaled nitric oxide in chronic rhinosinusitis.

BACKGROUND: Chronic rhinosinusitis (CRS) has been reported to be associated with increased values of exhaled nitric oxide (ENO), which could not be entirely explained by the association between CRS and asthma. The aim of this study was to investigate the variables associated with increased ENO in patients with CRS. METHODS: This was a prospective cross-sectional descriptive study of 93 consecutive patients with CRS. The effect on ENO of age, gender, atopy, asthma, respiratory symptoms without bronchial hyperresponsiveness (BHR), and nasal polyps was evaluated by multiple regression analysis. RESULTS: Nasal polyps (P = .01), asthma (P < .001), and respiratory symptoms without BHR (P = .01) were the only independent variables associated with increased ENO. The prevalence of asthma was significantly higher in subjects with nasal polyps (61% vs 29.4%), P = .005, whereas the prevalence of respiratory symptoms without BHR was higher in those without nasal polyps (44.1% vs 15.3%, P = .003). Respiratory symptoms without BHR were associated with significantly higher ENO and prevalence of sputum eosinophilia (eosinophils > 3%) in patients with nasal polyps compared with those without nasal polyps (68.2 vs 24.0 ppb, P = .001; 60% vs 8.3%, P = .03, respectively). CONCLUSIONS: The presence of nasal polyps in patients with CRS was associated with increased asthma prevalence as well as increased ENO levels. Respiratory symptoms without BHR were associated with eosinophilic airway inflammation and increased ENO only in patients with nasal polyps. These findings suggest important clinical and biologic differences between the two types of CRS, with and without nasal polyps.

Effect of arterial hypertension on chronic urticaria duration.

BACKGROUND: Reliable clinical or laboratory markers of chronic idiopathic urticaria (CIU) duration are not available. Angioedema, autologous serum skin test (ASST) results, and antithyroid antibodies have been inconsistently associated with longer urticaria duration. OBJECTIVE: To investigate the association of clinical and laboratory parameters with CIU duration, including systemic hypertension, because activation of the coagulation cascade pathway may contribute to the pathogenesis of CIU. METHODS: We performed a prospective study of a cohort of 228 consecutive adult patients with CIU of moderate to severe intensity referred to 2 outpatient allergy clinics and followed up for a 3- to 5-year period. The association of clinical and laboratory parameters (sex, atopy, markers of autoimmunity, antithyroid antibodies, positive ASST result, Helicobacter pylori infection, and hypertension) with urticaria duration was analyzed using semiparametric multivariable proportional hazards models (Cox regression) using remission as main outcome measure. RESULTS: Apart from systemic hypertension (hazard ratio, 0.71; 95% confidence interval, 0.53-0.95; P = .02), none of the considered parameters influenced CIU remission of our patients; 74% and 54% of our patients with and without hypertension, respectively, still had CIU after 5 years. CONCLUSIONS: Our results show, for the first time to our knowledge, that hypertension is associated with extended duration of CIU. This observation, together with the previous findings that point to vascular and coagulation involvement in CIU, may suggest a new approach to antihistamine-refractory CIU treatment, including adequate treatment of hypertension.

Nasal nitric oxide concentration in suspected chronic rhinosinusitis.

BACKGROUND: The role that nasal nitric oxide (nNO) plays in sinonasal diseases is increasingly appreciated. OBJECTIVE: To test the diagnostic value of measuring nNO levels in a symptomatic population undergoing evaluation for potential chronic rhinosinusitis (CRS). METHODS: Of the patients referred to an outpatient allergy clinic for persistent nasal symptoms, those reporting nasal blockage plus 1 or more additional symptoms (discolored discharge, anterior or postnasal drip, facial pain or pressure, and reduction or loss of smell) were categorized as having CRS according to sinus computed tomography scores, with (CRSwNP) and without (CRSsNP) nasal polyps on the basis of endoscopic signs. All the included patients underwent nNO measurement and skin prick tests for common inhalant allergens. Healthy individuals served as controls for nNO measurement. RESULTS: Levels of nNO were significantly lower in patients with CRSwNP (median, 340 ppb; 25th-75th percentile, 145-390 ppb) compared with patients with CRSsNP (762 ppb; 620-1,013 ppb), patients without CRS (917 ppb; 647-1,159 ppb), and controls (843 ppb; 762-962 ppb) (P < .001). Low values of nNO separated very well patients with CRSwNP, and the nNO cutoff value of less than 442 ppb was associated with the best combination of specificity (91%) and sensitivity (87%), resulting in a negative predictive value of 91% and a positive predictive value of 87%. A significant inverse relationship was observed between nNO level and sinus computed tomography score (r2 = -0.39, P < .001). CONCLUSION: Testing for nNO is highly predictive of CRSwNP in a selected population of patients with symptoms suggestive of CRS.

Exhaled nitric oxide in persistent rhinitis with or without lower airway involvement: a review of the literature.

The link between upper and lower respiratory airways has been investigated in the past decade leading to the concept of united airways disease. This hypothesis was suggested by several epidemiological observations, which had shown the high prevalence of rhinitis and sinusitis in patients with asthma, and indirectly, by observing the effects of drugs used for rhinitis on asthma symptoms. A broad spectrum of airway involvement severity can be associated with rhinitis or rhinosinusitis: from a subclinical/asymptomatic inflammatory involvement with an increase in eosinophils in induced sputum cell count, to asthma-like symptoms without functional features of asthma with or without extrathoracic airway hyperresponsiveness, to respiratory symptoms with clinical and functional criteria of asthma. The aim of this paper is to review the literature about the role of breath analysis in the relationship between nose and lung, focusing on exhaled nitric oxide (FE(NO)) measurement, a non-invasive marker of inflammation, in rhinitis and in chronic rhinosinusitis in patients complaining or not of asthma symptoms.