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Indolent systemic mastocytosis (ISM) has a favorable prognosis and normal life expectancy. However, many patients suffer from mast cell (MC) mediator-related symptoms, which significantly affect quality of life (QoL). Cutaneous, gastrointestinal, and neurological complaints, musculoskeletal pain, and the presence of skin lesions, anaphylaxis, and osteoporosis are the main symptoms and signs in ISM and must be assessed in all patients before and during treatment. Validated mastocytosis-specific patient-reported outcome measures (PROMs) should be used for this purpose. Serum tryptase and KIT D816V allele burden are recommended as secondary outcome parameters, noting that they do not reflect the severity of signs, symptoms, and related QoL impairment, but indirectly express MC burden. Changes from baseline of 90%, 60%, and 30% indicate complete response >90%, major response 60% to 90%, partial response 30% to 60%, and no response, M. C. Carter, J. J. Lyons, and D. D. Metcalfe were supported by the Division of Intramural Research, National Institutes of Allergic and Infectious Diseases, and National Institutes of Health. M. Niedoszytko was supported by the Medical University of Gdansk grant 02-0141/07/231. P. Valent was supported by the Austrian Science Fund (FWF) grant # P32470-B.

BackgroundThe efficacy of dupilumab as biological treatment of severe asthma and chronic rhinosinusitis with nasal polyps (CRSwNP) depends on its ability to inhibit the pathophysiologic mechanisms involved in type 2 inflammation.ObjectiveTo assess in a large sample of subjects with severe asthma, the therapeutic impact of dupilumab in real-life, with regard to positive or negative skin prick test (SPT) and CRSwNP presence or absence.MethodsClinical, functional, and laboratory parameters were measured at baseline and 24 weeks after the first dupilumab administration. Moreover, a comparative evaluation was carried out in relation to the presence or absence of SPT positivity and CRSwNP.ResultsAmong the 127 recruited patients with severe asthma, 90 had positive SPT, while 78 reported CRSwNP. Compared with the 6 months preceding the first dupilumab injection, asthma exacerbations decreased from 4.0 (2.0-5.0) to 0.0 (0.0-0.0) (p < 0.0001), as well as the daily prednisone intake fell from 12.50 mg (0.00-25.00) to 0.00 mg (0.00-0.00) (p < 0.0001). In the same period, asthma control test (ACT) score increased from 14 (10-18) to 22 (20-24) (p < 0.0001), and sino-nasal outcome test (SNOT-22) score dropped from 55.84 ± 20.32 to 19.76 ± 12.76 (p < 0.0001). Moreover, we observed relevant increases in forced expiratory volume in one second (FEV1) from the baseline value of 2.13 L (1.62-2.81) to 2.39 L (1.89-3.06) (p < 0.0001). Fractional exhaled nitric oxide (FeNO) values decreased from 27.0 ppb (18.0-37.5) to 13.0 ppb (5.0-20.0) (p < 0.0001). These improvements were quite similar in subgroups of patients characterized by SPT negativity or positivity, and CRSwNP absence or presence. No statistically significant correlations were detected between serum IgE levels, baseline blood eosinophils or FeNO levels and dupilumab-induced changes, with the exception of FEV1 increase, which was shown to be positively correlated with FeNO values (r = 0.3147; p < 0.01).ConclusionOur results consolidate the strategic position of dupilumab in its role as an excellent therapeutic option currently available within the context of modern biological treatments of severe asthma and CRSwNP, frequently driven by type 2 airway inflammation.

© The author(s). The origin and functions of mast cells (MCs) have been debated since their description by Paul Ehrlich in 1879. MCs have long been considered 'reactive bystanders' and 'amplifiers' in inflammatory processes, allergic reactions, and host responses to infectious diseases. However, knowledge about the origin, phenotypes and functions of MCs has increased substantially over the past 50 years. MCs are now known to be derived from multipotent hematopoietic progenitors, which, through a process of differentiation and maturation, form a unique hematopoietic lineage residing in multiple organs. In particular, MCs are distinguishable from basophils and other hematopoietic cells by their unique phenotype, origin(s), and spectrum of functions, both in innate and adaptive immune responses and in other settings. The concept of a unique MC lineage is further supported by the development of a distinct group of neoplasms, collectively referred to as mastocytosis, in which MC precursors expand as clonal cells. The clinical consequences of the expansion and/or activation of MCs are best established in mastocytosis and in allergic inflammation. However, MCs have also been implicated as important participants in a number of additional pathologic conditions and physiological processes. In this article, we review concepts regarding MC development, factors controlling MC expansion and activation, and some of the fundamental roles MCs may play in both health and disease. We also discuss new concepts for suppressing MC expansion and/or activation using molecularly-targeted drugs. P.V. was supported by the Austrian Science Fund (FWF), grants F4701-B28, F4704-B28 and P32470-B. DDM is supported by the Division of Intramural Research, NIAID. SJG's research is supported by the NIH, USA, the US-Israel Binational Foundation, and the Department of Pathology and the Sean N. Parker Center for Allergy and Asthma Research at Stanford University, Stanford, CA.

The COVID-19 (SARS-CoV-2) pandemic has massively distorted our health care systems and caused catastrophic consequences in our affected communities. The number of victims continues to increase and patients at risk can only be protected to a degree, since the virulent state may be asymptomatic. Risk factors concerning COVID-19-induced morbidity and mortality include advanced age, an impaired immune system, cardiovascular or pulmonary diseases, obesity, diabetes mellitus, and cancer treated with chemotherapy. Here within, we discuss the risk and impact of COVID-19 in patients with mastocytosis and mast cell activation syndromes. As no published data are yet available, expert opinions are, by necessity, based on case experience and reports from patients. Whereas the overall risk to acquire the SARS-CoV-2 virus may not be elevated in mast cell disease, certain conditions may increase the risk of infected patients to develop severe COVID-19. These factors include certain co-morbidities, mast cell activation-related events affecting the cardiovascular or bronchopulmonary system and chemotherapy or immunosuppressive drugs. Therefore, such treatments should be carefully evaluated on a case-by-case basis during a COVID-19 infection. By contrast, other therapies, such as anti-mediator-type drugs, venom immunotherapy, or vitamin D, should be continued. Overall, patients with mast cell disorders should follow the general and local guidelines in the COVID-19 pandemic and advice from their medical provider., P.V. was supported by the Austrian Science Fund (FWF), projects P32470-B and 46 F4704-B20. J.G. is supported by the Charles and Ann Johnson Foundation. 47 D.D.M. is supported by the Division of Intramural Research, NIAID.

Secreted phospholipases A(2) (sPLA(2)s) are molecules released in plasma and biological fluids of patients with systemic inflammatory, autoimmune and allergic diseases. These molecules exert proinflammatory effects by either enzymatic-mechanisms or through binding to surface molecules expressed on inflammatory cells. sPLA(2)s are released at low levels in the normal airways and tend to increase during respiratory allergies (e.g., rhinitis and bronchial asthma) as the result of local secretion. Several sPLA(2) isoforms are expressed in the human lung and some of them (e.g., group IIA and group X) are released in the airways of patients with rhinitis or asthma. Mast cells play a major role in the pathogenesis of respiratory allergies and other chronic inflammatory lung diseases. Recent evidence indicates that mast cells purified from human lung express most of the sPLA(2) isoforms so far described. IgE-mediated activation of these cells induce the release of sPLA(2)s suggesting that mast cells are a main source of extracellular sPLA(2)s during allergic reactions. Once released, sPLA(2)s may contribute to the generation of eicosanoids (e.g., PGD(2) and LTC(4)) and to the release of preformed mediators (e.g., histamine) by an autocrine loop involving the interaction of sPLA(2)s with surface molecules such as heparan sulphate proteoglycans or the M-type receptor. Thus, mast cell-derived sPLA(2)s may play an important role in the initiation and amplification of the inflammatory reactions in patients with allergic rhinitis and bronchial asthma.

Additional file 1: Survey wording (general practitioner, community pharmacist and patient surveys).

Clonal B-cell populations in non-lymphomatous processes have been sporadically reported in enlarged reactive lymph nodes and mucosa-associated lymphoid cell populations. These generally small clones are considered non-malignant proliferations of B-lymphocytes determined by an abnormal response to bacterial or viral antigen stimulation. In cases reported in literature, clonality was detected by light chain assessment and or by polymerase chain reaction (PCR) analysis of immunoglobulin heavy chain (IgH) gene in histologically and clinically proven non lymphomatous processes. In this study the clinical, cytological, phenotypical and pathological features of three HIV patients in which non-lymphomatous clonal B-cell populations detected in enlarged lymph nodes are reported. All the patients complained for later cervical lymph nodes enlargement, positive at the FDG-positron emission tomography scan. Fine needle cytology, coupled with flow cytometry showed atypical lymphoid cell proliferations and kappa (2 cases) or lambda (1 case) light chain restriction. Reactive, non lymphomatous nature of these processes were then proven by histological control in two cases and by clinical follow-up in the last one; corresponding clinical and pathological aspects are discussed. Clonal B-cell populations in non-lymphomatous processes can sporadically occur in enlarged reactive lymph nodes in immunodeficiency as well as in autoimmune processes. Awareness of the phenomenon and attention should be paid in the evaluation of corresponding pathological features and in the clinical management of corresponding patients.

Secretory phospholipases A(2) (sPLA(2)) are an emerging class of mediators of inflammation. These enzymes are released in vivo in patients with systemic inflammatory diseases and allergic disorders. sPLA(2)s may activate inflammatory cells by both enzymatic and nonenzymatic mechanisms. The aim of this study was to evaluate the effect of the inhaled glucocorticoid budesonide on sPLA(2)-induced activation of primary human macrophages.Macrophages isolated from human lung tissue were preincubated (3-18 h) with budesonide (1-1,000 nM) before stimulation with 2 distinct sPLA(2)s (group IA and group X). At the end of incubation the release of TNF-alpha, IL-6 and IL-8 was assessed by ELISA. Specific mRNA for these products was determined by quantitative RT-PCR. Activation of mitogen-activated kinases ERK 1/2 and p38 was assessed by Western blot.Budesonide inhibited the release of TNF-alpha, IL-6 and IL-8 from sPLA(2)-stimulated macrophages in a concentration-dependent manner. The inhibitory effect of budesonide was due to a reduction of gene expression and was complete after 18 h of preincubation. Budesonide had no effect on sPLA(2)-induced arachidonic acid mobilization and exocytosis, assessed as beta-glucuronidase release. Suppression of cytokine/chemokine production by budesonide was associated with inhibition of sPLA(2)-induced ERK 1/2 and p38 activation.Budesonide inhibits the production of proinflammatory cytokines/chemokines from human lung macrophages activated by sPLA(2). Budesonide represents the first example of a drug able to block the nonenzymatic effects of sPLA(2) on human inflammatory cells and, therefore, may provide a useful therapeutic options for diseases associated with enhanced release of sPLA(2)s in vivo.

Abstract 3805 Background: Mastocytosis is a rare disease characterized by an abnormal proliferation and accumulation of mast cells (MC) in several organs and tissues such as skin, bone marrow, liver, gastrointestinal tract and lymphnodes. The reported prevalence of mastocytosis (cutaneous or systemic) is lower than 1/50,000. Mastocytosis encompasses a wide range of clinical entities, extremely heterogeneous for symptoms, clinical course and prognosis. The heterogeneity and the complexity of its clinical signs lead to the definition of mastocytosis as a multidisciplinary pathology, involving different specialists such as hematologists, internists, dermatologists, immunologists and pediatricians. Mastocytosis is a MC clonal disease associated to a somatic mutation (D816V) of the proto-oncogene c-kit (KIT), which codifies for the stem cell factor (SCF) receptor. SFC is the main factor stimulating the proliferation, chemotaxis and activation of human mast cells. Different KIT mutations have been found in 15% of patients. Clinical signs and symptoms of mastocytosis mainly depend on the liberation of chemical mediators produced by the mast cells, on the tissue infiltration of the mast cells and on other associated hematological diseases. Aim of the Registry: promoting studies on mastocytosis in Italy aimed at investigating the epidemiology of the disease, its prognostic factors and health technology assessment (HTA) aspects associated to the management of a rare “orphan” disease. Methods: The Italian Mastocytosis Registry was constituted in 2009, with the aim of promoting communication between specialists and collecting data about patients diagnosed with mastocytosis at a national level. Anagraphical, anamnestic, clinical, biological, treatment and follow-up data of patients with mastocytosis are being routinely collected in 15 Italian centers after written informed consent. An on-line database (www.registroitalianomastocitosi.it) has been set up for this purpose. The collected data will allow specialists to: Results: At present, data on 175 patients have been collected. Seventy-nine (45%) have been diagnosed with systemic mastocytosis and 40 (50%) of them progressed from a cutaneous disease. Ninety-four (54%) are females; 81 (46%) are males. Among 49 patients for whom data on familiarity were available, 12 (24%) reported familiar cases of autoimmune diseases (n=3), allergies (n=5) or interestingly mastocytosis (n=4). Sixty-one (35%) patients reported allergies. Of 121 reported lines of therapy, 37 (31%) were described as not specified anti chemical mediators, 51 (42%) anti-H1, 21 (17%) anti-H2, 30 (25%) corticosteroids, 22 (18%) phototherapy, 7 (6%) alpha-interpheron, 8 (7%) chemotherapy and 13 (11%) tyrosine-kinase inhibitors (total exceeds 100% because multiple choice is allowed). As to the histological findings, 82 (47%) patients have data on bone marrow biopsy: 48 (59%) had a positive finding, with a median mast cells infiltrate of 30% (range 3–90%). Among 43 patients tested for tryptase serum level, 41 (95%) had levels above normal values (12.5 ng/ml). Conclusions: This is the first spontaneous observational study on mastocytosis in Italy. The on-line database is a useful tool for data collection at a national level. The Registry is an opportunity to carry out epidemiological studies aimed at estimating occurrence and geographical distribution of the disease. It will also allow specialists to investigate possible prognostic factors and provide a starting point for the research into ad hoc therapies and HTA studies. It will hopefully provide a link with other international registries to improve understanding of this disease. Last but not least, the Italian Registry may support a National Government policy to provide assistance by the Public Health System to patients with mastocytosis. Disclosures: No relevant conflicts of interest to declare.

Background The aims of this study were: to investigate the capacity of the rare disease healthcare network in Campania to diagnose patients with rare diseases during the outbreak of Covid-19; and to shed light on problematic diagnoses during this period. Methods To describe the impact of the Covid-19 pandemic on the diagnosis of patients with rare diseases, a retrospective analysis of the Campania Region Rare Disease Registry was performed. A tailored questionnaire was sent to rare disease experts to investigate major issues during the emergency period. Results Prevalence of new diagnoses of rare disease in March and April 2020 was significantly lower than in 2019 (117 versus 317, P Conclusions This study describes the effects of the Covid-19 outbreak on the diagnosis of rare disease in a single Italian region and investigates potential issues of diagnosis and management during this period.

Background: Seminal vesicle protein number 4 (SV-IV) is a small, basic, multifunctional, intrinsically disordered secretory protein synthesized in large amounts by rat seminal vesicle epithelium under androgen transcriptional control. SV-IV-immunorelated proteins occur in other rat tissues and in humans. Methods: The in vitro effect of SV-IV on human FcΕRI+ cells was investigated by standard immunologic, biochemical and molecular biology procedures. Results: SV-IV-induced histamine release from human basophils and lung mast cells without any influence on leukotriene C4 release and cell migration. The histamine release rate was slower compared with that induced by anti-IgE, the temperature dependence of the event being similar. SV-IV-induced histamine release was Ca2+-dependent, suggesting a physiological interaction of the protein with FcΕRI+ cells. SV-IV and anti-IgE acted synergistically on the histamine release. SV-IV did not induce de novo synthesis of cytokines and growth factors (transforming growth factor-β1, interleukin-10, interleukin-13, tumor necrosis factor-α, vascular endothelial growth factor A) in FcΕRI+ cells. Conclusions: SV-IV protein induces in human FcΕRI+ cells the release of histamine, a proinflammatory, antiapoptotic and immunosuppressive biogenic amine. These data: (1) are consistent with the antiapoptotic and immunosuppressive properties of SV-IV; (2) confirm a regulatory feature of SV-IV on mammal inflammatory reactivity by either inhibiting the arachidonate cascade pathway or stimulating proinflammatory cytokine release from lymphocyte/monocytes and histamine from FcΕRI+ cells; (3) raise the possibility of a protective role of SV-IV on implanting hemiallogenic blastocysts against maternal reactive oxygen species and immunological attacks at the uterine implantation site.

Human mast cells and basophils are conventionally considered primary effector cells of bronchial asthma. There is now compelling evidence that these cells differ immunologically, biochemically and pharmacologically, which suggests that they might have distinct roles in the appearance and fluctuation of the asthma phenotype. Recent data reveal the complexity of the roles of human mast cells and basophils in asthma and have shed light on the control of recruitment and activation of these cells in different lung compartments. Preliminary evidence suggests that these cells might not always be detrimental in asthma but, under some circumstances, have a protective role in modulating certain aspects of innate and acquired immunity and allergic inflammation.

Over the last few years, the demonstration of beneficial effects of leukotriene receptor antagonists in various forms of asthma has renewed clinical and pharmacologic interest in this class of lipid mediators. Several studies demonstrated an increased biosynthesis of cysteinyl leukotrienes (CysLT) in asthmatic patients. However, the reasons for the dysregulated production of CysLTs in asthmatic patients are not completely defined. An improved method of lipid mediator detection and the availability of cells isolated from human airways (by bronchoalveolar lavage [BAL] and bronchial biopsies) have allowed initial studies to address this issue. Eosinophils retrieved from inflamed airways of asthmatics have a larger arachidonic acid (AA) content than their blood counterpart. The high level of AA in these cells is primarily due to a remodeling of endogenous arachidonate pools with the accumulation of this fatty acid in a triglyceride-associated pool. In addition, elevated levels of a secretory form of phospholipase A2, the key enzyme initiating the cascade of CysLTs, are found in the BAL of asthmatics. Finally, eosinophils isolated from the BAL of asthmatics have an increased expression of LTC4 synthase. The level of expression of this enzyme correlates with the increased amount of CysLTs produced in the airways of these patients. Taken together, these data identify at least two possible mechanisms to explain the excessive CysLT production in asthmatics: 1) an increased content of AA in the glycerolipid pools of inflammatory cells 2) an enhanced activity of key biosynthetic enzymes involved in CysLT synthesis.

SummaryThe most dangerous and life-threatening manifestation of allergic diseases is anaphylaxis, a condition in which the cardiovascular system is responsible for the majority of clinical symptoms and for potentially fatal outcome. The heart is both a source and a target of chemical mediators released during allergic reactions. Mast cells are abundant in the human heart, where they are located predominantly around the adventitia of large coronary arteries and in close contact with the small intramural vessels. Cardiac mast cells can be activated by a variety of stimuli including allergens, complement factors, general anesthetics and muscle relaxants. Mediators released from immunologically activated human heart mast cells strongly influence ventricular function, cardiac rhythm and coronary artery tone. Histamine, cysteinyl leukotrienes and platelet-activating factor (PAF) exert negative inotropic effects and induce myocardial depression that contribute significantly to the pathogenesis of anaphylactic shock. Moreover, cardiac mast cells release chymase and renin that activates the angiotensin system locally, which further induces arteriolar vasoconstriction. The number and density of cardiac mast cells is increased in patients with ischaemic heart disease and dilated cardiomyopathies. This observation may help explain why these conditions are major risk factors for fatal anaphylaxis. A better understanding of the mechanisms involved in cardiac mast cell activation may lead to an improvement in prevention and treatment of systemic anaphylaxis.

BACKGROUND: Histamine modulates several functions in human monocytes, macrophages, and dendritic cells. However, responses elicited by histamine differ depending on cell type, suggesting variable expression of histamine receptors in the monocyte/macrophage lineage. OBJECTIVE: We sought to examine whether the expression of H(1) receptors was regulated by cell differentiation of human monocytes into macrophages or dendritic cells. METHODS: Expression of H(1) receptor was evaluated by RT-PCR and western blot in monocytes, monocyte-derived macrophages (MDMs), monocyte-derived dendritic cells (DCs) and human lung macrophages (HLMs). RESULTS: Expression of H(1) receptor mRNA and protein was higher in HLMs and DCs than in monocytes. H(1) expression was approximately 15-fold and 4-fold higher in MDMs and HLMs, respectively, as compared with that seen in monocytes. H(1) receptor protein was undetectable in monocytes, whereas it was conspicuous in MDMs. Simultaneous analysis of H(2) and H(1) mRNA expression indicated that the H(2)/H(1) ratio decreased from 202.7 +/- 14.8 in monocytes to 2.2 +/- 0.4 in MDM and 39.5 +/- 5.0 in DCs. Incubation of monocytes with histamine neither affected intracellular Ca(2+) concentrations nor influenced IL-8 production. In contrast, histamine rapidly induced a Ca(2+) signal and stimulated IL-8 production in MDMs. Both effects were inhibited by H(1) blockade with levocetirizine, but not by H(2) blockade with ranitidine. CONCLUSIONS: Differentiation of monocytes into macrophages or dendritic cells is associated with profound changes of histamine receptor expression. Upregulation of H(1) receptors confers on macrophages the capacity of being activated by histamine. CLINICAL IMPLICATIONS: Regulation of H(1) and H(2) receptor expression in the monocyte/macrophage lineage can be relevant to the pathogenesis of allergic inflammation.

The evaluation of specific IgE by using appropriate immunoassays represents a useful alternative diagnostic procedure where skin prick tests (SPTs) are not conclusive in clarifying the etiological role of suspected allergens. This study compares the results of the evaluation of specific IgE by using the CARLA system vs. other commercially available immunoassays (CAP system, Ala-STAT Medical system, ALLERgen IFCI Clone System) carried out on the same blood samples obtained from allergic/SPTs negative patients and vs. SPTs. We evaluated serum specific IgE produced against five selected allergens (Dermatophagoides pteronyssinus, Olea europaea, Parietaria judaica, Lolium perenne and Phleum pratense) by using these immunoassays and the correlations between the results of SPTs and IgE evaluations. We demonstrated a good correlation between these last parameters including a high degree of sensitivity and specificity. The reproducibility of the CARLA system was very high by comparing the results obtained by two different laboratories. The results of the CARLA system were well correlated to those of other well-known immunoassays such as CAP system and Ala STAT system. In conclusion, the CARLA system represents an efficient and reliable immunoassay for the evaluation of serum specific IgE.

Histamine is synthesized and released by human basophils, mast cells, and neurons. Its pleiotropic effects are mediated by the activation of 4 receptors: H(1), H(2), H(3), and H(4). With the advent of selective antagonists (the antihistamines widely used to treat allergic disorders), the H(1)-receptor was the first member of the receptor family to be pharmacologically defined. Increasing evidence indicates that, in addition to exerting immediate vascular and bronchial responses, histamine might modulate the immune reaction by interacting with T cells, macrophages, basophils, eosinophils, and monocytes. We have shown that, in vitro, histamine induces a concentration-dependent release of IL-6 and beta-glucuronidase from macrophages isolated from the human lung parenchyma. These effects are inhibited by fexofenadine, an H(1)-receptor antagonist, but not by ranitidine, an H(2)-receptor antagonist. This observation raises the possibility that long-term treatment with fexofenadine might have beneficial effects on immune dysregulation and tissue damage/remodeling associated with histamine-mediated macrophage activation.

Arachidonic acid (AA) is a key molecule in the modulation of several pathophysiological events in mammalian cells, including gene expression, membrane signal transduction, cell differentiation and apoptosis, exocytosis and generation of eicosanoids [1, 2, 3, 4]. It has been now convincingly demonstrated that the intracellular levels of free AA within mammalian cells are crucial for most of these events and, therefore, they are carefully regulated by complex biochemical reactions [5, 6]. These reactions are catalyzed by enzymes involved in both AA mobilization and reesterification into the storage sites and transfer from one intracellular pool to another [7, 8].

Background: Histamine plays a central role in the pathogenesis of allergic and inflammatory diseases by modulating vascular and airway responses. Increasing evidence suggests that histamine also regulates the function of inflammatory and immune cells. Macrophages are primarily involved in inflammatory diseases of the lung. We explored the ability of low concentrations of histamine to induce the release of proinflammatory mediators from human lung macrophages. Methods: Macrophages purified (>95%) from lung parenchyma by Percoll density gradients and adherence to polystyrene dishes were incubated (37°C, 2–24 h) with histamine (10–9–10–6M). At the end of incubation, the release of β-glucuronidase and IL-6 was determined. Results: Histamine induced a concentration-dependent release of β-glucuronidase and IL-6 with a maximum release after 2 and 6 h of incubation, respectively. Exocytosis induced by histamine was noncytotoxic and was Ca2+- and temperature-dependent. The effect of histamine was inhibited by the H1 receptor antagonist fexofenadine but not by the H2 antagonist ranitidine. Conclusions: These data indicate that histamine is an effective stimulus for exocytosis and cytokine production from human lung macrophages. These effects are inhibited by pharmacological concentrations of fexofenadine. Our results suggest that histamine may contribute to the long-term evolution of lung inflammation and tissue remodelling in allergic diseases by modulating the production of proinflammatory and immunoregulatory mediators by macrophages.

Human basophils were first identified by Paul Ehrlich (1878) thanks to the metachromatic staining properties of their cytoplasmic granules [1, 2]. In all mammalian species analysed so far, basophils and mast cells are the only cells that synthesize histamine and express plasma membrane receptors that bind with high affinity the Fce portion of IgE (FceRI) [3]. Human basophils derive from precursors that originate in the bone marrow and in foetal liver and that circulate in peripheral blood. Under normal conditions, basophils are never found in human healthy tissues. Basophils differentiate and mature in the bone marrow and circulate in the blood with a prevalence of ≅ 0.5% of total leukocytes [4]. Under certain circumstances, basophils can be recruited into the inflamed tissue during specific IgEdependent reactions and in association with a variety of pathologic conditions [5, 6, 7, 8]. Increasing evidence suggests that basophils and their mediators are involved in delayed-type hypersensitivity reactions in the human skin and in the lung [5,6, 8, 9].

Propionyl-L-carnitine (PrC) has been shown to exert beneficial effects in the treatment of myocardial and peripheral ischemia in man. These conditions are associated with the activation of circulating neutrophils and platelets. To determine whether PrC could affect the synthesis of lipid mediators known to influence neutrophil and platelet functions, we explored the effects of PrC on the synthesis of platelet-activating factor (PAF) and arachidonic acid (PLA) metabolites. Preincubation (90 min) of human neutrophils with PrC (0.1-100 mu M) inhib- ited the synthesis of PAF and of a PAF analog ( 1-alkyl-l 'enyl-2-acetyl-sn-glycero-3-phosphoethanolamine: AEGPE) induced in vitro by the calcium ionophore A23187. In contrast, concentrations of PrC up to 100 mu M did not influence the uptake of exogenous AA or the A23187-induced release of AA and eicosanoids from neutrophils in vitro. PrC (1 mu M) also inhibited PAF synthesis from human platelets stimulated in vitro with thrombin, but had no effect on thrombin-induced aggregation. Oral administration of PrC (2 g/day for two weeks) to five normal volunteers resulted in a significant inhibition of PAF and AEGPE synthesis by neutrophils stimulated with A23187 ex vivo, with no effect on AA or eicosanoid release. These data indicate that PrC selectively inhibits in vitro and ex vivo PAF synthesis from human neutrophils and platelets without influencing PLA metabolism or eicosanoid release. This effect of PrC might represent an additional mechanism by which this molecule can exert protective effects in tissue ischemia and in other inflammatory diseases associated with neutrophil and platelet activation. (C) 1999 Elsevier Science Inc.

Summary Histamine is an ubiquitous messenger molecule synthetized and released from human basophils, mast cells and neurons. Its various biological effects are mediated by three pharmacologically defined receptors termed the H1, H2 and H3-receptors. The H1-receptor was the first member of this family to be pharmacologically defined with the advent of selective antagonists, the « antihistamines , which are widely used to treat allergic disorders. Recent evidence indicates that certain antihistamines exert antiallergic effects not related to H1-antagonism. However, these effects require higher doses than those regularly used. We have demonstrated that histamine induces a concentration-dependent release of IL-6, TNF-α and β-glucuronidase from human lung macrophages. These effects are inhibited by fexofenadine, an H1-receptor antagonist, but not by cimetidine, an H2-receptor antagonist. The finding that fexofenadine inhibits the human lung macrophages-activating property of histamine raises the possibility that long-term treatment with fexofenadine might inhibit tissue damage caused by human lung macrophages activated by histamine immunologically released by basophils and mast cells.

Heart fragments obtained from human right atrium contain 1.5 ± 0.2 μg of histamine per gram of wet tissue. Human heart spontaneously synthetizes significant amounts of PGI2, PGF2α, PGE2 and TxA2. The Ca2+ ionophore A 23187 (0.5–3 μg/ml) dose-dependently induces histamine release and prostanoid production. Histamine (0.5–1 μg/kg/min) infusion in 10 normal donors produced an increase in heart rate and a significant depression of the ST segment. Selective H1 receptor stimulation in patients undergoing cardiac catheterization resulted in a decrease of the mean aortic pressure and of coronary vascular resistance.

Exogenous histamine in man induces significant cardiovascular effects mediated by activation of H1 and H2-receptors present on human heart and on coronary arteries. We studied the effects of selective H1-receptor stimulation on human coronary hemodynamics in 10 patients undergoing cardiac catheterization. All patients were pretreated with cimetidine before the histamine infusion (0.5 micrograms/kg/min i.v. for 5 min). Six of these patients had normal coronary arteries and four had single vessel coronary artery disease (CAD) and vasospastic angina. During the study heart rate was held constant (100 beats/min) by coronary sinus pacing. We measured mean aortic pressure (MAP), coronary sinus blood flow (CSBF), coronary vascular resistance (CVR) and myocardial oxygen consumption (MVO2) at rest, during histamine infusion, and 10 min after the end of the infusion. During infusion, MAP decreased from 103 +/- 5 to 85 +/- 6 mmHg (p less than 0.02) and CVR from 1.00 +/- 0.16 to 0.81 +/- 0.14 mmHg/ml/min (p less than 0.05); CSBF and MVO2 did not significantly change. All parameters returned to baseline at the end of the infusion. The response was similar in patients with normal coronary arteries and in 3 patients with CAD. Only one patient with CAD developed angina with ST segment elevation in D3, reduction in CSBF and an increase in CVR. These results indicate that H1-receptor stimulation in man induces significant coronary dilatation and that histamine infusion after cimetidine pretreatment is unlikely to provoke coronary spasm in patients with vasospastic angina.

Cutaneous application of the nonsteroidal anti-inflammatory drug (NSAID) ketoprofen has been reported to induce contact dermatitis. However, there is no report of intraoral symptoms after the use of solutions containing this drug. In this report we describe two cases of severe intraoral symptoms after the use of a gargle containing ketoprofen in two patients with NSAIDs hypersensitivity. The patients underwent diagnostic procedures 6 months after the episodes of intraoral symptoms. Procedures included skin prick test for inhalant and food allergens, and total- and specific-IgE determinations to evaluate the presence of atopy. A single-blind, placebo-controlled challenge with different dilutions (1/1000, 1/100, 1/10, and 1/1) of ketoprofen oral solution was carried out by a modified version of a standardized protocol. We used the same commercial solution without the drug as placebo. Diagnostic procedures failed to demonstrate allergic sensitization to the common inhalant and food allergens. Both patients experienced a slight intraoral itching and edema of the lips a few minutes after the intraoral use of 1/100 dilution of active drug. Our cases suggest that the contact of an oral solution containing ketoprofen with oral mucosa may induce locally severe oral manifestations. Patients with NSAIDs sensitivity should be warned on the potential risk of using an oral solution containing this class of drugs.