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The spectrum of gluten-related disorders (GRD) has emerged as a relevant phenomenon possibly impacting on health care procedures and costs worldwide. Current classification of GRD is mainly based on their pathophysiology, and the following categories can be distinguished: immune-mediated disorders that include coeliac disease (CD), dermatitis herpetiformis (DH), and gluten ataxia (GA); allergic reactions such as wheat allergy (WA); and non-coeliac gluten sensitivity (NCGS), a condition characterized by both gastrointestinal and extra-intestinal symptoms subjectively believed to be induced by the ingestion of gluten/wheat that has recently gained popularity. Although CD, DH, and WA are well-defined clinical entities, whose diagnosis is based on specific diagnostic criteria, a diagnosis of NCGS may on the contrary be considered only after the exclusion of other organic disorders. Neither allergic nor autoimmune mechanisms have been found to be involved in NCGS. Mistakes in the diagnosis of GRD are still a relevant clinical problem that may result in overtreatment of patients being unnecessary started on a gluten-free diet and waste of health-care resources. On the basis of our clinical experience and literature, we aim to identify the main pitfalls in the diagnosis of CD and its complications, DH, and WA. We provide a practical methodological approach to guide clinicians on how to recognize and avoid them.

Summary Background Whether blood eosinophil counts and exhaled nitric oxide (FeNO) are associated with important outcomes in mild asthma is unclear. In this prespecified subgroup analysis of a previously published open-label clinical trial, we aimed to assess associations between blood eosinophil counts and FeNO with outcomes and response to asthma treatment. Methods In the previously reported 52-week, open-label, randomised controlled trial, people with mild asthma receiving only β agonist reliever inhalers were enrolled at one of 16 clinical trials units in New Zealand, the UK, Italy, or Australia. Eligible participants were randomly assigned (1:1:1, stratified by country), to receive inhalers to take as-needed salbutamol (two inhalations of 100 μg in a pressurised metered dose inhaler), maintenance budesonide (200 μg twice per day by inhaler) plus as-needed salbutamol (two inhalations of 100 μg), or as-needed budesonide–formoterol (one inhalation of 200 μg budesonide and 6μg formoterol by inhaler). The primary outcome was the annual rates of asthma exacerbations per patient, and in this prespecified subgroup analysis, we assessed whether annual exacerbation rates in each treatment group were significantly different depending on levels of blood eosinophil count, FeNO, or a composite score of both. Analyses were done for patients with available biomarker measurements The study was registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12615000999538. Findings 675 participants were enrolled between March 17, 2016, and Aug 29, 2017, of whom 656 had results for blood eosinophil analysis and 668 had results for FeNO. Of the patients who received as-needed salbutamol, the proportion of patients having a severe exacerbation increased progressively with increasing blood eosinophil count (two [4%] of 49 participants with Interpretation In patients with mild asthma, the effects of as-needed budesonide–formoterol on exacerbations are independent of biomarker profile, whereas the benefits of maintenance inhaled budesonide are greater in patients with high blood eosinophil counts than in patients with low counts. Funding AstraZeneca, Health Research Council of New Zealand.

Apprenticeship is a period of increased risk of developing work-related respiratory allergic diseases. There is a need for documents to provide appropriate professional advice to young adults aiming to reduce unsuitable job choices and prevent impairment from their careers. The present document is the result of a consensus reached by a panel of experts from European and non-European countries addressed to allergologists, pneumologists, occupational physicians, primary care physicians, and other specialists interested in this field, which aims to reduce work-related respiratory allergies (rhinoconjunctivitis and asthma) among allergic or nonallergic apprentices and other young adults entering the workforce. The main objective of the document is to issue consensus suggestions for good clinical practice based on existing scientific evidence and the expertise of a panel of physicians.

To cite this article: Moscato G, Pala G, Perfetti L, Frascaroli M, Pignatti P. Clinical and inflammatory features of occupational asthma caused by persulphate salts in comparison with asthma associated with occupational rhinitis. Allergy 2010; 65: 784–790. Abstract Background: The relationships between asthma and rhinitis are still a crucial point in respiratory allergy and have scarcely been analysed in occupational setting. We aimed to compare the clinical and inflammatory features of subjects with occupational asthma only (OA) to subjects with OA associated to occupational rhinitis (OAR) caused by persulphate salts. Methods: The clinical charts of 26 subjects diagnosed in our Unit as respiratory allergy caused by ammonium persulphate (AP), confirmed by specific inhalation challenge (SIC), were reviewed. Twenty-two out of twenty-six patients underwent pre-SIC-induced sputum challenge test (IS) and 24/26 underwent nasal secretion collection and processing. Results: Twelve out of twenty-six patients received a diagnosis of OA-only and 14/26 of OAR. Duration of exposure before diagnosis, latency period between the beginning of exposure and asthma symptom onset, basal FEV1, airway reactivity to methacholine and asthma severity did not differ in the two groups. Eosinophilic inflammation of upper and lower airways characterized both groups. Eosinophil percentage in IS tended to be higher in OAR [11.9 (5.575–13.925)%] than in OA-only [2.95 (0.225–12.5)%] (P = 0.31). Eosinophilia in nasal secretions was present both in subjects with OAR [55 (46–71)%] and in subjects with OA-only [38 (15–73.5)%], without any significant difference. Discussion: Our results indicate that OA because of ammonium persulphate coexists with occupational rhinitis in half of the patients. Unexpectedly, rhinitis did not seem to have an impact on the natural history of asthma. The finding of nasal inflammation in subjects with OA-only without clinical manifestations of rhinitis supports the united airway disease concept in occupational respiratory allergy as a result of persulphates.

The present document is the result of a consensus reached by a panel of experts from European and nonEuropean countries on Occupational Rhinitis (OR), a disease of emerging relevance, which has received little attention in comparison to occupational asthma. The document covers the main items of OR including epidemiology, diagnosis, management, socio-economic impact, preventive strategies and medicolegal issues. An operational definition and classification of OR tailored to that of occupational asthma, as well as a diagnostic algorithm based on steps allowing different levels of diagnostic evidence, are proposed. The needs for future research are pointed out. Key messages are issued for each item.

Background: Several studies have provided evidence of a strong association between asthma and allergic or nonallergic rhinitis, leading to the hypothesis that allergic rhinitis (AR) and asthma represent a continuum of the same disease. Aim: The aims of our study were: (i) to measure the comorbidity of AR and asthma and asthma-like symptoms and (ii) to assess whether asthma, AR, and their coexistence share a common pattern of individual risk factors. Methods: The subjects are participants from the Italian multicentre, cross-sectional survey on respiratory symptoms in the young adult general population (Italian Study of Asthma in Young Adults, ISAYA). The relationship between individual risk factors and asthma, AR and their coexistence, was studied by means of a multinomial logistic regression. Results: About 60% of asthmatics reported AR. On the other hand, subjects with AR presented an eightfold risk of having asthma compared to subjects without AR. Age was negatively associated with asthma [OR = 0.89, 95% confidence interval (CI): 0.82–0.96], AR (OR = 0.92, 95% CI: 0.86–0.98), and asthma associated with AR (OR = 0.83, 95% CI: 0.79–0.88). The risk of AR without asthma was significantly higher in the upper social classes (OR = 1.23, 95% CI: 1.08–1.39). Active current smoking exposure was positively associated with asthma alone (OR = 1.24, 95% CI: 1.09–1.41) and negatively associated with AR with (OR = 0.69, 95% CI: 0.54–0.88) or without (OR = 0.76, 95% CI: 0.69–0.84) asthma. Conclusions: Asthma and AR coexist in a substantial percentage of patients; bronchial asthma and AR, when associated, seem to share the same risk factors as AR alone while asthma without AR seems to be a different condition, at least with respect to some relevant risk factors.

Background Two types of OA are distinguished: immunological (OA with sensitization) and non-immunological, i.e., irritant induced asthma or reactive airways dysfunction syndrome (RADS). Methods We describe the case of a worker who developed respiratory symptoms after a spill of diphenylmethane diisocyanate (MDI) at the workplace. RADS was initially diagnosed and the worker resumed working. The progressive worsening of symptoms and the appearance of symptoms–work relationship one year later, when concentrations of isocyanates were no longer “irritant,” suggested immunological OA. Results The diagnosis was confirmed by specific inhalation challenge test, followed by removal from exposure and complete recovery. Conclusions In the case of RADS due to an agent with both irritant and sensitizing properties, history should be repeatedly assessed for a possible symptom–work relationship. If this is found, further investigations should be carried out, including specific inhalation challenges, to confirm the possibility of immunological OA. Am. J. Ind. Med. 44:325–328, 2003. © 2003 Wiley-Liss, Inc.

Background: CD69 is a molecule expressed on human eosinophils after cytokine-activation. Different studies have described the eosinophil activation, evaluated by CD69 expression, at the site of an allergic inflammation. In this study we evaluated the expression of CD69 on peripheral blood eosinophils after a specific inhalation challenge (SIC), in order to better define the state of activation of peripheral blood eosinophils after exposure to sensitizers. Methods: CD69 expression was evaluated by flow cytometry in nine asthmatic patients before and after a positive SIC with high or low molecular weight agents (pollens, house dust mites, Penicillia, isocyanates) and in 11 asthmatic patients who underwent an inhalation challenge with placebo. CD69 expression was evaluated at baseline, 120 min, and 240 min after the SIC or the placebo. Results: Baseline (before challenge) CD69 expression was comparable between the group of SIC positive patients and the placebo group. CD69 expression on peripheral eosinophils significantly increased 240 min after the challenge in positive SIC patients compared to placebo. In patients with a positive SIC the percentage of peripheral blood eosinophils significantly decreased at 120 and 240 min after the inhalation challenge with respect to the baseline. Conclusion: CD69 expression on peripheral blood eosinophils is significantly increased in asthmatic patients after exposure to the sensitizing agent. These data show that the effects of a bronchial stimulation are also detectable on peripheral blood eosinophils.

Exposure to cat allergen at school might exacerbate symptoms in asthmatic children with cat allergy. To study this, we identified 410 children, 6-12 yr of age, who were being treated for asthma (inhaled steroids and beta-agonists), were allergic to cats, and had no cat at home. Peak expiratory flow (PEF), asthma symptoms, medication, fever and/or sore throat, and contact with furred pets were recorded twice daily during the last week of summer holidays and the second and third weeks of school. The number of cat owners in each class was recorded. Ninety-two children with asthma reported no contact with furred pets. Among these, children who attended classes with18% (median value) cat owners reported significantly decreased PEF, more days with asthma symptoms, and increased use of medication after school started. Those in classes withor = 18% cat owners reported no change. Children in classes with many cat owners ran a 9-fold increased risk of exacerbated asthma after school start compared with children in classes with few cat owners, after adjusting for age, sex, and fever and/or sore throat. Thus, asthma symptoms, PEF, and the use of asthma medication in children with cat allergy may be affected by indirect cat exposure at school.

Background: HDM distribution varies between geographic areas and may be affected by housing characteristics. We quantified Der p 1 and Der f 1 and assessed the relationships between their levels and housing characteristics in homes of nonallergic subjects. Methods: Der f 1 and Der p 1 were measured by ELISA in dust samples from living-room floors and mattresses of 44 homes of nonallergic subjects in Pavia. Information about household characteristics was obtained by questionnaire. Results: Der p 1 and Der f 1 concentrations (μg/g dust, median) were 0.34 and 7.8 on mattresses, and 0.15 and 0.83 on living-room floors. Higher Der f 1 levels on mattresses were associated with synthetic pillows (P

BACKGROUND Serum eosinophil cationic protein (sECP) has been proposed as a marker of disease activity in bronchial asthma. The study aimed to evaluate the role of sECP in screening asthmatics in a group of subjects with asthma and rhinitis symptoms, and the relationship between sECP and clinical and functional parameters of asthma. METHODS A total of 185 subjects with asthma symptoms, 149 of them with rhinitis as well, underwent skin tests, spirometry, methacholine (MCH) test, blood sampling for eosinophil percentage (bEOS%) and sECP determination, and nasal secretions smear for eosinophil percentage (nEOS%) determination; PEF values, symptoms, and medication over a period of 4 weeks after sampling for sECP quantitation were recorded on a diary. RESULTS A total of 99 (53%) subjects received a diagnosis of asthma (asthmatics), and 86 did not (nonasthmatics). In asthmatics, neither sECP nor bEOS% was significantly different from nonasthmatics. In asthmatics, sECP was higher in subjects with increased than in those with normal daily PEF variability (16.4, 6.8-24.4 vs 5.3, 3.9-8.4 microg/l; P

Aim To evaluate the clinical outcome and socioeconomic consequences of occupational asthma (OA). Subjects and methods Twenty-five patients with OA both to high- and low-molecular-weight agents (3 and 22, respectively) confirmed by specific inhalation challenge were followed up for 12 months after the diagnosis. Upon diagnosis, each patient received a diary on which to report peak expiratory flow rate (PEFR), symptoms, drug consumption, expenses directly or indirectly related to the disease, as well as information regarding personal socioeconomic status. At each follow-up visit (1, 3, 6, and 12 months), the patients underwent clinical examination, spirometry, methacholine (Mch) challenge, and assessment of diary-derived parameters and socioeconomic status. Asthma severity (AS) was classified into four levels, based on symptoms, drug consumption, and PEFR variability. Results At 12 months, 13 patients (group A) had ceased exposure; the remaining 12 patients (group B) continued to be exposed. At diagnosis, FEV1 percent and provocative dose causing a 20% fall in FEV1 (PD20) of Mch were lower in group A than in group B; patients of group A were also characterized by significantly higher basal AS levels. At 12 months, no significant variation in FEV1 percent or PD20 was found for either group, while AS levels improved in both groups, the change being more marked for group A than group B. Pharmaceutical expense at 12 months significantly (p Conclusions In OA, cessation of exposure to the offending agent results in a decrease in asthma severity and in pharmaceutical expenses, but it is associated with a deterioration of the individual's socioeconomic status (professional downgrading and loss of work-derived income). There appears to be a great need for legislation that facilitates the relocation of these patients.

Peak expiratory flow (PEF) monitoring is often used to establish the relationship between occupational exposure and asthma. FEV1 has been found to be a better physiologic index than PEF in the measurement of airflow obstruction. The aim of this study was to compare the accuracy of serial monitoring of PEF and FEV1 in the diagnosis of occupational asthma. Twenty consecutive subjects referred for possible occupational asthma were asked to perform serial monitoring of PEF and FEV1 using a portable ventilometer. Two sets of graphs were plotted for both PEF and FEV1: graphs with the best of all values and graphs with the best of two reproducible values. Three observers interpreted both PEF and FEV1 recordings by the visual method in a blind, randomized manner as either compatible with occupational asthma or not. Eleven of the subjects had a positive inhalation challenge test (high-molecular-weight agents, n = 6; low-molecular-weight agents, n = 5). In the case of analysis of the graphs plotted with the best of all values, the sensitivity of the PEF recording interpreted by the three observers was 82, 73, and 73%, and of the FEV1 recording as 55, 55, and 45%; specificity of PEF recording was 89, 100, and 100%, and of FEV1 was 56, 89, and 100%. When an agreement between two of the three readers was required to define occupational asthma, sensitivity and specificity were 73 and 100% for PEF and 55 and 89% for FEV1. Lower sensitivities were found when the same analyses were performed with the graphs plotted with the best of two reproducible values. It was concluded that unsupervised FEV1 is not more accurate than unsupervised PEF monitoring in the diagnosis of occupational asthma. Plotting graphs using the best value gives better diagnostic accuracy than plotting them with the best of two reproducible values.

This article examines the relationships between the indoor environment and the development of bronchial hyperreactivity and asthma. A large number of pollutants, both chemicals and biological agents, are detectable indoors, including several allergens, i.e. substances that can stimulate an IgE response. The sources most widely recognised as indoor allergens for asthma and rhinitis are mites and pets. A relationship between levels of exposure to these agents and the development of sensitisation or asthma in genetically susceptible indi viduals has been clearly demonstrated together with a reduction of symptoms after the application of avoidance procedures. Apart from preventative proce dures directed to the patient, which are expensive and time-consuming, great benefit could also come, in the future, from addressing the problems of inade quacy in buildings, for instance by improving ventilation rates and heating systems.

Background: Persulfate salts are components of bleaching powders widely used by hairdressers during hair-bleaching procedures. Hairdressers are at high risk for occupational asthma and rhinitis, and ammonium persulfate is the main etiologic agent. Objective: To explore the effects of ammonium persulfate on human albumin, mast cells, and basophils in order to evaluate a possible effect of ammonium persulfate oxidizing activity in the mechanism of ammonium persulfate-induced occupational asthma. Methods: High-performance liquid chromatography/mass spectrometry was performed on ammonium persulfate-incubated human albumin. The activation of LAD2 human mast cell and KU812 human basophil cell lines incubated with ammonium persulfate was evaluated. CD63 expression on persulfate-in-vitro-incubated blood basophils from nonexposed healthy controls (n = 31) and hairdressers with work-related respiratory symptoms (n = 29) was assessed by flow cytometry. Results: No persulfate-albumin conjugate was found. An oxidative process on tryptophan and methionine was detected. Ammonium persulfate induced reactive oxygen species (ROS) generation and the degranulation of LAD2 and KU812 cells. Human basophils from healthy controls, incubated in vitro with ammonium persulfate, showed increased CD63 expression and ROS production. In hairdressers with ammonium persulfate-caused occupational asthma (positive persulfate challenge), basophil-CD63 expression was higher than in those with a negative challenge and in healthy controls. Conclusions: Ammonium persulfate incubated with human albumin did not generate any adduct but oxidized some amino acids. This oxidizing activity induced human mast cell and basophil activation which might be crucial in the mechanism of persulfate-induced occupational asthma and rhinitis.

Exposure to indoor allergens can occur both at home and in public places such as schools and workplaces. To investigate and compare the presence of indoor allergens in different kind of environments (schools, offices and homes), dust samples were collected from furniture, desks, mattresses and floors with a standardized procedure. Samples were analyzed for Der p 1, Der f 1, Mite group 2 (mites) and Fel d 1(cat) by monoclonal antibody ELISA assay. Mite allergens were detected with low frequencies in schools and workplaces and with high frequency in homes. Fel d 1 was found with high frequency in every examined environment. Homes rather than public places can represent the environment where people can easier incur in mite allergy. All environments could be at risk for cat allergen exposure.

To investigate the usefulness of nasal blown secretion evaluation during specific nasal provocation test (sNPT) in diagnosing occupational rhinitis (OR). To validate the method, nasal blown secretions from 103 healthy subjects and 30 allergic rhinitis patients were analyzed. Furthermore, we analyzed nasal blown secretions, collected before and after sNPT, of 29 subjects with work-related rhinitis symptoms (WRRS) who underwent the diagnostic pathway for OR. Rhinoscopy and nasal symptom score were used to define a positive sNPT. A total of 89.6% WRRS subjects provided suitable nasal secretions. Eosinophils significantly increased after positive sNPTs compared to negative ones (P = 0.006). Four percent and/or 1 × 104 eosinophils/ml was the cut-off for a significant post-sNPT eosinophil increase. A total of 4/13 (33%) WRRS subjects with negative sNPT, assessed by rhinoscopy and nasal symptom score, presented a significant post-sNPT nasal eosinophil increase, and were identified as possible OR. Eosinophil evaluation in nasal blown secretions is an important tool in monitoring the response to occupational specific nasal challenges.

The present study assessed the usefulness of key items obtained from a clinical "open" questionnaire prospectively administered to 212 subjects, referred to four tertiary-care hospitals for predicting the diagnosis of occupational asthma (OA). Of these subjects, 72 (34%) were diagnosed as OA (53% with OA due to high-molecular-weight agents) according to results of specific inhalation challenges, and 90 (42%) as non-OA. Wheezing at work occurred in 88% of subjects with OA and was the most specific symptom (85%). Nasal and eye symptoms were commonly associated symptoms. Wheezing, nasal and ocular itching at work were positively, and loss of voice negatively associated with the presence of OA in the case of high-, but not low molecular-weight agents. A prediction model based on responses to nasal itching, daily symptoms over the week at work, nasal secretions, absence of loss of voice, wheezing, and sputum, correctly predicted 156 out of 212 (74%) subjects according to the presence or absence of OA by final diagnosis. In conclusion, key items, i.e. wheezing, nasal and ocular itching and loss of voice, are satisfactorily associated with the presence of occupational asthma in subjects exposed to high-molecular-weight agents. Therefore, these should be addressed with high priority by physicians. However, no questionnaire-derived item is helpful in subjects exposed to low-molecular-weight agents.

Background: Hairdressers are at risk for occupational respiratory diseases, but the risk factors, causal agents, and underlying mechanisms are not completely defined. Aim: To describe the features of a large group of hairdressers consecutively referred to our center for suspected occupational asthma (OA) over an 8-year period, the type of occupational respiratory diseases, the etiologic agents, and the diagnostic tests. Results: Forty-seven hairdressers (mean age, 25 years; range, 17 to 52 years) were studied. On the basis of the response to the specific inhalation challenge (SIC), 24 patients received a diagnosis of OA (51.1%), which was due to persulfate salts in 21 patients (87.5%), permanent hair dyes in 2 patients (8.3%), and latex in 1 patient (4.2%). Thirteen of these 24 patients (54.2%) also received a diagnosis of occupational rhinitis, which was due to persulfate salts in 11 patients (84.6%) and to paraphenylenediamine in two patients (15.4%). Patients with persulfate asthma had a long period of exposure to bleaching agents, a long latent period between the start of exposure and the onset of symptoms, and a prevalent eosinophilic airway inflammation in induced sputum. The skin-prick test with ammonium persulfate performed in a subset of patients gave negative results Conclusions: In the present study, we confirmed that persulfate salts are the major agents involved in OA and occupational rhinitis in hairdressers. The positive response to the SIC in only a part of the population of symptomatic exposed workers, the period between the starting of exposure and the onset of symptoms, the type of response to the SIC, and the high frequency of association of asthma with other diseases such as dermatitis and rhinitis suggest an immunologic mechanism that remains to be elucidated.

Objective This report describes a case of vocal cord dysfunction at first misdiagnosed as reactive airway dysfunction syndrome (RADS). Methods A woman developed recurrent episodes of cough, dyspnea, and wheezing unresponsive to asthma therapy after irritant exposure to glutaraldehyde. Direct laryngoscopy was performed immediately after the induction of symptoms. Results Laringoscopy showed a paradoxical adduction of the vocal cord on inspiration. Vocal cord dysfunction was diagnosed. Conclusions A case of vocal cord dysfunction occurred after exposure to glutaraldheyde in a person with a history highly suggestive of RADS. Vocal cord dysfunction should always be considered in the differential diagnosis of patients with acute respiratory symptoms after exposure to irritants and with asthma-like symptoms that fail to respond to conventional asthma therapy.

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The case history is described of a worker who presented with a history suggestive of reactive airways dysfunction syndrome which occurred after an acute high level inhalation of diphenylmethane diisocyanate. Further exposure at work, at a time when concentrations of isocyanates were no longer "irritant", suggested occupational asthma; this diagnosis was confirmed by a specific inhalation challenge test.

International audience; A novel experimental apparatus for time and angle-resolved photoemission on solid surfaces is presented. A 6.28 eV laser source operating at 250 kHz repetition rate is obtained by frequency mixing in nonlinear beta barium borate crystals. This UV light source has a high photon flux of 10(13) photons/s with relatively low number of photons/pulse so that Fermi surface mapping over a wide region of the Brillouin zone is possible while mitigating space charge effects. The UV source has been fully characterized spatially, spectrally, and temporally. Its potential for time and angle-resolved photoemission is demonstrated through Fermi surface mapping and photoexcited electron dynamics in Bismuth. True femtosecond time resolution

In order to evaluate the efficacy of topical khellin the vitiligo macules of one side only were painted in 41 patients with a 2% solution of khellin in acetone and propylene glycol (90 and 10%, respectively) and exposed to sunlight for a period of 4 months with 3 weekly applications and with exposure times up to 90 min. The macules of the other side were treated in 36 of the 41 patients with acetone and propylene glycol only and sun-exposed with the same schedule, while in the remaining 5 patients they were neither treated with khellin or placebo nor sun-exposed. No significant difference was evidenced between the khellin and placebo-treated sides: no excellent result (repigmentation more than 75% of the affected area) was found, and good results (repigmentation more than 50%) were found in 24.9% of khellin- plus sunlight-treated macules and in 22.3% of placebo- plus sunlight-treated macules.

The present document is the result of a consensus reached by a panel of experts from European and non-European countries on Occupational Rhinitis (OR), a disease of emerging relevance which has received little attention in comparison to occupational asthma. The document covers the main items of OR including epidemiology, diagnosis, management, socio-economic impact, preventive strategies and medicolegal issues. An operational definition and classification of OR tailored on that of occupational asthma, as well as a diagnostic algorithm based on steps allowing for different levels of diagnostic evidence are proposed. The needs for future research are pointed out. Key messages are issued for each item.