WAO - ARIA consensus on chronic cough: Executive summary

Abstract

Acute cough is a highly prevalent symptom in clinical practice. Chronic cough is a complex disease with significant impact on quality of life. The mechanistic pathways of chronic cough in cough-comorbid clinical phenotypes are elusive. Mounting evidence suggests presence of a hypersensitive cough reflex and implication of transient receptor potential channels and P2X receptors in cough neuronal pathways. Previously, the World Allergy Organization (WAO)/Allergic Rhinitis and its Impact on Asthma (ARIA) Joint Committee on Chronic Cough published updated experimental and clinical data on chronic cough, in addition to a multidisciplinary care pathway approach to its management. The goal of this manuscript is to provide clinicians with a succinct summary of chronic cough pathophysiology, clinical phenotypes, and management strategies in both primary and cough specialty care. This executive summary is a primer for clinicians on chronic cough. Increasing awareness on the topic among primary care physicians will improve the outcome of management of patients with chronic cough.

Introduction

The executive summary of chronic cough (CC) is developed as a conspectus of the previous WAO-ARIA joint consensus publications on CC.1, 2, 3 The goal of this manuscript is to provide clinicians, more so primary care physicians (PCPs), with succinct summary of CC epidemiology and pathophysiology, clinical phenotypes, and multidisciplinary management strategies.

Definitions of cough

Cough is a forced expulsive maneuver against a closed glottis. Arbitrarily, cough persisting for more than 4 or 8 weeks in children and adults, respectively, is termed CC.⁴ In normal individuals, up to 15 coughs are recorded per day compared to 794 coughs per day in chronic coughers.⁵ If exhaustive clinical investigations fail to determine a cough etiological factor, CC is termed Unexplained Chronic Cough (UCC).⁶ Alternatively, if CC fails conventional pharmacotherapy despite extensive exploration of probable etiologies, it is termed Refractory Chronic Cough (RCC) (see Fig. 1).⁷ As it will be discussed, CC can be considered as a distinct clinical illness with an underlying pathophysiological hypersensitivity of the cough neural reflex, occasionally linked to environmental triggers, cough-comorbid airway diseases, and/or gastroesophageal reflux disease (GERD).

Fig. 1.

Cough definition according to chronology of symptom, diagnostic workup, and response to management.

Epidemiology and burden of chronic cough

Cough represents one of the most common symptoms encountered in clinical practice.^8,9 CC prevalence ranges between 2.5% and 18% in primary care,^10,11 increases with age, and is predominant in females in their sixth decade of life.^12,13 It is estimated both UCC and RCC comprise 2%–5% of the CC found in the general population.⁶ CC poses a detrimental impact on the quality of life (QoL)14, 15, 16, 17 and a significant burden on the health care system.¹⁸

Anatomical considerations in chronic cough

The vagus nerve expresses 2 afferent cough neuronal pathways in the airway mucosa. These carry distinctive sensory functions in the cough reflex arc. One mechanosensitive pathway carries A-δ fibers and responds to light touch. Thus, it protects the airways from mucus, inhalation of foreign material, and intrinsic acid. Incorporated mechano-transducers can include transient receptor potential (TRP) channels, voltage-gated sodium channels subtype, and acid-sensing ion channels. Another chemosensitive pathway carries unmyelinated C fibers and responds to various noxious stimuli. These can include adenosine triphosphate (ATP) released during cell damage in the airways,¹⁹ inflammatory mediators such as prostaglandins,^20,21 irritants, temperature and acidity changes.^21,22 Activation of receptors in different pathways is not mutually exclusive but can occur simultaneously, according to the nature of trigger. Of note, cough can occur by itself, in the absence of triggers, reminiscent of neuropathic pain syndrome.²³

Pathophysiology of chronic cough

It is speculated the cough reflex undergoes both neurogenic and inflammatory alterations of its vagal neuronal pathways and thus becomes hypersensitive, the so-called hypersensitive cough reflex (HCR). This neuro-immune modulation of the cough reflex occurs via production of several neuromediators (ie, neurokinin and bradykinin, prostaglandin and calcitonin gene related peptide), in addition to immune cell activation (mast cells, eosinophils, and neutrophils).²⁴ The TRP channels and P2X receptors play a pivotal role in this neuro-immune cross-talk.²⁵ Consequently, HCR is a manifestation of a neuronal tussive threshold modulation, resulting in CC.²⁶

Clinical cough models use experimental inhaled tussigens such as capsaicin, citric acid, among others, to study cough mechanistic pathways in patients with CC. The resulting dose-response curves are expressed in terms of tussigen concentration which can elicit 2 (C₂) or 5 (C₅) coughs. Chronic coughers can exhibit smaller C₂ or C₅ levels when compared to healthy individuals,^23,27 denoting presence of HCR in the former.28, 29, 30, 31, 32, 33, 34

Phenotypes of chronic cough

CC phenotypes can be broadly divided according to their etiological anatomical origins, namely upper and lower airways, or GERD-related cough. Other important cough-comorbid pathologies include laryngeal hyperresponsiveness (LHR) and obstructive sleep apnea (OSA), drug-induced cough and post-COVID-19 cough, psychological cough, and UCC/RCC, in addition to multifactorial cough.³⁵ The prevalence of etiologic CC phenotypes are quite variable in epidemiologic studies,^36,37 and can be age-related. For example, rhinitis, adenoiditis, and rhinosinusitis are important etiologies of CC among pre-school and school-aged children.^38,39 This can be related to the poor maturation of the cough reflex in children.⁴⁰

Upper airway cough syndrome (UACS)

UACS is poorly characterized in terms of a universal definition and prevalence rates, likely due to confounding variables in epidemiological studies.^37,41,42 Pathogenesis of cough in UACS can be multifactorial. Mechanical or chemical triggers at peripheral sensory terminals of the trigeminal nerve and superior branches of vagus nerve can elicit cough, reminiscent of central neuronal convergence centers described elsewhere.^43,44 Other mechanistic pathways involve a hematogenous as well as a neural spread of inflammatory mediators between the upper and lower airways, in accordance with the united airway hypothesis.^45,46 Notwithstanding, cough challenge models indicate nasal triggers can potentiate the cough reflex in the lower airways denoting the presence of a HCR in the upper airways.^32,47

Rhinitis and rhinosinusitis

Epidemiological studies suggest patients with upper respiratory tract infection and post-viral cough,⁴⁸ in addition to allergic rhinitis (AR), can manifest CC. A longitudinal cohort study revealed, non-infectious rhinitis is a significant and independent risk factor for development of CC in adults.⁴⁹ This is further elucidated by cough challenge data which confirm presence of a decreased cough threshold to inhaled capsaicin (ie, presence of HCR) in patients with upper respiratory tract infection⁴⁸ and allergic rhinitis.^31,50 The increased tussive response (↓C₂ and/or ↓C₅) to capsaicin challenge in AR is in accordance with the “priming effect”, ie, reduced activation threshold of sensory nerves in response to IgE and non-IgE related stimuli following allergen exposure.^51,52 Non-allergic rhinopathies involve variable degrees of nasal hyperactivity,^53,54 yet CC is infrequently reported.⁵⁵ Clinically, cough is a major feature of chronic rhinosinusitis among pediatric population but not adults.⁵⁶ Also, pharmacotherapy of sinusitis improved cough in children, but not in adults.57, 58, 59

Obstructive sleep apnea syndrome and laryngeal hyperresponsiveness

OSA syndrome can present solely with CC.⁶⁰ When compared to the general population, OSA patients have a higher prevalence of cough (33%–39%).⁶¹ This has been linked to increased production of inflammatory mediators, exhaled nitric oxide, sputum neutrophilia, or dysfunctional tussive central inhibition by the obstructive respiratory events.^62,63 Continuous positive airway pressure therapy in patients with OSA and cough improves cough reflex sensitivity, cough related QoL, and cough scores.^60,61,64,65

Patients with vocal cord dysfunction, muscle tension dysphonia, and globus, collectively called LHR,⁶⁶ exhibit paradoxical vocal cord movements in response to noxious stimuli.⁶⁷ LHR can be present in up to 50% of CC patient population.⁶⁸ Epidemiological studies demonstrate a high association of LHR with cough as expressed in different CC phenotypes, irrespective of presence or absence of asthma. Chemosensitive receptors of the afferent laryngeal branch of vagus nerve and efferent recurrent laryngeal nerve are implicated, however comprehensive immunological and physiological data on neurogenic inflammatory pathways involved in LHR are currently lacking.⁶⁹

Lower airway cough syndrome

CC is a cardinal symptom in chronic inflammatory lower airway diseases, such as classic asthma (CA) and cough variant asthma (CVA), non-asthmatic eosinophilic bronchitis (NAEB) and chronic obstructive pulmonary disease (COPD).⁷⁰ The clinical and immunological characteristics of these cough phenotypic traits are complex. They can feature variable airway eosinophilia, airway hyperreactivity (preservation or loss of deep inspiration cough bronchoprotective reflex), prostaglandin E₂ receptor expression (bronchodilation), and hyperresponsiveness to bronchial challenge testing.² For example, methacholine-induced bronchial responsiveness can be present in patients with CA and COPD, but can be borderline in patients with CVA and absent in those with NAEB. Notwithstanding, cough challenge studies demonstrate the presence of HCR in all reactive lower airway diseases (vagal C fibers activation), except for NAEB where currently insufficient data exist.² The presence of atopy can further complicate the picture. In cough challenge studies, atopic patients with asthma had unexpectedly better cough scores when compared to patients with non-atopic asthma. However, both asthmatic groups in single or combination had worse cough scores when compared to healthy controls.²⁷ This suggest atopy is not a risk factor for CC in asthma although type 2 inflammation and airway eosinophilia are prominent features of CC phenotypes in the lower airways. Also, neuromechanical modifications of the bronchial tree diameter, its length and pressure, as occurs for example during bronchoconstriction in asthma, can also contribute to CC.⁷¹ How these factors interact collectively to modulate cough threshold is elusive.

CA is one of the most common etiologies of CC.⁷² The control of cough predicts the severity and prognosis of asthma.⁷³ The pathophysiology of cough in asthma is complex and includes a HCR, an increase in inflammatory mediators, abnormal neuromechanical properties, and loss of deep inspiration-broncho protective reflex. These factors can act either in single or in combination, which adds to the complexity of CC.² NAEB is an atopic or non-atopic cough phenotype with marked endogenous prostaglandin E₂ receptor expression (bronchodilation) and thus lacks bronchoconstriction and bronchial hyperresponsiveness.^74,75 Also, CVA lacks wheezing or dyspnea⁷⁶ and can present solely or predominantly with cough.⁷⁷ Patients with CVA demonstrate borderline airway hyperresponsiveness on methacholine challenge⁷⁸ and can respond properly to anti-asthma medications.⁷⁶ In patients with COPD, sputum production is a frequent cause of chronic cough which is associated with lower FEV1, more severe dyspnea and airflow limitation, and worse clinical outcomes compared to non-coughing COPD patients.^79,80

Reflux-related cough syndrome

The diagnosis of GERD is complex. The gastroesophageal refluxate can be liquid or gaseous, acidic or non-acidic, and occasionally exaggerated by esophageal impaired motility. Cough is an extra-esophageal symptom frequently experienced in GERD with high variability in reported prevalence rates.81, 82, 83 The “reflex theory” speculates the presence of central convergence centers linking esophageal afferent and bronchial efferent nerve fibers, which can trigger cough. Alternatively, the “reflux theory” hypothesizes a direct injury to the lower airway mucosa by esophageal refluxate.⁸⁴ Clinically, acid and non-acid reflux can be measured using pH and impedance probes, respectively, whereas esophageal motility disorders can be assessed using a pressure probe. Notwithstanding, pathogenic mechanisms linking CC and GERD are inconclusive.^85,86

Multifactorial cough

Multifactorial cough is poorly defined in terms of prevalence rates, symptomatology, and response to therapy.⁷⁰ It should be considered in coughing patients with severe symptoms who do not respond to classical treatment of a single cough-underlying condition. Epidemiological data suggest the most common combinations of cough phenotypes are CVA and UACS in children,³⁷ and atopic cough with GERD in adults.³⁶ Also, GERD-related cough in association with either upper or lower airway cough syndrome is reportedly more severe than airway only-related CC.⁸⁷ This is expressed in terms of utilization of health care resources (ie, emergency visits, hospitalization), and intake of anti-tussive medications.⁸⁷

Management of chronic cough

Management of CC entails exhaustive diagnostic evaluation and proper control of cough “treatable” traits, thus necessitating an integrated care pathway approach (see Fig. 2). PCPs encounter initially most of CC patients. They can identify risk factors and environmental triggers, such as drug-induced CC, tobacco smoke exposure, and recommend proper avoidance measures.^88,89 PCPs can also administer empirical therapy for common cough etiological diseases, such as upper respiratory tract infection and GERD, AR and asthma, among others.⁹⁰ If cough control fails, PCPs can then refer patients to cough specialists in view of a limited access of the formers to advanced cough diagnostic modalities. Multidisciplinary cough specialists hold a wide armamentarium of ancillary testing to improve cough diagnostic accuracy. Cough control using conventional, guideline-based recommendations can then be achieved in most CC patients.^4,91, 92, 93, 94, 95 Alternatively, a minority of patients with UCC or RCC necessitates therapy with neuromodulators. Hence, such a multidisciplinary approach enhances overdiagnosis of idiopathic cough and improves outcomes of cough management.^6,96

Fig. 2.

“Propeller” model for management of chronic cough in primary (central circle) and cough specialty (propeller “blades”) care. ACO (asthma COPD overlap), AR (allergic rhinitis), CA (classic asthma), CB (chronic bronchitis), COPD (chronic obstructive pulmonary disease), CRS (chronic rhinosinusitis), CVA (cough variant asthma), GERD (gastroesophageal reflux disease), LHR (laryngeal hyperresponsiveness), NAEB (non-asthmatic eosinophilic bronchitis), NP (nasal polyp), OSA (obstructive sleep apnea), PCPs (primary care physicians), RCC (refractory chronic cough), UCC (unexplained chronic cough).

Scope of management in primary care

Diagnosis

• -Risk factors can be habitual, environmental, natural or acquired, ie, smoking (active/passive), occupational or environmental pollutant exposure, travel history, OSA, along with age.
• -“Red flag” symptoms should alert the physician to more serious comorbid conditions with CC, eg, tumors, cardiovascular diseases, or severe infections.⁹⁷
• -Drug-induced cough encompasses a spectrum of frequently prescribed medications encountered in primary care, ie, angiotensin-converting enzyme inhibitors and opioids, prostanoid eye drops, statins, and non-steroidal anti-inflammatory drugs.98, 99, 100 Cough-induced by non-selective betablockers relates more to a direct bronchospasm effect rather than activation of cough receptors.¹⁰¹
• -A comprehensive physical examination
• -Radiology: a chest X-ray is routinely performed as an informative screening test for lower airway diseases, ie, pneumonia, tuberculosis, or foreign body inhalation; however, it has poor sensitivity for interstitial lung diseases (chronic dry cough) and bronchiectasis (chronic productive cough).¹⁰²
• -QoL cough questionnaire or visual analog score are recommended to quantitate the current impact of CC prior to or following therapy,¹⁰³ ie, Leicester cough questionnaire.¹⁰⁴

Pharmacotherapy

Based on the initial evaluation, a PCP can tailor pharmacotherapy according to suspected etiological trigger(s) of cough (ie, atopy, infection).⁹⁰ Listed below are recommended empirical therapies for CC, based on their level of evidence and consensus among authors.

• 1.Upper airways cough syndrome: An initial 4-week course of intranasal corticosteroids is recommended in atopic (ie, AR) and non-atopic (ie, chronic rhinosinusitis) cough-comorbid upper airway diseases, in view of data suggesting efficacy.105, 106, 107 Symptomatic improvement entails continuation of therapy for one additional month and reassessment later on.¹⁰⁸ The expert panel does not recommend use of second generation oral antihistamines and leukotriene receptor antagonists in UACS in absence of evidence suggesting efficacy in reducing cough.109, 110, 111
• 2.Lower airways cough syndrome: An initial 2-week course of inhaled beta 2 agonists and corticosteroids combination is recommended. If poorly tolerated, inhaled corticosteroids can be substituted with oral corticosteroids.¹¹² Symptomatic improvement entails continuation of therapy for one additional month and reassessment later on.¹¹³
• 3.Reflux cough syndrome: A 4- to 12-week course of proton pump inhibitors (PPIs) was recommended in the initial manuscript, as an off-label use.³ In view of recent data promoting a judicious use of PPIs (2023),¹¹⁴ the expert panel recommends a shorter empirical therapy of 4- to 8-weeks followed by tapering of dosage. Anti-reflux measures also include diet modification, weight loss, and use of antiacids, among others.

Scope of management in advanced care

Failure to control cough in primary care entails referral to one or multiple cough subspecialties (ie, multifactorial cough). Allergy, Ear-Nose-Throat, Pulmonary, and Gastroenterology specialists can conduct clinical investigations for guideline-based management of cough-comorbid conditions.

• -In the upper airways, naso-pharyngo-laryngoscopy¹¹⁵ and polysomnography¹¹⁶ are invaluable in diagnosing sinusitis and OSA, respectively. Laryngoscopy, at times coupled with stroboscopy, is helpful in diagnosing laryngeal pathologies such as LHR and tumors, foreign body inhalation and vocal cord mobility disorders.¹¹⁷ Evidence-based management of cough-associated upper airway disorders and its impact on CC awaits further investigation.
• -In the lower airways, spirometry with bronchodilator reversibility test and bronchial challenge testing (BCT) can be decisive in diagnosing cough-associated lower airway diseases.² For example, NAEB is marked by absence of hyperresponsiveness on spirometry and BCT. In CVA, bronchial hyperexcitability is absent (or borderline) on spirometry, but not on BCT. In asthma, both tests can be positive. In addition to asthma, abnormal spirometry is encountered in COPD and asthma-COPD overlap. Additionally, FeNO levels can assist in identifying subgroups with asthma, CVA, and NAEB as potential causes of chronic cough.² However, the lack of clear cut-off level of FeNO for the etiological diagnosis of the aforementioned subgroups limits its usefulness as a routine diagnostic and follow-up tool in CC.118, 119, 120 Blood eosinophil counts have a moderate diagnostic value for identifying sputum eosinophilia in patients with chronic cough.¹²¹ Despite its inherent technical difficulties, induced sputum is a proper surrogate marker for airway eosinophilia.^122,123 CT scan of lung is informative in parenchymal lung diseases, such as bronchiectasis. Efficacy data on pharmacotherapy of cough-comorbid diseases of the lower airways is overwhelming. Yet, its efficacy in improving CC is currently unknown.^124,125
• -GERD-related cough which is refractory to PPI therapy can suggest non-acid or gas reflux. The multichannel impedance and pH-metry (MII-pH-metry) is the gold standard diagnostic modality for non-acid reflux, yet it is an invasive 24-hr ambulatory test with limited availability.¹²⁶ An EGD is performed concomitantly to rule out other diagnoses which can aggravate cough but are not necessarily related to it, such as eosinophilic esophagitis and Barrett's esophagus, among others.^127,128 Esophageal manometry is reserved for patients with suspected esophageal motility disorders. Patients with non-PPI-responsive cough and negative MII-pH-metry studies are unlikely to have GERD-related cough. Alternately, those with confirmed GERD-related cough can benefit from surgery.¹²⁹

Neuromodulator pharmacotherapy

Neuromodulators can be indicated in UCC or RCC patients who fail a significant response to therapy with various medications for a long period, in some cases over a year.⁹⁵ In principle, neuromodulators can “attenuate” or “modulate” the HCR, thus improving cough. They can be classified into peripherally acting or centrally acting drugs.⁷

Central neuromodulators, such as morphine and amitriptyline, gabapentin and pregabalin can improve cough severity, frequency, and cough related QoL, albeit to variable degrees.³ They exhibit significant central side effects (ie, drowsiness, confusion) and low evidence of efficacy (Grade IIC) in reported studies, which precludes their approval for CC management in Europe or in the United States.^7,130,131 Interestingly, overpitant, a neurokinin antagonist, improved cough qualities with an acceptable safety profile in a phase II pilot study, thus awaiting further investigation.¹³²

Peripheral neuromodulators, such as P2X3 antagonist (gefapixant), have an anti-tussive effect. ATP, a breakdown product of cellular damage, is a neurotransmitter in the purinergic system and has a high predilection to P2X channels present on peripheral cough neuronal networks. Once depolarized by ATP, P2X3 channels desensitize the cough neuronal pathway, thus suppressing cough.¹³³ In a proof-of-concept study, gefapixant improved cough qualities in patients with UCC. Though self-limited, dysgeusia was noted in majority of patients.⁹⁶ Of note, more recent data suggest consistent efficacy of gefapixant in UCC/RCC.⁹⁶ However, this compound has yet been to be approved by the Food and Drug Administration (FDA) in the United States.

Speech therapy

Speech therapy is a behavioral modification technique for patients with RCC. The cough suppression strategy consists of several training protocols including breathing and swallowing exercises, avoidance of cough-triggering diets, and psychogenic counselling vis-a-vis cough-impacted QoL.134, 135, 136 This strategy can be implemented prior, during, or following medical therapy for CC, with limited benefit noted in some patients.^134,135,137

Conclusion

Chronic cough is a challenging clinical entity characterized by complex neuro-anatomical networks and intricate pathophysiological mechanisms, resulting in hypersensitivity of the cough neural reflex. The management of chronic cough comorbid conditions involves an integrated care pathway approach. Initially, PCPs have a cardinal role in a comprehensive assessment and management of CC patients. Referral to cough specialty care for further investigations is recommended if cough control fails or is partially achieved. In patients with RCC/UCC, neuromodulator pharmacotherapy targeting peripheral cough neuronal receptors (eg, P2X3) is promising, yet further data is needed regarding efficacy and safety.

Abbreviations

ATP, adenosine triphosphate; CA, classic asthma; CC, chronic cough; COPD, chronic obstructive pulmonary disease; CVA, cough variant asthma; GERD, gastroesophageal reflux disease; HCR, hypersensitive cough reflex; LHR, laryngeal hyperresponsiveness; NAEB, non-asthmatic eosinophilic bronchitis; OSA, obstructive sleep apnea; PCPs, primary care physicians; PPI, proton pump inhibitor; QoL, quality of life; RCC, refractory chronic cough; TRP, transient receptor potential; UACS, upper airway cough syndrome; UCC, unexplained chronic cough.

Author contributions

Philip Rouadi (PR) designed the plan of the article, contributed to the data collection. He wrote the manuscript draft, conceived and designed the tables/figures, and reviewed all parts of the article. Samar Idriss contributed to data collection, tables/figures, and manuscript draft. Jean Bousquet participated in the manuscript draft and reviewed the whole article. All other others contributed to the manuscript draft each according to his/her specialty and domain of interest. They reviewed closely the whole article and added their remarks.

Ethics statement

No patients were involved in the development of this executive summary. No consent was required.

Availability of materials and methods

N/a.

Author consent for publication

All authors reviewed and approved the final version of the work and consented to its publication in WAO Journal and take full responsibility for the content.

Funding

N/a.

Declaration of competing interest

Talal Nsouli: speaker for AstraZeneca.

Jonathan A Bernstein: Merck and GSK related to chronic cough.

Georges S Juvelekian: speaker for AstraZeneca, Abbott, Boehringer Ingelheim, Sanofi Aventis, Organon, Novartis, and Pfizer. Member of the Advisory board of AstraZeneca, Novartis, and Pfizer.

Pete Smith: PI/Consultant GSK, Sanofi Regeneron, Viatris.

Glenis Scadding: Honoraria for articles and speaker for GSK, advisory boards for GSK, ALK, Bayer, Chiesi, GlaxoSmithKline, Haleon, Noucor, Sanofi- Regeneron, and Viatris. Chair of BSACI rhinitis guidelines, Scientific Chief Editor, Rhinology Section of Frontiers in Allergy, Vice President, and AR lead for EUFOREA, and Chair/member Data Monitoring Committees on SLIT for ALK. Scientific Chief Editor, Rhinology Section, Frontiers in Allergy.

L Klimek (LK) has received research grants from Allergy Therapeutics/Bencard, Great Britain/Germany; ALK-Abelló, Denmark; Allergopharma, Germany; Aimmune, USA; ASIT Biotech, Belgium; AstraZeneca, Sweden, Bionorica, Germany; BioNTech, Germany, Biomay, Austria, Boehringer Ingelheim, Germany, Circassia, USA; Chiesi, Italy; Cytos, Switzerland; Curalogic, Denmark; HAL, Netherlands; Lofarma, Italy; Menarini, Italy; MSD, USA, Viatris/Mylan, USA; Novartis, Switzerland, Leti, Spain; ROXALL, Germany; GlaxoSmithKline (GSK), Great Britain; Sanofi, France; Stallergenes, France; Thermofisher, USA and/or has served on the speaker's bureau or was consulting for the above mentioned pharmaceutical companies.

Alessandro Fiocchi: Member of an advisory board: Abbott S.A., Danone, Ferrero SpA,

Sponsored research: Ferrero SpA, Novartis S.A., Astrazeneca S.A, Vertex S.A., GSK S.A., Sanofi S.A., DVB S.A.

Pedro Giavina-Bianchi: speaker and member for advisory board for: AstraZeneca, Abbvie, CSL Behring, GSK, Novartis, Sanofi, Takeda/Shire.