Causes of chronic productive cough: An approach to management

Open ArchivePublished:July 06, 2015DOI:https://doi.org/10.1016/j.rmed.2015.05.020

      Highlights

      • Conditions most likely to cause chronic productive cough outlined.
      • Epidemiology, clinical presentation, pathology and treatment of these conditions discussed.
      • Cohort of patients with potential diagnosis of ‘adult protracted bacterial bronchitis’ described.
      • Diagnostic algorithm for patients with chronic productive cough outlined.

      Abstract

      A chronic ‘productive’ or ‘wet’ cough is a common presenting complaint for patients attending the adult respiratory clinic. Most reviews and guidelines suggest that the causes of a productive cough are the same as those of a non-productive cough and as such the same diagnostic pathway should be followed.
      We suggest a different diagnostic approach for patients with a productive cough, focussing on the conditions that are the most likely causes of this problem.
      This review is intended to briefly summarise the epidemiology, clinical features, pathophysiology and treatment of a number of conditions which are often associated with chronic productive cough to aid decision making when encountering a patient with this often distressing symptom. The conditions discussed include bronchiectasis, chronic bronchitis, asthma, eosinophilic bronchitis and immunodeficiency.
      We also propose an adult version of the paediatric diagnosis of protracted bacterial bronchitis (PBB) in patients with idiopathic chronic productive cough who appear to respond well to low dose macrolide therapy.

      Keywords

      Abbreviations:

      GERD (Gastroesophageal Reflux Disease), HRCT (High Resolution CT), PBB (Protracted Bacterial Bronchitis)

      1. Introduction

      A chronic ‘productive’ or ‘wet’ cough is a common presenting complaint for patients attending the adult respiratory clinic. Most reviews and guidelines suggest that the causes of a productive cough are the same as those of a non-productive cough and as such the same diagnostic pathway should be followed [
      • Smyrnios N.A.
      • Irwin R.S.
      • Curley F.J.
      Chronic cough with a history of excessive sputum production: the spectrum and frequency of causes, key components of the diagnostic evaluation, and outcome of specific therapy.
      ].
      Although it seems likely that all of the conditions which may present as a productive cough could present as non-productive cough our experience suggests that some conditions are much more likely to result in productive cough than others whilst some of the common causes of dry cough such as gastroesophageal reflux disease (GERD) less commonly cause productive cough. There is a lack of data on an association between upper airway causes of cough such as post nasal drip syndrome and productive cough and hence these have not been discussed in this review.
      As such, this article is not a detailed systematic review of cough, but is intended to briefly summarise a number of conditions which are often associated with a chronic productive cough to aid decision making when encountering a patient with this often distressing symptom. We also propose an adult version of the paediatric diagnosis of protracted bacterial bronchitis (PBB).

      2. Causes of chronic productive cough

      For the purposes of this review the definition of a “chronic productive cough” was considered to be a cough regularly leading to the expectoration of sputum with the same duration as the standard definition of chronic cough i.e. more than 8 weeks [
      • Irwin R.S.
      Introduction to the diagnosis and management of cough: Accp evidence-based clinical practice guidelines.
      ].
      Conditions causing productive cough have been listed in an approximate order of prevalence from most to least frequent.

      2.1 Bronchiectasis

      Bronchiectasis is defined as the “irreversible abnormal dilatation of the bronchi”. It is a common cause of chronic productive cough which is diagnosed by a high resolution CT (HRCT) scan demonstrating a bronchus with an internal diameter wider than its adjacent pulmonary artery which fails to taper and bronchi visualised 1–2 cm from the pleural surface [
      • McGuinness G.
      • Naidich D.P.
      CT of airways disease and bronchiectasis.
      ].

      2.1.1 Epidemiology

      The prevalence of bronchiectasis is increasing in the UK and the USA, although it is unclear if this reflects a true increase in the number of cases or increased recognition of the condition due to more widespread HRCT scanning [
      • Seitz A.E.
      • Olivier K.N.
      • Adjemian J.
      • Holland S.M.
      • Prevots R.
      Trends in bronchiectasis among medicare beneficiaries in the United States, 2000 to 2007.
      ,
      • Quint J.
      • Millett E.
      • Hurst J.
      • Smeeth L.
      • Brown J.
      P172 Time trends in incidence and prevalence of bronchiectasis in the UK.
      ]. Prevalence generally rises with age and is highest in those aged ≥70 years. The condition is more prevalent in women. Total prevalence in the UK was estimated at 227/100,000 men and 309/100,000 women in 2011 [
      • Quint J.
      • Millett E.
      • Hurst J.
      • Smeeth L.
      • Brown J.
      P172 Time trends in incidence and prevalence of bronchiectasis in the UK.
      ].

      2.1.2 Clinical presentation

      The condition usually presents as a chronic productive cough [
      • Rosen M.J.
      Chronic cough due to bronchiectasis: Accp evidence-based clinical practice guidelines.
      ], with daily sputum production [
      • King P.T.
      • Holdsworth S.R.
      • Freezer N.J.
      • Villanueva E.
      • Holmes P.W.
      Characterisation of the onset and presenting clinical features of adult bronchiectasis.
      ]. Other factors that suggest the diagnosis include haemoptysis, systemic features of weight loss and fatigue and multiple positive sputum cultures [
      • King P.T.
      • Holdsworth S.R.
      • Freezer N.J.
      • Villanueva E.
      • Holmes P.W.
      Characterisation of the onset and presenting clinical features of adult bronchiectasis.
      ,
      • Nicotra M.B.
      • Rivera M.
      • Dale A.M.
      • Shepherd R.
      • Carter R.
      Clinical, pathophysiologic, and microbiologic characterization of bronchiectasis in an aging cohort.
      ].

      2.1.3 Pathology

      Bronchiectasis may be secondary to a multitude of other conditions (as listed in Table 1), with the most common predisposing factor thought to be post respiratory infection [
      • Pasteur M.C.
      • Helliwell S.M.
      • Houghton S.J.
      • Webb S.C.
      • Foweraker J.E.
      • Coulden R.A.
      • et al.
      An investigation into causative factors in patients with bronchiectasis.
      ,
      • Shoemark A.
      • Ozerovitch L.
      • Wilson R.
      Aetiology in adult patients with bronchiectasis.
      ]. However, a significant proportion of cases have no obvious discernable cause, although the number of these idiopathic cases reported differs markedly between studies [
      • Pasteur M.C.
      • Helliwell S.M.
      • Houghton S.J.
      • Webb S.C.
      • Foweraker J.E.
      • Coulden R.A.
      • et al.
      An investigation into causative factors in patients with bronchiectasis.
      ,
      • Shoemark A.
      • Ozerovitch L.
      • Wilson R.
      Aetiology in adult patients with bronchiectasis.
      ,
      • McShane P.J.
      • Naureckas E.T.
      • Strek M.E.
      Bronchiectasis in a diverse US population: effects of ethnicity on etiology and sputum culture.
      ].
      Table 1Causes of Bronchiectasis in approximate order of frequency from most to least common. Based on data from Pasteur et al.
      • Pasteur M.C.
      • Helliwell S.M.
      • Houghton S.J.
      • Webb S.C.
      • Foweraker J.E.
      • Coulden R.A.
      • et al.
      An investigation into causative factors in patients with bronchiectasis.
      and Shoemark et al.
      • Shoemark A.
      • Ozerovitch L.
      • Wilson R.
      Aetiology in adult patients with bronchiectasis.
      .
      Table thumbnail fx1
      It has been suggested that bronchiectasis is largely a result of dysregulation of the immune system, as it is often seen in patients with either immunodeficiencies or “hyperimmune” (autoimmune) conditions such as Rheumatoid Arthritis or Inflammatory Bowel Disease [
      • McShane P.J.
      • Naureckas E.T.
      • Strek M.E.
      Bronchiectasis in a diverse US population: effects of ethnicity on etiology and sputum culture.
      ,
      • McShane P.J.
      • Naureckas E.T.
      • Tino G.
      • Strek M.E.
      Non-cystic fibrosis bronchiectasis.
      ]. Although the initial step in the pathogenesis of the condition is not yet clear, it is broadly accepted that it progresses in a largely similar way, based on the ‘’vicious circle’ hypothesis proposed by Cole [
      • Cole P.J.
      Inflammation: a two-edged sword–the model of bronchiectasis.
      ], which describes a cycle of airway inflammation, leading to structural airway damage and resultant mucous stasis, with the pooled mucus becoming colonised with bacteria, which initiate further inflammation (Fig. 1).
      Figure thumbnail gr1
      Fig. 1Illustrating the ‘vicious circle’ hypothesis of bronchiectasis.
      The most common sputum isolates, using standard microbiological approaches, from patients with bronchiectasis are the gram negative bacteria Haemophilus influenzae and Pseudomonas aerugenosa[
      • King P.T.
      • Holdsworth S.R.
      • Freezer N.J.
      • Villanueva E.
      • Holmes P.W.
      Microbiologic follow-up study in adult bronchiectasis.
      ,
      • Davies G.
      • Wells A.U.
      • Doffman S.
      • Watanabe S.
      • Wilson R.
      The effect of Pseudomonas aeruginosa on pulmonary function in patients with bronchiectasis.
      ]. Colonisation of the sputum by first H. influenzae, and later P. aerugenosa, coincide with worsening of the clinical features of bronchiectasis including lung function and frequency of exacerbation [
      • King P.T.
      • Holdsworth S.R.
      • Freezer N.J.
      • Villanueva E.
      • Holmes P.W.
      Microbiologic follow-up study in adult bronchiectasis.
      ,
      • Davies G.
      • Wells A.U.
      • Doffman S.
      • Watanabe S.
      • Wilson R.
      The effect of Pseudomonas aeruginosa on pulmonary function in patients with bronchiectasis.
      ].

      2.1.4 Treatment

      Guidance on the treatment of bronchiectasis can be found in the BTS guidelines on bronchiectasis [
      • Pasteur M.C.
      • Bilton D.
      • Hill A.T.
      British thoracic society guideline for non-CF bronchiectasis.
      ].
      Broad principles in the management of the condition include treatment of the underlying cause, monitoring of disease activity using lung function and regular sputum cultures, airway clearance techniques and antibiotic treatment. These principles are further outlined in Table 2 below:
      Table 2Principles of management of bronchiectasis.
      Principle of managementSpecific management points
      Treatment of underlying causee.g. ABPA treatment, immunoglobulin replacement, treatment of rheumatoid arthritis or inflammatory bowel disease
      Monitoring of disease activity
      • Lung function measured annually
        • King P.T.
        • Holdsworth S.R.
        • Freezer N.J.
        • Villanueva E.
        • Gallagher M.
        • Holmes P.W.
        Outcome in adult bronchiectasis.
        ,
        • Martinez-Garcia M.A.
        • Soler-Cataluna J.J.
        • Perpina-Tordera M.
        • Roman-Sanchez P.
        • Soriano J.
        Factors associated with lung function decline in adult patients with stable non-cystic fibrosis bronchiectasis.
      Airway clearance techniques
      • Active cycle of breathing techniques
        • Patterson J.E.
        • Bradley J.M.
        • Elborn J.S.
        Airway clearance in bronchiectasis: a randomized crossover trial of active cycle of breathing techniques (incorporating postural drainage and vibration) versus test of incremental respiratory endurance.
      • Postural drainage
        • Eaton T.
        • Young P.
        • Zeng I.
        • Kolbe J.
        A randomized evaluation of the acute efficacy, acceptability and tolerability of flutter and active cycle of breathing with and without postural drainage in non-cystic fibrosis bronchiectasis.
      • Positive expiratory pressure devices e.g. Flutter
        • Figueiredo P.H.
        • Zin W.A.
        • Guimaraes F.S.
        Flutter valve improves respiratory mechanics and sputum production in patients with bronchiectasis.
        , Acapella
        • Patterson J.E.
        • Bradley J.M.
        • Hewitt O.
        • Bradbury I.
        • Elborn J.S.
        Airway clearance in bronchiectasis: a randomized crossover trial of active cycle of breathing techniques versus Acapella.
        ,
        • Murray M.P.
        • Pentland J.L.
        • Hill A.T.
        A randomised crossover trial of chest physiotherapy in non-cystic fibrosis bronchiectasis.
        devices
      • High frequency chest wall oscillation devices
        • Nicolini A.
        • Cardini F.
        • Landucci N.
        • Lanata S.
        • Ferrari-Bravo M.
        • Barlascini C.
        Effectiveness of treatment with high-frequency chest wall oscillation in patients with bronchiectasis.
      Antibiotic treatmentTreatment of exacerbations
      • Definition of ‘exacerbation’ not universally agreed
      • No randomised controlled trials of antibiotic treatment for bronchiectasis exacerbations
      • Consensus opinion currently antibiotic treatment for 14 days
        • Pasteur M.C.
        • Bilton D.
        • Hill A.T.
        British thoracic society guideline for non-CF bronchiectasis.
      • Antibiotic choice based on likely causative organisms and sensitivities
      • Sputum culture should be sent prior to treatment
      Pseudomonas eradication
      • If cultured for first time an attempt should be made to eradicate pseudomonas
        • White L.
        • Mirrani G.
        • Grover M.
        • Rollason J.
        • Malin A.
        • Suntharalingam J.
        Outcomes of Pseudomonas eradication therapy in patients with non-cystic fibrosis bronchiectasis.
      Regular prophylactic antibiotic therapy
      • Patients having ≥3 exacerbations per year requiring antibiotic therapy or those with <3 exacerbations but with significant morbidity should be considered for long term antibiotics
        • Pasteur M.C.
        • Bilton D.
        • Hill A.T.
        British thoracic society guideline for non-CF bronchiectasis.
        such as macrolides
        • Wu Q.
        • Shen W.
        • Cheng H.
        • Zhou X.
        Long-term macrolides for non-cystic fibrosis bronchiectasis: A systematic review and meta-analysis.

      2.2 Chronic bronchitis

      Chronic bronchitis is defined as “the presence of a chronic productive cough for more than 3 months in 2 successive years” [

      Braman SS. Chronic cough due to chronic bronchitis: ACCP evidence-based clinical practice guidelines. Chest.129 (1 Suppl):104S-115S.

      ]. It is almost invariably described as a feature of Chronic Obstructive Pulmonary Disease (COPD) secondary to smoking [

      Braman SS. Chronic cough due to chronic bronchitis: ACCP evidence-based clinical practice guidelines. Chest.129 (1 Suppl):104S-115S.

      ].

      2.2.1 Epidemiology

      The prevalence of chronic bronchitis in the general population is unclear, with many estimates ranging from 3 to 7% of adults experiencing symptoms [
      • Cerveri I.
      • Accordini S.
      • Verlato G.
      • Corsico A.
      • Zoia M.C.
      • Casali L.
      • et al.
      Variations in the prevalence across countries of chronic bronchitis and smoking habits in young adults.
      ,
      • Ferre A.
      • Fuhrman C.
      • Zureik M.
      • Chouaid C.
      • Vergnenegre A.
      • Huchon G.
      • et al.
      Chronic bronchitis in the general population: influence of age, gender and socio-economic conditions.
      ,
      • de Oca M.M.
      • Halbert R.J.
      • Lopez M.V.
      • Perez-Padilla R.
      • Tálamo C.
      • Moreno D.
      • et al.
      The chronic bronchitis phenotype in subjects with and without COPD: the PLATINO study.
      ,
      • Guerra S.
      • Sherrill D.L.
      • Venker C.
      • Ceccato C.M.
      • Halonen M.
      • Martinez F.D.
      Chronic bronchitis before age 50 years predicts incident airflow limitation and mortality risk.
      ,
      • Huchon G.J.
      • Vergnenegre A.
      • Neukirch F.
      • Brami G.
      • Roche N.
      • Preux P.M.
      Chronic bronchitis among French adults: high prevalence and underdiagnosis.
      ,
      • Harmsen L.
      • Thomsen S.F.
      • Ingebrigtsen T.
      • Steffensen I.E.
      • Skadhauge L.R.
      • Kyvik K.O.
      • et al.
      Chronic mucus hypersecretion: prevalence and risk factors in younger individuals.
      ], although higher rates of up to 22% have been reported [
      • von Hertzen L.
      • Reunanen A.
      • Impivaara O.
      • Malkia E.
      • Aromaa A.
      Airway obstruction in relation to symptoms in chronic respiratory disease–a nationally representative population study.
      ,
      • Pelkonen M.
      • Notkola I.L.
      • Nissinen A.
      • Tukiainen H.
      • Koskela H.
      Thirty-year cumulative incidence of chronic bronchitis and COPD in relation to 30-year pulmonary function and 40-year mortality: a follow-up in middle-aged rural men.
      ]. This uncertainty is likely owing to different definitions of the condition, variable reporting of symptoms and the inclusion of subjects in these estimates with other conditions such as bronchiectasis.
      It is clear that individuals who are current or ex-smokers are more likely to have chronic bronchitis [
      • Cerveri I.
      • Accordini S.
      • Verlato G.
      • Corsico A.
      • Zoia M.C.
      • Casali L.
      • et al.
      Variations in the prevalence across countries of chronic bronchitis and smoking habits in young adults.
      ,
      • Ferre A.
      • Fuhrman C.
      • Zureik M.
      • Chouaid C.
      • Vergnenegre A.
      • Huchon G.
      • et al.
      Chronic bronchitis in the general population: influence of age, gender and socio-economic conditions.
      ,
      • Huchon G.J.
      • Vergnenegre A.
      • Neukirch F.
      • Brami G.
      • Roche N.
      • Preux P.M.
      Chronic bronchitis among French adults: high prevalence and underdiagnosis.
      ,
      • Harmsen L.
      • Thomsen S.F.
      • Ingebrigtsen T.
      • Steffensen I.E.
      • Skadhauge L.R.
      • Kyvik K.O.
      • et al.
      Chronic mucus hypersecretion: prevalence and risk factors in younger individuals.
      ,
      • Pelkonen M.
      • Notkola I.L.
      • Nissinen A.
      • Tukiainen H.
      • Koskela H.
      Thirty-year cumulative incidence of chronic bronchitis and COPD in relation to 30-year pulmonary function and 40-year mortality: a follow-up in middle-aged rural men.
      ] and patients with COPD have a higher prevalence of chronic bronchitis, with up to 74% affected [
      • Kim V.
      • Han M.K.
      • Vance G.B.
      • Make B.J.
      • Newell J.D.
      • Hokanson J.E.
      • et al.
      The chronic bronchitic phenotype of COPD: an analysis of the COPD gene study.
      ,
      • Agusti A.
      • Calverley P.M.
      • Celli B.
      • Coxson H.O.
      • Edwards L.D.
      • Lomas D.A.
      • et al.
      Characterisation of COPD heterogeneity in the ECLIPSE cohort.
      ]. However, there seems to be a significant proportion of the general population experiencing these symptoms who do not have a formal respiratory diagnosis [
      • Huchon G.J.
      • Vergnenegre A.
      • Neukirch F.
      • Brami G.
      • Roche N.
      • Preux P.M.
      Chronic bronchitis among French adults: high prevalence and underdiagnosis.
      ,
      • Harmsen L.
      • Thomsen S.F.
      • Ingebrigtsen T.
      • Steffensen I.E.
      • Skadhauge L.R.
      • Kyvik K.O.
      • et al.
      Chronic mucus hypersecretion: prevalence and risk factors in younger individuals.
      ,
      • von Hertzen L.
      • Reunanen A.
      • Impivaara O.
      • Malkia E.
      • Aromaa A.
      Airway obstruction in relation to symptoms in chronic respiratory disease–a nationally representative population study.
      ,
      • Pelkonen M.
      • Notkola I.L.
      • Nissinen A.
      • Tukiainen H.
      • Koskela H.
      Thirty-year cumulative incidence of chronic bronchitis and COPD in relation to 30-year pulmonary function and 40-year mortality: a follow-up in middle-aged rural men.
      ]. This group may be at greater risk of morbidity/mortality than healthy subjects; a study by Guerra et al. [
      • Guerra S.
      • Sherrill D.L.
      • Venker C.
      • Ceccato C.M.
      • Halonen M.
      • Martinez F.D.
      Chronic bronchitis before age 50 years predicts incident airflow limitation and mortality risk.
      ] demonstrated that subjects under the age of 50 with symptoms of chronic bronchitis were significantly more likely to develop airflow limitation with increased risk of mortality than subjects without chronic bronchitis.

      2.2.2 Clinical presentation

      Patients with chronic bronchitis present with a productive cough, although this symptom is often more unpredictable than the classic epidemiological definition of chronic bronchitis with much variation in the pattern of sputum production [
      • Vestbo J.
      • Lange P.
      Can GOLD Stage 0 provide information of prognostic value in chronic obstructive pulmonary disease?.
      ]. Due to the large crossover of chronic bronchitis with COPD, many patients present with other features of COPD including dyspnoea and wheeze [

      Pauwels RA, Rabe KF. Burden and clinical features of chronic obstructive pulmonary disease (COPD), Lancet.364 (9434):613–620.

      ].

      2.2.3 Pathology

      Productive cough in chronic bronchitis is secondary to excessive mucus secretions in the airways. Mucus is present in excessive amounts owing to the overproduction and hypersecretion of mucus from mucus-producing goblet cells and decreased airway clearance mechanisms.
      Mucus overproduction is caused by exposure to inflammatory stimuli such as cigarette smoke [
      • Takeyama K.
      • Jung B.
      • Shim J.J.
      • Burgel P.R.
      • Dao-Pick T.
      • Ueki I.F.
      • et al.
      Activation of epidermal growth factor receptors is responsible for mucin synthesis induced by cigarette smoke.
      ,
      • Deshmukh H.S.
      • Case L.M.
      • Wesselkamper S.C.
      • Borchers M.T.
      • Martin L.D.
      • Shertzer H.G.
      • et al.
      Metalloproteinases mediate mucin 5AC expression by epidermal growth factor receptor activation.
      ], viral [
      • Holtzman M.J.
      • Tyner J.W.
      • Kim E.Y.
      • Lo M.S.
      • Patel A.C.
      • Shornick L.P.
      • et al.
      Acute and chronic airway responses to viral infection: implications for asthma and chronic obstructive pulmonary disease.
      ] or bacterial [
      • Burgel P.R.
      • Nadel J.A.
      Epidermal growth factor receptor-mediated innate immune responses and their roles in airway diseases.
      ] infection which lead to increased transcription of mucin genes due to activation of the epidermal growth factor receptor by inflammatory cells [
      • Deshmukh H.S.
      • Case L.M.
      • Wesselkamper S.C.
      • Borchers M.T.
      • Martin L.D.
      • Shertzer H.G.
      • et al.
      Metalloproteinases mediate mucin 5AC expression by epidermal growth factor receptor activation.
      ,
      • Burgel P.R.
      • Nadel J.A.
      Epidermal growth factor receptor-mediated innate immune responses and their roles in airway diseases.
      ]. Unlike in asthma, in which mucous metaplasia is known to be a result of Th2 inflammation, the corresponding inflammatory response in COPD causing mucus overproduction is not entirely clear, although it is thought to be Th17 mediated [
      • Di Stefano A.
      • Caramori G.
      • Gnemmi I.
      • Contoli M.
      • Vicari C.
      • Capelli A.
      • et al.
      T helper type 17-related cytokine expression is increased in the bronchial mucosa of stable chronic obstructive pulmonary disease patients.
      ,
      • Chen Y.
      • Thai P.
      • Zhao Y.H.
      • Ho Y.S.
      • DeSouza M.M.
      • Wu R.
      Stimulation of airway mucin gene expression by interleukin (IL)-17 through IL-6 paracrine/autocrine loop.
      ].
      Continual exposure to inflammatory stimuli leads to increased numbers of goblet cells and mucin storage in the airways [
      • Holtzman M.J.
      • Tyner J.W.
      • Kim E.Y.
      • Lo M.S.
      • Patel A.C.
      • Shornick L.P.
      • et al.
      Acute and chronic airway responses to viral infection: implications for asthma and chronic obstructive pulmonary disease.
      ,
      • Burgel P.R.
      • Nadel J.A.
      Epidermal growth factor receptor-mediated innate immune responses and their roles in airway diseases.
      ,
      • Innes A.L.
      • Woodruff P.G.
      • Ferrando R.E.
      • Donnelly S.
      • Dolganov G.M.
      • Lazarus S.C.
      • et al.
      Epithelial mucin stores are increased in the large airways of smokers with airflow obstruction.
      ]. As the severity of disease, i.e. extent of airway obstruction, worsens in COPD, the degree of mucous metaplasia and occlusion of the small airways by mucus tends to increase [
      • Kim V.
      • Kelemen S.E.
      • Abuel-Haija M.
      • Gaughan J.P.
      • Sharafkaneh A.
      • Evans C.M.
      • et al.
      Small airway mucous metaplasia and inflammation in chronic obstructive pulmonary disease.
      ,
      • Hogg J.C.
      • Chu F.
      • Utokaparch S.
      • Woods R.
      • Elliott W.M.
      • Buzatu L.
      • et al.
      The nature of small-airway obstruction in chronic obstructive pulmonary disease.
      ]. Mucus hypersecretion is caused by increased goblet cell degranulation due to neutrophil elastase [
      • Kim S.
      • Nadel J.A.
      Role of neutrophils in mucus hypersecretion in COPD and implications for therapy.
      ].
      In conjunction with the increased amounts of mucus secreted into the airways, clearance of this mucus is impaired in patients with established COPD, owing to reduced ciliary function, occlusion of distal airways and respiratory muscle weakness leading to ineffective cough [
      • Hogg J.C.
      • Chu F.
      • Utokaparch S.
      • Woods R.
      • Elliott W.M.
      • Buzatu L.
      • et al.
      The nature of small-airway obstruction in chronic obstructive pulmonary disease.
      ,
      • Verra F.
      • Escudier E.
      • Lebargy F.
      • Bernaudin J.F.
      • De Cremoux H.
      • Bignon J.
      Ciliary abnormalities in bronchial epithelium of smokers, ex-smokers, and nonsmokers.
      ].

      2.2.4 Treatment

      Treatment of chronic bronchitis is largely based on treatment of the underlying COPD, as per NICE COPD guidelines [
      • O'Reilly J.
      • Jones M.M.
      • Parnham J.
      • Lovibond K.
      • Rudolf M.
      Management of stable chronic obstructive pulmonary disease in primary and secondary care: summary of updated NICE guidance.
      ].
      Certain treatment considerations that may particularly apply to patients with chronic bronchitis include the use of mucolytic therapy and judicious use of antibiotic therapy based on sputum colour and culture results. Another promising emerging treatment that has demonstrated efficacy in this patient group is the phosphodiesterase inhibitor roflumilast.

      2.2.4.1 Mucolytic therapy

      Mucolytic agents are widely prescribed to patients with chronic bronchitis in an attempt to improve their symptoms related to sputum production. The evidence for their use is mixed although a 2012 Cochrane review concluded that they may produce a small reduction in the exacerbation rate of patients with chronic bronchitis and COPD albeit with no difference in quality of life [
      • Poole P.
      • Black P.N.
      • Cates C.J.
      Mucolytic agents for chronic bronchitis or chronic obstructive pulmonary disease.
      ]. There are some suggestions that chest physiotherapy [
      • van der Schans C.P.
      Conventional chest physical therapy for obstructive lung disease.
      ] and inhalation of nebulised saline [
      • Valderramas S.R.
      • Atallah A.N.
      Effectiveness and safety of hypertonic saline inhalation combined with exercise training in patients with chronic obstructive pulmonary disease: a randomized trial.
      ] may be beneficial in patients with patients with COPD but no randomised controlled trial data assessing the impact of these interventions.

      2.2.4.2 Antibiotics

      It is generally accepted that for subjects with chronic bronchitis a change in the amount or nature of sputum produced, beyond day-to-day variation, may signify an exacerbation [
      • O'Reilly J.
      • Jones M.M.
      • Parnham J.
      • Lovibond K.
      • Rudolf M.
      Management of stable chronic obstructive pulmonary disease in primary and secondary care: summary of updated NICE guidance.
      ,
      • Vestbo J.
      • Hurd S.S.
      • Agusti A.G.
      • Jones P.W.
      • Vogelmeier C.
      • Anzueto A.
      • et al.
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary.
      ] and the production of green (purulent) sputum has been found to be highly sensitive (94.4%) and specific (77%) for the yield of a high bacterial sputum load [
      • Stockley R.A.
      • O'Brien C.
      • Pye A.
      • Hill S.L.
      Relationship of sputum color to nature and outpatient management of acute exacerbations of COPD.
      ]. Guidelines therefore recommend antibiotic treatment following change in sputum quantity or quality [
      • O'Reilly J.
      • Jones M.M.
      • Parnham J.
      • Lovibond K.
      • Rudolf M.
      Management of stable chronic obstructive pulmonary disease in primary and secondary care: summary of updated NICE guidance.
      ,
      • Vestbo J.
      • Hurd S.S.
      • Agusti A.G.
      • Jones P.W.
      • Vogelmeier C.
      • Anzueto A.
      • et al.
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary.
      ].
      Sending sputum for culture undoubtedly has a role in the management of chronic bronchitis, especially when there is a lack of response to an initial antibiotic treatment [
      • Vestbo J.
      • Hurd S.S.
      • Agusti A.G.
      • Jones P.W.
      • Vogelmeier C.
      • Anzueto A.
      • et al.
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary.
      ]. However, potentially pathogenic micro-organisms that often permanently colonise the respiratory tract of symptomatically stable patients with COPD are frequently not isolated on standard sputum cultures [
      • Murphy T.F.
      • Brauer A.L.
      • Schiffmacher A.T.
      • Sethi S.
      Persistent colonization by Haemophilus influenzae in chronic obstructive pulmonary disease.
      ]. These colonising bacteria, most frequently Haemophilus influenzae, are associated with increased levels of airway inflammation, symptom burden and risk of exacerbation [
      • Finney L.J.
      • Ritchie A.
      • Pollard E.
      • Johnston S.L.
      • Mallia P.
      Lower airway colonization and inflammatory response in COPD: a focus on Haemophilus influenzae.
      ] and the lack of sensitivity of standard sputum cultures to detect them has led to increasing interest in DNA-based bacterial detection techniques [
      • Garcha D.S.
      • Thurston S.J.
      • Patel A.R.C.
      • Mackay A.J.
      • Goldring J.J.P.
      • Donaldson G.C.
      • et al.
      Changes in prevalence and load of airway bacteria using quantitative PCR in stable and exacerbated COPD.
      ,

      Huang YJ, Kim E, Cox MJ, Brodie EL, Brown R, Wiener-Kronish JP, et al. A persistent and diverse airway microbiota present during chronic obstructive pulmonary disease exacerbations. Omics a J. Integr. Biol. 14 (1):9–59.

      ].
      The long term use of low dose azithromycin has demonstrated efficacy in the treatment of patients with COPD with improved quality of life measures and decreased frequency of exacerbations [
      • Albert R.K.
      • Connett J.
      • Bailey W.C.
      • Casaburi R.
      • Cooper Jr., J.A.
      • Criner G.J.
      • et al.
      Azithromycin for prevention of exacerbations of COPD.
      ]. Long term macrolides should be used with some caution however owing to the recognised potential side effects including QT interval prolongation, disturbance of liver function, hearing loss and development of bacterial macrolide resistance [
      • Herath S.C.
      • Poole P.
      Prophylactic antibiotic therapy for chronic obstructive pulmonary disease (COPD).
      ].

      2.2.4.3 Roflumilast

      Roflumilast is a phosphodiesterase 4 inhibitor which has anti-inflammatory effects in the airways by preventing the breakdown of intracellular cyclic AMP, a substance that when degraded leads to the release of inflammatory mediators [
      • Hatzelmann A.
      • Morcillo E.J.
      • Lungarella G.
      • Adnot S.
      • Sanjar S.
      • Beume R.
      • et al.
      The preclinical pharmacology of roflumilast–a selective, oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease.
      ].
      Two clinical trials assessing the effects of rofluminast (in addition to either salmeterol or tiotropium) vs placebo in patients with moderate to severe COPD and symptoms of chronic bronchitis both found that rofluminast significantly improved prebronchodilator FEV1 and exacerbation rate [
      • Fabbri L.M.
      • Calverley P.M.
      • Izquierdo-Alonso J.L.
      • Bundschuh D.S.
      • Brose M.
      • Martinez F.J.
      • et al.
      Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials.
      ].

      2.3 Asthma

      2.3.1 Epidemiology

      Limited data is available regarding the prevalence of chronic productive cough (or “chronic mucus hypersecretion”) in asthmatic patients, but there are reports of a significant subgroup of asthmatics in which these symptoms may be prominent. Two large scale European epidemiological studies reported the prevalence of chronic productive cough (≥3 months sputum production for 2 successive years) symptoms in populations of asthmatic non-smokers of 39% [
      • Lange P.
      • Parner J.
      • Vestbo J.
      • Schnohr P.
      • Jensen G.A.
      15-Year follow-up study of ventilatory function in adults with asthma.
      ] and 42% [
      • Cerveri I.
      • Cazzoletti L.
      • Corsico A.G.
      • Marcon A.
      • Niniano R.
      • Grosso A.
      • et al.
      The impact of cigarette smoking on asthma: a population-based international cohort study.
      ]. These proportions were significantly higher for smokers with asthma, a finding replicated in a recent cross-sectional study by Thomson et al. [
      • Thomson N.C.
      • Chaudhuri R.
      • Messow C.M.
      • Spears M.
      • MacNee W.
      • Connell M.
      • et al.
      Chronic cough and sputum production are associated with worse clinical outcomes in stable asthma.
      ].

      2.3.2 Clinical presentation

      The symptom of chronic productive cough seems to be associated with an accelerated decline in FEV1 in asthmatic patients regardless of smoking status [
      • Lange P.
      • Parner J.
      • Vestbo J.
      • Schnohr P.
      • Jensen G.A.
      15-Year follow-up study of ventilatory function in adults with asthma.
      ,
      • de Marco R.
      • Marcon A.
      • Jarvis D.
      • Accordini S.
      • Almar E.
      • Bugiani M.
      • et al.
      Prognostic factors of asthma severity: A 9-year international prospective cohort study.
      ]. Thomson et al. found that asthmatic smokers with chronic productive cough had worse asthma control than those without a cough and asthmatic non-smokers with a productive cough had more exacerbations than those without cough [
      • Thomson N.C.
      • Chaudhuri R.
      • Messow C.M.
      • Spears M.
      • MacNee W.
      • Connell M.
      • et al.
      Chronic cough and sputum production are associated with worse clinical outcomes in stable asthma.
      ].

      2.3.3 Pathology

      The cause of chronic productive cough in asthmatic patients is not entirely clear. Possible pathologies underlying this symptom include mucus hypersecretion or chronic bacterial infection/colonisation.

      2.3.3.1 Mucus hypersecretion

      Mucus hypersecretion has long been recognised as a feature of asthma with mucus plugging of the airways acknowledged as a contributing factor in cases of fatal asthma [
      • Sidebotham H.J.
      • Roche W.R.
      Asthma deaths; persistent and preventable mortality.
      ].
      Pathophysiological features of mucus hypersecretion in asthma include goblet cell hyperplasia [
      • Rogers D.F.
      The airway goblet cell.
      ] and submucosal gland hypertrophy [
      • Green F.H.
      • Williams D.J.
      • James A.
      • McPhee L.J.
      • Mitchell I.
      • Mauad T.
      Increased myoepithelial cells of bronchial submucosal glands in fatal asthma.
      ], both of which lead to increased sputum production. These changes are thought to be driven by TH2 lymphocyte release of cytokines IL-9 [
      • Reader J.R.
      • Hyde D.M.
      • Schelegle E.S.
      • Aldrich M.C.
      • Stoddard A.M.
      • McLane M.P.
      • et al.
      Interleukin-9 induces mucous cell metaplasia independent of inflammation.
      ] and IL-13 [
      • Atherton H.C.
      • Jones G.
      • Danahay H.
      IL-13-induced changes in the goblet cell density of human bronchial epithelial cell cultures: MAP kinase and phosphatidylinositol 3-kinase regulation.
      ] as well as mast cell infiltration of submucosal glands, with subsequent mast cell degranulation leading to increased amounts of luminal mucus [
      • Carroll N.G.
      • Mutavdzic S.
      • James A.L.
      Increased mast cells and neutrophils in submucosal mucous glands and mucus plugging in patients with asthma.
      ].

      2.3.3.2 Respiratory infections/colonisation

      Certain groups of asthmatic patients have been identified with stable clinical features of disease that have sputum cultures positive for potentially pathogenic organisms.
      Studies by Wood et al. [
      • Wood L.G.
      • Simpson J.L.
      • Hansbro P.M.
      • Gibson P.G.
      Potentially pathogenic bacteria cultured from the sputum of stable asthmatics are associated with increased 8-isoprostane and airway neutrophilia.
      ] and Green et al. [
      • Green B.
      • Kehagia V.
      • Sammut D.
      • Wiriyachaiporn S.
      • Carroll M.P.
      • Bruce K.D.
      • et al.
      Pathogenic bacteria in induced sputum in severe asthma.
      ] both identified subgroups of ‘stable’ asthmatic patients with significant loads of potentially pathogenic bacteria (including Haemophilus influenzae) in sputum culture with high sputum neutrophil counts. All of these patients were taking high dose inhaled corticosteroids, which have been linked with increased risk of respiratory infection. Inhaled fluticasone propionate has recently been shown to increase the risk of lower respiratory tract infections in patients with COPD [
      • Calverley P.M.
      • Anderson J.A.
      • Celli B.
      • Ferguson G.T.
      • Jenkins C.
      • Jones P.W.
      • et al.
      Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease.
      ,
      • Calverley P.M.
      • Stockley R.A.
      • Seemungal T.A.
      • Hagan G.
      • Willits L.R.
      • Riley J.H.
      • et al.
      Reported pneumonia in patients with COPD: findings from the INSPIRE study.
      ] and also asthma [
      • McKeever T.
      • Harrison T.W.
      • Hubbard R.
      • Shaw D.
      Inhaled corticosteroids and the risk of pneumonia in people with asthma: a case-control study.
      ] and it is possible that inhaled corticosteroids lead to chronic bronchitis in some patients by reducing host defence mechanisms, contributing to chronic infection.
      A more recent investigation by Zhang et al. [
      • Zhang Q.L.
      • Illing R.
      • Hui C.K.
      • Downey K.
      • Carr D.
      • Stearn M.
      • et al.
      Bacteria in sputum of stable severe asthma and increased airway wall thickness.
      ] found that 29/56 (52%) of a cohort of patients with severe but stable asthma (and bronchiectasis excluded by HRCT) had positive sputum cultures, with H. influenzae most commonly cultured. Of the 29 patients with positive sputum cultures 23 had repeat sputum cultures and 16 of these were again positive, with 14 having the same bacteria isolated on both occasions, suggesting these bacteria were colonising the airways. The investigators did not identify any particular distinguishing characteristics of the group with positive sputum cultures, except for a significantly longer duration of asthma and a greater number of exacerbations in the preceding year in those who were ‘colonised’.

      2.3.4 Treatment

      Guidance on the treatment of asthma can be found in the BTS/SIGN asthma guidelines [
      British guideline on the management of asthma.
      ].
      The association between severe neutrophilic asthma and airway colonisation by potentially pathogenic bacteria [
      • Green B.J.
      • Wiriyachaiporn S.
      • Grainge C.
      • Rogers G.B.
      • Kehagia V.
      • Lau L.
      • et al.
      Potentially pathogenic airway bacteria and neutrophilic inflammation in treatment resistant severe asthma.
      ] may suggest a mechanism for the reduction in asthma exacerbations and LRTI in a sub group of patients with non-eosinophilic asthma treated with a prolonged course of azithromycin in the AZIZAST study [

      Brusselle GG, Vanderstichele C, Jordens P, Deman R, Slabbynck H, Ringoet V, et al. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax 68 (4):322–329.

      ], although this finding is yet to be verified. The use of antibiotics in asthmatics with sputum production as a main symptom should probably be guided by the results of sputum culture if possible, although the limitations of sputum cultures as described above should be considered.

      2.4 Eosinophilic bronchitis

      Eosinophilic bronchitis (EB) describes a group of patients with cough (which may be productive) secondary to eosinophilic airway inflammation but with no bronchial reactivity [
      • Brightling C.E.
      Chronic cough due to nonasthmatic eosinophilic bronchitis: ACCP evidence-based clinical practice guidelines.
      ].

      2.4.1 Epidemiology

      EB is thought to account for between 10 and 30% of cases of chronic cough referred to the specialist respiratory clinic [
      • Brightling C.E.
      • Ward R.
      • Goh K.L.
      • Wardlaw A.J.
      • Pavord I.D.
      Eosinophilic bronchitis is an important cause of chronic cough.
      ,
      • Ayik S.O.
      • Basoglu O.K.
      • Erdinc M.
      • Bor S.
      • Veral A.
      • Bilgen C.
      Eosinophilic bronchitis as a cause of chronic cough.
      ]. Further data regarding incidence and prevalence are lacking as establishing the diagnosis requires the confirmation of eosinophilic inflammation either at bronchoscopy or by sputum differential cell count which is primarily a research investigation only available at a limited number of specialist centres.

      2.4.2 Clinical presentation

      Diagnosis of the condition is made in patients with an appropriate clinical history, negative bronchial challenge and significant sputum eosinophilia, usually accepted as being a proportion of the total sputum cell count of ≥3% [
      • Simpson J.L.
      • McElduff P.
      • Gibson P.G.
      Assessment and reproducibility of non-eosinophilic asthma using induced sputum.
      ].

      2.4.3 Pathology

      EB shares many similar pathological features to asthma with equivalent levels of eosinophilic inflammation and sputum eosinophilia, airway remodelling and basement membrane thickening [
      • Brightling C.E.
      • Symon F.A.
      • Birring S.S.
      • Bradding P.
      • Wardlaw A.J.
      • Pavord I.D.
      Comparison of airway immunopathology of eosinophilic bronchitis and asthma.
      ]. It has been suggested that the key difference in pathogenesis and hence clinical features of the two conditions is the localisation of activated mast cells [
      • Brightling C.E.
      Eosinophils, bronchitis and asthma: pathogenesis of cough and airflow obstruction.
      ]. Bronchial brushings from patients with eosinophilic bronchitis contained increased numbers of mast cells in comparison to those from asthma patients, suggesting activated mast cells are more abundant in superficial layers of bronchial epithelium in EB than in asthma [
      • Gibson P.G.
      • Zlatic K.
      • Scott J.
      • Sewell W.
      • Woolley K.
      • Saltos N.
      Chronic cough resembles asthma with IL-5 and granulocyte-macrophage colony-stimulating factor gene expression in bronchoalveolar cells.
      ]. By contrast, asthmatic patients demonstrate increased numbers of activated mast cells in airway smooth muscle compared to subjects with EB [
      • Brightling C.E.
      • Bradding P.
      • Symon F.A.
      • Holgate S.T.
      • Wardlaw A.J.
      • Pavord I.D.
      Mast-cell infiltration of airway smooth muscle in asthma.
      ].
      This difference in location of mast cells [
      • Siddiqui S.
      • Gupta S.
      • Cruse G.
      • Haldar P.
      • Entwisle J.
      • McDonald S.
      • et al.
      Airway wall geometry in asthma and nonasthmatic eosinophilic bronchitis.
      ] and increased IL-13 release [
      • Park S.W.
      • Jangm H.K.
      • An M.H.
      • Min J.W.
      • Jang A.S.
      • Lee J.H.
      • et al.
      Interleukin-13 and interleukin-5 in induced sputum of eosinophilic bronchitis: comparison with asthma.
      ] observed in asthma compared to EB may help to explain the features of airway hyperresponsiveness and airflow obstruction observed in asthma which are not features of EB.

      2.4.4 Treatment

      The first line treatment for eosinophilic bronchitis is inhaled steroids which usually lead to a marked symptomatic improvement and decrease in sputum eosinophil count [
      • Gibson P.G.
      • Hargreave F.E.
      • Girgis-Gabardo A.
      • Morris M.
      • Denburg J.A.
      • Dolovich J.
      Chronic cough with eosinophilic bronchitis: examination for variable airflow obstruction and response to corticosteroid.
      ,
      • Brightling C.E.
      • Ward R.
      • Wardlaw A.J.
      • Pavord I.D.
      Airway inflammation, airway responsiveness and cough before and after inhaled budesonide in patients with eosinophilic bronchitis.
      ]. A recent randomised controlled trial suggests that the leukotriene receptor antagonist montelukast may provide some additional benefit to inhaled corticosteroid therapy in improving quality of life measures and markers of eosinophilic inflammation [
      • Bao W.
      • Liu P.
      • Qiu Z.
      • Yu L.
      • Hang J.
      • Gao X.
      • et al.
      Efficacy of add-on montelukast in nonasthmatic eosinophilic bronchitis: the additive effect on airway inflammation, cough and life quality.
      ]. In a few cases intermittent oral corticosteroids may be required to control symptoms [
      • Brightling C.E.
      Cough due to asthma and nonasthmatic eosinophilic bronchitis.
      ].

      2.5 Immunodeficiency

      A small group of patients presenting with recurrent lower respiratory tract infections are shown to have immunodeficiencies, including IgG/IgA deficiency or Combined Variable Immunodeficiency (CVID). These patients may present with recurrent but discrete episodes of infection punctuated by periods of recovery, but over time are at risk of developing bronchiectasis [
      • Wood P.
      • Stanworth S.
      • Burton J.
      • Jones A.
      • Peckham D.G.
      • Green T.
      • et al.
      Recognition, clinical diagnosis and management of patients with primary antibody deficiencies: a systematic review.
      ].
      The natural history of the clinical, pathological and radiological features displayed by these patients is unclear. Previous studies have reported significant rates of bronchitis symptoms in patients with primary immunodeficiencies [
      • Thickett K.M.
      • Kumararatne D.S.
      • Banerjee A.K.
      • Dudley R.
      • Stableforth D.E.
      Common variable immune deficiency: respiratory manifestations, pulmonary function and high-resolution CT scan findings.
      ,
      • Kainulainen L.
      • Nikoskelainen J.
      • Ruuskanen O.
      Diagnostic findings in 95 Finnish patients with common variable immunodeficiency.
      ,
      • Oksenhendler E.
      • Gerard L.
      • Fieschi C.
      • Malphettes M.
      • Mouillot G.
      • Jaussaud R.
      • et al.
      Infections in 252 patients with common variable immunodeficiency.
      ], but it is uncertain if these patients have symptoms secondary to established bronchiectasis or if they progress through a state of ‘pre bronchiectasis’ with bacterial airway colonisation and persistent cough but no significant bronchiectasis on HRCT scan.

      2.5.1 IgA deficiency

      Diagnosis of IgA deficiency has been defined by international consensus as “an IgA level of 0.07 g/l after the age of 4 years in the absence of IgG and IgM deficiency” [
      • Conley M.E.
      • Notarangelo L.D.
      • Etzioni A.
      Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies).
      ].

      2.5.1.1 Epidemiology

      Selective IgA deficiency is the most common primary immunodeficiency with a prevalence in Caucasians of 1/300 to 1/1200 [
      • Singh K.
      • Chang C.
      • Gershwin M.E.
      IgA deficiency and autoimmunity.
      ].

      2.5.1.2 Clinical presentation

      Although the majority of cases (estimated at around 85–90%) are asymptomatic, there are a significant number who develop clinical disease as listed in Table 3. This mostly consists of recurrent respiratory tract and gastrointestinal tract infections and autoimmune conditions such as coeliac disease [
      • Yel L.
      Selective IgA deficiency.
      ]. These complications are not unexpected given that IgA is the immunoglobulin found at the highest concentrations in secretions at mucosal surfaces, especially in the gut and respiratory tract [
      • Cunningham-Rundles C.
      Physiology of IgA and IgA deficiency.
      ].
      Table 3The clinical manifestations of IgA deficiency.
      Clinical manifestation of IgA deficiencyDetails
      Asymptomatic85–90% of patients may have no symptoms
      Recurrent sinopulmonary infectionsMostly bacterial e.g. Haemophilus influenzae and Streptococcus pneumoniae. May lead to bronchiectasis
      Gastrointestinal infections/disordersInfections include Giardiasis, other disorders linked with IgA deficiency include coeliac disease, lactose intolerance, malabsorption and ulcerative colitis
      Allergic disordersIncreased frequency of asthma, atopy, food and drug allergies reported
      AutoimmunityIncluding idiopathic thrombocytopaenic purpura (ITP), haemolytic anaemia, juvenile rheumatoid arthritis and systemic lupus erythematosus (SLE)
      MalignancyThere may be an association between IgA deficiency and malignancies including lymphoid and GI malignancies
      Respiratory tract infections are usually caused by bacteria including H. influenzae and Streptococcus pneumoniae. Some patients go on to develop bronchiectasis presumably secondary to recurrent infection causing airway damage and scarring [
      • Yel L.
      Selective IgA deficiency.
      ,
      • Chipps B.E.
      • Talamo R.C.
      • Winkelstein J.A.
      IgA deficiency, recurrent pneumonias, and bronchiectasis.
      ].

      2.5.1.3 Treatment

      In general, IgA antibody replacement therapy is not indicated in patients with IgA deficiency, and such therapy may in fact be harmful [
      • Schaffer F.M.
      Clinical assessment and management of abnormal IgA levels.
      ]. However a subgroup of patients with IgA deficiency and recurrent sinopulmonary infections may benefit from extended courses of prophylactic antibiotics or sometimes intravenous gamma globulin (IVGG) therapy if they have other associated antibody deficiencies [
      • Yel L.
      Selective IgA deficiency.
      ,
      • Schaffer F.M.
      Clinical assessment and management of abnormal IgA levels.
      ].

      2.5.2 Combined variable immunodeficiency

      Combined Variable Immunodeficiency (CVID) is a disease defined by the defective production of immunoglobulins [
      • Ameratunga R.
      • Woon S.T.
      • Gillis D.
      • Koopmans W.
      • Steele R.
      New diagnostic criteria for common variable immune deficiency (CVID), which may assist with decisions to treat with intravenous or subcutaneous immunoglobulin.
      ]. Diagnosis of CVID can be made using internationally agreed diagnostic criteria, of which 1 of the 3 parts required for diagnosis states there should be “hypogammaglobulinaemia with IgG levels two standard deviations below the mean” [
      • Ameratunga R.
      • Woon S.T.
      • Gillis D.
      • Koopmans W.
      • Steele R.
      New diagnostic criteria for common variable immune deficiency (CVID), which may assist with decisions to treat with intravenous or subcutaneous immunoglobulin.
      ].

      2.5.2.1 Epidemiology

      The epidemiology of the condition is unclear but the prevalence is thought to be around 1:30000 in Northern European populations [
      • Ameratunga R.
      • Woon S.T.
      • Gillis D.
      • Koopmans W.
      • Steele R.
      New diagnostic criteria for common variable immune deficiency (CVID), which may assist with decisions to treat with intravenous or subcutaneous immunoglobulin.
      ,
      • Hammarstrom L.
      • Vorechovsky I.
      • Webster D.
      Selective IgA deficiency (SIgAD) and common variable immunodeficiency (CVID).
      ].

      2.5.2.2 Clinical presentation

      Clinically the disease manifests with recurrent respiratory tract infections/pneumonias, progressing later in life to bronchiectasis [
      • Oksenhendler E.
      • Gerard L.
      • Fieschi C.
      • Malphettes M.
      • Mouillot G.
      • Jaussaud R.
      • et al.
      Infections in 252 patients with common variable immunodeficiency.
      ,
      • Quinti I.
      • Soresina A.
      • Spadaro G.
      • Martino S.
      • Donnanno S.
      • Agostini C.
      • et al.
      Long-term follow-up and outcome of a large cohort of patients with common variable immunodeficiency.
      ,
      • Kirkpatrick P.
      • Riminton S.
      Primary immunodeficiency diseases in Australia and New Zealand.
      ]. Patients with CVID may also experience repeated infections of other sites of the body including the skin, soft tissues, nervous system and gastrointestinal tract [
      • Oksenhendler E.
      • Gerard L.
      • Fieschi C.
      • Malphettes M.
      • Mouillot G.
      • Jaussaud R.
      • et al.
      Infections in 252 patients with common variable immunodeficiency.
      ,
      • Quinti I.
      • Soresina A.
      • Spadaro G.
      • Martino S.
      • Donnanno S.
      • Agostini C.
      • et al.
      Long-term follow-up and outcome of a large cohort of patients with common variable immunodeficiency.
      ]. There is some evidence that asthmatics may be at greater risk of CVID than non-asthmatics, and this has been suggested as a potential reason for the increased risk of respiratory infection noted in asthmatic patients [
      • Urm S.H.
      • Yun H.D.
      • Fenta Y.A.
      • Yoo K.H.
      • Abraham R.S.
      • Hagan J.
      • et al.
      Asthma and risk of selective IgA deficiency or common variable immunodeficiency: a population-based case-control study.
      ].
      Respiratory infections are usually caused by encapsulated bacteria, especially H. influenzae, S. pneumoniae and Staphlococcus sp [
      • Oksenhendler E.
      • Gerard L.
      • Fieschi C.
      • Malphettes M.
      • Mouillot G.
      • Jaussaud R.
      • et al.
      Infections in 252 patients with common variable immunodeficiency.
      ,
      • Sicherer S.H.
      • Winkelstein J.A.
      Primary immunodeficiency diseases in adults.
      ], due to the inability of the immune system to produce IgG antibodies against these pathogens. Usually, the cumulative effect of these repeated infections leads to complications such as empyema, lung abscesses or, most commonly bronchiectasis [
      • Oksenhendler E.
      • Gerard L.
      • Fieschi C.
      • Malphettes M.
      • Mouillot G.
      • Jaussaud R.
      • et al.
      Infections in 252 patients with common variable immunodeficiency.
      ,
      • Kirkpatrick P.
      • Riminton S.
      Primary immunodeficiency diseases in Australia and New Zealand.
      ]. However, despite the prominent burden of symptoms this condition can cause the sufferer, there may often be delays in the diagnosis and treatment of the condition due to either a lack of awareness of its existence, or the misperception that the condition only presents in childhood, when in fact the average age of presentation is thought to be around 30 years [
      • Thickett K.M.
      • Kumararatne D.S.
      • Banerjee A.K.
      • Dudley R.
      • Stableforth D.E.
      Common variable immune deficiency: respiratory manifestations, pulmonary function and high-resolution CT scan findings.
      ,
      • Oksenhendler E.
      • Gerard L.
      • Fieschi C.
      • Malphettes M.
      • Mouillot G.
      • Jaussaud R.
      • et al.
      Infections in 252 patients with common variable immunodeficiency.
      ].

      2.5.2.3 Treatment

      The management of pulmonary complications of CVID usually consists of regular immunoglobulin replacement and suppressive antimicrobial treatment, although there are no RCT data to support these measures [
      • Abolhassani H.
      • Sagvand B.T.
      • Shokuhfar T.
      • Mirminachi B.
      • Rezaei N.
      • Aghamohammadi A.
      A review on guidelines for management and treatment of common variable immunodeficiency.
      ].
      Several other interventions to maintain or improve lung function in patients with CVID have also shown some efficacy including the maintenance of higher IgG trough levels, chest physiotherapy techniques including postural drainage, azithromycin and nebulised antibiotics for eradication of Pseudomonas [
      • Abolhassani H.
      • Sagvand B.T.
      • Shokuhfar T.
      • Mirminachi B.
      • Rezaei N.
      • Aghamohammadi A.
      A review on guidelines for management and treatment of common variable immunodeficiency.
      ].

      2.6 Idiopathic chronic productive cough

      We have observed a cohort of adult patients with chronic productive cough which improves with antibiotic treatment but quickly relapses. Many have suspected poorly controlled asthma but investigations including spirometry, bronchial challenges, chest X-ray, screen for immunodeficiency and HRCT scan are normal. Sputum culture is often positive for Haemophilus influenzae, and less commonly S. pneumoniae and Moraxella catarrhalis on more than one occasion. We have found prolonged treatment with low dose azithromycin to be highly effective when standard antibiotic therapy has failed.
      Similar patients may have been described previously by other authors. Weatherall et al. [
      • Weatherall M.
      • Travers J.
      • Shirtcliffe P.M.
      • Marsh S.E.
      • Williams M.V.
      • Nowitz M.R.
      • et al.
      Distinct clinical phenotypes of airways disease defined by cluster analysis.
      ] used cluster analysis to classify 175 patients with airways disease into 5 separate phenotypes. They identified a ‘chronic bronchitic in nonsmokers’ phenotype (n = 38) with similarities to patients in our cohort. This group tended to have relatively preserved lung function compared to the other phenotypic groups. However, these patients did not have HRCT scans to rule out bronchiectasis, so it is unclear if this may have been the cause for their symptoms.
      Our observed cohort have many similar features in common with the paediatric diagnosis of protracted bacterial bronchitis (PBB). PBB is a common diagnosis in children and is thought to account for up to 40% of cases of paediatric chronic cough [

      Chang AB, Redding GJ, Everard ML. Chronic wet cough: Protracted bronchitis, chronic suppurative lung disease and bronchiectasis. Pediatr. Pulmonol. 43 (6):519–531.

      ]. It has been clinically defined as the presence of an isolated chronic ‘wet’ cough, in the absence of an alternative cause, which resolves with a prolonged course of antibiotic treatment [
      • Chang A.B.
      • Landau L.I.
      • Van Asperen P.P.
      • Glasgow N.J.
      • Robertson C.F.
      • Marchant J.M.
      • et al.
      Cough in children: definitions and clinical evaluation.
      ]. Children with the condition do not usually respond to bronchodilator therapy, but like our patients are often misdiagnosed as having asthma.
      The pathogenesis of PBB is as yet unclear, but the main finding on investigation of the condition is persistent infection of the airways with bacteria including H. influenzae, S. pneumoniae and M. catarrhalis and neutrophilic airway inflammation [

      Chang AB, Yerkovich ST, Gibson PG, Anderson-James S, Petsky HL, Carroll ML, et al. Pulmonary innate immunity in children with protracted bacterial bronchitis. J. Pediatr. 161 (4):621–625.e1.

      ,
      • De Schutter I.
      • Dreesman A.
      • Soetens O.
      • De Waele M.
      • Crokaert F.
      • Verhaegen J.
      • et al.
      In young children, persistent wheezing is associated with bronchial bacterial infection: a retrospective analysis.
      ,
      • De Schutter I.
      • De Wachter E.
      • Crokaert F.
      • Verhaegen J.
      • Soetens O.
      • Pierard D.
      • et al.
      Microbiology of bronchoalveolar lavage fluid in children with acute nonresponding or recurrent community-acquired pneumonia: identification of nontypeable Haemophilus influenzae as a major pathogen.
      ]. It is thought that bacteria may colonise the airways from the upper respiratory tract following a period of impaired mucociliary clearance, as may occur following a viral respiratory tract infection. Once present in sufficient numbers in the conducting airways, bacteria (especially non typeable H. influenzae) may form biofilms as a means of defence against airway clearance mechanisms and antibiotics [
      • Craven V.
      • Everard M.L.
      Protracted bacterial bronchitis: reinventing an old disease.
      ].
      PBB is suspected to be a potential precursor to the development of bronchiectasis in adulthood [

      Chang AB, Redding GJ, Everard ML. Chronic wet cough: Protracted bronchitis, chronic suppurative lung disease and bronchiectasis. Pediatr. Pulmonol. 43 (6):519–531.

      ] and some authors have suggested the condition be renamed ‘pre-bronchiectasis’ [
      • Eastham K.M.
      • Fall A.J.
      • Mitchell L.
      • Spencer D.A.
      The need to redefine non-cystic fibrosis bronchiectasis in childhood.
      ]. In retrospective studies the majority of adult patients with idiopathic bronchiectasis give a history of persistent wet cough from childhood [
      • Pasteur M.C.
      • Helliwell S.M.
      • Houghton S.J.
      • Webb S.C.
      • Foweraker J.E.
      • Coulden R.A.
      • et al.
      An investigation into causative factors in patients with bronchiectasis.
      ,
      • Kelly M.G.
      • Murphy S.
      • Elborn J.S.
      Bronchiectasis in secondary care: a comprehensive profile of a neglected disease.
      ]. There are very few, if any, descriptions of PBB in adults, although one previous study identified 15 adult subjects with chronic productive cough secondary to ‘unsuspected bacterial suppurative disease of the airways’ and grossly normal HRCT scans [
      • Schaefer O.P.
      • Irwin R.S.
      Unsuspected bacterial suppurative disease of the airways presenting as chronic cough.
      ].
      We therefore hypothesise that our patient cohort represents an adult version of PBB (APBB). We are investigating this cohort further in an ongoing programme of research which is prospectively identifying patients. We aim to describe the clinicopathological features of their condition and evaluate the effectiveness of a 3 month open-label trial of low dose azithromycin therapy.

      3. Summary

      Chronic productive cough is a common presenting complaint in the respiratory clinic. We suggest a diagnostic approach focussing on the conditions described in this review as outlined in Fig. 2 above.
      Figure thumbnail gr2
      Fig. 2A diagnostic approach for patients with chronic productive cough.
      We propose an adult version of PBB (APBB) in patients with idiopathic chronic productive cough who appear to respond well to low dose macrolide therapy.

      References

        • Smyrnios N.A.
        • Irwin R.S.
        • Curley F.J.
        Chronic cough with a history of excessive sputum production: the spectrum and frequency of causes, key components of the diagnostic evaluation, and outcome of specific therapy.
        Chest J. 1995; 108: 991-997
        • Irwin R.S.
        Introduction to the diagnosis and management of cough: Accp evidence-based clinical practice guidelines.
        Chest J. 2006; 129: 25S-27S
        • McGuinness G.
        • Naidich D.P.
        CT of airways disease and bronchiectasis.
        Radiologic Clin. N. Am. 2002; 40: 1-19
        • Seitz A.E.
        • Olivier K.N.
        • Adjemian J.
        • Holland S.M.
        • Prevots R.
        Trends in bronchiectasis among medicare beneficiaries in the United States, 2000 to 2007.
        Chest. 2012; 142: 432-439
        • Quint J.
        • Millett E.
        • Hurst J.
        • Smeeth L.
        • Brown J.
        P172 Time trends in incidence and prevalence of bronchiectasis in the UK.
        Thorax. 2012; 67: A138
        • Rosen M.J.
        Chronic cough due to bronchiectasis: Accp evidence-based clinical practice guidelines.
        Chest J. 2006; 129: 122S-131S
        • King P.T.
        • Holdsworth S.R.
        • Freezer N.J.
        • Villanueva E.
        • Holmes P.W.
        Characterisation of the onset and presenting clinical features of adult bronchiectasis.
        Respir. Med. 2006; 100: 2183-2189
        • Nicotra M.B.
        • Rivera M.
        • Dale A.M.
        • Shepherd R.
        • Carter R.
        Clinical, pathophysiologic, and microbiologic characterization of bronchiectasis in an aging cohort.
        Chest. 1995; 108: 955-961
        • Pasteur M.C.
        • Helliwell S.M.
        • Houghton S.J.
        • Webb S.C.
        • Foweraker J.E.
        • Coulden R.A.
        • et al.
        An investigation into causative factors in patients with bronchiectasis.
        Am. J. Respir. Crit. Care Med. 2000; 162: 1277-1284
        • Shoemark A.
        • Ozerovitch L.
        • Wilson R.
        Aetiology in adult patients with bronchiectasis.
        Respir. Med. 2007; 101: 1163-1170
        • McShane P.J.
        • Naureckas E.T.
        • Strek M.E.
        Bronchiectasis in a diverse US population: effects of ethnicity on etiology and sputum culture.
        Chest. 2012; 142: 159-167
        • McShane P.J.
        • Naureckas E.T.
        • Tino G.
        • Strek M.E.
        Non-cystic fibrosis bronchiectasis.
        Am. J. Respir. Crit. Care Med. 2013; 188: 647-656
        • Cole P.J.
        Inflammation: a two-edged sword–the model of bronchiectasis.
        Eur. J. Respir. Dis. Suppl. 1986; 147: 6-15
        • King P.T.
        • Holdsworth S.R.
        • Freezer N.J.
        • Villanueva E.
        • Holmes P.W.
        Microbiologic follow-up study in adult bronchiectasis.
        Respir. Med. 2007; 101: 1633-1638
        • Davies G.
        • Wells A.U.
        • Doffman S.
        • Watanabe S.
        • Wilson R.
        The effect of Pseudomonas aeruginosa on pulmonary function in patients with bronchiectasis.
        Eur. Respir. J. 2006; 28: 974-979
        • Pasteur M.C.
        • Bilton D.
        • Hill A.T.
        British thoracic society guideline for non-CF bronchiectasis.
        Thorax. 2010; 65: i1-58
        • King P.T.
        • Holdsworth S.R.
        • Freezer N.J.
        • Villanueva E.
        • Gallagher M.
        • Holmes P.W.
        Outcome in adult bronchiectasis.
        Copd. 2005; 2: 27-34
        • Martinez-Garcia M.A.
        • Soler-Cataluna J.J.
        • Perpina-Tordera M.
        • Roman-Sanchez P.
        • Soriano J.
        Factors associated with lung function decline in adult patients with stable non-cystic fibrosis bronchiectasis.
        Chest. 2007; 132: 1565-1572
        • Patterson J.E.
        • Bradley J.M.
        • Elborn J.S.
        Airway clearance in bronchiectasis: a randomized crossover trial of active cycle of breathing techniques (incorporating postural drainage and vibration) versus test of incremental respiratory endurance.
        Chronic Respir. Dis. 2004; 1: 127-130
        • Eaton T.
        • Young P.
        • Zeng I.
        • Kolbe J.
        A randomized evaluation of the acute efficacy, acceptability and tolerability of flutter and active cycle of breathing with and without postural drainage in non-cystic fibrosis bronchiectasis.
        Chronic Respir. Dis. 2007; 4: 23-30
        • Figueiredo P.H.
        • Zin W.A.
        • Guimaraes F.S.
        Flutter valve improves respiratory mechanics and sputum production in patients with bronchiectasis.
        Physiotherapy Res. Int.: J. Res. Clin. Phys. Ther. 2012; 17: 12-20
        • Patterson J.E.
        • Bradley J.M.
        • Hewitt O.
        • Bradbury I.
        • Elborn J.S.
        Airway clearance in bronchiectasis: a randomized crossover trial of active cycle of breathing techniques versus Acapella.
        Respiration. 2005; 72: 239-242
        • Murray M.P.
        • Pentland J.L.
        • Hill A.T.
        A randomised crossover trial of chest physiotherapy in non-cystic fibrosis bronchiectasis.
        Eur. Respir. J. 2009; 34: 1086-1092
        • Nicolini A.
        • Cardini F.
        • Landucci N.
        • Lanata S.
        • Ferrari-Bravo M.
        • Barlascini C.
        Effectiveness of treatment with high-frequency chest wall oscillation in patients with bronchiectasis.
        BMC Pulm. Med. 2013; 13: 21
        • Kellett F.
        • Robert N.M.
        Nebulised 7% hypertonic saline improves lung function and quality of life in bronchiectasis.
        Respir. Med. 2011; 105: 1831-1835
        • Nicolson C.H.
        • Stirling R.G.
        • Borg B.M.
        • Button B.M.
        • Wilson J.W.
        • Holland A.E.
        The long term effect of inhaled hypertonic saline 6% in non-cystic fibrosis bronchiectasis.
        Respir. Med. 2012; 106: 661-667
        • White L.
        • Mirrani G.
        • Grover M.
        • Rollason J.
        • Malin A.
        • Suntharalingam J.
        Outcomes of Pseudomonas eradication therapy in patients with non-cystic fibrosis bronchiectasis.
        Respir. Med. 2012; 106: 356-360
        • Wu Q.
        • Shen W.
        • Cheng H.
        • Zhou X.
        Long-term macrolides for non-cystic fibrosis bronchiectasis: A systematic review and meta-analysis.
        Respirology. 2014; 19: 321-329
      1. Braman SS. Chronic cough due to chronic bronchitis: ACCP evidence-based clinical practice guidelines. Chest.129 (1 Suppl):104S-115S.

        • Cerveri I.
        • Accordini S.
        • Verlato G.
        • Corsico A.
        • Zoia M.C.
        • Casali L.
        • et al.
        Variations in the prevalence across countries of chronic bronchitis and smoking habits in young adults.
        Eur. Respir. J. 2001; 18: 85-92
        • Ferre A.
        • Fuhrman C.
        • Zureik M.
        • Chouaid C.
        • Vergnenegre A.
        • Huchon G.
        • et al.
        Chronic bronchitis in the general population: influence of age, gender and socio-economic conditions.
        Respir. Med. 2012; 106: 467-471
        • de Oca M.M.
        • Halbert R.J.
        • Lopez M.V.
        • Perez-Padilla R.
        • Tálamo C.
        • Moreno D.
        • et al.
        The chronic bronchitis phenotype in subjects with and without COPD: the PLATINO study.
        Eur. Respir. J. 2012; 40: 28-36
        • Guerra S.
        • Sherrill D.L.
        • Venker C.
        • Ceccato C.M.
        • Halonen M.
        • Martinez F.D.
        Chronic bronchitis before age 50 years predicts incident airflow limitation and mortality risk.
        Thorax. 2009; 64: 894-900
        • Huchon G.J.
        • Vergnenegre A.
        • Neukirch F.
        • Brami G.
        • Roche N.
        • Preux P.M.
        Chronic bronchitis among French adults: high prevalence and underdiagnosis.
        Eur. Respir. J. 2002; 20: 806-812
        • Harmsen L.
        • Thomsen S.F.
        • Ingebrigtsen T.
        • Steffensen I.E.
        • Skadhauge L.R.
        • Kyvik K.O.
        • et al.
        Chronic mucus hypersecretion: prevalence and risk factors in younger individuals.
        Int. J. Tuberc. lung Dis.: Official J. Int. Union against Tuberc. Lung Dis. 2010; 14: 1052-1058
        • von Hertzen L.
        • Reunanen A.
        • Impivaara O.
        • Malkia E.
        • Aromaa A.
        Airway obstruction in relation to symptoms in chronic respiratory disease–a nationally representative population study.
        Respir. Med. 2000; 94: 356-363
        • Pelkonen M.
        • Notkola I.L.
        • Nissinen A.
        • Tukiainen H.
        • Koskela H.
        Thirty-year cumulative incidence of chronic bronchitis and COPD in relation to 30-year pulmonary function and 40-year mortality: a follow-up in middle-aged rural men.
        Chest. 2006; 130: 1129-1137
        • Kim V.
        • Han M.K.
        • Vance G.B.
        • Make B.J.
        • Newell J.D.
        • Hokanson J.E.
        • et al.
        The chronic bronchitic phenotype of COPD: an analysis of the COPD gene study.
        Chest. 2011; 140: 626-633
        • Agusti A.
        • Calverley P.M.
        • Celli B.
        • Coxson H.O.
        • Edwards L.D.
        • Lomas D.A.
        • et al.
        Characterisation of COPD heterogeneity in the ECLIPSE cohort.
        Respir. Res. 2010; 11: 122
        • Vestbo J.
        • Lange P.
        Can GOLD Stage 0 provide information of prognostic value in chronic obstructive pulmonary disease?.
        Am. J. Respir. Crit. Care Med. 2002; 166: 329-332
      2. Pauwels RA, Rabe KF. Burden and clinical features of chronic obstructive pulmonary disease (COPD), Lancet.364 (9434):613–620.

        • Takeyama K.
        • Jung B.
        • Shim J.J.
        • Burgel P.R.
        • Dao-Pick T.
        • Ueki I.F.
        • et al.
        Activation of epidermal growth factor receptors is responsible for mucin synthesis induced by cigarette smoke.
        Am. J. Physiol. Lung Cell. Mol. Physiol. 2001; 280: L165-L172
        • Deshmukh H.S.
        • Case L.M.
        • Wesselkamper S.C.
        • Borchers M.T.
        • Martin L.D.
        • Shertzer H.G.
        • et al.
        Metalloproteinases mediate mucin 5AC expression by epidermal growth factor receptor activation.
        Am. J. Respir. Crit. Care Med. 2005; 171: 305-314
        • Holtzman M.J.
        • Tyner J.W.
        • Kim E.Y.
        • Lo M.S.
        • Patel A.C.
        • Shornick L.P.
        • et al.
        Acute and chronic airway responses to viral infection: implications for asthma and chronic obstructive pulmonary disease.
        Proc. Am. Thorac. Soc. 2005; 2: 132-140
        • Burgel P.R.
        • Nadel J.A.
        Epidermal growth factor receptor-mediated innate immune responses and their roles in airway diseases.
        Eur. Respir. J. 2008; 32: 1068-1081
        • Di Stefano A.
        • Caramori G.
        • Gnemmi I.
        • Contoli M.
        • Vicari C.
        • Capelli A.
        • et al.
        T helper type 17-related cytokine expression is increased in the bronchial mucosa of stable chronic obstructive pulmonary disease patients.
        Clin. Exp. Immunol. 2009; 157: 316-324
        • Chen Y.
        • Thai P.
        • Zhao Y.H.
        • Ho Y.S.
        • DeSouza M.M.
        • Wu R.
        Stimulation of airway mucin gene expression by interleukin (IL)-17 through IL-6 paracrine/autocrine loop.
        J. Biol. Chem. 2003; 278: 17036-17043
        • Innes A.L.
        • Woodruff P.G.
        • Ferrando R.E.
        • Donnelly S.
        • Dolganov G.M.
        • Lazarus S.C.
        • et al.
        Epithelial mucin stores are increased in the large airways of smokers with airflow obstruction.
        Chest. 2006; 130: 1102-1108
        • Kim V.
        • Kelemen S.E.
        • Abuel-Haija M.
        • Gaughan J.P.
        • Sharafkaneh A.
        • Evans C.M.
        • et al.
        Small airway mucous metaplasia and inflammation in chronic obstructive pulmonary disease.
        Copd. 2008; 5: 329-338
        • Hogg J.C.
        • Chu F.
        • Utokaparch S.
        • Woods R.
        • Elliott W.M.
        • Buzatu L.
        • et al.
        The nature of small-airway obstruction in chronic obstructive pulmonary disease.
        N. Engl. J. Med. 2004; 350: 2645-2653
        • Kim S.
        • Nadel J.A.
        Role of neutrophils in mucus hypersecretion in COPD and implications for therapy.
        Treat. Respir. Med. 2004; 3: 147-159
        • Verra F.
        • Escudier E.
        • Lebargy F.
        • Bernaudin J.F.
        • De Cremoux H.
        • Bignon J.
        Ciliary abnormalities in bronchial epithelium of smokers, ex-smokers, and nonsmokers.
        Am. J. Respir. Crit. Care Med. 1995; 151: 630-634
        • O'Reilly J.
        • Jones M.M.
        • Parnham J.
        • Lovibond K.
        • Rudolf M.
        Management of stable chronic obstructive pulmonary disease in primary and secondary care: summary of updated NICE guidance.
        BMJ. 2010; 340: c3134
        • Poole P.
        • Black P.N.
        • Cates C.J.
        Mucolytic agents for chronic bronchitis or chronic obstructive pulmonary disease.
        Cochrane Database Syst. Rev. 2012; 8: Cd001287
        • van der Schans C.P.
        Conventional chest physical therapy for obstructive lung disease.
        Respir. care. 2007; 52 (discussion 206–9): 1198-1206
        • Valderramas S.R.
        • Atallah A.N.
        Effectiveness and safety of hypertonic saline inhalation combined with exercise training in patients with chronic obstructive pulmonary disease: a randomized trial.
        Respir. Care. 2009; 54: 327-333
        • Vestbo J.
        • Hurd S.S.
        • Agusti A.G.
        • Jones P.W.
        • Vogelmeier C.
        • Anzueto A.
        • et al.
        Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary.
        Am. J. Respir. Crit. Care Med. 2013; 187: 347-365
        • Stockley R.A.
        • O'Brien C.
        • Pye A.
        • Hill S.L.
        Relationship of sputum color to nature and outpatient management of acute exacerbations of COPD.
        Chest. 2000; 117: 1638-1645
        • Murphy T.F.
        • Brauer A.L.
        • Schiffmacher A.T.
        • Sethi S.
        Persistent colonization by Haemophilus influenzae in chronic obstructive pulmonary disease.
        Am. J. Respir. Crit. Care Med. 2004; 170: 266-272
        • Finney L.J.
        • Ritchie A.
        • Pollard E.
        • Johnston S.L.
        • Mallia P.
        Lower airway colonization and inflammatory response in COPD: a focus on Haemophilus influenzae.
        Int. J. Chron. Obstruct Pulmon Dis. 2014; 9: 1119-1132
        • Garcha D.S.
        • Thurston S.J.
        • Patel A.R.C.
        • Mackay A.J.
        • Goldring J.J.P.
        • Donaldson G.C.
        • et al.
        Changes in prevalence and load of airway bacteria using quantitative PCR in stable and exacerbated COPD.
        Thorax. 2012; 67: 1075-1080
      3. Huang YJ, Kim E, Cox MJ, Brodie EL, Brown R, Wiener-Kronish JP, et al. A persistent and diverse airway microbiota present during chronic obstructive pulmonary disease exacerbations. Omics a J. Integr. Biol. 14 (1):9–59.

        • Albert R.K.
        • Connett J.
        • Bailey W.C.
        • Casaburi R.
        • Cooper Jr., J.A.
        • Criner G.J.
        • et al.
        Azithromycin for prevention of exacerbations of COPD.
        N. Engl. J. Med. 2011; 365: 689-698
        • Herath S.C.
        • Poole P.
        Prophylactic antibiotic therapy for chronic obstructive pulmonary disease (COPD).
        Cochrane Database Syst. Rev. 2013; 11: CD009764
        • Hatzelmann A.
        • Morcillo E.J.
        • Lungarella G.
        • Adnot S.
        • Sanjar S.
        • Beume R.
        • et al.
        The preclinical pharmacology of roflumilast–a selective, oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease.
        Pulm. Pharmacol. Ther. 2010; 23: 235-256
        • Fabbri L.M.
        • Calverley P.M.
        • Izquierdo-Alonso J.L.
        • Bundschuh D.S.
        • Brose M.
        • Martinez F.J.
        • et al.
        Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials.
        Lancet. 2009; 374: 695-703
        • Lange P.
        • Parner J.
        • Vestbo J.
        • Schnohr P.
        • Jensen G.A.
        15-Year follow-up study of ventilatory function in adults with asthma.
        N. Engl. J. Med. 1998; 339: 1194-1200
        • Cerveri I.
        • Cazzoletti L.
        • Corsico A.G.
        • Marcon A.
        • Niniano R.
        • Grosso A.
        • et al.
        The impact of cigarette smoking on asthma: a population-based international cohort study.
        Int. Arch. Allergy Immunol. 2012; 158: 175-183
        • Thomson N.C.
        • Chaudhuri R.
        • Messow C.M.
        • Spears M.
        • MacNee W.
        • Connell M.
        • et al.
        Chronic cough and sputum production are associated with worse clinical outcomes in stable asthma.
        Respir. Med. 2013; 107: 1501-1508
        • de Marco R.
        • Marcon A.
        • Jarvis D.
        • Accordini S.
        • Almar E.
        • Bugiani M.
        • et al.
        Prognostic factors of asthma severity: A 9-year international prospective cohort study.
        J. Allergy Clin. Immunol. 2006; 117: 1249-1256
        • Sidebotham H.J.
        • Roche W.R.
        Asthma deaths; persistent and preventable mortality.
        Histopathology. 2003; 43: 105-117
        • Rogers D.F.
        The airway goblet cell.
        Int. J. Biochem. Cell Biol. 2003; 35: 1-6
        • Green F.H.
        • Williams D.J.
        • James A.
        • McPhee L.J.
        • Mitchell I.
        • Mauad T.
        Increased myoepithelial cells of bronchial submucosal glands in fatal asthma.
        Thorax. 2010; 65: 32-38
        • Reader J.R.
        • Hyde D.M.
        • Schelegle E.S.
        • Aldrich M.C.
        • Stoddard A.M.
        • McLane M.P.
        • et al.
        Interleukin-9 induces mucous cell metaplasia independent of inflammation.
        Am. J. Respir. Cell. Mol. Biol. 2003; 28: 664-672
        • Atherton H.C.
        • Jones G.
        • Danahay H.
        IL-13-induced changes in the goblet cell density of human bronchial epithelial cell cultures: MAP kinase and phosphatidylinositol 3-kinase regulation.
        Am. J. Physiol. Lung Cell. Mol. Physiol. 2003; 285: L730-L739
        • Carroll N.G.
        • Mutavdzic S.
        • James A.L.
        Increased mast cells and neutrophils in submucosal mucous glands and mucus plugging in patients with asthma.
        Thorax. 2002; 57: 677-682
        • Wood L.G.
        • Simpson J.L.
        • Hansbro P.M.
        • Gibson P.G.
        Potentially pathogenic bacteria cultured from the sputum of stable asthmatics are associated with increased 8-isoprostane and airway neutrophilia.
        Free Radic. Res. 2010; 44: 146-154
        • Green B.
        • Kehagia V.
        • Sammut D.
        • Wiriyachaiporn S.
        • Carroll M.P.
        • Bruce K.D.
        • et al.
        Pathogenic bacteria in induced sputum in severe asthma.
        Thorax. 2008; 63: A49
        • Calverley P.M.
        • Anderson J.A.
        • Celli B.
        • Ferguson G.T.
        • Jenkins C.
        • Jones P.W.
        • et al.
        Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease.
        N. Engl. J. Med. 2007; 356: 775-789
        • Calverley P.M.
        • Stockley R.A.
        • Seemungal T.A.
        • Hagan G.
        • Willits L.R.
        • Riley J.H.
        • et al.
        Reported pneumonia in patients with COPD: findings from the INSPIRE study.
        Chest. 2011; 139: 505-512
        • McKeever T.
        • Harrison T.W.
        • Hubbard R.
        • Shaw D.
        Inhaled corticosteroids and the risk of pneumonia in people with asthma: a case-control study.
        Chest. 2013; 144: 1788-1794
        • Zhang Q.L.
        • Illing R.
        • Hui C.K.
        • Downey K.
        • Carr D.
        • Stearn M.
        • et al.
        Bacteria in sputum of stable severe asthma and increased airway wall thickness.
        Respir. Res. 2012; 13
      4. British guideline on the management of asthma.
        Thorax. 2008; 63: iv1-121
        • Green B.J.
        • Wiriyachaiporn S.
        • Grainge C.
        • Rogers G.B.
        • Kehagia V.
        • Lau L.
        • et al.
        Potentially pathogenic airway bacteria and neutrophilic inflammation in treatment resistant severe asthma.
        PLoS One. 2014; 9: e100645
      5. Brusselle GG, Vanderstichele C, Jordens P, Deman R, Slabbynck H, Ringoet V, et al. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax 68 (4):322–329.

        • Brightling C.E.
        Chronic cough due to nonasthmatic eosinophilic bronchitis: ACCP evidence-based clinical practice guidelines.
        Chest. 2006; 129: 116s-121s
        • Brightling C.E.
        • Ward R.
        • Goh K.L.
        • Wardlaw A.J.
        • Pavord I.D.
        Eosinophilic bronchitis is an important cause of chronic cough.
        Am. J. Respir. Crit. Care Med. 1999; 160: 406-410
        • Ayik S.O.
        • Basoglu O.K.
        • Erdinc M.
        • Bor S.
        • Veral A.
        • Bilgen C.
        Eosinophilic bronchitis as a cause of chronic cough.
        Respir. Med. 2003; 97: 695-701
        • Simpson J.L.
        • McElduff P.
        • Gibson P.G.
        Assessment and reproducibility of non-eosinophilic asthma using induced sputum.
        Respiration. 2010; 79: 147-151
        • Brightling C.E.
        • Symon F.A.
        • Birring S.S.
        • Bradding P.
        • Wardlaw A.J.
        • Pavord I.D.
        Comparison of airway immunopathology of eosinophilic bronchitis and asthma.
        Thorax. 2003; 58: 528-532
        • Brightling C.E.
        Eosinophils, bronchitis and asthma: pathogenesis of cough and airflow obstruction.
        Pulm. Pharmacol. Ther. 2011; 24: 324-327
        • Gibson P.G.
        • Zlatic K.
        • Scott J.
        • Sewell W.
        • Woolley K.
        • Saltos N.
        Chronic cough resembles asthma with IL-5 and granulocyte-macrophage colony-stimulating factor gene expression in bronchoalveolar cells.
        J. Allergy Clin. Immunol. 1998; 101: 320-326
        • Brightling C.E.
        • Bradding P.
        • Symon F.A.
        • Holgate S.T.
        • Wardlaw A.J.
        • Pavord I.D.
        Mast-cell infiltration of airway smooth muscle in asthma.
        N. Engl. J. Med. 2002; 346: 1699-1705
        • Siddiqui S.
        • Gupta S.
        • Cruse G.
        • Haldar P.
        • Entwisle J.
        • McDonald S.
        • et al.
        Airway wall geometry in asthma and nonasthmatic eosinophilic bronchitis.
        Allergy. 2009; 64: 951-958
        • Park S.W.
        • Jangm H.K.
        • An M.H.
        • Min J.W.
        • Jang A.S.
        • Lee J.H.
        • et al.
        Interleukin-13 and interleukin-5 in induced sputum of eosinophilic bronchitis: comparison with asthma.
        Chest. 2005; 128: 1921-1927
        • Gibson P.G.
        • Hargreave F.E.
        • Girgis-Gabardo A.
        • Morris M.
        • Denburg J.A.
        • Dolovich J.
        Chronic cough with eosinophilic bronchitis: examination for variable airflow obstruction and response to corticosteroid.
        Clin. Exp. Allergy. 1995; 25: 127-132
        • Brightling C.E.
        • Ward R.
        • Wardlaw A.J.
        • Pavord I.D.
        Airway inflammation, airway responsiveness and cough before and after inhaled budesonide in patients with eosinophilic bronchitis.
        Eur. Respir. J. 2000; 15: 682-686
        • Bao W.
        • Liu P.
        • Qiu Z.
        • Yu L.
        • Hang J.
        • Gao X.
        • et al.
        Efficacy of add-on montelukast in nonasthmatic eosinophilic bronchitis: the additive effect on airway inflammation, cough and life quality.
        Chin. Med. J. 2015; 128: 39-45
        • Brightling C.E.
        Cough due to asthma and nonasthmatic eosinophilic bronchitis.
        Lung. 2010; 188: S13-S17
        • Wood P.
        • Stanworth S.
        • Burton J.
        • Jones A.
        • Peckham D.G.
        • Green T.
        • et al.
        Recognition, clinical diagnosis and management of patients with primary antibody deficiencies: a systematic review.
        Clin. Exp. Immunol. 2007; 149: 410-423
        • Thickett K.M.
        • Kumararatne D.S.
        • Banerjee A.K.
        • Dudley R.
        • Stableforth D.E.
        Common variable immune deficiency: respiratory manifestations, pulmonary function and high-resolution CT scan findings.
        QJM: Mon. J. Assoc. Physicians. 2002; 95: 655-662
        • Kainulainen L.
        • Nikoskelainen J.
        • Ruuskanen O.
        Diagnostic findings in 95 Finnish patients with common variable immunodeficiency.
        J. Clin. Immunol. 2001; 21: 145-149
        • Oksenhendler E.
        • Gerard L.
        • Fieschi C.
        • Malphettes M.
        • Mouillot G.
        • Jaussaud R.
        • et al.
        Infections in 252 patients with common variable immunodeficiency.
        Clin. Infect. Dis.: official Publ. Infect. Dis. Soc. Am. 2008; 46: 1547-1554
        • Conley M.E.
        • Notarangelo L.D.
        • Etzioni A.
        Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies).
        Clin. Immunol. Orl. Fla). 1999; 93: 190-197
        • Singh K.
        • Chang C.
        • Gershwin M.E.
        IgA deficiency and autoimmunity.
        Autoimmun. Rev. 2014; 13: 163-177
        • Yel L.
        Selective IgA deficiency.
        J. Clin. Immunol. 2010; 30: 10-16
        • Cunningham-Rundles C.
        Physiology of IgA and IgA deficiency.
        J. Clin. Immunol. 2001; 21: 303-309
        • Chipps B.E.
        • Talamo R.C.
        • Winkelstein J.A.
        IgA deficiency, recurrent pneumonias, and bronchiectasis.
        Chest. 1978; 73: 519-526
        • Schaffer F.M.
        Clinical assessment and management of abnormal IgA levels.
        Ann. Allergy Asthma Immunol. 2008; 100: 280-282
        • Ameratunga R.
        • Woon S.T.
        • Gillis D.
        • Koopmans W.
        • Steele R.
        New diagnostic criteria for common variable immune deficiency (CVID), which may assist with decisions to treat with intravenous or subcutaneous immunoglobulin.
        Clin. Exp. Immunol. 2013; 174: 203-211
        • Hammarstrom L.
        • Vorechovsky I.
        • Webster D.
        Selective IgA deficiency (SIgAD) and common variable immunodeficiency (CVID).
        Clin. Exp. Immunol. 2000; 120: 225-231
        • Quinti I.
        • Soresina A.
        • Spadaro G.
        • Martino S.
        • Donnanno S.
        • Agostini C.
        • et al.
        Long-term follow-up and outcome of a large cohort of patients with common variable immunodeficiency.
        J. Clin. Immunol. 2007; 27: 308-316
        • Kirkpatrick P.
        • Riminton S.
        Primary immunodeficiency diseases in Australia and New Zealand.
        J. Clin. Immunol. 2007; 27: 517-524
        • Urm S.H.
        • Yun H.D.
        • Fenta Y.A.
        • Yoo K.H.
        • Abraham R.S.
        • Hagan J.
        • et al.
        Asthma and risk of selective IgA deficiency or common variable immunodeficiency: a population-based case-control study.
        Mayo Clin. Proc. 2013; 88: 813-821
        • Sicherer S.H.
        • Winkelstein J.A.
        Primary immunodeficiency diseases in adults.
        JAMA. 1998; 279: 58-61
        • Abolhassani H.
        • Sagvand B.T.
        • Shokuhfar T.
        • Mirminachi B.
        • Rezaei N.
        • Aghamohammadi A.
        A review on guidelines for management and treatment of common variable immunodeficiency.
        Expert Rev. Clin. Immunol. 2013; 9 (quiz 75): 561-574
        • Weatherall M.
        • Travers J.
        • Shirtcliffe P.M.
        • Marsh S.E.
        • Williams M.V.
        • Nowitz M.R.
        • et al.
        Distinct clinical phenotypes of airways disease defined by cluster analysis.
        Eur. Respir. J. 2009; 34: 812-818
      6. Chang AB, Redding GJ, Everard ML. Chronic wet cough: Protracted bronchitis, chronic suppurative lung disease and bronchiectasis. Pediatr. Pulmonol. 43 (6):519–531.

        • Chang A.B.
        • Landau L.I.
        • Van Asperen P.P.
        • Glasgow N.J.
        • Robertson C.F.
        • Marchant J.M.
        • et al.
        Cough in children: definitions and clinical evaluation.
        Med. J. Aust. 2006; 184: 398-403
      7. Chang AB, Yerkovich ST, Gibson PG, Anderson-James S, Petsky HL, Carroll ML, et al. Pulmonary innate immunity in children with protracted bacterial bronchitis. J. Pediatr. 161 (4):621–625.e1.

        • De Schutter I.
        • Dreesman A.
        • Soetens O.
        • De Waele M.
        • Crokaert F.
        • Verhaegen J.
        • et al.
        In young children, persistent wheezing is associated with bronchial bacterial infection: a retrospective analysis.
        BMC Pediatr. 2012; 12: 83
        • De Schutter I.
        • De Wachter E.
        • Crokaert F.
        • Verhaegen J.
        • Soetens O.
        • Pierard D.
        • et al.
        Microbiology of bronchoalveolar lavage fluid in children with acute nonresponding or recurrent community-acquired pneumonia: identification of nontypeable Haemophilus influenzae as a major pathogen.
        Clin. Infect. Dis.: Official Publ. Infect. Dis. Soc. Am. 2011; 52: 1437-1444
        • Craven V.
        • Everard M.L.
        Protracted bacterial bronchitis: reinventing an old disease.
        Archives Dis. Child. 2013; 98: 72-76
        • Eastham K.M.
        • Fall A.J.
        • Mitchell L.
        • Spencer D.A.
        The need to redefine non-cystic fibrosis bronchiectasis in childhood.
        Thorax. 2004; 59: 324-327
        • Kelly M.G.
        • Murphy S.
        • Elborn J.S.
        Bronchiectasis in secondary care: a comprehensive profile of a neglected disease.
        Eur. J. Intern. Med. 2003; 14: 488-492
        • Schaefer O.P.
        • Irwin R.S.
        Unsuspected bacterial suppurative disease of the airways presenting as chronic cough.
        Am. J. Med. 2003; 114: 602-606