Common and Uncommon Causes of Chronic Cough Douglas

Common and Uncommon Causes of Chronic Cough Douglas B. Hornick, MD Professor Division of Pulmonary, Critical Care, and Occupational Medicine University of Iowa

Objectives • Differentiate acute from chronic cough • Review the most common causes as well as uncommon causes of chronic cough • Discuss treatment strategies

Great Reference Irwin RS, et al: Diagnosis & Management of Cough: ACCP Evidence-based Clinical Practice Guidelines. Chest 2006; 129: 1 S-292 S.

How do you define chronic cough?

Definitions & Epidemiology • Cough persisting > 3 weeks – Acute = up to 3 weeks – Subacute = 3 -8 weeks – Chronic = >8 weeks • 2008: Most common symptom among outpatients (>26 million office visits US) • ~40% of outpatient pulmonary practice • Cost > $1 billion/yr. (excludes diag. tests & meds) • Cough complications – Intrathoracic pressures 300 mm. Hg; exp velocity 500 mph – Exhaustion, insomnia, headache, musculoskel pain, dizziness, urinary incontinence, xs persperation --ACCP: Consensus Statement on Cough. Chest 2006

Spectrum of Reasons Patients Seek Medical Care for Cough • • Reassurance nothing serious (77%) Concern that something serious is wrong (72%) Frequent retching (56%) Exhaustion (54%) Others think something wrong (53%) Embarrassment/self-consciousness (47%) Difficulty speaking on the phone (39%) Hoarseness (39%) --ACCP: Consensus Statement on Cough. Chest 2006

Cough Reflex *Chemical Receptors (type 1 vanilloid): acid, heat, capsaicin-like compounds Mechanical Receptors: Touch/displacement Note: sex-related difference in sensitivity…women more likely to develop chronic cough UTD 2009

What are the most common causes of chronic cough? …after excluding smoker’s cough & ACE inhibiter

Common Causes of Chronic Cough • Upper Airway Cough Syndrome (38 -87%) (formerly post nasal drip syndrome) • Asthma (14 -43%) • GERD (10 -40%) • Chronic Bronchitis (0 -12%) • More than one cause (24 -72%) --Irwin et al: Chest 1998; 114: 133 S; Irwin et al: ARRD 1990; 141: 640; Irwin et al: ARRD 1981; 123: 413; Pratter et al: Ann Int Med 1993; 119: 977

Upper Airway Cough Syndrome (UACS) Formerly Post Nasal Drip • 3/4 studies: UACS most common cause chronic cough • DDx: Allergic, perennial (non)allergic, vasomotor • • rhinitis, nasopharyngitis, sinusitis, rhinitis medicamentosa, pregnancy, abnl nasal/sinus anatomy Symptoms: nasal discharge, post nasal drip, frequent throat clearing May not be apparent to the patient Exam: cobblestone/secretions in nasopharynx Response to Rx usually secures diagnosis • Try empiric Rx for UACS before extensive w/up for cause of cough

Asthma • History includes episodic wheezing and dyspnea • “Cough variant asthma”…no wheezing/dyspnea, only • • • cough, normal spirometry Other clues from history: atopy, family history of asthma, seasonal, follows URI, worsens with exposure to cold/dry air, fragrances or fumes, exacerbated by -blocker Rx Bronhoprovocation tests: Good negative predictive value; + test c/w but not diagnostic (false + ~ 33%) Diagnosis: improvement post therapeutic trial (e. g. , -agonist x 1 week)

Eosinophilic Bronchitis or Non-Asthmatic EB • Distinct from asthma; no bronchospasm • Recognized 2002; frequency uncertain (European • studies 10 -15%), probably under diagnosed Clinical characteristics – – Unexplained nonproductive cough Atopic; normal spirometry & bronchoprovocation tests (Induced) Sputum eosinophilia & airway inflammation Bronchial biopsy is diagnostic: Eosinophilic inflammation, but no Mast cells (or BAL w/ lots of Eosinophils) • Treatment: Inhaled steroid • Natural history not certain (N=367; 1 yr f/u): – 55% persistent symptoms; 33% asymptomatic – 12% develop asthma… Gibson et al: Thorax 2002

Gastroesophageal Reflux (GERD) • Second most common cause of cough in elderly • Up to 40% cases (Mello et al: Arch Int Med 1996; 156: 997) • Experimental data: Acid in distal esoph. can mimic • cough, blunted by lidocaine or inhaled ipatropium, does not elicit cough in normals Laryngeal-Pharyngeal Reflux (LPR): consider Oto eval (Clues: throat clearing, hoarseness, globus sensation, VCD) • Empiric 2 week trial with proton pump inhibitor =/more • reliable than p. H monitor (Ours et al: Am J. Gastroent 1999) NB: May take >8 wks of PPI Rx Acid suppression may not Rx reflux GERD can contribute to asthma exacerbation

Chronic Bronchitis “Smoker’s Cough” • Definition • Most are smokers, but most smokers don’t • • seek attention for “smoker’s cough” Sputum clear/white Change in character – purulent sputum: infection (viral, bacterial) – ? Neoplasm

Common Causes of Chronic Cough • Upper Airway Cough Syndrome (38 -87%) • Asthma (14 -43%) • GERD (10 -40%) • Chronic Bronchitis (0 -12%) • More than one cause (24 -72%) Hickam’s Dictum vs. Occum’s Razor A patient may have as many diagnoses as he darn well pleases! --Irwin et al: Chest 1998; 114: 133 S; Irwin et al: ARRD 1990; 141: 640; Irwin et al: ARRD 1981; 123: 413; Pratter et al: Ann Int Med 1993; 119: 977

Can you name some of the uncommon causes of chronic cough?

Less Common Causes of Chronic Cough • • • Bronchiectasis (0 -5%) • Broncholith ACE inhibitor Rx • Eosinophilic Bronchitis Post-infectious • Industrial bronchitis Occult aspiration • Nasal polyps Lung Cancer • Problems with: – Auditory canal Obstructive Sleep Apnea – Larynx Occult CHF – Diaphragm Interstitial Pulmonary – Pleura Fibrosis – Pericardium – Esophagus Occult infection (eg, TB, • Psychogenic NTM, suppurative bronchitis) --Irwin et al: Chest 1998; 114: 133 S; Irwin et al: ARRD 1990; 141: 640; Foreign body Irwin et al: ARRD 1981; 123: 413; Pratter et al: Ann Int Med 1993; 119: 977

Cough & Sleep Cough suppression during REM & non-REM sleep occurs naturally “Cough Variant Obstructive Sleep Apnea”… • 44% chronic cough pts have OSA • Hx not suggestive of OSA, cough only manifestation • Risk Factors: Female, nocturnal heartburn, rhinitis • Not associated: BMI, Epworth Sleepiness Scale, Dyspnea, snoring • CPAP treatment relieves cough Chan KK et al. Eur Resp J 2010; 35: 368 -72 Sundar KM et al. Cough 2010; 6: 2 -8

Bronchiectasis • Repeated/persistent airway inflammation & damage – poor mucous clearance; secretion pooling – dilated bronchi; thickened bronchial wall – chronic infection • Cough with mucopurulent sputum • Chest x-ray insensitive, but may show crowded • lung markings, thickened bronchial walls, fluidfilled cystic bronchi, “tram-tracks”, “signet ring” High resolution chest CT more specific

• Thin Section CT (1. 5 -3 mm) • Normal: Bronchus Vessel • Engagement (Signet) ring: Bronchus Vessel • Other Characteristics – Lack of tapering of bronchi – Clusters = Grape-like appearance – Enlarged bronchi can appear cystic vs. Bullae of emphysema (thinner walls) – Distribution of bronchiectasis suggests Dx • Central ABPA; Upper lobe CF; Lobar Post-infectious; obstructive (eg, LN, FB)

Bronchiectasis Differential Diagnosis • Post-infectious (e. g. Pertussis, severe pneumonia, • • Mycobacterium tuberculosis or avium complex) Airway obstruction or recurrent aspiration Cystic Fibrosis (Case report: Dx made at 65) Immunodeficiency (Agammaglobulinemia) Esoterica… – – – Alpha-1 -Antitrypsin Deficiency Inflammatory Disease (eg, Sjogren’s) Allergic Bronchopulmonary Aspergillosis Dyskinetic Cilia Syndrome Diffuse Pan Bronchiolitis Young’s Syndrome

Mnemonic: IA-SPICE • • Idiopathic Airway Obstruction Sjogren’s & other inflammatory (RA, IBD) Post-Infectious (Pertussis, Pneumonia, MAC, Mtb) Immunodeficiency (Agammaglobulinemia Cystic Fibrosis Esoterica – – – Alpha-1 -Antitrypsin Deficiency Dyskinetic Cilia Syndrome Allergic Bronchopulmonary Aspergillosis Diffuse Pan Bronchiolitis Young’s Syndrome

Pulmonary Fascinoma with an Infectious Attitude • 77 yo WF, persistent non-productive cough x 4. 5 yrs • Nonsmoker, denies S/S of PND, GERD, Asthma • H/O ovarian cancer resection 4. 5 years ago – Right middle lobe infiltrate on CXR – Bronchoscopy by local surgeon: Mycobacterium avium complex – Advice: nonpathogen, no treatment • Cough worsening severity over the last 1 year – Intermittent night sweats, temp 99 – More fatigue, increased dyspnea, no weight loss • CXR & CT

WF. 77 y. o. F

Case Summary (cont’d) • CXR varies little, going back 4. 5 years • 1 year ago (another university MD) bronchoscopy: – Biopsy: non-caseating granulomas; AFB – Lavage: Mycobacterium avium complex (MAC) – Advice: nonpathogen, no specific treatment – Failed therapeutic trials: bronchodilators, steroids (oral/inhaled), & H 2 blockers What is your working diagnosis? What would you do now?

Page 3, The Rest of the Story. . . Nodular Bronchiectais (Lady Windemere’s Syndrome) • AM Sputa x 3 smear positive AFB; grew MAC • Treated for MAC • Sputa cleared; cough/fatigue/night sweats resolved • by 6 mos. Non-productive cough returned at 9 months; AM sputa remained negative for MAC – W/u revealed GERD; possibly allergic rhinitis – Resolved with proton pump inhibitor & nasal steroid

MAC Lung Infections • Majority of NTM respiratory isolates are MAC and • • • are pathogenic in 50% cases Incidence rising…~8/100, 000 Worldwide, most common in temperate regions Isolated in bedding mat’l, house dust, soil, plants, swimming pools, hospital H 2 O, natural bodies of H 2 O Most infections: rural locations in SE, Atlantic & Pacific coastal regions of US Reactivity with PPD-B (70%) highest in southeast

MAC Skin Test Reactors Distribution Edwards et al: ARRD 1969

MAC Lung Infection— Nodular/Bronchiectasis Form • Persistent cough, dyspnea, malaise, weakness • Symptoms antedate MAC diagnosis (months-years) • Elderly>>young, Non-smoking female >>male w/o pre-existing • lung disease Pathogenesis uncertain – Medically uninitiated women; Lady Windermere’s syndrome implies pathogenesis linked to fastidiousness, habitual cough suppression – Body morphotype: Tall/thin plus increased a/w Pectus excavatum, Scoliosis, Mitral valve prolapse, Joint hypermobility – Undetectable defect in muco-cilliary fxn or mucosal immunity – Linked to gene for multi-drug intolerance • Chronic indolent process (symptoms can spontaneously abate) • MAC Infection is not the disease, but symptom of the disease • Patients die with, rather than from disease (Mortality estimates: 5 -20%)

Anthropometrics of women w/ N/B NTM Disease

MAC Lung Infection— Nodular/Bronchiectasis Form • Persistent cough, dyspnea, malaise, weakness • Symptoms antedate MAC diagnosis (months-years) • Elderly>>young, Non-smoking female >>male w/o pre-existing • lung disease Pathogenesis uncertain – Medically uninitiated women; Lady Windermere’s syndrome implies pathogenesis linked to fastidiousness, habitual cough suppression – Body morphotype: Tall/thin plus increased a/w Pectus excavatum, Scoliosis, Mitral valve prolapse, Joint hypermobility – Undetectable defect in muco-cilliary fxn or mucosal immunity – Linked to gene for multi-drug intolerance • Chronic indolent process (symptoms can spontaneously • • abate) MAC Infection is not the disease, but symptom of the disease Patients die with, rather than from disease (Mortality estimates: 5 -20%)

MAC Lung Infection-Nodular/Bronchiectasis Form (cont’d) • Episodic co-infection by other organisms (P. aeruginosa, Nocardia, rapidly growing mycobacteria) • Chest x-ray: (non-cavitary) infiltrates in middle lobe or lingula…Inadequate to appreciate N/B pattern • High resolution chest CT: – Bronchiectasis (multi-lobe more common) – Large and small (<5 mm) nodules (centrilobular) – Peripheral “tree-in-bud” pattern

Location of Infiltrates Kennedy & Weber: AJRCCM 1994

MAC Lung Infection-Nodular/Bronchiectasis (cont’d) • Episodic co-infection by other organisms (P. aeruginosa, Nocardia, rapidly growing mycobacteria) • Chest x-ray: (non-cavitary) infiltrates in middle lobe or lingula…Inadequate to appreciate N/B pattern • High resolution chest CT: – bronchiectasis (multi-lobe) – Large and small (<5 mm) nodules (centrilobular) – Peripheral “tree-in-bud” pattern

General MAC Lung Infection Treatment • Careful patient selection – ~50% nonpathogen – ATS/IDSA criteria – Expensive, long duration, intolerance & toxicity (elderly), compliance • Extended spectrum macrolides – Clarithro- > azithromycin – Improved outcomes to ~80% clinical cure (40%) – >90% susceptibility if previously untreated • Continue treatment until culture neg. x 12 months

MAC Lung Infection Treatment (cont’d) • Nodular/Bronchiectasis: – Clarithro- 1 gm TIW or Azithro- 500 mg TIW – Ethambutol 25 mg/kg TIW – Rifampin 600 mg TIW • Adjunctive measures: nutrition, chest • • physiotherapy, surgery Susceptibility testing unreliable except Clarithro. Severe disease: Strep or Amikacin; Rifabutin vs Rifampin

Nodular Bronchiectasis/MAC (Lady Windemere’s) Take Home Points • Mycobacteria avium complex is an unusual cause of • • • cough in the general clinic MAC as a pathogen in the “normal host” is frequently not appreciated…Recall Morphotype CT will show nodular bronchiectasis, tree-in-bud, inflammatory nodules Symptoms for years before diagnosis common Specific antibiotic treatment successful in some but not all cases (medication intolerance common) Some patients may exhibit several causes for cough that require treatment simultaneously. …Hickam’s Dictum!

Post-Infectious Cough • Diagnosis of exclusion • Cough post viral or other URI can persist for 8 weeks – Mycoplasma, Chlamydia, B. pertussis • Proposed mechanisms: – Post nasal discharge – Enhanced sensitivity of airway (exposure of cough afferent nerves in epithelia due to epithelial necrosis) – Airway hyper-responsiveness

Return of the 100 day Cough… No. & Incidence of Pertussis Cases Among Adults (19 -64 yo) 2000 -2004 CDC: MMWR Rec&Rep Dec 15, 2006

Post-infectious Cough: Pertussis in Adults • B. pertussis (GNB)…very contagious – Household: 70 -100% of contacts – School: 50 -80% of contacts • Increased incidence (highest among 10 -19 yo) – Immunization effect wanes during 1 st 10 yrs post vaccination – Decreasing # adults carrying natural immunity obtained during pre-vaccine era • Clinical characteristics – Incubation period: 1 -3 wks – Viral-like initial phase (catarrhal): ~2 weeks (conjunctivitis, rhinorrhea, fever, cough late) – Paroxysmal phase: 3 -6 months, Worsening cough (whoop uncommon…post-tussive vomiting) – Note: Protracted cough may be the only symptom, & Many infection can result in no cough (elderly)

Pertussis in Adults II • Diagnosis – – NP aspirate or polymer swab of NP for culture PCR costly supplement dx (CDC rec w/ culture) Acute & convalescent Ig. G or Ig. A titers (PT or FHA) Cough & linkage w/ confirmed case • Treatment Catarrhal Phase – Macrolide (erythro-, azithro-, clarithromycin) – Don’t delay Rx waiting for confirmation tests – Isolation for 5 days from start or Rx • Treatment Paroxysmal Phase: – See Post-infectious cough recommendations • Prevention after exposure – Macrolide Rx same as Treatment dose/duration – Vaccination w/ acellular pertussis vaccine (Tdap)

Pertussis in Adults: Vaccination Issues ACIP Recommendations • Tdap: Tetanus, Diphtheria, Acellular Pertussis • Booster Tdap in adolescents, 11 -18 yr • Single Tdap booster for Adults 19 -65 yr recommended – Improve adult coverage for pertussis, but also tetanus & diphtheria. – Single dose replacing Td at q 10 year booster – <10 yr interval Td (as short as 2 years) – HCW high risk for exposure (Cost benefit for vaccination program over outbreak control cost) CDC: MMWR Rec&Rep Dec 15, 2006

ACE Inhibitor • • • 3 -20% of patients on ACE Inhibitor Rx 72% recur, if re-administered Accumulation of bradykinin (normally degraded by ACE) Note: Angiotensin II receptor antagonists (e. g. losartan) do not cause cough General features: – – – Starts ~1 wk after start of Rx (delayed up to 6 months) Resolves 1 -4 d after stopping Rx (can take up to 4 weeks) Recurs with same or different ACE inhib Women > men Incidence no greater in asthmatics No change in spirometry • Rx = Stop ACE inhib. ( Angiotensin II receptor blocker)

General Approach • UACS, Asthma, and GERD cause 90% chronic cough • If nonsmoker, not on ACE inhibitor, normal or stable • • CXR, then 99% cases due to above 3 causes Pratter et al: Antihistamine-decongestant Rx was only Rx needed in 36% & another 50% noted improvement in symptoms. Guidelines – – Recall Hickam’s Dictum! Hx, Px, CXR, Rx aimed at clues in evaluation If no clues, start antihistamine-decongestant or nasal steroid If no improvement, check spirometry/bronchoprovocation; add bronchodilators – If no improvement, 24 hr esoph p. H monitoring

Specific Treatments Upper Airway Cough Syndrome (UACS) • Anti-histamine/decongestant – 1 st generation sedating anti-histamines more effective – Effect takes ~1 week • Nasal steroids – May take up to 2 weeks for full effect • Add nasal ipratropium if anti-histamine or decong. failing (Vasomotor rhinitis) • Trial monteleukast if allergic rhinitis & above insufficient • Sinusitis – Document with limited sinus CT – Anti-histamine/decong. + abx (bactrim, cefurox) up to 6 wks – Short term nasal decongestant spray

Antihistamine and Driving Performance • Randomized, double-blinded, double dummy, N=40 • • (ages 25 -40) Compared fexofenadine, diphenhydramine, Et. OH (0. 1%), & placebo, 4 period x-over trial Results (Driving Simulator): – Driving performance was poorest with diphenhydramine (vs. Et. OH or fexofenadine) – Drowsiness self-assessment scores did not predict worse driving performance – Drivers perception of drowsiness on diphenhydramine (50 mg) not a good indicator of when they should not drive Weiler et al: AIM 2000

Specific Treatments Upper Airway Cough Syndrome (UACS) • Anti-histamine/decongestant – 1 st generation sedating anti-histamines more effective – Effect takes ~1 week • Nasal steroids (and/or nasal antihistamine) – May take up to 2 weeks for full effect • Add nasal ipratropium if anti-histamine or decong. • • failing (Vasomotor rhinitis) Trial Monteleukast if allergic rhinitis & above insufficient Sinusitis – Document with limited sinus CT – Anti-histamine/decong. + abx (bactrim, cefurox) up to 6 wks – Short term nasal decongestant spray

Specific Treatments Cough Variant Asthma • Same principles as asthma • Inhaled bronchodilator trial; consider 1 -2 week course of Prednisone (diagnostic & therapeutic) • Most require maintenance inhaled steroid • Limited data for leukotriene receptor antagonists --Cheriyan et al: Ann All 1994

Specific Treatments GERD • Avoidance of reflux-inducing food (e. g. , fatty foods, • • chocolate, Et. OH) Smoking cessation Avoid snacking No eating within 3 hrs of lying down for sleep Elevation of head of bed H 2 antagonist or Proton pump inhibitor (preferred) Length of time for response may be 3 -6 mos. Refractory cases: – LPR requires high dose PPI – May be d/t dyskinesis (trial metocolpromide) – Rare pt, acid suppressed still cough d/t reflux surgery --Irwin et al: ARRD 1990 & Irwin et al: Chest 1993

Non-specific Treatments • Post-infectious: nasal steroid or ipratropium MDI (steroid B/T) • Ipratropium MDI – Blocks afferent limb of cough reflex – Alters mucociliary factors less stimulation of cough receptors • Central acting anti-tussive agents – Codeine 30 mg – Dextramethoraphan, up to 60 mg – Meta analysis (Yancy et al. Chest 2013; 144: 1827 -38) both > placebo; no good comparison studies, no studies examine chronic/refractory cough • Peripherally acting agents – Benzonatate: inhibits stretch receptors (Rx x 50 yrs) – Guaifenesin: hydrates mucous for expectoration; may suppress hypersensitive cough receptors • Studied but not generally useful when used empirically – Inhaled steroids • Inhaled lidocaine

Summary • Differentiate acute from chronic cough • Reviewed the most common causes as well as uncommon causes of chronic cough • Identified treatment strategies