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; 129:1S-292S.
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 mmHg; 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
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;114:133S; 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 pH 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;114:133S; 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:
• Obstructive Sleep Apnea – Auditory canal
– Larynx
• Occult CHF – Diaphragm
• Interstitial Pulmonary – Pleura
Fibrosis – Pericardium
• Occult infection (eg, TB, – Esophagus

NTM, suppurative bronchitis) • Psychogenic

• Foreign body --Irwin et al: Chest 1998;114:133S; Irwin et al: ARRD 1990; 141:640;
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, fluid-
filled 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), & H2 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 H2O, natural bodies of
H2O
• 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 (19-64yo) 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 1st 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 IgG or IgA 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 q10 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, 24hr esoph pH monitoring
 Specific Treatments
Upper Airway Cough Syndrome (UACS)
• Anti-histamine/decongestant
– 1st 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, EtOH
(0.1%), & placebo, 4 period x-over trial
• Results (Driving Simulator):
– Driving performance was poorest with diphenhydramine
(vs. EtOH 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
– 1st 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, EtOH)
• Smoking cessation
• Avoid snacking
• No eating within 3 hrs of lying down for sleep
• Elevation of head of bed
• H2 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 x50yrs)
– 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