sublingual immunotherapy: an introduction

Sublingual Immunotherapy: An Introduction

AAOA Basic Course ©

Chronic Cough

Cecelia Damask, DO, FAAOA

Lake Mary ENT & Allergy

Disclosures

• Teva Respiratory – Speakers Bureau

• Audigy Medical -- Consultant

Thank you…

Sarah Wise, MD

Objectives

Understand the:• Broad differential diagnosis of chronic

cough• Top 3 - 4 causes of chronic cough • Diagnostic work up of chronic cough



What? A forced expulsive maneuver, usually against a partially closed glottis, associated with a characteristic sound.

Why? Cough is designed to clear the airway of secretions and particulates, and is also a reflex to protect the lower airway.

Cough

image: www.adclinic.com

Anatomy of a cough...RegionParanasalPharynx Larynx/tracheobronchial

tree*

External auditory canal/TMEsophagus, stomach, pleuraDiaphragm, pericardium

Afferents converge in the medulla

Upper AW, intercostals, abdominals, pelvic musculature

*Greatest concentration cough receptors.

(Simpson, 2006)

Afferent nerve

Trigeminal (V) Glossopharyngeal (IX)Vagus (X), S. A. (XI)Vagus (X) (Arnold’s N)Vagus (X)Vagus (X) Phrenic

Efferents Vagus (X)

image: www.intranet.tdmu.edu.ua

Classification of cough

• Acute cough• < 3 weeks duration

• Subacute cough• 3-8 weeks duration

• Chronic cough• >8 weeks duration (adults)• >4 weeks duration (kids)

(Irwin, 2000)



Postinfectious cough syndrome

Cough for 3-8 weeks after URI.

Treatment :• Reassurance and support• Inhaled ipratropium• Inhaled corticosteroid• Severe paroxysms: prednisone 30-40 mg/day• Codeine or dextromethorphan

If paroxysmal, with whooping or posttussive emesis, consider testing for pertussis.

image: memecenter.com

Chronic cough

• 18% of US population• Annual cost in US >$1billion• Female > male

• Due to cough reflex sensitivity

(Barbee, 1991; Fujimura, 1996; Kastelik, 2002; Morice 2006)

Zenker’s diverticulum TE fistula SarcoidosisCongestive heart

failureThyroid Disease

….etc.

Possible etiologies:AsthmaGERD/LPDUACSForeign body: tracheobronchial

tree, aryngopharynx, sinonasal, external auditory canal

Chronic bronchitis BronchiectasisLung carcinoma Subglottic stenosisTracheomalacia Chronic aspiration

Diagnostic protocol (anatomic-diagnostic)Irwin, et al. 1998

**



Probability-based algorithmKastelik et al. 2005

*

*

ACCP Evidence Based Clinical Practice GuidelinesPratter, et al. 2006

**

Smoker’s cough

• Increased prevalence of cough in smokers

• Up to 50% of smokers >75 years old = COPD

• Consequences:• Ciliary paralysis• Toxins accumulate

• Cough worse in am, improves throughout day

image: www.thelancet.com

(Jansen, 1999; Dicpinigaitis, 2003; Lundback, 2003)



Smoker’s cough:surgical implications

Preop smoking cessation - Timing is essential!Respiratory complication rates vs. smokers:

• Stop smoking <4 weeks preop: not significant• Stop smoking 4-8 weeks preop: 23% RR reduction• Stop smoking >8 weeks preop: 47% RR reduction

Optimum time to stop preoperatively?• 120 pts, cessation or 50% reduction 6-8 weeks prior

to THA and TKA• 18% vs 52% overall complication rate (p<0.0003)• 5% vs 31% wound complications (p<0.001)• 0% vs 10% cardiovascular complications (p<0.08)• 4% vs 15 % secondary surgery rate (p<0.07)

(Wong 2012; Moller 2002)

Wiggins & Kelly. Kidney International. 2009image: www.nature.com

ACE inhibitors

ACE inhibitors

• 20% or more develop dry hacking cough days to months into treatment

• Women, ACE genotype II, black or asian ethnicity increased risk

• Randomized double-blind parallel group studies suggest that ARBs carry no significant risk of cough, despite overlap in mechanism.

(Dykewicz, 2004)



ACE inhibitor cough

Treatment: medication cessation

Can’t stop the medication?•Other medications may help•Cromolyn, baclofen, theophylline, local anesthetics, sulindac (COXi) and intermediate dose ASA (500 mg/day)

Hoofbeats...think horses, not zebras

Etiology of 99% of chronic cough cases can be identified in healthy, nonsmoking adults. – Immunocompetent, nonsmokers with normal chest x-ray not

on ACE inhibitors, no B symptoms

Think “common triad”…– UACS (allergic rhinitis/chronic sinusitis) – Cough-variant asthma– GERD/LPR

and also…– Nonasthmatic eosinophilic bronchitis (depending on source)

image: dailymail.co.uk

(Simpson, 2006)

Upper Airway Cough Syndrome

• Cough may be caused by– Post-nasal drip itself

– Irritation or inflammation of upper airway structures that directly stimulate cough receptors

• Unified airway concept

Irwin RS, et al. Chest 2006;129 (Suppl. 1): 1S–23S.Pratter MR. Chest 2006;129 (Suppl. 1): 220S–221S.



Syndrome…

Diagnosis based on:– Symptoms– PE findings (may be few/none)– Radiographic findings (may be few/none)– Response to specific treatment***

Treatment:– Avoidance of allergens/irritants– Treatment to block or reduce inflammation and secretions– Treatment of infection– Correction of structural alterations

Pratter MR. Chest 2006;129 (Suppl. 1): 220S–221S.


• May consider empiric therapy based on suspicion of disease

• Consider diagnostic tests including CT sinus and allergy testing if suspicion is there despite lack of response


Pratter MR. Chest 2006;129 (Suppl. 1): 220S–221S.

Cough Variant Asthma

• Don’t forget about asthma!• Physical exam and spirometry• If nondiagnostic, consider methacholine challenge

(Irwin et. al., 2006)image: www.cmaj.ca



image: Marciniuk DD, ACCP Pulmonary Medicine Board Review, 26th ed. Ch. 6.

20% or greater drop in FEV1

Goal of treatment: Resolution of cough with specific anti-asthmatic therapy of inhaled bronchodilators and/or inhaled corticosteroids

** Response to steroid therapy will not exclude NAEB **

(Irwin et. al., 2006)image: www.iconarchive.com

Cough Variant Asthma

LPR/GERD cough

• Prevalence of GERD-related cough can be as high

as 40% (Harding, 1997)

• If CXR, allergy testing, sinus CT scan and PFTs are

normal...think LPR (Irwin, 1989)

• Consider entire symptom complex

• Including 24-hour pH monitoring diagnoses LPR in

up to 21% of chronic cough patients

• Sensitivity/specificity/NPV/PPV = 100% (Irwin, 1990; Irwin 1994)

• Multiple causes (PND/asthma/GERD) in 26%



Mechanisms…• Acid exposure in the distal esophagus stimulates

esophageal-tracheobronchial cough reflex via vagus nerve• Volume reflux (acid or non-acid) stimulates cough reflex via

vagus nerve• Microaspiration (or macroaspiration) of esophageal contents

into the laryngopharynx and tracheobronchial tree• Increased cough reflex sensitivity• Esophageal dysmotility, decreased clearance• Self-perpetuating cough-reflux cycle

(Harding, 1997)

LPR/GERD cough

GERD + Asthma…• GERD present in 34-89% of asthmatics• Improvement of asthma (symptoms and medication

use) in 75% of patients with aggressive GERD treatment (BID PPI or surgical treatment)

Treatment of LPR/GERD cough…• Trial PPI BID x at least 8 weeks • Additional if needed: H2 blocker QHS, prokinetics,

elimination of GERD-worsening medications• Dietary modifications

(Harding, 1997)

LPR/GERD cough

Reflux-associated cough treatment failures:• Multiple etiologies?• Inadequate length of treatment?

– 179 days mean until cough resolved in one study (Irwin,

2000)

• Nonacid reflux? (i.e. volume reflux, gastric enzymes, bile salts)

• Irwin et al, 2002: 8 pts persistent cough despite total/near total acid suppression

• Negative 24-hour pharyngeal pH probe on Rx• Marked improvement in cough for all 8 patients after

antireflux surgery

LPR/GERD cough



Eosinophilic Bronchitis

• Identified as etiology of chronic cough in 1989 by Gibson

• 10-30% of specialist referrals

(Brightling, 2006)

• Chronic cough in patient with• No symptoms or objective evidence of variable

airflow obstruction• Normal airway hyperresponsiveness• Sputum eosinophilia

• Often associated with exposure to occupational sensitizer or inhaled allergen

• Corticosteroid responsive


(Gibson, 1989)

Induced sputum studies

• Technique: patient inhales increasingly concentrated hypertonic saline: 3%, 4% then 5% in sequence for 5 min each via ultrasonic nebulizer after premedication with bronchodilator

• Expectorated sputum collected, then dispersed, filtered and spun,cells evaluated

image: pathology.jhu.edu



Occupational causes:• Flour• Natural rubber latex• Mushroom spores• Acrylates• MMTH-phthalic anhydride• Bucillamine• Lysozyme• Isocyanates

(Quirce, 2004; Di Stefano, 2005)


www.thehawkseye.com

Features EB Asthma Cough v. asthma

Symptoms cough cough/SOB/wheeze

cough

Atopy same as population

common common

Airway hyperresponsiveness

absent present present

cough reflex hypersensitivity

increased normal or increased

normal or increased

bronchodilator response absent good good

corticosteroid response good good (if eos) good (if eos)

sputum eosinophilia always usually usually

bronchial biopsy eosinophilia

very common common common

mast cells in AW sm. muscle

no yes yes

(Brightling, 2006)

Treatment…•If causal allergen or occupational sensitizer identified… avoidance•Inhaled corticosteroids (budesonide 400 mcg inhaled BID best studied) •Oral antihistamines or leukotriene modifiers need more study•Rarely, oral corticosteroids needed

(Brightling, 2006)




Idiopathic cough

Typically, initial insult or etiology resolves, but cough remains.

• Preponderance of females, especially peri- or postmenopausal (up to 80% of referrals in some cough clinics)

• Females generally have heightened cough reflex

(McGarvey, 2005)

Pathophysiology…•Inflammatory/neuropathic changes in sensory nerves (post-insult)•Repetitive mechanical and physical effects of coughing can enhance airway inflammation•Airway inflammation and remodeling can increase cough reflex sensitivity•“Cough hypersensitivity syndrome”?

Idiopathic cough

Cough hypersensitivity syndrome

(Chung, 2014)



Taskforce of the European Respiratory Society:

“A clinical syndrome characterised by troublesome coughing often triggered by low levels of thermal, mechanical, or chemical exposure.”

Cough hypersensitivity syndrome

(Morice et al, 2014)

Treatment…Neuralgia medications:• 32 patients, 30/32 responded to at least one:

• Final dose response – significant symptom reduction: • 77% on amitriptyline• 73% on desipramine• 69% on gabapentin

These drugs have also been studied individually, with good results.

Idiopathic cough

(Bastian, 2015)

Treatment protocol: Bastian & Bastian

Step 1: first line medication trial– amitriptyline or desipramine (10 mg QHS, max 80 mg)

Step 2: phone follow up

Step 3: second line medication trial (if needed)– gabapentin (300 mg; incr. to 2400 mg/day over 12 days)

Step 4: third, fourth, or fifth line medications if needed– citalopram, pregabalin, oxycarbazepine, capsaicin spray

Step 5: gradual discontinuation trial (optional)



Treatment…

Maybe coming soon?• Retrospective series and case reports:

• Pregabalin• Baclofen• Botulinum toxin

• Further studies needed

(Altman, 2015)

Idiopathic cough

Psychogenic cough

• AKA habitual cough or tic cough• Nonproductive, tinny or harsh cough• Severe frequency up to Q2-3 seconds• NOT during sleep, enjoyable activities• Diagnosis of exclusion only• Psychological evaluation or psychiatric

intervention useful

And now…

The zebras…Foreign body:

tracheobronchial tree,laryngopharynx,sinonasal, externalauditory canal

BronchiectasisCystic fibrosisLung carcinoma Subglottic stenosis

Tracheomalacia Chronic aspiration Zenker’s diverticulum TE fistula SarcoidosisCongestive heart failureThyroid DiseaseTuberculosis

…etc.

image: www.clipartpanda.com



Summary

• Determine duration of cough• Smoker? ACE inhibitor? • Immunocompetent? B symptoms?• 99% of cases: UACS, Asthma, GERD/LPR,

+/- NAEB• May be a combination of these

• Remember diagnostic studies: CXR, PFTs, allergy testing, CT sinus, pH probe

• If lack of response think of the rare causes

Suggested algorithm for chronic cough

Chronic Cough

(No tob Hx)

• No hx of sig tobacco abuse

• What is the cough like?– Wet, thick, productive vs. dry, barky, non-prod.

• Where is cough coming from?– Laryngeal vs. chest

• Thorough pulmonary screening– CXR and/or CT Chest (Bronchiectasis)

– PFT’s and MCC

• Stop ACE Inhibitor and ARB– Up to 12% of pts on ACI have cough!

• Remaining diagnoses:

44

CXR, PFTs, MCCCXR, PFTs, MCC

VideostrobscopyVideostrobscopy

Stop ACEIStop ACEI

Impedence Testing(MII Testing)


Speech TxBehavioral Retraining


Pertussis IgGPertussis IgG

Trial MedsTrial Meds

Allergy TestingAllergy Testing

Suggested algorithm for chronic cough

Chronic Cough

(No tob Hx)

• Remaining diagnoses:– Pertussis—test IgG, history questions

• “Worst cough in my life”

• Worse at night

• Post-tussive syncopy/emesis

– Behavioral—Speech therapy referral

– LPR---pH probe—MII testing• Majority do NOT have LPR

– UACS---consider allergy testing

– Post-viral vagal neuropathy• Dry and irritative

• Worse with talking, temp changes, spices, acids

45

CXR, PFTs, MCCCXR, PFTs, MCC

VideostrobscopyVideostrobscopy

Stop ACEIStop ACEI





Pertussis IgGPertussis IgG

Trial MedsTrial Meds

Allergy TestingAllergy Testing



Case Study 1

Recognizing the Etiology of Cough and Institution of the Appropriate Treatment

46

6 Year-Old Girl With Chronic DryCough of 10 Weeks DurationHistory• Dry cough occurs almost daily, no present wheeze.• Sight chest tightness and dyspnea with exertion.• Nocturnal awakening several times a month with cough.• History of “croup” with wheezing in past.• URI’s several times a year associated with wheezing that improves

with SABAs.• No reported nasal symptoms or heartburn• No prior history of food allergy or eczema (AD)

Family History• Father and one sibling have asthma• Mother and another sibling have Allergic rhinitisMedication History• OTC cough and cold medications, without benefit

47

Case 1 continued

Physical Exam• Well nourished girl, alert and cooperative who appears normal

except for her intermittent coughing• Nasal membranes pale but not swollen or wet, no discharge or post

nasal drip• No sinus tenderness• Chest clear to auscultation: no wheezes rales or rhonchi• No organomegaly or abdominal tenderness

48



Question 1

Differential diagnosis might includea) Asthmab) Habit coughc) GERDd) Vocal cord dysfunctione) Rhinosinusitisf) All of the above

Global Initiative for Asthma. Global strategy for asthma management and prevention. 2006;1:16-25.Grayson MH, Holtzman MJ. 14 Respiratory Medicine, II Asthma, ACP Medicine Online, 2002.

49

Study Results• Chest X-ray: normal, no hyperinflation, no infiltrates• Peak flow: 100% of predicted• Spirometry: within normal limits, Normal flow/volume

loop• Exhaled NO: 31 ppb (elevated) • Sinus imaging: not indicated given absence of upper

respiratory symptoms• Skin tests positive to dust mite

Malmberg LP et al. Pediatr Pulmonol. 2006;41:635-642.Malmberg LP. J Asthma. 2004;41:511-520.

Profita M et al. J Allergy Clin Immunol. 2006;118:1068-1074.Buchvald F et al. J Allergy Clin Immunol. 2005;115:1130-1136.

Olin AC et al. Chest. 2006;130:1319-1325.

50

Fractional exhaled nitric oxide(FeNO)

• Measurement by single-breath exhalation through a mouthpiece into a nitric oxide (NO) analyzer

• FeNO measurement correlates well with Th2 inflammation

• FeNO clinical value– Assessing the underlying inflammatory disease activity of

diagnosed asthma– Monitoring and managing asthmatic’s response to therapy—

including assessment of complianceBukstein D et al. Allergy Asthma Proc. 2011; 32(3): 185-192.

51



The AAAAI and ACAAI Recognize and Endorse the 2011 American Thoracic Society Guidelines

“…measurement of airway inflammation, using FeNO, is a paradigm change in asthma diagnosis and management “

“…it provides a perspective otherwise unavailable to the clinician”

ACAAI/AAAAI Joint Work Group

FeNO Significantly ELEVATED in Asthma

• FeNO levels significantly increased in both asthma groups

• FeNO levels significantly higher in patients with allergic asthma versus patients with nonallergic asthma

Zietkowski et al. J Investig Allergol Clin Immunol. 2006;16(4):239-246.

FeN

O,

pp

b

P=0.0001160

140

120

100

80

60

40

Nonallergic asthma

n=45

Allergic asthma

n=56

Healthy volunteers

n=39

0

20

P=0.0001P=0.0001

FeNO For Assessment of Chronic Cough

FeNO significantly higher in asthmatics with chronic cough compared with healthy volunteers (P=0.007) and non-asthmatic patients with chronic cough (P=0.0014)

Chatkin et al. Am J Respir Crit Care Med. 1999; 159(6): 1810-1813..

150

Fe

NO

, p

pb

100

50

0Healthy controls(n=23)

Patients with asthma and wheezing or

dyspnea(n=44)

Patients with asthma and

chronic cough(n=8)

Nonasthmatic patients with

chronic cough(n=30)

NPV 93% at 30ppb



FeNO Interpretation: Patients with suspected asthma

Question 2Which course of therapy is most appropriate?

A) Watch and wait approach; Reassurance, Instructions to call if symptoms worsen and make f/u visit in 1 month

B) Broad spectrum antibiotic for URI to cover atypical organisms such as mycoplasma or chlamydia

C) Albuterol MDI q4h PRN as monotherapy

D) Single entity controller asthma medication I.e. inhaled corticosteroid (ICS) or Leukotriene Receptor Antagonost (LTRA) along with albuterol MDI PRN and/or pre exercise.

E) Combination therapy with an ICS and Long Acting Beta Agonist (LABA) to control both exercise induced bronchospasm and cough due to airway inflammation

RESULTS OF THERAPEUTICCHOICES

CHOICE A) Watch and Wait (Poor choice)

• 3 weeks later, mother still reports persistent cough increased by recent heavy dust exposure; wheezing is now observed

• She requests re-evaluation

• FeNO 37 ppb (still elevated)

• Alternative diagnosis and therapy indicated



RESULTS OF THERAPEUTICCHOICESCHOICE B) BROAD SPECTRUM ANTIBIOTIC (poor choice)

• Dry cough persists without change after completion of 2 week antibiotic course

• No fever, myalgia or discolored sputum,

• Mother returns for reevaluation and change in therapy

• FENO 31 ppb (still elevated)

• Elevated exhaled NO indicative of eosinophilic inflammation rather than neutrophilic inflammation associated with infection

RESULTS OF THERAPEUTICCHOICES

CHOICE C) PRN ALBUTEROL MDI as sole therapy (Poor Choice)

• Minimal decrease in daytime cough. Nocturnal awakening 3x/month

• Exercise induced cough prevented with albuterol MDI pretreatment

• FeNO 30 (Still elevated) Initial impression of asthma was appropriate

• BUT:PRN albuterol only helpful in preventing EIB and controlling the bronchospastic aspect of cough and inadequate in controlling underlying bronchial inflammation as indicated by elevated exhaled NO level

RESULTS OF THERAPEUTICCHOICESD) Daily ICS plus PRN Albuterol MDI (BEST Choice)

• Cough subsided, No further nocturnal awakening

• FeNO 7 ppb

• Mild Persistent Asthma is the most likely diagnosis

• Cough in an atopic child with elevated exhaled NO suggests atopic asthma despite normal peak flow and spirometry or impulse oscillometry

• Allergic asthma is likely because of sensitization to mite

• Maintenance asthma controller [ICS (preferred) or LTRA] is recommended

Kim CK et al. Clin Exp Allergy. 2003;33:1409-1414.

Malmberg LP et al. Thorax. 2003;58:494-499.

Guilbert TW et al. N Engl J Med. 2006;354:1985-1997.



RESULTS OF THERAPEUTICCHOICESE) ICS +LABA (Over-treatment: Poor Choice)

• Mother informed at Pharmacy that Insurance Company would not pay for a combination ICS/LABA drug for patient who had not tried and failed a single entity controller

• Mother would not pay for drug out of pocket and returned to office for alternative therapy

• Physician chastised by Quality Control HMO Director for prescribing a ICS/LABA for mild persistent asthma, when a less expensive single entity controller has been shown to be equally efficacious and less expensive!

Friedman et al. Curr Med Res Opin 2007;23:427-434

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