Publish in this journal
Journal Information
Vol. 51. Num. 11.November 2015
Pages e53-e56Pages 535-610
Visits
2547
Vol. 51. Num. 11.November 2015
Pages e53-e56Pages 535-610
Recommendations of SEPAR
DOI: 10.1016/j.arbr.2015.09.009
Full text access
Chronic Cough
Tos crónica
Visits
2547
Adalberto Pachecoa,
Corresponding author
apacheco.hrc@salud.madrid.org

Corresponding author.
, Alfredo de Diegob, Christian Domingoc, Adelaida Lamasd, Raimundo Gutierreze, Karlos Naberanf, Vicente Garriguesg, Raquel López Vimeh
a Servicio de Neumología, Hospital Ramón y Cajal, Madrid, Spain
b Servicio de Neumología, Hospital La Fe, Valencia, Spain
c Servicio de Neumología, Hospital Parc Taulí, Sabadell, Barcelona, Spain
d Servicio de Pediatría, Hospital Ramón y Cajal, Madrid, Spain
e Servicio de Otorrinolaringología, Hospital Rey Juan Carlos, Móstoles, Madrid, Spain
f Centro de Salud Belchite, Zaragoza, Spain
g Servicio de Gastroenterología, Hospital La Fe, Valencia, Spain
h Servicio de Neumología, Hospital Severo Ochoa, Madrid, Spain
This item has received
2547
Visits
Article information
Abstract
Full Text
Bibliography
Download PDF
Statistics
Figures (7)
Show moreShow less
Tables (8)
Table 1. Causes of chronic cough and warning symptoms.
Table 2. Differential Diagnosis Between Various Diseases With Eosinophilic Inflammation of the Airways Associated With Chronic Cough.
Table 3. Grades of Recommendation/Evidence of Antireflux Treatment in Patients With Chronic Cough.
Table 4. Laryngeal Reflux Symptom Index.
Table 5. Index of Endoscopic Signs of Laryngopharyngeal Reflux.
Table 6. Sensitivity and Specificity of Signs and Symptoms of Chronic Cough.
Table 7. Warning Signs and Symptoms in Children With Chronic Cough.
Table 8. Causes of Unexplained Cough in Adults.
Show moreShow less
Abstract

Chronic cough (CC), or cough lasting more than 8 weeks, has attracted increased attention in recent years following advances that have changed opinions on the prevailing diagnostic and therapeutic triad in place since the 1970s. Suboptimal treatment results in two thirds of all cases, together with a new notion of CC as a peripheral and central hypersensitivity syndrome similar to chronic pain, have changed the approach to this common complaint in routine clinical practice. The peripheral receptors involved in CC are still a part of the diagnostic triad. However, both convergence of stimuli and central nervous system hypersensitivity are key factors in treatment success.

Keywords:
Cough
Antitussive agents
Respiratory aspiration
Gastroesophageal reflux
Vocal cord dysfunction
Abbreviations:
ACEI
BCT
BHR
CC
CNS
CPAP
CUACS
EB
FeNO
GABA
GER
GERD
LCQ
LHS
CCHS
LPR
PBI
PC
PCR
RAST
RCT
SAHS
TRP
TRPV1
VCD
Resumen

La tos crónica (TC), o tos que perdura más de 8semanas, ha merecido un interés creciente en los últimos años debido a los avances producidos que han motivado un cambio de visión respecto a la clásica tríada diagnóstica y terapéutica en vigor desde la década de los setenta. Unos resultados no óptimos en el tratamiento que alcanza los dos tercios de casos, junto a una nueva concepción de la TC como síndrome de hipersensibilidad con 2 polos, periférico y central, similares al dolor crónico, ocasionan que se contemple este problema tan frecuente en la práctica clínica de una nueva manera. Los receptores periféricos de la TC siguen teniendo vigencia bajo la tríada diagnóstica; sin embargo, tanto la convergencia de estímulos como la hipersensibilidad adquirida a nivel del sistema nervioso central son hechos que tienen una repercusión clave en el éxito del tratamiento.

Palabras clave:
Tos
Agentes antitusivos
Aspiración respiratoria
Reflujo gastroesofágico
Disfunción de cuerdas vocales
Full Text
Introduction

Chronic cough (CC), or cough lasting more than 8 weeks, is the most common symptom encountered in outpatient medical practice. Research into the mechanisms causing chronic pain and CC has detected similar neuronal pathways in both conditions, enabling investigational advances in chronic pain to be used to improve the understanding of CC. These guidelines discuss the medical problems associated with CC, either as an isolated entity or as the major symptom of a syndrome, and make proposals that take into account the level of evidence and grade of recommendations (GRADE system).1 In this respect, it should be pointed out that in CC, the available evidence is based mainly on observational studies.2

These guidelines are presented in 3 sections: (a) description and management of CC; (b) management of CC in the various clinical care scales; and (c) problems and future perspectives in CC.

Each section may contain several subsections.

Description and Management of Chronic CoughDefinition

Cough is an inherent protective respiratory tract symptom. Duration of cough has been defined as acute (lasting up to 4 weeks), subacute (up to 8 weeks), and chronic (more than 8 weeks).3 In this document, CC will be called specific, if it is associated with a known cause, or non-specific, if not. Finally, we will examine current knowledge and the available guidelines on refractory CC (RCC), i.e., CC that persists despite treatment targeting known associated conditions.

Epidemiology

CC is a very common symptom in clinical practice, and prevalence in the general population ranges from 12% to 3.3%.4,5 It is closely related with tobacco use, and the prevalence of CC in smokers is 3 times that of never-smokers or former smokers.6 A higher prevalence of CC has also been associated with environmental pollution.7

During the initial contact with the CC patient, the physician should determine the general causes of CC and the associated warning symptoms (Table 1). In all CC guidelines currently in use, if the patient has a normal chest X-ray, does not smoke and is not receiving angiotensin-converting enzyme inhibitors (ACEI), the causes associated with CC that will directly impact on the initial treatment are considered.

Table 1.

Causes of chronic cough and warning symptoms.

Causes of chronic cough  • Acute tracheobronchial infections including pertussis• Chronic infections: bronchiectasis, tuberculosis, cystic fibrosis• Airway problems: chronic bronchitis, osteoplastic tracheopathy, asthma, post-nasal drip• Pulmonary parenchymal diseases: diffuse interstitial fibrosis, emphysema, sarcoidosis• Tumors: lung cancer, bronchioloalveolar carcinoma, benign airway tumors, mediastinal tumors• Foreign bodies in the airways• Irritation of external auditory meatus• Cardiovascular diseases: left ventricular dysfunction, pulmonary infarction, aortic aneurysm• Other diseases: gastroesophageal reflux or bronchoesophageal reflux, Zenker's diverticulum, achalasia, recurrent aspiration, endobronchial sutures• Drugs: angiotensin-converting enzyme inhibitors, covertine 
Warning symptoms  Hemoptysis, snoring, significant production of sputum, systemic symptoms, gastroesophageal reflux complicated with weight loss, anemia, hematemesis, dysphagia, or no response to specific treatment, choking or vomiting, recurrent pneumonia, or abnormal chest X-ray 
Physiopathology of Chronic Cough

CC is reported by patients as either a single isolated symptom or one of several. Neurobiological mechanisms in chronic pain and in CC are similar,8 so the patient with chronic pain or CC responds more intensely to a painful stimulus or tussigenic stimulus of a specific magnitude than a healthy individual; this effect has been called hypertussia (similar to hyperalgesia). If the patient receives a stimulus that is not at all painful or tussigenic and responds excessively, the condition is called allotussia (or allodynia, in the case of pain).9 Hypertussia or allotussia are clinical conditions that are now grouped under the heading of “chronic cough hypersensitivity syndrome” (CCHS). The cough circuit is unquestionably complex, and may involve interaction between the different stimuli from the very start8 (Fig. 1). In short, the possible impact of CC on physiology means that the following must be taken into consideration when treating this condition: (a) cough neural pathways themselves may be affected, or (b) an aggravating factor that alters the cough reflex may need to be treated (Fig. 2).

Fig. 1.
(0.17MB).

Interactions among peripheral stimuli of cough reflex.

Fig. 2.
(0.19MB).

Two possible access pathways of stimuli of chronic cough.

The neurological mechanism of cough in humans originates from stimulation of 2 types of neuron terminals that converge in the cough center: unmyelinated C fibers and myelinated Aδ fibers.10,11 Most C fibers respond to a range of irritant stimuli of inflammatory origin, while Aδ fibers respond to mechanical and acid stimuli.12

Excitability of the CNS cough center is increased by 3 mechanisms13: peripheral, central and secondary hypersensitivities (Fig. 3). In the case of central sensitization, paresthesia is often observed in the area of the larynx, as well as hypertussia or allotussia, indicating a neuropathic response.14 In the second mechanism, connections with the cough center via the emotional brain lead to participation of consciousness and the emotional status in the control of cough.

Fig. 3.
(0.36MB).

Neurological feedback circuit of chronic cough.

Adapted from Pacheco.13

Furthermore, it is important to remember that the phenomenon of different converging peripheral stimuli can have a practical application, as suggested by the Australian cough guidelines of 2010, which recommend simultaneous triple therapy, proton pump inhibitors (PPIs), and speech pathology intervention for RCC15 (Strong recommendation/very low evidence). When central hypersensitivity has developed, a mechanism that is much more sensitive to mild peripheral stimuli is established, and this may be the cause of the phenomenon known as visceral hypersensitivity, also called secondary hypersensitivity (Fig. 3). The problem is that central hypersensitivity may decrease clinically, without changes being observed in the CC capsaicin challenge test due to peripheral hypersensitivity.16

Cough Study: Clinical Characterization and Laboratory Determinations

Patients’ perception of cough may be expressed differently, depending on the causative pathology. In general, cough accompanying upper airway diseases or laryngopharyngeal reflux (LPR) manifests as irritation in the throat. The “urge to cough” has been the subject of recent research which has located the origin of this impulse within the brain.17,18 Several standardized questionnaires have recently been developed to determine the characteristics of cough. These need further studies before they can be validated,19 and their utility in practice is still limited (Weak recommendation/low evidence). The intensity and frequency of cough have little diagnostic value, and these parameters are of most use when studying the therapeutic effect of antitussive agents. The intensity of cough can be determined with symptom questionnaires or quantified scales, mainly of the visual analog type (Weak recommendation/low evidence). The impact of cough on health-related quality of life is a useful parameter that can be measured objectively. To date, the most widely accepted tool is the Leicester Cough Questionnaire (LCQ).20 The importance of measuring the impact of cough on quality of life is high (Strong recommendation/moderate evidence).

The second aspect to consider is the study of the tussigenic reflex and its sensitivity with objective challenge techniques using inhaled substances. These methods have been described in recent guidelines published by the European Respiratory Society.21 Capsaicin acts directly on specific TRPV1 receptors. New ways of expressing results have been recently proposed, including the complete analysis of dose–response curve, measuring ED50 and Emax.22 Sensitivity and specificity of the capsaicin test in the differential diagnosis of CC and in healthy individuals are low.23,24 It is currently recommended for use in epidemiological studies or for determining the effect of drugs (Strong recommendation/moderate evidence). Inhalation of mannitol in dry powder correlates well with the capsaicin test, but the sensitivity and specificity of the technique are similarly low (Strong recommendation/low evidence). Quantification of the fraction of nitric oxide in exhaled air (FeNO), when high (>30 or 38 parts per billion [ppb], depending on the author), predicts a favorable response to corticosteroid treatment of CC.25 Likewise, the quantification of eosinophils in sputum and peripheral blood can characterize a group of CC patients with eosinophilic inflammation of the airways who are potential responders to corticosteroid treatment26 (Strong recommendation, low quality of evidence).

Specific Causes of Chronic Cough

The physiopathological interpretation of CC has changed recently, and it is now understood as a unitary neurological response to stimuli received from distinct but interactive anatomical origins27,28 (Strong recommendation/moderate evidence) (Fig. 1). Current thinking is that (a) CC is partially or totally resistant to specific treatment in up to 2/3 of patients,29 and (b) most individual carriers of the anatomical-diagnostic triad of conditions do not present CC.

New perspectives in the mechanism of the cough reflex suggest that in these patients, most symptoms are centered in the larynx.30 This has produced the concept of the “laryngeal hypersensitivity syndrome” (LHS) as a fundamental clinical basis for CC, particularly in its refractory form.31

Chronic Cough and Lower Airway Diseases

In prolonged or persistent bacterial bronchitis, extended treatment of over 2 weeks with antibiotics targeting the causative pathogen leads to complete resolution of CC32 (Strong recommendation/moderate evidence). It is now agreed that there are 2 asthma phenotypes: eosinophilic and neutrophilic asthma. It was reported recently that 75% of patients with neutrophilic asthma have moderate to severe CC33 (Weak recommendation/low evidence). Studies of eosinophilic airway inflammation measured by FeNO and eosinophils in sputum are highly specific and sensitive and predict good response to corticosteroids34 (Strong recommendation/moderate evidence). The diagnosis of asthma is defined as reversible bronchial obstruction, variable maximum expiratory flow and bronchial hyperreactivity (BHR), as determined by spirometry with bronchodilator testing, monitoring of maximum expiratory flow, or bronchial challenge testing (BCT) (Strong recommendation/high evidence). Asthma can be ruled out by a negative BCT, but if it is positive, the positive predictive value ranges between 60% and 80%35 (Strong recommendation/high evidence). BHR with no evidence of variable flow obstruction associated with CC suggests a diagnosis of cough-equivalent asthma or cough-variant asthma36; in this entity, antileukotrienes appear to be more effective than in conventional asthma37 (Strong recommendation/low evidence). A form of CC called eosinophilic bronchitis (EB), characterized by eosinophils in induced sputum, absence of BHR and good response to corticosteroids, was recently defined: prevalence is 7%–33%.38 Similarities and differences between these entities are summarized in Table 2. With respect to the recently described entity of neutrophilic asthma associated with CC and gastroesophageal reflux (GER), treatment with macrolides has been proposed, but the effect on CC has not been specified39 (Weak recommendation/low evidence). Similarly, treatment with the monoclonal antibody mepolizumab has shown success in eosinophilic asthma, although it failed to resolve the accompanying CC,40 suggesting that the inflammation may be mast cell-mediated.

Table 2.

Differential Diagnosis Between Various Diseases With Eosinophilic Inflammation of the Airways Associated With Chronic Cough.

  Eosinophilic Bronchitis  Eosinophilic Asthma  Cough Equivalent Asthma 
Symptoms  Cough  Dyspnea, cough and wheezing  Cough 
Atopy  No  Yes  Yes 
Bronchial hyperreactivity  No  Yes  Yes 
FEM viability  No  Yes  No 
Eosinophils in sputum  Yes  Yes  Yes 
Response to bronchodilators  No  Yes  Yes 
Response to corticosteroids  Yes  Yes (if eosinophils in sputum)  Yes (if eosinophils in sputum) 

Adapted from Desai and Brightling (Cough: Asthma, eosinophilic diseases. Otorlaryngol Clin North Am. 2010;43:123) and Morice (Epidemiology of cough. Pulm Pharmacol Ther. 2002;15:253–259). Adapted from Desai and Brightling.86

Chronic Cough and Upper Airway Diseases

Laryngeal conditions have usually been considered in the diagnostic triad as chronic upper airway cough syndrome (CUACS), formerly known as post-nasal drip; nevertheless, in view of the high rate of laryngeal symptoms in CC, LHS has recently been associated with laryngeal neuropathy.

There are 5 upper airway conditions that may present with CC: allergic rhinitis, chronic rhinosinusitis in the adult, obstructive sleep apnea, vocal cord dysfunction (VCD), and extra-esophageal manifestation of ERG or LPR.

Allergic rhinitis: this is diagnosed from signs and symptoms of nasal inflammation and the identification of specific allergens in skin prick testing or RAST. This condition should be managed according to the recommendations of the recent guidelines.41Chronic rhinosinusitis: treatment consists of irrigation of the nostrils with saline solution, oral corticosteroids for at least 1 month, and oral antibiotics for up to 3 months, in the case of purulent sinusitis (Strong recommendation/moderate evidence).

Obstructive sleep apnea (see section on “Chronic cough and sleep apnea–hypopnea syndrome”).

Vocal cord dysfunction: VCD is diagnosed from episodic narrowing of the vocal cords during inspiration producing dyspnea on inspiration and CC.42 CC occurs in more than 50% of adults with this condition. VCD is diagnosed by the observation of glottic narrowing on laryngoscopy or by a fall of more than 25% in inspiratory flow during the serum saline challenge maneuver.43 Management consists of the treatment of associated comorbidities such as asthma, rhinosinusitis, GER or the use of ACEI (Weak recommendation/low evidence), and the application of speech pathology intervention43 (Strong recommendation/moderate evidence).

Laryngopharyngeal reflux (LPR): see below.

Chronic Cough and Gastroesophageal Reflux. Laryngopharyngeal Reflex

Gastroesophageal reflux disease (GERD) has been associated with a variety of extra-esophageal manifestations, including CC.44

Relationship Between Chronic Cough and Gastroesophageal Reflux

In a study performed in a series of CC patients exploring the temporal association between episodes of cough, recorded by acoustic analysis, and episodes of GER, recorded by outpatient esophageal pH impedance, Smith et al.45 found that cough could appear before or after (50% of the time) episodes of GER. Wu et al.46 showed that distal esophageal acid infusion increases cough reflex sensitivity in asthmatic patients but not in normal subjects. Finally, it has been proposed recently that CC may be caused by the harmful effects of GER products on the larynx, causing laryngeal neuropathy,47,48 suggesting that CC may be a neuropathic disease caused by GER.

Diagnosis of Chronic Cough Associated With Reflux

The most useful test for corroborating the GER-cough association is 24-h outpatient recording of both pH and esophageal impedances. This technique can detect episodes of both liquid and aerosolized acid (pH<4), mildly acid (pH 4–7) and alkaline (pH>7) GER.45

Treatment of Chronic Cough Associated With Gastroesophageal Reflux

Anti-reflux treatment for CT is specified in Table 3. Two systematic reviews have been published on this topic.49,50 In adults, there is insufficient evidence to conclude definitively that PPIs are beneficial in GER-associated cough. However, the presence of abnormal GER or the temporal association of GER with cough are factors for improved response to treatment.50 In patients with no signs of GER, a 2-month treatment may be justified if the following criteria are present: non-smoker, no use of ACEI, normal chest X-ray, no asthma, no post-nasal drip, and no non-asthmatic eosinophilic bronchitis.51

Table 3.

Grades of Recommendation/Evidence of Antireflux Treatment in Patients With Chronic Cough.

Treatment  Grade of Recommendation
General and Dietary Measures  Strong Recommendation  Low Quality of Evidence 
H2 antagonists  Strong recommendation  Low quality of evidence 
PPIs  Strong recommendation  Moderate quality of evidence 
Prokinetics  Weak recommendation  Very low quality of evidence 
Antireflux surgery  Weak recommendation  Low quality of evidence 

Laryngopharyngeal reflux: LPR is defined as GER reaching the laryngopharyngeal region. Diagnosis is confirmed by: (a) symptoms of extra-esophageal reflux, or (b) laryngeal endoscopy. Validated indices are available – for the first, the “Reflux Symptoms Index”, and for the second, the “Reflux Findings Score”52; both have a qualification of Weak recommendation/moderate evidence (Tables 4 and 5).

Table 4.

Laryngeal Reflux Symptom Index.

How Have These Symptoms Affected You in the Last Month?  Not At AllSeverely 
 
Snoring, hoarseness or other problem with your voice             
Clearing your throat, constantly swallowing saliva             
Excessive phlegm in your throat, mucus down the back of your throat             
Cough after going to bed             
Breathing difficulties             
Paroxysmal dry cough (coughing fit)             
Sensation of a foreign body in the throat             
Chest pain, heartburn, dyspepsia             

More than 13 points suggest laryngopharyngeal reflux.

Table 5.

Index of Endoscopic Signs of Laryngopharyngeal Reflux.

SUBGLOTTIC edema  2: If present       
Ventricular obliteration  2: Partial      4: Complete 
Erythema–hyperemia  2: Only interarytenoidal      4: Complete 
Vocal cord edema  1: Moderate  2: Moderate  3: Severe  4: Polypoidal 
Diffuse laryngeal edema  1: Moderate  2: Moderate  3: Severe  4: Obstructive 
Posterior commissure hypertrophy  1: Moderate  2: Moderate  3: Severe  4: Obstructive 
Granuloma. Granulation  2: If present       
Thick endolaryngeal mucus  2: If present       

More than 6 points suggests laryngopharyngeal reflux.

The treatment of GER complicated by LPR is similar to that described for GER associated with CC: high doses of PPIs (20 or 40mg every 12h), for at least 2 months. If there is no response after this time, PPIs should be discontinued (Strong recommendation/moderate evidence), but if the patient shows improvement of CC, administration of PPIs should be reduced to once daily, after which the minimum dose required to maintain sufficient acid suppression should be introduced. If, on the other hand, the patient does not improve and CC due to GER is still suspected, a pH-metry/impedance test with additional manometry should be performed (Weak recommendation/high evidence). If suspected LPR is confirmed but treatment with PPIs fails, some authors have reported improvement with GABA inhibitors, such as baclofen, at escalating doses of up to 30mg/day,53 or the addition of alginates (e.g., Gaviscon®).54 Fundoplication for the treatment of LPR with CC would require a major GER complication or risk of massive aspiration (Weak recommendation/low evidence) (Table 3). Good outcomes in tussigenic hypersensitivity caused by concomitant laryngeal sensory neuropathy and LPR have been demonstrated with neuromodulating drugs.55

If interaction between LPR and laryngeal neuropathy is clinically suspected, there are 2 complementary approaches: changes in patient care and diet, and speech pathology interventions. Raising the head of the bed, adopting a left lateral decubitus position, and weight loss have been shown to improve the total time that esophageal pH is less than 4 (Strong recommendation/low evidence).56 A recent study in GER found that a period of less than 3h between eating dinner and going to bed was significantly related with GER relapse.57 Speech pathology intervention reduces response to capsaicin-induced cough reflex.43

Chronic Cough and Sleep Apnea–Hypopnea Syndrome

In both healthy individuals and patients with CC, cough is generally more frequent during the day. In some sleep-related diseases, such as sleep apnea–hypopnea syndrome (SAHS), the situation is different.58 The prevalence of CC in this population can be as high as 33%–39%.59 In our experience,60 42% of patients with SAHS reported CC, of whom 31% had high GER symptom scores. With regard to the effects of CPAP on cough, a significant improvement was found, with resolution of cough in 67%. Similarly, when the prevalence of SAHS was analyzed in patients with CC,61 44% were found to have criteria for SAHS. To summarize, CC is frequently associated with SAHS, particularly in patients with associated GER (Strong recommendation/moderate evidence). CPAP treatment may be indicated for the treatment of CC (Weak recommendation/moderate evidence), although more research is required.

Miscellaneous: Post-Infectious Chronic Cough, Psychogenic Chronic Cough. Other Entities Involving Chronic CoughPost-Infectious Chronic Cough

Numerous publications suggest that most coughs related with upper respiratory tract infections resolve within a period of up to 3 weeks. Nevertheless, cough may persist longer in a small proportion of adult patients. Bordetella pertussis, the causative agent of pertussis, is increasingly recognized as the cause of CC. Diagnosis is established from culture and polymerase change reaction (PCR) analysis of upper respiratory tract samples (Weak recommendation/low evidence). Antibiotic treatment with azithromycin should be considered in suspected cases, although this will only prevent transmission, rather than improve symptoms (Strong recommendation/high evidence).62

Psychogenic Chronic Cough

In a recent review of psychogenic cough, 223 patients were identified from a total of 18 uncontrolled studies,63 96% of whom were children and teenagers: 95% of patients did not have cough during sleep. Hypnosis is effective in resolving cough in 78% of patients. The large majority of improvements were seen in the pediatric population. To conclude, there is low quality evidence to support a specific strategy that defines and treats psychogenic cough, habit cough and tic cough. In general, the diagnosis of psychogenic cough should be made after ruling out more common causes of CC, and when CC improves with behavioral modification and/or psychiatric therapy.64

Other Types of Chronic Cough

CC in occupational exposure has been described in glass workers and in environments with high concentrations of dust and organic material in the air.65 A sensory neuropathy syndrome with autonomous nervous system dysfunction, cough and GER66 indicates genetic dysfunction in the neurological network of the digestive tract. CT due to irritation of the auricular branch of the vagus nerve (Arnold's nerve) may occur rarely, as may CC associated with osteoplastic tracheobronchopathy. Other rare cases of CC must be systematically determined according to Table 1.

Management of Chronic Cough in the Different Levels of Medical CareChronic Cough in Primary Care

Most patients with CC who present in primary care (PC) can be diagnosed by following the algorithm presented in Fig. 4 (Strong recommendation/moderate evidence). In 1 study, only 31% of the patients had any radiological changes that might guide diagnosis.67 Protocolized empirical and sequential treatment has been shown to be cost-effective.68,69 In a recent study of 112 patients with CC,69 sensitivity and specificity of symptoms for 3 of the diseases most frequently associated with CC were determined, as shown in Table 6.

Fig. 4.
(0.22MB).

Algorithm for the management of chronic cough in primary care.

Table 6.

Sensitivity and Specificity of Signs and Symptoms of Chronic Cough.

Disease  Symptoms and Parameters  Sensitivity (%)  Specificity (%)  P 
Asthma  Wheezing  94  66  <.001 
  Dyspnea  82  51  .009 
  Airway obstructiona  35  80  .07 
  Bronchial reversibility  11  95  .2 
Gastroesophageal reflux  Acid taste in the mouth  50  80  .01 
  Retrosternal pyrosis  72  68  .001 
Rhinitis  Post-nasal drip  100  67  .002 
  Clearing of the throat  100  37  .07 
a

Airway obstruction measured as FEV1/FVC ratio<70%.

Chronic Cough in Specialized Care

Algorithms for the management of patients with CC referred from PC to a higher level of medical care are given in Figs. 5 and 6. After ruling out neutrophilic asthma in the CC patient, treatment alternatives are neuromodulators, basically gabapentin (300–1800mg/day) and amitriptyline (10–20mg/day), and speech pathology intervention. The recommendation for both options is strong, while evidence remains weak (Fig. 7).

Fig. 5.
(0.2MB).

Practical management of patients with chronic cough.

Fig. 6.
(0.13MB).

Algorithm for the management of refractory chronic cough.

Fig. 7.
(0.33MB).

Management of chronic cough in specialized units.

Chronic Cough in Pediatric Patients

The American and Australian-New Zealand guidelines define CC as cough lasting more than 4 weeks,70 while the British guidelines71 set it at more than 8 weeks. According to several epidemiological studies, causes of CC in the child vary depending on age (Strong recommendation/high evidence). In schoolchildren, the most common causes are asthma (27%), cough-equivalent asthma (15.5%) and GER (10%). After adolescence, causes for CT are considered the same as in adults.

Diagnostic Evaluation of Chronic Cough in Children

Clinical history, symptoms and warning signs (Table 7) and the physical examination and initial diagnostic tests are similar to those proposed for adults.

Table 7.

Warning Signs and Symptoms in Children With Chronic Cough.

Warning Signs and Symptoms  Comments 
Abnormal auscultation  Asthma, bronchitis, foreign body, CF, congenital abnormalities, etc. 
Productive cough with mucus  Suppurative diseases (CF, BE, PCD, PBB, etc.), bronchitis 
Sudden onset of cough after episode of choking  Foreign body aspiration 
Cough associated with food or swallowing  Aspiration syndromes 
Chronic dyspnea  Chest disease (airway or parenchymal), heart disease, etc. 
Dyspnea with exercise  Asthma, lung disease, etc. 
Heart murmur  Heart disease 
Neurological disease  Aspiration syndromes, muscle weakness, etc. 
Chest wall deformities  Malformations, severe chronic lung disease, etc. 
Hemoptysis  Suppurative disease, vascular abnormalities, bronchitis, etc. 
Recurrent pneumonia  Asthma, foreign body, malformations, immunodeficiencies, etc. 
Failure to thrive  Lung disease, suppurative heart disease 
Nail clubbing  Chronic diseases 
Comorbidities  PBB 

BE: bronchiectasis; CF: cystic fibrosis; PBB: persistent bacterial bronchitis; PCD; primary ciliary dyskinesia.

Treatment of Chronic Cough in Children

The aim of CC treatment must be to eliminate the causative agent.70,71 If non-specific CC is predominantly dry, treatment with medium-dose inhaled corticosteroids for 2–12 weeks should be attempted, but withdrawn in the absence of response.72 In cases of non-specific productive CC, an initial 2 or 3-week course of antibiotics should be evaluated73 (Strong recommendation/high evidence). Central-acting antitussives are not indicated (Strong recommendation/high evidence).

Problems and Perspectives in Chronic CoughChronic Refractory Cough and New Treatments

It is currently assumed that if partial control of cough can be achieved, this may be sufficient, since it is difficult to eradicate completely, except in some cases (Fig. 5). Unsatisfactory treatment in CC may be due to several causes74 (Table 8). In RCC, treatment possibilities must first be optimized (Fig. 6), and then 2 aspects should be given special attention: (a) LHS, and (b) central hypersensitivity75 (Strong recommendation/moderate evidence). Antitussive treatments should be used for “urge-to-cough”, but designed to avoid modification of the protective reflex cough. The available evidence suggests that nebulized lidocaine is an option for second-line treatment.76

Table 8.

Causes of Unexplained Cough in Adults.

• The doctor does not follow the treatments recommended in accredited practice guidelines 
• The patient does not follow the recommended treatment 
• Development of serious comorbidities requiring the patient to discontinue examinations or not follow treatment plans 
• Diagnosis is correct, but cough is refractory to prescribed treatment 
• A combination of the three above 
• The patient was not informed about active participation in cough control 
• Cough is truly refractory 

Adapted from Irwin.74

In the second case, central hypersensitivity and treatment in CC, there is growing interest in the use of gabapentin in RCC, with positive responses in around 60% of patients (Strong recommendation/moderate evidence).77 Neuromodulator therapy is being proposed as the future in the treatment of central hypersensitivity.78 Other similar agents that have been studied in small, observational studies include pregabalin, amitriptyline, and baclofen. Amitriptyline or low-dose morphine have shown subjective improvement in the LCQ (Weak recommendation/moderate evidence).79

The efficacy of over-the-counter cough suppressants on CC has not been demonstrated.80 A recent review of dextromethorphan found a modest decrease in cough severity and frequency when compared to placebo.81 Codeine has shown no improvement in capsaicin-induced cough reflex testing.82 Its use in CC that does not respond to non-narcotic antitussives is currently recommended (Weak recommendation/low evidence).

Drugs for reducing peripheral hypersensitivity focusing on TRP receptor blockade have recently been evaluated.83 Inhaled tiotropium has recently been seen in laboratory animals to inhibit TRPV1 receptors.84 Another promising agent in the treatment of CC is AF-219, a receptor antagonist that acts against the purinergic receptor P2X3, and also against peripheral C fibers,85 and is effective in reducing CC frequency.

References
[1]
H.J. Schünemann, R. Jaeschke, D.J. Cook, W.F. Bria, A.A. El-Solh, A. Ernst
An official ATS statement: grading the quality of evidence and strength of recommendations in ATS guidelines and recommendations
Am J Respir Crit Care Med, 174 (2006), pp. 605-614 http://dx.doi.org/10.1164/rccm.200602-197ST
[2]
I.D. Pavord, K.F. Chung
Management of chronic cough
[3]
R.S. Irwin, M.H. Baumann, D.C. Bolser, L.P. Boulet, S.S. Braman, C.E. Brightling
Diagnosis and management of cough executive summary: ACCP evidence-based clinical practice guidelines
[4]
A.H. Morice
Chronic cough: epidemiology
Chron Respir Dis, 5 (2008), pp. 43-47 http://dx.doi.org/10.1177/1479972307084252
[5]
K. Lai, R. Chen, J. Lin, K. Huang, H. Shen, L. Kong
A prospective multicenter on causes of chronic cough in China
Chest, 143 (2013), pp. 613-620 http://dx.doi.org/10.1378/chest.12-0441
[6]
E. Zemp, S. Elsasser, C. Schindler, N. Künzli, A.P. Perruchoud, G. Domenighetti
Long-term ambient air pollution and respiratory symptoms in adults (SAPALDIA study). The SAPALDIA Team
Am J Respir Crit Care Med, 159 (1999), pp. 1257-1266 http://dx.doi.org/10.1164/ajrccm.159.4.9807052
[7]
D. McCabe, K. Altman
Laryngeal hypersensitivity in the World Trade Center: exposed population
Am J Respir Crit Care Med, 186 (2012), pp. 402-403 http://dx.doi.org/10.1164/rccm.201205-0808OE
[8]
J. O’Neill, S.B. McMahon, B.J. Undem
Chronic cough and pain: Janus faces in sensory neurobiology?
Pulm Pharmacol Ther, 26 (2013), pp. 476-485 http://dx.doi.org/10.1016/j.pupt.2013.06.010
[9]
M. Bende, E. Millqvist
Prevalence of chronic cough in relation to upper and lower airway symptoms: the Skövde population-based study
Front Physiol, 3 (2012), pp. 251 http://dx.doi.org/10.3389/fphys.2012.00251
[10]
B.J. Canning, S.B. Mazzone, S.N. Meeker, N. Mori, S.M. Reynolds, B.J. Undem
Identification of the tracheal and laryngeal afferent neurons mediating cough in anaesthezited guinea-pigs
[11]
B.J. Canning
Afferent nerves regulating the cough reflex: mechanisms and mediators of cough in disease
Otolaryngol Clin North Am, 43 (2010), pp. 15-25 http://dx.doi.org/10.1016/j.otc.2009.11.012
[12]
M.A. MacAlexander, A.C. Myers, B.J. Undem
Adaptation of guinea-pig vagal airway afferent neurons to mechanical stimulation
J Physiol, 521 (1999), pp. 239-247
[13]
A. Pacheco
Chronic cough: from a complex dysfunction of the neurological circuit to the production of persistent cough
[14]
K.F. Chung, L. McGarvey, S.B. Mazzone
Chronic cough as a neuropathic disorder
Lancet Respir Med, 3 (2013), pp. 414-422
[15]
P.G. Gibson, A.B. Chang, N.J. Glasgow, P.W. Holmes, P. Katelaris, A.S. Kemp
CICADA: cough in children and adults: diagnosis and assessment. Australian cough guidelines summary statement
Med J Aust, 192 (2010), pp. 265-271
[16]
K.F. Chung
Gabapentin: a suppressant for refractory chronic cough
[17]
P.W. Davenport
Urge-to-cough: what can it teach us about cough?
[18]
S.B. Mazzone, L. McLennan, A.E. McGovern, G.F. Egan, M.J. Farrell
Representation of capsaicin-evoked urge-to-cough in the human brain using functional magnetic resonance imaging
Am J Respir Crit Care Med, 176 (2007), pp. 327-332 http://dx.doi.org/10.1164/rccm.200612-1856OC
[19]
P.W. Dettmar, V. Strugala, H. Fathi, H.J. Dettmar, C. Wright, A.H. Morice
The online Cough Clinic: developing guideline-based diagnosis and advice
Eur Respir J, 34 (2009), pp. 819-824 http://dx.doi.org/10.1183/09031936.00126908
[20]
S.S. Birring, B. Prudon, A.J. Carr, S.J. Singh, M.D. Morgan, I.D. Pavord
Development of a symptom specific health status measure for patients with chronic cough: Leicester Cough Questionnaire (LCQ)
Thorax, 58 (2003), pp. 339-343
[21]
A.H. Morice, G.A. Fontana, M.G. Belvisi, S.S. Birring, K.F. Chung, P.V. Dicpinigaitis
European Respiratory Society guidelines on the assessment of cough
Eur Respir J, 29 (2007), pp. 1256-1276 http://dx.doi.org/10.1183/09031936.00101006
[22]
E.C. Hilton, P.G. Baverel, A. Woodcock, P.H. van der Graaf, J.A. Smith
Pharmacodynamic modeling of cough responses to capsaicin inhalation calls into question the utility of the C5 end point
J Allergy Clin Immunol, 132 (2013), pp. 847-855 http://dx.doi.org/10.1016/j.jaci.2013.04.042
[23]
M. Couto, A. de Diego, M. Perpiñá, L. Delgado, A. Moreira
Cough reflex testing with inhaled capsaicin and TRPV1 activation in asthma and comorbid conditions
J Investig Allergol Clin Immunol, 23 (2013), pp. 289-301
[24]
L. Nieto, A. de Diego, M. Perpiña, L. Compte, V. Garrigues, E. Martínez
Cough reflex testing with inhaled capsaicin in the study of chronic cough
Respir Med, 97 (2003), pp. 393-400
[25]
P.Y. Hahn, T.Y. Morgenthaler, K.G. Lim
Use of exhaled nitric oxide in predicting response to inhaled corticosteroids for chronic cough
Mayo Clin Proc, 82 (2007), pp. 1350-1355
[26]
J.M. Chatkin, K. Ansarin, P.E. Silkoff, P. McLean, C. Gutierrez, N. Zamel
Exhaled nitric oxide as noninvasive assessment of chronic cough
Am J Respir Crit Care Med, 159 (1999), pp. 1810-1813 http://dx.doi.org/10.1164/ajrccm.159.6.9809047
[27]
P.C. Lavinka, X. Dong
Molecular signaling and targets from itch: lessons from cough
[28]
S.B. Mazzone, A.E. McGovern, S.K. Yang, A. Woo, S. Phipps, A. Ando
Sensorimotor circuitry involved in the higher brain control of coughing
[29]
A. Woodcok, E.C. Young, J.A. Smith
New insights in cough
Br Med Bull, 96 (2010), pp. 61-73 http://dx.doi.org/10.1093/bmb/ldq034
[30]
G.S. Sandhu
The larynx in cough
[31]
A.H. Morice
Chronic cough hypersensitivity syndrome
[32]
A.B. Chang, G.J. Redding, M.L. Everard
Chronic wet cough: protracted bronchitis, chronic suppurative lung disease and bronchiectasis
Pediatr Pulmonol, 43 (2008), pp. 519-531 http://dx.doi.org/10.1002/ppul.20821
[33]
J.L. Simpson, K.J. Baines, N. Ryan, P.G. Gibson
Neutrophilic asthma is characterized by increased rhino-sinusitis with sleep disturbances and GERD
Asian Pac J Allergy Immunol, 32 (2014), pp. 67-75
[34]
S. Birring
Controversies in the evaluation and management of chronic cough
Am J Respir Crit Care Med, 183 (2011), pp. 708-715 http://dx.doi.org/10.1164/rccm.201007-1017CI
[35]
A. De Diego Damiá, V. Plaza Moral, V. Garrigues Gil, J.L. Izquierdo Alonso, A. López Viña, J.J. Mullol Miret
Tos crónica. Normativa SEPAR
Arch Bronconeumol, 38 (2002), pp. 236-245
[36]
W.M. Corrao, S.S. Braman, R.S. Irwin
Chronic cough as the sole presenting manifestation of bronchial asthma
N Eng J Med, 300 (1979), pp. 633-637
[37]
P.V. Dicpinigaitis, J.B. Dobkin, J. Reichel
Antitussive effect of the leukotriene receptor antagonist zafirlukast in subjects with cough-variant asthma
J Asthma, 39 (2002), pp. 291-297
[38]
C.E. Brightling, R. Ward, K.L. Goh, A.J. Wardlaw, I.D. Pavord
Eosinophilic bronchitis is an important cause of chronic cough
Am J Respir Crit Care Med, 160 (1999), pp. 406-410 http://dx.doi.org/10.1164/ajrccm.160.2.9810100
[39]
J.L. Simpson, H. Powell, M.J. Boyle, R.J. Scott, P.G. Gibson
Clarithromycin targets neutrophilic airway inflammation in refractory asthma
Am J Respir Crit Care Med, 177 (2008), pp. 148-155 http://dx.doi.org/10.1164/rccm.200707-1134OC
[40]
P. Haldar, C.E. Brightling, B. Hargadon, S. Gupta, W. Monteiro, A. Sousa
Mepolizumab and exacerbations of refractory eosinophilic asthma
N Engl J Med, 360 (2009), pp. 973-984 http://dx.doi.org/10.1056/NEJMoa0808991
[41]
D.V. Wallace, M.S. Dykewicz, D.I. Bernstein, J. Blessing-Moore, L. Cox, D.A. Khan
The diagnosis and management of rhinitis: an update practice parameter
J Allergy Clin Immunol, 122 (2008), pp. S1-S84 http://dx.doi.org/10.1016/j.jaci.2008.06.003
[42]
P.G. Gibson, A.E. Vertigan
Speech pathology for chronic cough: a new approach
Pulm Pharmacol Ther, 22 (2009), pp. 159-162 http://dx.doi.org/10.1016/j.pupt.2008.11.005
[43]
A.E. Vertigan, D.G. Theodoros, P.G. Gibson, A.L. Winkworth
Efficacy of speech pathology management for chronic cough: a randomised placebo controlled trial of treatment efficacy
Thorax, 61 (2006), pp. 1065-1069 http://dx.doi.org/10.1136/thx.2006.064337
[44]
N. Vakil, S.V. van Zanten, P. Kahrilas, J. Dent, R. Jones
The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus
Am J Gastroenterol, 101 (2006), pp. 1900-1920 http://dx.doi.org/10.1111/j.1572-0241.2006.00630.x
[45]
J.A. Smith, S. Decalmer, A. Kelsall, K. McGuinness, H. Jones, S. Galloway
Acoustic cough-reflux associations in chronic cough: potential triggers and mechanisms
Gastroenterology, 139 (2010), pp. 754-762 http://dx.doi.org/10.1053/j.gastro.2010.06.050
[46]
D.N. Wu, K. Yamauchi, H. Kobayashi, Y. Tanifugi, C. Kato, K. Suzuki
Effects of esophageal acid perfusion on cough responsiveness in patients with bronchial asthma
Chest, 122 (2002), pp. 505-509
[47]
P.G. Gibson, J.L. Simpson, N.M. Ryan, A.E. Vertigan
Mechanisms of cough
Curr Opin Allergy Clin Immunol, 14 (2014), pp. 55-61 http://dx.doi.org/10.1097/ACI.0000000000000027
[48]
A. Pacheco, I. Cobeta
Refractory chronic cough, or the need to focus on the relationship between the larynx and the esophagus
[49]
A.B. Chang, T.J. Lasserson, J. Gaffney, F.L. Connor, L.A. Garske
Gastro-oesophageal reflux treatment for prolonged non-specific cough in children and adults
Cochrane Database Syst Rev, (2011), pp. CD004823
[50]
P.J. Kahrilas, C.W. Howden, N. Hughes, M. Molloy-Bland
Response of chronic cough to acid-suppressive therapy in patients with gastroesophageal reflux disease
Chest, 143 (2013), pp. 605-612 http://dx.doi.org/10.1378/chest.12-1788
[51]
R.S. Irwin, C.L. French, F.J. Curley, J.K. Zawacki, F.M. Bennett
Chronic cough due to gastroesophageal reflux: clinical, diagnostic and pathogenetic aspects
Chest, 104 (2009), pp. 1511-1517
[52]
P.C. Belafsky, C.J. Rees
Laryngopharyngeal reflux: the values of otolaryngoloy examination
Curr Gastroenterol Rep, 10 (2008), pp. 278-282
[53]
G.H. Koek, D. Sifrim, T. Lerut, J. Janssens, J. Tack
Effect of the GABA agonist baclofen in patients with symptoms and duodeno-gastro-oesophageal reflux refractory to proton pump inhibitors
Gut, 52 (2003), pp. 1397-1402
[54]
M.A. Kwiatek, S. Roman, A. Fareeduddin, J.E. Pandolfino, P.J. Kahrilas
An alginate-antacid formulation (Gaviscon Double Action Liquid) can eliminate or displace the postprandial ‘acid pocket’ in symptomatic GERD patients
Aliment Pharmacol Ther, 34 (2011), pp. 59-66 http://dx.doi.org/10.1111/j.1365-2036.2011.04678.x
[55]
S.M. Greene, C.B. Simpson
Evidence for sensory neuropathy and pharmacologic management
Otolaryngol Clin North Am, 43 (2010), pp. 67-72 http://dx.doi.org/10.1016/j.otc.2009.11.003
[56]
T. Kaltenbach, S. Crockett, B. Lauren, L.B. Gerson
Are lifestyle measures effective in patients with gastroesophageal reflux disease? An evidence-based approach
Arch Intern Med, 166 (2006), pp. 965-971 http://dx.doi.org/10.1001/archinte.166.9.965
[57]
J.H. Yang, H.S. Kang, S.Y. Lee, J.H. Kim, I.K. Sung, H.S. Park
Recurrence of gastroesophageal reflux disease is correlated with a short dinner-to-bedtime interval
J Gastroenterol Hepatol, 29 (2014), pp. 730-735 http://dx.doi.org/10.1111/jgh.12455
[58]
S.S. Birring, A.J. Ing, K. Chan, G. Cossa, S. Matos, M.D. Morgan
Obstructive sleep apnoea: a cause of chronic cough
[59]
K. Chan, A.J. Ing, L. Laks, G. Cossa, P. Rogers, S.S. Birring
Chronic cough in patients with sleep-disordered breathing
Eur Respir J, 35 (2010), pp. 368-372 http://dx.doi.org/10.1183/09031936.00110409
[60]
J.P. Reig, M. Ballestes, M. Leon, A. de Diego, M. Martinez, L. Compte
Estudio del reflejo tusígeno en pacientes con SAOS
Arch Bronconeumol, 49 (2013), pp. 6
[61]
K.M. Sundar, S.E. Daly, M.J. Pearce, W.T. Alward
Chronic cough and obstructive sleep apnea in a community-based pulmonary practice
[62]
J.M. Kline, W.D. Lewis, E.A. Smith, L.R. Tracy, S.K. Moerschel
Pertussis: a remerging infection
Am Fam Physician, 88 (2013), pp. 507-514
[63]
Q. Haydour, F. Alahdab, M. Farah, P.B. Moreno, A.E. Vertigan, P.A. Newcombe
Management and diagnosis of psychogenic cough, habit cough, and tic cough: a systematic review
Chest, 146 (2014), pp. 355-372 http://dx.doi.org/10.1378/chest.14-0795
[64]
R.S. Irwin, W.B. Glomb, A.B. Chang
Habit cough, tic cough, and psychogenic cough in adult and pediatric populations. ACCP evidence-based clinical practice guidelines
[65]
S.B. Gordon, A.D. Curran, A. Turley, C.H. Wong, S.N. Rahman, K. Wiley
Glass bottle workers exposed to low-dose irritant fumes cough but do not wheeze
Am J Respir Crit Care Med, 156 (1997), pp. 206-210 http://dx.doi.org/10.1164/ajrccm.156.1.9610042
[66]
C. Kok, M.L. Kennerson, P.J. Sprimg, A.J. Ing, J.D. Pollard, G.A. Nicholson
A locus for hereditary sensory neuropathy with cough and gastroesophageal reflux on chromosome 3p22-p24
Am J Hum Genet, 73 (2003), pp. 632-637 http://dx.doi.org/10.1086/377591
[67]
L.P.A. McGarvey, L.G. Heaney, J. MacMahan
A retrospective survey of diagnosis and management of patients presenting with chronic cough to a general chest clinic
Int J Clin Pract, 52 (1998), pp. 158-161
[68]
L. Lin, K. Poh, T. Lim
Empirical of treatment chronic cough: a cost-effectiveness analysis
Proc AMIA Symp, 2001 (2001), pp. 383-387
[69]
J.C. Ojoo, C.F. Everett, S.A. Mulrennan, S. Faruqi, J. Kastelik, A.H. Morice
Management of patients with chronic cough using a clinical protocol: a prospective observational study
[70]
A.B. Chang, L.I. Landau, P.P. van Asperen, N.J. Glasgow, C.F. Robertson, J.M. Marchant
Cough in children: definitions and clinical evaluation
Med J Aust, 184 (2006), pp. 398-403
[71]
M.D. Shields, A. Bush, M.L. Everard, S. McKenzie, R. Primhak
BTS guidelines: recommendations for the assessment and management of cough in children
Thorax, 63 (2008), pp. iii1-iii15 http://dx.doi.org/10.1136/thx.2007.077370
[72]
M. Karabel, S. Kelekci, D. Karabel, M.F. Gurkan
The evaluation of children with prolonged cough accompanied by American College of Chest Physicians guidelines
Clin Respir J, 8 (2014), pp. 152-159 http://dx.doi.org/10.1111/crj.12052
[73]
J. Marchant, I.B. Masters, A. Champion, H. Petsky, A.B. Chang
Randomised controlled trial of amoxycillin clavulanate in children with chronic wet cough
[74]
R.S. Irwin
Unexplained cough in the adult
Otolaryngol Clin North Am, 43 (2010), pp. 167-180 http://dx.doi.org/10.1016/j.otc.2009.11.009
[75]
N.M. Ryan, A. Vertigan, S. Bone, P. Gibson
Cough reflex sensitivity improves with speech language pathology management of refractory chronic persistent cough
[76]
K.G. Lim, M.A. Rank, P.Y. Hahn, K.A. Keogh, T.I. Morgenthaler, E.J. Olson
Long-term safety of nebulized lidocaine for adults with difficult-to-control chronic cough: a case series
Chest, 143 (2013), pp. 1060-1065 http://dx.doi.org/10.1378/chest.12-1533
[77]
N.M. Ryan, S.S. Birring, P.G. Gibson
Gabapentin for refractory chronic cough: a randomised, double-blind, placebo-controlled trial
[78]
B. Lee, P. Woo
Chronic cough as a sign of laryngeal sensory neuropathy: diagnosis and treatment
Ann Otol Rhinol Laryngol, 114 (2005), pp. 253-257
[79]
A.H. Morice, M.S. Menon, S.A. Mulrennan, C.F. Everett, C. Wright, J. Jackson
Opiate therapy in chronic cough
Am J Respir Crit Care Med, 175 (2007), pp. 312-315 http://dx.doi.org/10.1164/rccm.200607-892OC
[80]
S.M. Smith, K. Schroeder, T. Fahey
Over-the-counter medications for acute cough in children and adults in ambulatory settings
Cochrane Database Syst Rev, (2008), pp. CD001831
[81]
W.S. Yanci Jr., D.C. McCrory, R.R. Coeytaux, K.M. Schmit, A.R. Kemper, A. Goode
Efficacy and tolerability of treatments for chronic cough: a systematic review and meta-analysis
[82]
P.W. Davenport, D.C. Bolser, T. Vickrov, R.B. Berry, A.D. Martin, J.A. Hev
The effect of codeine of the urge-to-cough response to inhaled capsaicin
Pulm Pharmacol Ther, 20 (2007), pp. 338-346 http://dx.doi.org/10.1016/j.pupt.2006.10.012
[83]
D. Preti, A. Szallasi, R. Patacchini
TRP channels as therapeutic targets in airway disorders: a patient review
Expert Opin Ther Pat, 22 (2012), pp. 663-695 http://dx.doi.org/10.1517/13543776.2012.696099
[84]
M.A. Birrell, S.J. Bonvini, E. Dubuis, S.A. Maher, M.A. Wortley, M.S. Grace
Tiotropium modulates transient receptor potential V1 (TRPV1) in airway sensory nerves: a beneficial off-target effect?
J Allergy Clin Immunol, 133 (2014), pp. 679-687 http://dx.doi.org/10.1016/j.jaci.2013.12.003
[85]
A.B. Ford
In pursuit of P2X3 antagonists: novel therapeutics for chronic pain and afferent sensitization
Purinergic Signal, 8 (2012), pp. 3-26 http://dx.doi.org/10.1007/s11302-011-9271-6
[86]
D. Desai, C. Brightling
Cough due to asthma, cough-variant asthma and non-asthmatic eosinophilic bronchitis
Otolaryngol Clin North Am, 43 (2010), pp. 123-130 http://dx.doi.org/10.1016/j.otc.2009.11.006

Please cite this article as: Pacheco A, de Diego A, Domingo C, Lamas A, Gutierrez R, Naberan K, et al. Tos crónica. Arch Bronconeumol. 2015;51:579–589.

Copyright © 2014. SEPAR
Idiomas
Archivos de Bronconeumología (English Edition)

Subscribe to our Newsletter

Article options
Tools
es en
Política de cookies Cookies policy
Utilizamos cookies propias y de terceros para mejorar nuestros servicios y mostrarle publicidad relacionada con sus preferencias mediante el análisis de sus hábitos de navegación. Si continua navegando, consideramos que acepta su uso. Puede cambiar la configuración u obtener más información aquí. To improve our services and products, we use "cookies" (own or third parties authorized) to show advertising related to client preferences through the analyses of navigation customer behavior. Continuing navigation will be considered as acceptance of this use. You can change the settings or obtain more information by clicking here.
es en

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?