Clinical Practice Guideline
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Background: Chronic cough, i.e., cough lasting longer than eight weeks, affects approximately 10% of the population and is a common reason for outpatient medical consultation. Its differential diagnosis is extensive, and it is generally evaluated in poorly structured fashion with a variety of diagnostic techniques. The German Clinical Practice Guideline on Acute and Chronic Cough was updated in 2021 and contains a description of the recommended stepwise, patient-centered, and evidence-based procedure for the management of chronic cough.
Methods: The guideline has been updated in accordance with the findings of a systematic search of the literature for international guidelines and systematic reviews. All recommendations were developed in an interdisciplinary manner and agreed upon by formal consensus. The target group consists of adult patients with cough.
Results: History-taking, after the exclusion of red flags, should include questioning about smoking status, medications, and relevant present and past illnesses (COPD, asthma). Subsequent diagnostic testing should include a chest x-ray and pulmonary function tests. If the patient is taking an ACE inhibitor, a test of drug discontinuation can be carried out first. Radiologically detected pulmonary masses or evidence of rare diseases (interstitial lung diseases, bronchiectasis) are an indication for chest CT or for direct referral to an appropriate specialist. If the imaging studies and pulmonary function tests are normal, the patient is most likely suffering from a disease entity that can be treated empirically, such as upper airway cough syndrome or cough variant asthma. Any patient with an unexplained or refractory cough must receive proper patient education; individual therapeutic trials of physiotherapeutic or speech-therapeutic methods are possible, as is the off-label use of gabapentin or morphine.
Conclusion: Chronic cough should be evaluated according to an established diagnostic algorithm in collaboration with specialists. Treatments such as inhaled corticosteroids should be tested exhaustively in accordance with the guidelines, and the possibility of multiple causes as well as the role of patient compliance should be kept in mind before a diagnosis of unexplained or intractable cough is assigned.
Cough is the symptom responsible for almost one in ten primary care consultations (1). The internationally established classification of cough is based on duration. It is distinguished between acute cough (up to 8 weeks in duration) and chronic cough (> eight weeks in duration). In addition, cough that lasts for three to eight weeks is classified as subacute cough by some authors (2). Given the lack of comprehensive prevalence and incidence data, it is estimated that about 10% of the adult population suffers from chronic cough (3).
Chronic cough can be debilitating as the resulting distress significantly impairs the patient’s quality of life (4). While most cases of acute cough are related to infection, the diagnostic work-up of chronic cough is made difficult by the long list of differential diagnoses. This can lead to both over-treatment and under-treatment. Key differential diagnoses include chronic obstructive pulmonary disease (COPD) in smokers, bronchial asthma, drug-related cough, and empirically treated conditions such as upper airway cough syndrome (UACS), cough variant asthma, eosinophilic bronchitis, and gastroesophageal reflux disease (GERD), while diseases such as tuberculosis and interstitial lung diseases are among the rare causes (5).
The diagnosis “unexplained or refractory cough “ is typically assigned hastily and without a structured approach. On the other hand, even after numerous consultations with specialists many patients with chronic cough have still not been diagnosed and consequently miss out on adequate treatment (6). Nonpharmacological management options are not widely known, and off-label therapeutic trials can compromise patient safety if not carried out properly.
Under the leadership of the German College of General Practitioners and Family Physicians (DEGAM, Deutsche Gesellschaft für Allgemein- und Familienmedizin), the update of the S3-level Clinical Practice Guideline on Acute and Chronic Cough of the Association of the Scientific Medical Societies in Germany (AWMF, Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften) was completed in June 2021 with the participation of the German Society for Infectious Diseases, the German Respiratory Society and the German Society for Phytotherapy.
In the elaborations on chronic cough, a stepwise clinical approach with targeted diagnostic testing, empirical treatments, patient-centered consultations, and a structured procedure for unexplained or refractory cough (Checklist) was developed and summarized in a clinical algorithm (Figure).
In order to establish the existing evidence base, a systematic search of the literature was conducted in Medline (via PubMed) and in the guideline portals. In addition, a search for updates of the source guidelines of the 2014 version of the AWMF guideline was carried out. The AGREE II tool was used to assess the quality of the guidelines included (5).
Furthermore, a systematic search for reviews was conducted and the methodological quality was assessed using the AMSTAR-2 tool. The search strategies and evaluations are described in the eMethods. In terms of patient involvement, a search of the literature on the patient perspective in people living with chronic cough was conducted. In the AWMF-coordinated consensus conference, the recommendations were discussed and agreed upon. All stakeholders involved in the guideline development are listed in the eBox.
Seven source guidelines, 20 guidelines identified by the search of the guideline portals and 40 guidelines identified by the systematic search in Medline (via PubMed) were evaluated (eFigure). A total of three guidelines of high methodological quality and relevance for the key questions were identified (2, 7, 8). An additional guideline was later included by consensus (6).
The search for reviews and meta-analyses on unexplained or refractory cough carried out in Medline (via PubMed) yielded 16 hits; of these, two systematic reviews of high quality and relevance were included (eTable). As the evidence base compiled from guidelines and reviews was adequate, no systematic search for original articles was performed.
The guideline recommendations cited below are stated with strength of recommendation and levels of evidence, while statements are accompanied by levels of evidence.
Guideline content and recommendations
Preventable high-risk disease courses and red flags
Identifying red flags during history-taking and examinations (Figure) is crucial as a vital threat may be present or imminent. The following high-risk disease course must be identified or ruled out:
- Left heart failure with cardiac asthma: Many of these patients have known cardiac disease and experience increasing signs and symptoms of backward heart failure, such as tachypnea and dyspnea on exertion, culminating in orthopnea with pulmonary congestion.
- Neoplasms: Lung cancer is most common among smokers and may be associated with unintended weight loss, night sweats, hemoptysis, chest pain, and hoarseness.
- Foreign body aspiration: If unnoticed, foreign body aspiration may cause prolonged cough and occasionally recurrent pneumonia, especially in children and the elderly.
- Small recurrent pulmonary embolisms: Warning signs include exertional dyspnea and exercise intolerance, especially in patients with coagulation disorders and malignancies.
Consequently, the following evidence-based clinical management recommendations for chronic cough should only be followed after the red flags (Figure) have been ruled out.
History, physical examination and consultation
According to the established nomenclature, chronic cough is defined as a cough that lasts more than eight weeks (statement, evidence level IV). If red flags are present in patients with subacute cough of three to eight weeks’ duration or if the cough is not associated with respiratory tract infection, a differential diagnostic work-up of causes of chronic cough is useful even before eight weeks have passed. Other distinctions, such as between productive and dry cough, are not relevant.
A systematic approach based on the medical history (Table 1) and physical examination is useful. In the majority of cough-related consultations, an accurate diagnosis can be established in this way (9). Questioning about tobacco consumption (including e-cigarettes/nebulizer) is key (strength of recommendation A, level of evidence Ia), as tobacco use increases the likelihood of cough due to smoking and of cough due to tobacco-associated differential diagnoses, such as chronic (obstructive) bronchitis and lung cancer (2). Patient with a history of currently smoking should be motivated with personal relevance to stop smoking (A, Ia). After initial worsening, cough reduction can be expected within a few months. (10, 11). Cough is also more prevalent among patients smoking cannabis (12). Further questions to be asked include the long-term medication (especially ACE inhibitors [ACE, angiotensin-converting enzyme]), allergies, present and past illnesses, as well as occupational and private exposures (8).
Besides inspection of the upper airways (nose, throat) and auscultation of the chest, the physical examination should pay attention to signs of respiratory insufficiency (increased respiratory rate, clammy, bluish skin) and decompensated heart failure (crackles on auscultation, leg edema). Targeted technical equipment-based investigations contribute to establishing the diagnosis in an additional almost one quarter of cases (13).
In an online survey on chronic cough with 1120 respondents from 29 European countries, nearly half of the patients reported that they had never received a diagnosis. Only one-third of the respondents thought they had been thoroughly examined, and fewer than 10% of patients reported relief from medication. More than 90% of the respondents frequently felt depressed and joyless due to the cough (4). Consequently, the aim should be to provide early patient-centered medical advice, addressing the most common causes of cough and the further diagnostic procedures.
Differential diagnosis, investigation and treatment
The steps of the clinical management of chronic cough are summarized in an algorithm (Figure). The first step of the diagnostic work-up comprises a 2-view chest x-ray and pulmonary function tests (with provocation and allergy testing, if indicated) to rule out common diseases of the respiratory system, such as asthma and chronic (obstructive) bronchitis (2). If the patient is taking an ACE inhibitor and has a cough which is unlikely caused by an underlying pulmonary disease, the medication can be discontinued or the patient can be switched to another medication (e.g. an AT1 receptor blocker) prior to the chest x-ray; subsequently, the cough should subside completely within four weeks (14). If the chest x-ray shows a pulmonary mass or masses or if an underlying rare disease is suspected (Table 2), the next step is either to obtain a chest CT scan or direct referral to an appropriate specialist.
Which approach is chosen to treat chronic cough depends on the underlying disease. For the most common disease entities, such as asthma and COPD, pertinent guidelines are available (see 15, 16). If imaging studies and lung function testing are normal, other disease entities are likely to be present which are treated empirically and thus diagnosed secondarily, based on the alleviation of cough (Figure). For example, after an infection a patient may develop cough variant asthma and experience persistent dry and nocturnal cough triggered by temperature changes, airway stimuli, laughter, and exercise. Cough variant asthma should be treated with an inhaled corticosteroid over a period of four weeks (B, Ib). However, while it usually takes several weeks for the cough to resolve, symptoms may improve in the first week of treatment (6). If the cough is not alleviated by the treatment, it is recommended to refer the patient to a pulmonologist. The differential diagnosis includes eosinophilic bronchitis, a condition which is also treated empirically in therapeutic trials.
In patients with chronic cough and concomitant symptoms characteristic of gastroesophageal reflux disease (GERD), a therapeutic trial with a proton pump inhibitor ought to be made under the assumption that the cough is caused by GERD (B, Ib). In many cases, high-dose long-term treatment is required (17). Alleviation of the cough occurs after a few weeks at the earliest.
Chronic disorders of the upper respiratory tract, such as inflammatory nasal and sinus conditions as well as pharyngitis sicca, can trigger, or in some patients cause, an upper airway cough syndrome (18). If, based on clinical and/or radiographic findings, chronic rhinosinusitis is suspected to trigger such a cough syndrome, patients ought to be treated with nasal corticosteroids for at least six weeks (B, Ib). If the diagnosis is unclear or in refractory cases, it is recommended that the patient is seen by an office-based ENT specialist.
While approximately 10% of patients taking ACE inhibitors experience a dry, irritating cough (19), other substances may also cause chronic cough via various mechanisms, although at much lower rates. Examples include antiarrhythmic agents, nonsteroidal anti-inflammatory drugs, anti-infective agents, methotrexate, tricyclic antidepressants, and cholinesterase inhibitors (20).
Unexplained or refractory chronic cough
An unexplained cough is present if, despite a structured approach, no cause can be determined (8). If treatment of one or more suspected causes has been unsuccessful, the cough is classified as refractory. Since the above mentioned empirical treatment attempts are part of the standard diagnostic strategies, a clear distinction cannot always be made. The proportion of unexplained or refractory cases in specialized outpatient clinics varies widely, with reports ranging from 0 to 46% (21). No data are available for the primary care setting. It is common that patients with unexplained or refractory cough report high levels of psychological distress, are more frequently nervous and show symptoms of depression (22, 23). Their suffering can be severe. Middle-aged women are especially vulnerable as they are more commonly affected by both chronic cough with resulting distress (e.g. increased levels of stress incontinence due to the cough) and comorbidities such as depression (24).
One of the suspected causes is increased cough reflex sensitivity following an initial trigger, such as an infection. In addition, cough may represent a distinct disease entity that is diagnosed clinically. Before that, patients with chronic cough should be evaluated according to an established diagnostic algorithm in collaboration with specialists. During the process, empirical treatments should be tested exhaustively in accordance with the guidelines, and the possibility of multiple causes as well as the role of patient compliance should be considered (A, V). A pragmatic checklist has been developed in the updated guideline to support the implementation of this recommendation in everyday clinical practice (Box).
Treatment options include pharmacotherapy (mainly off-label treatments) as well as physiotherapeutic or speech-therapeutic methods. Patients can already be educated about basic cough suppression techniques during the medical consultation (Table 3).
Following consultation and patient education, nonpharmacological management strategies, such as physiotherapeutic or speech-therapeutic methods, are trained in two to four sessions, including exercises and postures which help to suppress an increased urge to cough and reduce compulsive throat clearing (25). Given the few controlled studies with small sample sizes, the available evidence is limited. The most commonly used instrument in studies on cough is the Leicester Cough Questionnaire (LCQ) which defines an improvement by 1.3 points as a clinically relevant change (26). One of the two available randomized controlled trials (RCTs) on the nonpharmacological treatment of cough showed a clinically significant LCQ score improvement for cough symptoms (mean difference: 1.53 points; 95% confidence interval [0.21; 2.85]; p = 0.024) (25). The other trial also demonstrated an improvement, based on a less established score (27). Overall, this treatment strategy requires a limited effort with few treatment sessions and the level of patient safety is high. Thus, in adult patients with unexplained or refractory chronic cough associated with high levels of symptom-related distress, speech therapy or physiotherapy (primarily respiratory physiotherapy) may be offered (0, V). This can be received alongside drug treatment for unexplained or refractory cough (0, V).
Drug treatment options with proven efficacy include only agents for off-label therapeutic trials (Table 3). Based on the currently available study data, long-term improvements after discontinuation of these substances are unlikely to be seen.
In the included guidelines and systematic reviews, studies with the active ingredients gabapentin, pregabalin, morphine, amitriptyline, erythromycin, azithromycin, tramadol, and various receptor antagonists (NMDA, TRPV1, P2X3, NK1) were analyzed with regard to their effectiveness in treating chronic cough (2, 6, 9, 28, 29). In most of the underlying controlled trials, the sample size was small. In these studies, the substances morphine, gabapentin and pregabalin showed clinically relevant effectiveness in treating chronic cough.
In some of the patients, opioids can alleviate chronic cough, starting from a dose of 5 mg morphine per day (6, 8, 29). In a frequently cited RCT (30), responders had a rapid onset of action, with the maximum benefit being seen on day five (improved LCQ score, mean difference: 2 points [0.93; 3.07]; p = 0.02). In patients with subtherapeutic response, the dose was increased to 10 mg twice daily, resulting in a further decrease in cough severity, but also an increased occurrence of sleepiness. In the low-dose range used here, the risk of serious side effects is considered to be comparatively low (6).
Gabapentin has a favorable side-effect profile with regard to tolerance development and addiction potential. Furthermore, its efficacy and safety has been evaluated extensively in trials (8, 31). Two RCTs included in a review without meta-analysis (28) showed a clinically significant LCQ score improvement in patients treated with gabapentin compared to placebo within a period of eight weeks, with maximum daily doses of up to 1800 mg (improved LCQ score, mean difference: 1.8 points [0.56; 3.04], p = 0.004, number needed to treat [NNT]: 3.6) (32). Side effects (Table 3) were dose-dependent and occurred in 31–40% of patients in the intervention group and in 10–23% in the placebo group (28).
Pregabalin is a related substance, but because it can produce feelings of euphoria and relaxation, misuse is common (29, 33). Adverse events, such as blurred vision, cognitive changes, dizziness or weight gain, were reported by 75% of subjects. At the same time, the rate of placebo effects was comparatively high. On the other hand, studies evaluating pregabalin showed that in combination with speech therapy it helped to optimize the treatment of chronic cough (improved LCQ score versus placebo plus speech therapy; mean difference: 3.5 points [1.11; 5.89]; p = 0.024, NNT: 20). The sustained effectiveness noted after discontinuation of pregabalin was attributed to speech therapy (34).
Codeine and noscapine can be prescribed for the treatment of cough, but have not been systematically evaluated in patients with refractory cough. Given its side-effect profile and the inter-individual genetic variability in the breakdown (CYP2D6) of the substance to morphine and the thus difficult to control response to treatment, codeine is not recommended.
In summary, patients with unexplained or refractory cough associated with high levels of distress can be offered at their request treatment with gabapentin or low-dose morphine after comprehensive discussion of potential side effects (0, Ia).
There is still little experience with novel drugs such as gefapixant, a P2X3 receptor antagonist. A randomized, placebo-controlled, double-blind phase 2b trial showed comparatively high placebo effects in patients with chronic cough. Dysgeusia was the most relevant side effect (35).
Need for research
The update of the guideline resulted in the following additional research questions:
- What relevant comorbidities are associated with chronic cough?
- What is the age- and sex-dependent incidence of unexplained or refractory cough in the primary care setting in Germany?
- What are the long-term effects of speech-therapeutic and physiotherapeutic treatments in patients with chronic cough, and what duration/intensity of treatment is required to achieve an effect?
- What long-term effects (sustained symptom relief, patient compliance, side effects, habituation effects, quality of life) are associated with pharmacological treatments for unexplained or refractory cough?
We would like to thank all other authors and stakeholders of the DEGAM S3-level Clinical Practice Guideline on Acute and Chronic Cough: Prof. Dr. med. Jost Langhorst, Dr. med. Peter Kardos, PD Dr. med. Guido Schmiemann, Prof. Dr. med. Thomas Kühlein, Dr. rer. hum. Cathleen Muche-Borowski
The guideline was financed by DEGAM’s own funds as well as funds of the Institute of General Practice and Family Medicine, Charité Universitätsmedizin Berlin.
Conflict of interest statement
The authors declare that no conflict of interest exists.
Manuscript received on 5 November 2021, revised version accepted on 24 November 2021.
Translated from the original German by Ralf Thoene, MD.
Clinical guidelines are not peer-reviewed in the Deutsche Ärzteblatt, as well as in many other journals, because clinical (S3-level) guidelines are texts which have already been repeatedly evaluated, discussed and broadly consented by experts (peers).
Dr. med. Karen Krüger
Institut für Allgemeinmedizin, Charité,
Charitéplatz 1, 10117 Berlin, Germany
Cite this as:
Krüger K, Holzinger F, Trauth J, Koch M, Heintze C, Gehrke-Beck S: Clinical practice guideline: Chronic cough. Dtsch Arztebl Int 2022; 119: 59–65. DOI: 10.3238/arztebl.m2021.0396
eBox, eTable, eFigure, eMethods:
Department of Internal Medicine II, Division of Infectious Diseases, University Hospitals of Giessen and Marburg, Giessen site, Giessen, Germany: Dr. med. Janina Trauth
Department of Internal Medicine II, University Hospital of Regensburg, Regensburg, Germany: Dr. med. Myriam Koch
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