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Guidelines for Evaluating Chronic Cough in Pediatrics

ACCP Evidence-Based Clinical Practice Guidelines

Correspondence to: Anne B. Chang, MBBS, PhD, Pediatric Respiratory and Sleep Physician, NHMRC Practitioner Fellow, Associate Professor in Pediatrics and Child Health, Department of Respiratory Medicine, Royal Children’s Hospital, Herston Rd, Brisbane, QLD 4029, Australia; e-mail: annechang{at}ausdoctors.net

	Abstract

TOP Abstract Introduction Defining Cough in Children Clinical History, Examination,... Etiologic Associations Evidence-Based Treatment Introduction and Background Literature Review of... Chronic Cough Investigating Children With... Recommendations Treatment of Nonspecific Cough Recommendations Conclusion Summary of Recommendations References

 
Objectives: To review relevant literature and present evidence-based guidelines to assist general and specialist medical practitioners in the evaluation and management of children who present with chronic cough.

Methodology: The Cochrane, MEDLINE, and EMBASE databases, review articles, and reference lists of relevant articles were searched and reviewed by a single author. The date of the last comprehensive search was December 5, 2003, and that of the Cochrane database was November 7, 2004. The authors’ own databases and expertise identified additional articles.

Results/conclusions: Pediatric chronic cough (ie, cough in children aged < 15 years) is defined as a daily cough lasting for > 4 weeks. This time frame was chosen based on the natural history of URTIs in children and differs from the definition of chronic cough in adults. In this guideline, only chronic cough will be discussed. Chronic cough is subdivided into specific cough (ie, cough associated with other symptoms and signs suggestive of an associated or underlying problem) and nonspecific cough (ie, dry cough in the absence of an identifiable respiratory disease of known etiology). The majority of this section focuses on nonspecific cough, as specific cough encompasses the entire spectrum of pediatric pulmonology. A review of the literature revealed few randomized controlled trials for treatment of nonspecific cough. Management guidelines are summarized in two pathways. Recommendations are derived from a systematic review of the literature and were integrated with expert opinion. They are a general guideline only, do not substitute for sound clinical judgment, and are not intended to be used as a protocol for the management of all children with a coughing illness. Children (aged < 15 years) with cough should be managed according to child-specific guidelines, which differ from those for adults as the etiologic factors and treatments for children are sometimes different from those for adults. Cough in children should be treated based on etiology, and there is no evidence for using medications for the symptomatic relief of cough. If medications are used, it is imperative that the children are followed up and therapy with the medications stopped if there is no effect on the cough within an expected time frame. An evaluation of the time to response is important. Irrespective of diagnosis, environmental influences and parental expectations should be discussed and managed accordingly. Cough often impacts the quality of life of both children and parents, and the exploration of parental expectations and fears is often valuable in the management of cough in children.

Key Words: asthma • children • cough • evidence-based medicine • guideline • treatment

	Introduction

TOP Abstract Introduction Defining Cough in Children Clinical History, Examination,... Etiologic Associations Evidence-Based Treatment Introduction and Background Literature Review of... Chronic Cough Investigating Children With... Recommendations Treatment of Nonspecific Cough Recommendations Conclusion Summary of Recommendations References

 
Clinicians specializing in children’s health are well aware of the limitations and possible adversity in the extrapolation of data from adults to children.¹² Child-specific guidelines are differentiated from those for adults in common respiratory diseases such as community-acquired pneumonia³⁴⁵ and asthma.⁶ However, rigidity in the adherence to child-specific data may also be disadvantageous to children, given the relative paucity in pediatric research in comparison to research in adults.¹ In the area of cough, there are similarities but also clear clinical and physiologic differences between children and adults. Some adult definitions (eg, chronic bronchitis and COPD are not recognized diagnostic entities in the pediatric respiratory literature and main textbooks⁷⁸) are inappropriate for children. Etiologic differences and frequency etiologies associated with cough are also evident from the literature.⁹¹⁰¹¹ Furthermore, adults and children also have different responses to some medications (eg, first-generation antihistamines that are efficacious for treating cough in adults are not only not beneficial in children when the evidence is critically evaluated,¹²¹³ but their use is also associated with more morbidity¹⁴¹⁵ in children when compared to adults). Personal and institutional practice may well differ from the evidence reviewed and presented in this article. This review is focused on chronic cough, and the data are limited to children unless specifically stated. Although the cutoff age for pediatric care in the United States is 18 years, we have chosen a lower cutoff age here (ie, 14 years of age) based on the limited evidence in the cough literature that adolescents are more like adults (eg, the response to over-the-counter (OTC) medications for cough as summarized in a Cochrane review¹⁶).

The Cochrane, MEDLINE, and EMBASE databases, review articles, and reference lists of relevant articles were searched and reviewed by a single author. All recommendations were based on the pediatric literature and current evidence, and were accepted by the panel on December 5, 2004.

	Defining Cough in Children

TOP Abstract Introduction Defining Cough in Children Clinical History, Examination,... Etiologic Associations Evidence-Based Treatment Introduction and Background Literature Review of... Chronic Cough Investigating Children With... Recommendations Treatment of Nonspecific Cough Recommendations Conclusion Summary of Recommendations References

 
Cough can be defined based on time frame (ie, duration of cough), quality (eg, dry or wet,¹⁷ brassy, or staccato), or suggested etiology (ie, specific and nonspecific).¹¹ The majority of the terms defined below have been used in various publications.¹¹¹⁸¹⁹ The background for justification of the use of these terms has been reviewed elsewhere.²⁰ Chronic cough in children is defined as a cough of > 4 weeks duration based on the current data of cough related to acute upper respiratory infections in children.²¹²² This review and the evidence presented are also focused on nonspecific chronic cough (ie, cough in the absence of symptoms outlined in Table 1 ) as data on specific cough would encompass the entire spectrum of pediatric respiratory disease.

	Clinical History, Examination, and Investigations

TOP Abstract Introduction Defining Cough in Children Clinical History, Examination,... Etiologic Associations Evidence-Based Treatment Introduction and Background Literature Review of... Chronic Cough Investigating Children With... Recommendations Treatment of Nonspecific Cough Recommendations Conclusion Summary of Recommendations References

	Etiologic Associations

TOP Abstract Introduction Defining Cough in Children Clinical History, Examination,... Etiologic Associations Evidence-Based Treatment Introduction and Background Literature Review of... Chronic Cough Investigating Children With... Recommendations Treatment of Nonspecific Cough Recommendations Conclusion Summary of Recommendations References

	Evidence-Based Treatment

TOP Abstract Introduction Defining Cough in Children Clinical History, Examination,... Etiologic Associations Evidence-Based Treatment Introduction and Background Literature Review of... Chronic Cough Investigating Children With... Recommendations Treatment of Nonspecific Cough Recommendations Conclusion Summary of Recommendations References

In general, the management of specific cough should be based on etiology. When the underlying condition or exacerbating factor is managed, cough subsequently resolves. For example, the severity and frequency of wet cough resolves following the management of an acute exacerbation of chronic suppurative lung disease. The management of specific cough encompasses the entire spectrum of pediatric pulmonology, which is well beyond the scope of this article. (A guideline for nonspecific cough, with its limited evidence, is presented in Figures 2 and 3 , and the evidence is presented in the text and summarized in Table 4 ^{12131415167475799091122207208211215225226227231232233237265266267268269270271}.) Irrespective of the cause of cough, particular attention to tobacco smoke exposure as well as parental expectations and concerns are advised, based on data on acute upper respiratory infections. When appropriate and when no pediatric data exist, readers are referred to the adult guideline, but this extrapolation should be cautiously accepted. If a trial of medications is warranted, "time response" (Table 4) should be considered, the child’s case should be reviewed within the relevant time frame, and therapy with medications should be stopped when appropriate.

View larger version (34K): [in this window] [in a new window] [Download PPT slide]   Figure 2. Approach to a child < 15 years of age with chronic cough. There are limitations to the algorithm, which should be read with the accompanying text. Spirometry can usually be reliably performed in children > 6 years of age and in some children > 3 years of age if trained pediatric personnel are present.81 CXR = chest radiograph.

View larger version (31K): [in this window] [in a new window] [Download PPT slide]   Figure 3. Approach to a child 14 years of age with chronic specific cough (ie, cough associated with other features suggestive of an underlying pulmonary and/or systemic abnormality). Children > 14 years of age should be managed as outlined in adult guidelines, but there is no good evidence concerning where the age cutoff for treatment should be. TB = tuberculosis; TEF = tracheoesophageal fistula.

	Introduction and Background

TOP Abstract Introduction Defining Cough in Children Clinical History, Examination,... Etiologic Associations Evidence-Based Treatment Introduction and Background Literature Review of... Chronic Cough Investigating Children With... Recommendations Treatment of Nonspecific Cough Recommendations Conclusion Summary of Recommendations References

The physiology of the respiratory system in children is similar to that in adults in many ways. However, there are also distinct differences between young children and adults, including maturational differences in airway, respiratory muscle, and chest wall structure, sleep-related characteristics, respiratory reflexes, and respiratory control.³²³³³⁴ In the physiology of cough, gender differences in cough sensitivity that are well-recognized in adults³⁵ are absent in children.³⁶ In children, cough sensitivity is instead influenced by airway caliber (ie, FEV₁) and age.³⁶ the plasticity or adaptability of the cough reflex has been shown in animals,³⁷ and one can speculate that there are also maturational differences in the cough reflex.³⁸ In young children, the medical history is limited to parental perception and availability. The combination of these factors results in variations in differential diagnoses. As an example, the unknown inhalation of a foreign body (delayed diagnosis can result in permanent lung damage³⁹) is not uncommon in children; the frequency of acute upper respiratory tract infections (URTIs) is age-related; studies from the 1940s to the 1960s have shown that children have 5 to 8 acute respiratory infection (ARI) episodes per year,⁴⁰ while in more recent studies⁴¹ children aged < 5 years have 3.8 to 5 infections per person per year and adults have only 2. Respiratory tract carcinomas, which are not uncommon in adults, are very rare in children, and radiation from high-resolution CT (HRCT) scans of the chest in children carry higher risks.⁴² While cough may be a manifestation of asthma in both adults and children, other common causes of cough and respiratory diseases in adults such as chronic bronchitis⁴³ and COPD are not recognized diagnostic entities in the pediatric respiratory literature and textbooks.⁷⁸ Thus, the management of childhood cough should be distinguished from that of adult cough, and it mandates a separate guideline that focuses on cough in children that is relevant to children < 15 years of age. This guideline, which is applicable in more affluent countries like the United States, the United Kingdom, and Australia, requires appropriate adaptations in other population settings⁴⁴ such as in Native American⁴⁵ and Australian¹⁹ aboriginal communities in which bronchiectasis is relatively common (ie, 147 to 200 cases per 10,000 children).

Pediatric cough can be classified in several ways, including those based on etiology,²³ time frame,¹¹ characteristics (eg, moist vs dry),¹⁷ and specific and nonspecific cough (Fig 1 ) with a degree of overlap. The definition of chronic cough in children, however, varies from 3 weeks⁴⁶⁴⁷ to 12 weeks in duration.¹¹⁴⁸ There are no studies that have clearly defined when cough should be defined as chronic or persistent. A systematic review²² showed that cough related to an acute URTI resolves within 1 to 3 weeks in most children. A prospective cohort study²¹ by the same group conducted in preschool children presenting to primary care showed that 10% of children were still coughing 25 days after a URTI. They did not describe whether those children with prolonged cough had complications of URTI such as pneumonia or bacterial bronchitis. Based on the natural history of URTIs and differences between adults and children, we define pediatric chronic cough as a daily cough lasting for > 4 weeks. In this guideline, only chronic cough will be discussed and its management summarized in two pathways (Fig 2, 3).

View larger version (16K): [in this window] [in a new window] [Download PPT slide]   Figure 1. Classification of types of cough in children. The figure was reproduced from the article by Chang.272

1. "Normal" children occasionally cough as has been described by two studies⁵²⁵³ that objectively measured cough frequency. The "medicalization" of an otherwise common symptom can foster exaggerated anxiety about perceived disease, and lead to unnecessary medical product delivery and services.⁵⁴ Cough in this situation is termed expected cough.
   
2. Questions about isolated cough are largely poorly reproducible,⁵⁵ and nocturnal cough in children is unreliably reported.⁵⁶⁵⁷ The value relating the chance-corrected agreement between answers to questions on cough ranges widely from 0.02 to 0.57.²⁷⁵⁵⁵⁸ In contrast, questions about isolated wheezing and asthma attacks are highly reproducible with values of 0.7 to 1.0.⁵⁵
   
3. Cough is subjected to the period effect (ie, the spontaneous resolution of cough).⁵⁹ The therapeutic benefit of placebo treatment for cough has been reported to be as high as 85%.⁶⁰ The results of nonplacebo controlled intervention studies must be interpreted with caution.
   
4. In older children, cough is also subjected to psychological influences⁶¹⁶² because, as in adults, cough is cortically modulated.⁹ Rietveld and colleagues⁶¹⁶³ showed that children were more likely to cough under certain psychological settings.
   
5. The subjective perception of cough severity is dependent on the population that is being studied.⁵³ The reporting of childhood respiratory symptoms is biased, and parental perceptions of childhood cough play an important role.²⁷²⁸
   

	Literature Review of Recommendations

TOP Abstract Introduction Defining Cough in Children Clinical History, Examination,... Etiologic Associations Evidence-Based Treatment Introduction and Background Literature Review of... Chronic Cough Investigating Children With... Recommendations Treatment of Nonspecific Cough Recommendations Conclusion Summary of Recommendations References

 
To develop an evidence-based guideline, the following search strategy was utilized. Articles on diagnosis, etiology, treatment, and complications were searched separately. Articles published in the English language between January 1966 and December 2003 were identified from The Cochrane Register of Controlled Trials (CENTRAL), PubMed (1966 to December 2003), EMBASE (from 1997 to 2003), the list of references in relevant publications, and the authors’ collection of references. The search strategy is presented in Table 5 . A single author reviewed all abstracts identified from the search, and relevant articles were retrieved for full review. The searches were performed between September 1 and December 5, 2003. A final search of the Cochrane database only was conducted on November 7, 2004, using the search term "cough and children." All data presented are restricted to pediatric studies unless otherwise stated.

	Chronic Cough

TOP Abstract Introduction Defining Cough in Children Clinical History, Examination,... Etiologic Associations Evidence-Based Treatment Introduction and Background Literature Review of... Chronic Cough Investigating Children With... Recommendations Treatment of Nonspecific Cough Recommendations Conclusion Summary of Recommendations References

	Investigating Children With Chronic Cough: Diagnostic Approaches

TOP Abstract Introduction Defining Cough in Children Clinical History, Examination,... Etiologic Associations Evidence-Based Treatment Introduction and Background Literature Review of... Chronic Cough Investigating Children With... Recommendations Treatment of Nonspecific Cough Recommendations Conclusion Summary of Recommendations References

 
Medical History and Physical Examination
Chronic cough in children secondary to respiratory diseases such as suppurative lung disease¹⁹ and interstitial disease usually have a variety of other specific clinical symptoms and signs.⁶⁴ However, a review of the medical literature found no reports on the specificity and sensitivity of these signs and symptoms. Based on expert opinion, children with chronic cough need to be carefully evaluated for the following:

Symptoms and signs of an underlying respiratory or systemic disease (termed specific pointers) [Table 1]. When any of these symptoms and signs are present, the cough is referred to as specific cough.

In some children, the quality of cough is recognizable and suggestive of a specific etiology (Table 6 ^{1762137139177184247248249250251}). This significantly differs from the situation in adults in whom detailed questioning about the characteristics of cough was not diagnostically useful.⁶⁵ However, most of these cough characteristics recognized by pediatricians as "classical" or "traditional" have not been formally examined (ie, sensitivity and specificity are undefined). Of the cough characteristics presented in Table 6, only that of brassy cough has been formally evaluated.¹⁷ The sensitivity and specificity for brassy cough (ie, for tracheomalacia) were 0.57 and 0.81, respectively.¹⁷ The score for both intraobserver and interobserver clinician agreement for brassy cough was 0.79 (95% confidence interval, 0.73 to 0.86).¹⁷

Possible exacerbating factors (see below) should also be evaluated, irrespective of the underlying etiology.

Use of Chest and Sinus CT Scans
The chest HRCT scan is the current "gold standard" for evaluating small airway structural integrity and is more sensitive than spirometric indexes.¹⁹⁶⁶⁶⁷ The utility of CT scans has to be balanced with the reported increased lifetime cancer mortality risk, which is age-dependent and dose-dependent. Although the risk is relatively negligible, children have 10 times the increased risk compared to middle-aged adults.⁴² For a single CT scan examination of 200 mA, the lifetime attributable cancer mortality risk is 1 in 1,000 to 2,500 for a 2.5-year-old child.⁴² Thus, while chest CT scans and, to a much lesser extent, sinus CT scans have definite roles in the evaluation of a child with cough, these should be uncommonly performed unless other symptoms are present. As radiation exposure and indications for conventional, spiral, and HRCT chest scans are different and are dependent on the type of suspected lesion, prior consultation with a pediatric pulmonologist is recommended.

Flexible Bronchoscopy
Indications for flexible bronchoscopy in children with chronic cough include the following: (1) suspicion of airway abnormality, (2) localized radiology changes, (3) suspicion of an inhaled foreign body, (4) evaluation of aspiration lung disease and, (5) microbiological studies and lavage. In a European series,⁶⁸ chronic cough was the indication for 11.6% of the 1,233 pediatric bronchoscopies performed. Utility for flexible bronchoscopy is dependent on the child’s medical history and the available expertise.

Airway Fluid/Lavage and Cellular Assessment
Currently, other than the assessment of airway specimens for microbiological purposes, the use of an airway cellular and inflammatory profile in children with chronic cough is currently limited to a supportive diagnosis and research rather than a definitive diagnosis. This is in contrast to that in adults with chronic cough in whom some have suggested the use of an airway inflammatory profile (ie, levels of primarily eosinophils) to direct therapy.⁶⁹⁷⁰

Tests for Airway Hyperresponsiveness
Tests for airway hyperresponsiveness (AHR) are not used in routine practice in most pediatric pulmonary laboratories to diagnose asthma.⁷¹ The presence of AHR does not mean that asthma is present in children,⁷² and the demonstration of AHR in a child with isolated cough is unlikely to be helpful in predicting the later development of asthma⁷³ or the response to asthma medications.⁷⁴ Older studies^75767778 have stated that the presence of AHR in children with cough is said to be representative of asthma. However, these studies^75767778 were not placebo-controlled, and in them confounders were not adjusted for or unconventional definitions of AHR were used.

Spirometry
Spirometry is valuable in the diagnosis of reversible airway obstruction in children with chronic cough if an abnormality is present.⁷⁹⁸⁰ Spirometry can usually be reliably performed in children aged > 6 years and in some children > 3 years if trained pediatric personnel are present.⁸¹

Other Investigative Techniques
Airways resistance determined by the interrupter technique, which has not yet been established in clinical practice, may prove to be useful in detecting isolated cough associated with asthma.⁸² Despite its application in research, there are still problems with intersubject variability and, hence, with the validity of its measurements when undertaken by different investigators.⁸³ To date, there have been no studies that have evaluated the role of nitric oxide (NO) or breath condensate in determining the etiology of chronic cough in children. There has been only one study⁸⁴ on bronchial biopsy in children with chronic cough. Heino and colleagues⁸⁴ described the association between ARI in children before the age of 1 year and epithelial inflammation in seven children with chronic cough (> 3 months).⁸⁴

Several studies¹⁸⁸⁵⁸⁶ have described altered cough sensitivity (to capsaicin or acetic acid) in different disease processes. Increased cough sensitivity has been found in children with recurrent cough,³⁶ cough-dominant asthma,⁸⁶ and acute and postviral respiratory infections. However, tests for cough sensitivity are currently nondiagnostic, their sensitivity and specificity undefined, and their use still limited to research purposes.

Evaluation and Management of Children With Chronic Cough
For clinically practical reasons, we have divided cough into specific cough and nonspecific cough (Fig 1).¹¹ In specific cough, the etiology and necessity of further investigations is usually evident from the presence of coexisting symptoms and signs (Table 1). The presence of any of these symptoms suggests that the cough is likely indicative of an underlying disorder and that further complex investigations may be indicated. The type and depth of these investigations depend on clinical findings. Diagnoses that need to be considered include bronchiectasis, retained foreign body, aspiration lung disease, atypical respiratory infections, cardiac anomalies and interstitial lung disease, among others (see Fig 2, 3).

There are no published studies on the etiology of "dry cough" vs "moist/productive cough" in children. A moist cough putatively represents excess airway secretions.¹⁷ Even in children with moist cough, though, a specific pediatric diagnostic category may not be found.⁸⁷ A chronic dry cough, on the other hand, may represent a dry phase of an otherwise usually moist cough.¹⁷ Chronic cough in the absence of specific pointers (Table 1) in the medical history and physical examination is termed nonspecific cough (ie, cough is the only symptom). In nonspecific cough, the etiology is ill-defined; it has been speculated that the majority of cases are related to postviral cough and/or increased cough receptor sensitivity.¹⁸³⁶ In the study by Callahan,⁸⁸ however, an asthma-like condition was the most common diagnosis (the quality of cough was not specified in the study). After investigations are conducted (if necessary), some children may be found to have an underlying serious abnormality.⁸⁹ However, in the majority of children, nonspecific cough is most likely related to a nonserious etiology²³ or may spontaneously resolve, as evidenced in the placebo arms of RCTs⁷⁴⁹⁰⁹¹ and cohort studies.⁹²⁹³⁹⁴ The remainder of this guideline discusses the available data on nonspecific cough. There is, though, an overlap among specific cough, nonspecific cough, and expected cough (Fig 1), and hence the need for a review of the case of any child with a chronic cough. Evidence-based management guidelines for cough associated with acute infections, as well as that associated with underlying respiratory and systemic disorders, are beyond the scope of this section, and disease-specific guidelines and/or evidence-based reviews for children are available for some diseases such as asthma,⁶ community-acquired pneumonia,³⁴⁵ bronchiolitis,⁹⁵ airway clearance methods,⁹⁶ and selective aspects of cystic fibrosis management,⁹⁷⁹⁸⁹⁹ in addition to that those provided by a United States-based resource (The National Guideline Clearinghouse [www.guideline.gov]). The list is far from exhaustive, and, although none of these guidelines are cough-specific, cough usually improves when the underlying disease is treated.

	Recommendations

TOP Abstract Introduction Defining Cough in Children Clinical History, Examination,... Etiologic Associations Evidence-Based Treatment Introduction and Background Literature Review of... Chronic Cough Investigating Children With... Recommendations Treatment of Nonspecific Cough Recommendations Conclusion Summary of Recommendations References

 
1. Children with chronic cough require careful and systematic evaluation for the presence of specific diagnostic indicators. Level of evidence, expert opinion; benefit, substantial; grade of recommendation, E/A

2. Children with chronic cough should undergo, as a minimum, a chest radiograph and spirometry (if age appropriate). Level of evidence, expert opinion; benefit, intermediate; grade of recommendation, E/B

3. In children with specific cough, further investigations may be warranted, except when asthma is the etiologic factor. Level of evidence, expert opinion; benefit, intermediate; grade of recommendation, E/B

4. Children with chronic productive purulent cough should always be investigated to document the presence or absence of bronchiectasis and to identify underlying and treatable causes such as cystic fibrosis and immune deficiency. Level of evidence, low; benefit, substantial; grade of recommendation, B

Asthma, Asthma-Like Conditions, and Cough in Children
Children with asthma may present with cough. However, the majority of children with isolated cough do not have asthma.⁹¹⁰¹⁰⁰ The use of isolated cough as a marker of asthma is indeed controversial with more recent evidence¹¹¹⁰⁰ showing that in most children, isolated cough does not represent asthma. Some hospital-based clinical studies¹⁰¹¹⁰² of children presenting with chronic cough have found asthma to be the most common cause, but others have not.⁸⁷⁸⁹ There is little doubt that the etiology of cough would depend on the setting, selection criteria of the children studied,⁸⁹¹⁰³ follow-up rate,¹⁰⁴ and depth of the clinical history, physical examination, and investigations performed. When airway profiles have been examined in children with isolated chronic cough, the studies^103105106 have shown very few children with airway inflammation that is consistent with asthma. Cough associated with asthma without a coexistent respiratory infection is usually dry.⁶ This topic has been previously reviewed.⁹ With space limitations, only an update of further studies (in addition to the studies on airway fluid assessment outlined in Table 2) is summarized in Table 3. A review¹⁰⁷ relating measurements of cough severity to those of asthma severity is also available. A further difficulty relating cough and asthma is the fact that cough is the most common symptom in patients presenting to doctors in the United States and Australia,¹⁰⁸¹⁰⁹ and viral respiratory infections, which also cause cough, are said to account for 80% of childhood asthma exacerbations.¹¹⁰ It would be difficult to ascertain whether cough is secondary to asthma or to the respiratory viral infection.

Upper Airways Disorders and Cough in Children
In adults, upper airway cough syndrome (previously referred to as postnasal drip syndrome) has been reported¹¹¹¹¹² as a common cause of chronic cough. In children, although nasal discharge and cough have been reported as the two most prominent symptoms in children with chronic sinusitis (for 30 to 120 days),¹¹³ the supportive evidence of cause and effect in children is less convincing.¹¹⁴ Although sinusitis is commonly diagnosed in childhood, it can be rarely proven, and it is not associated with cough once atopy and doctor-diagnosed allergic rhinitis are controlled for.¹¹⁵ The relationship between nasal secretions and cough is more likely linked by common etiology (infection and/or inflammation causing both) or is due to the clearing of secretions reaching the larynx. Abnormal sinus radiographs may be found in 18 to 82% of asymptomatic children.¹¹⁶ A systematic review of acute sinusitis in children concluded that "diagnostic modalities showed poor concordance, and treatment options were based on inadequate data."¹¹⁷

Turktas and colleagues¹¹⁸ described increased extrathoracic AHR without bronchial AHR to methacholine in a group of children presenting with chronic cough, and other studies¹¹⁹¹²⁰ have linked extrathoracic AHR to sinusitis and rhinitis in adults. Whether the presence of upper airway abnormalities causes or is the consequence of extrathoracic AHR is unknown. The repeatability and validity of extrathoracic AHR in children is also ill-defined. Therapeutic approaches in managing children with allergic rhinitis have been well-summarized by Fireman.¹²¹ A single RCT¹²² on adolescents and adults (n = 245) with allergic rhinitis using cough as an outcome measure showed that daytime cough difference between the active treatment arm (with mometasone furoate) and placebo was significant (p = 0.049). In comparison, a larger difference between groups was found for nasal symptoms, and there was no difference in nighttime cough.¹²² There have been no RCTs on therapies for upper airway disorders in younger children with nonspecific cough.

GERD and Cough in Children
Several studies¹²³¹²⁴ have reported that esophageal disorders can trigger cough in children, and this occurs by several mechanisms. Whether the sensory pathway stimulation described in animal studies¹²⁵ also occurs in children is unknown. However, while GERD can be the reason for persistent cough,¹²⁴¹²⁶ cough can also provoke gastroesophageal reflux (GER) episodes in adults.¹²⁷¹²⁸ Data on cough itself causing GER described in adults is unavailable in children.¹²⁸ Proof that GERD causes chronic cough in children is rare,¹²³ and the relationship between the two is most likely complex.¹²⁹ As cough is very common in children and respiratory symptoms may exacerbate GER, it is difficult to differentiate cause and effect.¹³⁰ Infants often regurgitate,¹³¹ yet few well infants cough with these episodes. The effects of fundoplication on cough and other respiratory symptoms are inconsistent.¹³²¹³³ There are a limited number of studies that have looked at the causes of chronic cough in children prospectively, but those that are available suggest that GERD is infrequently the sole cause of isolated cough in children. One prospective study¹⁰¹ of the causes of chronic cough in children found only one child with GERD out of a series of 38. A more recent retrospective study⁸⁹ found coexistent GERD in 4 of 49 children with chronic cough. In contrast to data in adults whereby GERD is a frequent cause of chronic cough,¹³⁴¹³⁵ there is indeed little current convincing evidence that GERD is a common cause of isolated chronic cough in children.

Airway Lesions and Cough
Chronic cough has also been well-described in children with airway lesions.^136137138139 Gormley and colleagues¹³⁹ described that 75% of children with congenital tracheomalacia secondary to congenital vascular anomaly had persistent cough at presentation. How commonly airway lesions are found in asymptomatic children is unknown, and how the symptom of cough relates to airway lesions can only be postulated. Airway malacia impedes the clearance of secretions,¹³⁸ and it is plausible that the prolonged duration of cough in these children relates to a bronchitic process distal to the lesion. Stradling¹⁴⁰ has described bronchomalacia secondary to chronic bronchitis in adults. However, which is the cause and which is the effect are unknown. Nevertheless, recurrent infections and pneumonia on the side of the airway lesion have been well-described,¹³⁸ and so has the misdiagnosis of asthma in children with airway malacia disorders.¹³⁸¹⁴¹ The relationship between airway lesions and cough is not straightforward. Although persistent cough is listed as an indication for flexible bronchoscopy,⁶⁸¹⁴² its role in this context has yet to be defined prospectively.

Environmental Pulmonary Toxicants
Exposure to environmental smoke increases the susceptibility to respiratory infections,¹⁴³¹⁴⁴ causes adverse respiratory health outcomes,¹⁴⁵ and increases coughing illnesses.¹⁴⁶¹⁴⁷ Increased environmental tobacco smoke (ETS) exposure has also been described in cohorts of children with chronic cough compared to children without cough.¹⁰³¹⁴⁸ However, the Tucson study¹⁴⁹ concluded that, "cough was not associated with parental smoking during the first decade of life," which contrasts with other epidemiologic and clinical studies^103145146150 showing a close link between childhood cough and ETS exposure.

Exposure to indoor biomass combustion increases coughing illness associated with respiratory infections with an exposure-response effect.¹⁵¹ Exposure to other ambient pollutants (eg, particulate matter,¹⁵²¹⁵³ nitrogen dioxide, and gas cooking¹⁵⁴) is also associated with increased cough in children in both cross-sectional studies¹⁵²¹⁵³ and longitudinal studies,¹⁵⁵ especially in the presence of other respiratory illness such as asthma.¹⁵² Some studies,¹⁵⁶¹⁵⁷ however, have not shown this effect, and this may be related partially to problems in questionnaire-based epidemiologic studies on isolated and nocturnal cough.⁹²⁷

Nonasthmatic Eosinophilic Bronchitis and Allergy
Nonasthmatic eosinophilic bronchitis, which is a well-described cause of chronic cough in adults,¹⁵⁸ has not been recognized in children. "Allergic cough" is a poorly defined condition even in adults, and its relationship to childhood cough probably represents an overlap with asthma, nonasthmatic eosinophilic bronchitis, allergic rhinitis, and adenoid tonsillar hypertrophy.¹⁵⁹ The association between atopy and respiratory symptoms has been the subject of many epidemiologic studies.¹⁶⁰¹⁶¹ Some have described¹⁶⁰¹⁶¹ greater respiratory symptom chronicity,¹⁶² while others have not. Inconsistent findings regarding cough and atopy are also present in the literature; reports of increased atopy (or diseases associated with atopy) in children with cough have been found in cohort and cross-sectional studies¹⁶³¹⁶⁴ as has as the absence of influence of atopy.^7490165166 Cough as a functional symptom can also be mistaken for an allergic disorder in children.¹⁶⁷

Chronic Nocturnal Cough
The major problem in utilizing the symptom of nocturnal cough is the unreliability and inconsistency of its reporting when compared to objective measurements.^5657168 This has been reviewed,¹⁰⁷¹⁶⁹ and hence only salient points and recent articles will be mentioned. Nocturnal cough is often used as a direct indicator of asthma as children with asthma are often reported to have troublesome nocturnal cough.¹⁷⁰ However, in the community-based study by Ninan and colleagues,¹⁶⁵ only a third of children with isolated nocturnal cough (ie, the absence of wheezing, shortness of breath, or chest tightness) had an asthma-like illness. To date, there have been no studies that have objectively documented that nocturnal cough is worse than daytime cough in children with unstable asthma. One study¹⁷¹ has shown that cough frequency was higher during the day than at night in a group of children with stable asthma who were receiving treatment with inhaled corticosteroids (ICSs) yet had elevated levels of NO but not sputum eosinophils, which is arguably the best marker for eosinophilic inflammation in adults with stable asthma.¹⁷² Whether the increased NO is a marker of asthma instability or is related to other causes of elevated NO levels (such as environmental pollutants)¹⁷³¹⁷⁴ is unknown. It is possible that nocturnal cough is considered to be more troublesome than daytime cough.

Respiratory Infections and Postinfections Cough
Recurrent URTIs and infections such as pertussis can cause chronic cough (Table 3). The natural history of cough associated with URTIs in children 0 to 4 years of age in the community has been summarized.²² Postviral cough is a term that refers to the presence of cough after an acute viral respiratory infection. However, this has not been well-studied, and little is known about its pathophysiology or natural history beyond 25 days.²¹ When a child who has not fully recovered from a URTI-related cough acquires a subsequent URTI, the coughing illness may seem prolonged. In the review by Monto,⁴⁰ the mean annual incidence of total respiratory illness per person-year ranges from 5 to 8 in children < 4 years of age to 2.4 to 5.0 in children 10 to 14 years of age.⁴⁰

Although pertussis, pertussis-like, and Mycoplasma infections classically cause cough that is associated with other symptoms, (eg, cough from pertussis infection is usually spasmodic,¹⁷⁵ and cough from Mycoplasma infection may be associated with other symptoms of a respiratory infection such as pharyngitis),¹⁷⁶ these infections can also cause persistent cough without other symptoms,¹⁷⁷ especially in the presence of process modifiers such as antibiotics and vaccination.¹⁷⁵ Pertussis should be suspected, especially if the child has had known contact with someone with a pertussis infection even if the child is fully immunized, as partial vaccine failure can occur.¹⁷⁸

Medications and Treatment Side Effects
Chronic cough has been reported^179180181 as a side effect of the use of angiotensin-converting enzyme (ACE) inhibitors and of asthma medications immediately after inhalation,¹⁸² and as a complication of chronic vagus nerve stimulation.¹⁸³ In one review,¹⁸¹ chronic cough developed in only 1 of the 51 children (2%) who were treated with ACE inhibitors; yet, another study¹⁸⁰ reported cough in 7 of the 42 children (16.7%). In children, cough associated with ACE inhibitors resolves within days (ie, 3 to 7 days) after withdrawing the medication,¹⁷⁹¹⁸⁰ and may not recur when therapy with the medication is recommenced.¹⁸⁰

Functional Respiratory Disorder (Psychogenic)
The many descriptions of cough with a functional or psychogenic overlay include the following: (1) habit cough, (2) tic cough, and (3) psychogenic cough. The distinctions between these categories may be unclear and possibly may reflect a spectrum of different severity.⁶²¹⁸⁴ This topic is covered in a combined adult and pediatric section devoted to "habit cough and psychogenic cough."

Otogenic Causes: Arnold Ear-Cough Reflex
In approximately 2.3 to 4.2% of people, the auricular branch of the vagus nerve is present and the Arnold ear-cough reflex can be elicited (with bilateral occurrence in 0.3 to 2% of people).^185186187 The reflex can be elicited by palpation of the posteroinferior wall and rarely by palpation of the anteroinferior wall of the external acoustic meatus (ear canal).¹⁸⁵¹⁸⁷ Case reports^188189190 of chronic cough associated with ear canal stimulation from wax impaction, cholesteatoma, and acquired aberrant sensory referral post-cardiac transplant have been reported. In children, the significance of the ear reflex and cough was described as early as 1963,¹⁹¹ although in 2002 it was reported again.¹⁹² In our experience, this is a very rare cause of childhood chronic cough.

Inhalation of Foreign Body
Cough is the most common symptom in some series of foreign material inhalation but not in others.¹⁹³ In one series,¹⁹⁴ cough was present in 70% of patients, while other dominant symptoms included decreased breath sounds (53%) and wheezing (45%). A history of a choking episode was reported in 32% of patients, but when families were questioned in more detail the rate increased to 51%.¹⁹⁴ Presentations are usually acute,¹⁹⁵ but chronic cough can also be the presenting symptom in a previously missed foreign body inhalation.¹⁹⁶ A normal chest radiograph finding does not exclude foreign body inhalation, and a specific medical history should be sought because a missed foreign body can result in long-term pulmonary damage.³⁹

Parental and Physician Expectations
Providing parents with information on the expected length of time until the resolution of ARIs may reduce their anxiety, and the need for medication use and additional consultation.¹⁹⁷ The appreciation of specific concerns and anxieties, and an understanding of why children present are thus important when caring for children with nonspecific cough. It has been argued¹⁹⁸ that quality of life is determined by expectations rather than by experience. Parental and professional expectations as well as the doctor’s perceptions of patients’ expectations influences consulting rates and the prescription of medications.^22199200 The use of cough medications and presentation to doctors were less likely in children with more highly educated mothers.²⁰¹ Mangione-Smith et al²⁰² described that "physicians’ perceptions of parental expectations for antimicrobials was the only significant predictor of prescribing antimicrobials for conditions of presumed viral etiology and hellip." Earlier, Hutton et al²⁸ had showed that "parents who wanted medicine at the initial visit reported more improvement at follow-up, regardless of whether the child received drug, placebo, or no treatment." Physicians should be cognizant that "a parent navigating the Internet for information on the home management of cough in children will no doubt find incorrect advice among the search results."²⁰³

The concerns of parents presenting to general practitioners in the United States for their children’s cough can be extreme and can include the following: fear of the child dying from choking; fear of asthma attack or cot death; and fear of permanent chest damage.²⁰⁴ Other concerns that parents express are disturbed sleep and relief of discomfort.²⁰⁴ Findings from a London specialist respiratory clinic were similar.²⁰⁵ However, the burden of illness on children and their families has not been well-described.

	Treatment of Nonspecific Cough

TOP Abstract Introduction Defining Cough in Children Clinical History, Examination,... Etiologic Associations Evidence-Based Treatment Introduction and Background Literature Review of... Chronic Cough Investigating Children With... Recommendations Treatment of Nonspecific Cough Recommendations Conclusion Summary of Recommendations References

 
A summary of the treatment of nonspecific cough in children, the time to response, and the level of evidence is presented in Table 4. In the interest of space, only salient points will be discussed below, and readers are referred to the relevant studies for further information.

OTC Cough Medications
Systematic reviews have concluded that OTC cough medications have little, if any, benefit in the symptomatic control of acute cough in children,¹²¹⁶ and the American Academy of Pediatrics has advised²⁰⁶ against the use of codeine and dextromethorphan for treating any type of cough. Moreover, the use of OTC cough remedies has been associated with significant morbidity and even with mortality.²⁰⁷ OTC drugs are common unintentional ingestion medications in children < 5 years of age.²⁰⁸ A Cochrane review²⁰⁹ of symptomatic treatment of cough related to pertussis also found no significant benefit for therapy with diphenhydramine. A recent RCT¹³ on two commonly used OTC cough medications and OTC medications containing antihistamine combinations are discussed below under the heading "Antihistamines." A review of these medications is available.¹⁴

Asthma Therapy
A systematic review²¹⁰ has shown that "there is no evidence to support using ß₂-agonists in children with acute cough and no evidence of airflow obstruction." There has been only one study⁷⁴ on the use of inhaled salbutamol in patients with chronic cough that also showed no benefit. There is also no evidence to support the use of anticholinergic agents²¹¹ for the treatment of nonspecific cough in children. Nedocromil and cromoglycate reduce cough associated with asthma²¹²²¹³ and in children born prematurely.²¹⁴ A Cochrane review²¹⁵ has described an absence of data for its use. Old cohort studies have described the benefit of asthma therapy for that era (ie, oral orciprenaline, ^<