PrefaceCough is one of the most common symptoms of respiratory diseases in children. According to the duration of the disease, children’s cough is classified as acute (less than 2 weeks), prolonged (2-4 weeks) and chronic (more than 4 weeks). The definition of chronic cough in children differs from that of adults (adults with a duration of more than 8 weeks are defined as having chronic cough), and the causes are different from those of adults and vary according to age.
Chronic cough can be divided into specific cough, in which cough is accompanied by other symptoms or signs that can suggest a specific cause, i.e. cough is one of these clearly diagnosed disease symptoms, and non-specific cough, in which cough is the main or only manifestation and no significant abnormalities are seen on chest X-ray.
The clinical diagnosis of the cause of chronic cough is a process, and “non-specific” indicates that no disease can be identified to which the cough can be attributed, and this “failure” is likely to be temporary. The differential diagnosis of atopic cough is often made in the context of non-atopic cough, which is inevitably mixed with atypical atopic cough. Therefore, the etiologic diagnosis of chronic cough in children is complex and individually variable, and adult guidelines cannot be fully followed.
In December 2007, the Respiratory Group of the Pediatrics Branch of the Chinese Medical Association and the Editorial Board of the Chinese Journal of Pediatrics developed the Guidelines for the Diagnosis and Treatment of Chronic Cough in Children (Trial) with commentary, which mainly refers to the 2006 American College of Chest Physicians (ACCP) Guidelines for the Evaluation of Chronic Cough in Children – ACCP Evidence-Based Clinical Practice Guidelines”, combined with research data and expert opinions on chronic cough in children in China at that time.
Since then, the editorial board of the Chinese Journal of Pediatrics has organized expert discussions and published five related interpretive monographs to further analyze the 2007 edition of the Guidelines for the Diagnosis and Treatment of Chronic Cough in Children from different perspectives and levels.
In 2008, the “Multicenter Study on the Causes of Chronic Cough in Children in China” (hereinafter referred to as the “Composition Ratio Study”) was funded by the Special Fund for Research on Chronic Respiratory Diseases in Clinical Medicine of the Chinese Medical Association, which involved 19 provinces, autonomous regions and municipalities directly under the Central Government. The study involved 29 hospitals in 19 provinces, autonomous regions and municipalities directly under the Central Government of China, and lasted for nearly 2 years since May 2009.
”The summary report of the Composition Ratio Study and the related review were published in the Chinese Journal of Pediatrics, Vol. 2, 2012, which revealed that the top 3 causes of chronic cough in Chinese children were cough variant asthma, upper airway cough syndrome, and cough after respiratory tract infection. The importance of multiple etiologies, the overlap of etiologies, and the reality of unknown etiologies are clearly presented.
”The new insights and conclusions derived from the Composition Ratio Study, combined with the latest literature in recent years, led us to update and present the Chinese Guidelines for the Diagnosis and Treatment of Chronic Cough in Children (2013 Revision).
This guideline still focuses on non-specific cough.
1. Evidence-based guidelines and recommendation levels
The level of evidence and level of recommendation for this guideline are shown in Table 1.
2. Definition of chronic cough in children
Cough is the main or only clinical manifestation, with a duration of >4 weeks and no significant abnormalities on chest radiographs.
3. Etiology of chronic cough in children
3.1 Age characteristics
The clinical diagnosis of chronic cough in children should take full account of the age factor, which is an important feature that distinguishes children from adults. The common etiologies of chronic cough in children of different ages are shown in Table 2.
3.2 Common causes of chronic cough in children
Table 1 Levels of evidence and recommendation levels for guidelines on the diagnosis and management of chronic cough in children
Table 2 Common causes of chronic cough in children of different ages
Cough variant asthma (CVA): CVA is the most common cause of chronic cough in our children, especially in preschool and school-age children [Liang].
Clinical features and diagnostic clues of CVA.
Persistent cough >4 weeks, usually dry, often with nocturnal and/or early morning onset, aggravated by exercise, exposure to cold air, no clinical signs of infection or ineffective after longer antimicrobial therapy ;
Diagnostic treatment with bronchodilators significantly relieves cough symptoms;
Normal pulmonary ventilation and bronchial excitation tests suggesting airway hyperresponsiveness;
History of allergic disease, as well as a positive family history of allergic disease. A positive allergen test may aid in the diagnosis;
Chronic cough caused by other diseases, among others.
Upper airway cough syndrome (UACS).
UACS is the second leading cause of chronic cough in children, especially in preschool and school-age children [Good]. Various rhinitis, sinusitis, chronic pharyngitis, hypertrophy of the palatine tonsils and/or proliferators, nasal polyps, and other upper airway diseases may cause chronic cough. until 2006, the diagnostic name for UACS was postnasal drainage syndrome (PNDs).
Clinical features and diagnostic clues of UACS.
Persistent cough >4 weeks with white foamy sputum (allergic rhinitis) or yellow-green pus sputum (sinusitis), the cough is worse in the morning or with change of position, accompanied by nasal congestion, runny nose, dry throat with foreign body sensation and repeated clearing of the throat;
The follicles in the posterior pharyngeal wall are obviously hyperplastic, sometimes with cobblestone changes, or with mucus-like or purulent secretions;
Antihistamines, leukotriene antagonists and nasal glucocorticoids are effective in chronic cough caused by allergic rhinitis; chronic cough caused by purulent sinusitis requires antibacterial medication for 2-4 weeks;
Nasopharyngoscopy or lateral head and neck radiographs, sinus radiographs or CT films may be helpful in diagnosis.
Post (respiratory) infection cough (PIC): PIC is a common cause of chronic cough in young children and preschoolers and has the highest diagnostic revision rate among the causes of chronic cough in children [Tertullian].
Clinical features and diagnostic clues of PIC.
Recent history of definite respiratory tract infection ;
Cough lasting >4 weeks with an irritating dry cough or with a little white mucous sputum ;
Chest radiography without abnormalities or showing only increased texture in both lungs;
Normal pulmonary ventilation or transient airway hyperresponsiveness;
The cough is usually self-limiting, but if the cough lasts longer than 8 weeks, other diagnoses should be considered;
Chronic cough caused by other than other causes.
Gastroesophageal reflux cough (GERC).
GERC has been reported to account for 4.7% of chronic cough in children. “The composition ratio study reported GERC in only 0.62% of cases, but in 30.77% of cases where 24-hour lower esophageal pH monitoring was completed. 24-hour lower esophageal pH monitoring is the gold standard for diagnosing GERC, but it is difficult to perform and/or parents do not agree to perform this invasive procedure. This may underestimate the incidence of GERC in our country, and it is not possible to conclude that GERC is rare in our country without this monitoring [expert opinion]. It is important to note that prolonged coughing may also lead to GERC in children.
Clinical features and diagnostic clues of GERC in children.
The best onset of paroxysmal cough is at night;
The cough may also worsen after eating;
Positive 24-hour lower esophageal pH monitoring;
Chronic cough from other causes.
Psychogenic cough (psychogenic cough).
The ACPP recommends that psychogenic cough in children should be diagnosed only when multiple tics are excluded and the cough improves with behavioral interventions or psychotherapy, and is commonly seen in school-age and adolescent children [Tertullian].
Clinical features and diagnostic clues of psychogenic cough.
It is more common in older children ;
A predominantly daytime cough that disappears when focused on an event or at rest at night, which can be a high-pitched cough like a goose’s call;
It is often accompanied by anxiety symptoms, but not by organic disease;
Chronic cough caused by other causes, among others.
Chronic cough from other causes.
Non-asthma eosinophilic bronchitis (NAEB): first reported by Gibson in 1989, NAEB accounts for 13.5% of the causes of chronic cough in adults, and only 0.57% of NAEB was reported in the Composition Ratio Study. The low composition ratio also needs to be considered, perhaps related to the fact that sputum induction techniques and eosinophil counts are not yet widespread in domestic pediatrics [expert opinion].
Clinical features and diagnostic clues of NAEB.
Irritant cough lasting >4 weeks ;
Normal chest radiographs ;
Normal pulmonary ventilation and no airway hyperresponsiveness ;
Relative percentage of eosinophils in sputum > 3%;
Bronchodilator therapy is ineffective and oral or inhaled glucocorticoid therapy is effective;
Chronic cough of other causes.
Allergic (allergic) cough (AC): Some children with chronic cough have an atopic constitution and are effectively treated with antihistamines and glucocorticoids, but they do not have bronchial asthma, CVA or NAEB, etc. This type of cough is referred to as allergic (allergic) cough in the literature [expert opinion].
AC clinical features and diagnostic clues.
Cough lasting >4 weeks with an irritating dry cough;
Normal pulmonary ventilation and negative bronchial excitation test;
Increased sensitivity of cough receptors;
History of other allergic diseases, positive allergen skin test, elevated serum total IgE and/or specific IgE;
Chronic cough from other causes, among others.
Drug-induced cough: Although uncommon in children, it should still be a cause for alarm. Drugs such as angiotensin-converting enzyme inhibitors and β-adrenergic receptor blockers such as Tretinoin can induce a chronic cough, which usually presents as a persistent dry cough, aggravated at night or when lying down, and which is significantly reduced or even disappears 3-7 d after stopping the drug.
Otogenic cough: 2%-4% of the population has the vagus nerve branch (amold nerve), and when lesions occur in the middle ear, stimulation of the vagus nerve can cause a chronic cough. Otogenic cough is a rare cause of chronic cough in children.
Chronic cough of multiple etiologies.
It is important to note the complexity and variability of the causes of chronic cough in children, some of which overlap with each other [Tertullian]. “The Composition Ratio Study reported that children with chronic cough of multiple etiologies accounted for 8.54% of the total eligible cases, especially UACS combined with CVA, which accounted for 50.13% of the multiple etiologies, followed by PIC combined with UACS (26.10%).
3.3 Specific cough etiologies requiring differential diagnosis
Congenital respiratory disorders.
It is mainly seen in infants and children, especially up to 1 year of age. These include congenital esophagotracheal fistula, congenital vascular malformation compressing the airway and larynx, tracheobronchial softening and/or stenosis, broncho-pulmonary cysts, primary ciliary dyskinesia, and embryogenic mediastinal tumors. Once it is clear that these disorders cause a chronic cough, it is classified as an atopic cough.
Foreign body aspiration.
Cough is the most common symptom of foreign body aspiration in the airways and should be classified as atopic cough once the diagnosis is clear. Foreign body aspiration is an important cause of chronic cough in children, especially in children 1-3 years of age. Studies have found that 70% of patients with airway foreign body aspiration present with cough and other symptoms such as decreased breath sounds and wheezing, and may have a history of asphyxia. Once the foreign body enters below the small bronchi, there can be no cough, which is also known as entering the “silent zone”.
Respiratory tract infections caused by specific pathogens.
Respiratory infections caused by a variety of pathogenic microorganisms such as Mycobacterium pertussis, Mycobacterium tuberculosis, viruses, Mycoplasma pneumoniae and Chlamydia can also cause chronic cough in children, and once a clear diagnosis is made, it is classified as an atopic cough. In our country, pertussis is a severely underestimated pediatric acute respiratory infection, especially in infants under 3 months of age who have not yet received the DPT vaccine and in those for whom the level of antibodies produced by the DPT vaccine is no longer sufficient for effective protection (school-age children) [expert opinion].
Protracted bacterial bronchitis (PBB).
PBB is one of the causes of atopic chronic cough in infants and preschool children and needs to be of concern to pediatric clinicians [Liang]. It has been referred to as purulent bronchitis, migratory bronchitis, and pre-bronchodilatation, among others, and refers to a persistent infection of the bronchial lining caused by bacteria. PBB is caused by Haemophilus influenzae (especially Haemophilus influenzae untyped) and Streptococcus pneumoniae, but rarely by gram-negative bacilli. the occurrence of PBB is closely related to the formation of bacterial biofilm in the airway and the mucociliary clearance dysfunction of the airway, systemic immune deficiency and airway malformation (e.g. airway flaccidity).
PBB clinical features and diagnostic clues.
Wet (sputum-bearing) cough lasting >4 weeks;
Bronchial wall thickening and suspected bronchiectasis are seen on high-resolution CT films of the chest, but there is rarely hyperinflation of the lungs, which is distinct from asthma and fine bronchiectasis;
Antibacterial medication for more than 2 weeks may significantly improve the cough;
Elevated neutrophils and/or positive bacterial cultures on bronchoalveolar lavage fluid examination;
Chronic cough caused by other causes.
4. Diagnostic and differential diagnostic procedures for chronic cough in children
4.1 Diagnostic methods
History questioning.
Detailed history includes the child’s age, duration of cough, nature of cough (e.g., barking, goose, intermittent or paroxysmal, dry or sputum cough, cough at night or aggravated by exercise, etc.), presence of snoring, history of foreign body or suspected foreign body inhalation, history of drug use, especially prolonged use of angiotensin-converting enzyme inhibitors, previous history of wheezing, presence of allergic diseases or positive allergic diseases Family history, etc. Pay attention to the environmental factors to which the child is exposed (such as passive smoking, environmental pollution, atmospheric pollution, etc.).
Physical examination.
Pay attention to the assessment of the child’s growth and development, respiratory rate, the presence of thoracic deformities, the presence of hypertrophy/enlargement of the palatine tonsils and/or proliferators, the presence of follicular hyperplasia in the posterior pharyngeal wall, the presence of adherent secretions, the presence of cyanosis, pestle finger, etc. Pay particular attention to the examination of the lungs and heart.
Ancillary examinations.
Imaging: Children with chronic cough should routinely undergo chest X-ray examinations and decide on the next diagnostic treatment or examination based on the presence or absence of abnormalities on the chest X-ray. If the diagnosis is still not clear on chest X-ray or if the condition is complicated, a chest CT examination can be performed to clarify the diagnosis. In children with suspected hypertrophy/enlargement of the proliferators, lateral head and neck radiographs can be taken to understand the enlargement of the proliferators. If the CT film of the sinuses shows a mucosal thickening of 4
mm or more, or air-fluid planes in the sinus cavity, or blurred opacities, are characteristic changes of sinusitis. Considering the possible damage of radiation to children, CT of the sinuses should not be included as a routine examination, and the interpretation of its results, especially in children under 1 year of age, should be done with caution, because the sinuses of children are not yet well developed (maxillary and septal sinuses are present at birth but small, frontal and pterygoid sinuses appear only at 5-6 years of age), and the bone structure is not clear, so imaging alone can easily cause “sinusitis The diagnosis of “sinusitis” is too much.
Pulmonary function: Pulmonary ventilation function tests should be routinely performed in children over 5 years of age, and further bronchodilatation tests or bronchial excitation tests can be performed based on the first second forceful expiratory volume to aid in the diagnosis and differential diagnosis of CVA, NAEB and AC.
Nasopharyngolaryngoscopy: For children with suspected rhinitis, sinusitis, nasal polyps, and hypertrophy/enlargement of proliferators, nasopharyngolaryngoscopy can be done to clarify the diagnosis.
Bronchoscopy: Bronchoscopy and lavage can be done for chronic cough caused by suspected airway developmental malformations, airway foreign bodies (including airway endogenous foreign bodies and sputum plugs), etc.
Induced sputum or bronchoalveolar lavage fluid cytology and pathogenic microorganism isolation and culture can clarify or suggest respiratory tract infection etiology, and the diagnosis of NAEB can also be clarified based on eosinophil percentage.
Total serum IgE, specific IgE and skin prick test: they are useful for suspicion of chronic cough associated with allergy and for understanding whether the child has atopic constitution.
24-hour lower esophageal pH monitoring: the gold standard for confirming the diagnosis of GERC. This test should be performed in children with suspected GERC.
Exhaled breath NO (eNO) measurement: Elevated eNO is associated with eosinophil-associated airway inflammation. Measurement of eNO can be used as a non-invasive test to assist in the diagnosis of CVA and EB.
Cough receptor sensitivity testing: This test is feasible when AC is suspected, and experience with this technique in childhood is still needed.
4.2 Diagnostic and differential diagnostic process
It is important to recognize that chronic cough is only a symptom and to identify the cause of chronic cough as clearly as possible. The diagnostic procedure should range from simple to complex and from common to rare diseases. Attention should be paid to age as a hint to the possible etiology of chronic cough in children, and to the time phase of each etiology causing cough within 24
The chronological phase of the onset of cough within 24 h should be noted. Diagnostic treatment contributes to the diagnosis of chronic cough in children and is based on the principles of CVA, UACS and PIC in the order of CVA, UACS and PIC in the absence of clear etiologic hints.
See the flow chart (Figure 1) for specific diagnostic steps and ideas.
5. Treatment of chronic cough in children
The principle of management of chronic cough in children is to define the etiology and treat it for the cause [E/A]. If the cause is unknown, empirical symptomatic treatment can be administered; if the cough does not resolve after treatment, it should be re-evaluated. Both the ACCP view and the results of the Composition Ratio Study suggest that the expectations of parents should be taken into account during the diagnosis and treatment of chronic cough [E/B], emphasizing the importance of post-treatment follow-up and re-evaluation The importance of post-treatment follow-up and re-evaluation is emphasized, i.e., watch, wait and review. In children with chronic cough, attention should be paid to removing or avoiding exposure to allergens, smoke, and other environmental triggers and aggravators of cough [B].
The principles of treatment for common causes of chronic cough in children are as follows.
5.1 CVA treatment
Oral β2 agonists (e.g., procaterol, terbutaline, salbutamol, etc.) may be administered for 1-2 weeks as diagnostic therapy, and transdermal absorbable β2 agonists (tolterol) have also been used, with relief of cough symptoms contributing to the diagnosis. Once the diagnosis of CVA is clear, long-term standardized treatment of asthma is followed, with the choice of inhaled glucocorticoids or oral leukotriene receptor antagonists or a combination of both for at least 8 weeks [B].
5.2 UACS treatment
Depending on the different diseases of the upper airway that cause chronic cough in children, different treatment regimens are used.
Allergic (allergic) rhinitis: treatment with antihistamines, nasal spray glucocorticoids, or a combination of nasal mucosal decongestants and leukotriene receptor antagonists [B].
Sinusitis: treat with antibacterial drugs, either amoxicillin or amoxicillin + potassium clavulanate or azithromycin orally for at least 2 weeks, supplemented by nasal irrigation, topical nasal decongestants [E/B] or expectorant drugs [C].
Proliferative hypertrophy: depending on the degree of proliferative hypertrophy, mild-moderate cases can be treated with nasal spray of glucocorticoids combined with leukotriene receptor antagonists for 1-3 months and watchful waiting, and surgical treatment can be taken if ineffective [C].
5.3 PIC treatment
PIC is usually self-limiting, and treatment with oral leukotriene receptor antagonists or inhaled glucocorticoids may be considered for those with severe symptoms [C].
5.4 GERC treatment
The H2 receptor antagonist cimetidine and the gastroprokinetic agent domperidone are advocated [E/B], and proton pump inhibitors may also be used in older children [E/B]. Changing the position to semi-recumbent or prone with a 30-degree forward tilt, changing the nature of food, and eating small and frequent meals are effective for GERC [E/B].
5.5 NAEB treatment
Bronchodilator treatment is ineffective and inhaled or oral glucocorticoid treatment is effective [B].
5.6 AC treatment
Treatment with antihistamines and glucocorticoids is advocated [B].
5.7 Drug-induced cough
The best treatment is to discontinue the drug for observation [A].
5.8 Psychogenic cough
Psychotherapy may be given [E/B].
5.9 PBB treatment
Antimicrobial drugs are given, preferably 7:1 amoxicillin-clavulanic acid preparations or oral cephalosporins or azithromycin of 2nd generation or higher, usually requiring a course of 2-4 weeks [B].