Acute Bronchitis in Childhood

Abstract

There will be a discussion of the manifestation of acute bronchitis in children and note differences with that seen in the adult population. In particular, the need for identifying the specific cause of coughing such as inhalation of a foreign body or diagnosing the newly recognized protracted bacterial bronchitis (PBB) in children is emphasized. Understanding the differing pathophysiology of afferent hypersensitivity and inflammatory infiltrates in the bronchial epithelium enables for different therapeutic approaches. Therefore, the chapter concludes with a discussion on the role for anti-inflammatory and antimicrobial therapies in children, as well as possible intervention to the neuronal hypersensitivity. Anti-tussive and mucolytic modes of treatment are also reviewed.

1. Introduction

The inflammatory response in the lung protects the person from microorganisms or particles which may reach the airway surface. It augments other host defense mechanisms such as mucociliary clearance, defensins, and immunoglobulins. If the response is inadequate to eradicate offending substances, the subsequent inflammatory process can damage lung tissue in addition to any direct toxic or deleterious effects by the infectious organisms or particles. Also, if the immune response is excessive or poorly-regulated, the subsequent inflammation can be destructive to lung tissue and contribute to chronic lung disease.

Technically, the term “bronchitis” indicates inflammation of the bronchial tubes. However, functionally, the presence of coughing can indicate bronchial inflammation and therefore most reviews of acute and chronic bronchitis are actually discussions of acute and chronic coughing. Coughing is the body’s effort to clear the airways of mucus or any foreign substances which may be present in bronchial tubes. As such, it augments the body’s mucociliary clearance mechanism. As a symptom, coughing is one of the most frequent reasons for seeking medical attention and intervention in children worldwide. Therefore there are socioeconomic implications and consequences for the patient and patient’s family as well as the health care system and society in general. However, this paper will examine the practitioner’s approach in evaluating and managing these patients with attention to the various pathogenic mechanisms which may be involved.

Although it is uniformly accepted that chronic cough in adults is defined as coughing lasting greater than 8 weeks, there is some ambiguity for children. The American College of Chest Physicians (ACCP) through its CHEST Expert Cough Panel and the European Respiratory Society (ERS) both defined chronic cough in children as coughing greater than 4 weeks in duration [1, 2]. Acute coughing is further defined to last less than 2 weeks and subacute cough 2–4 weeks. In contrast, the British Thoracic Society (BTS) defined acute cough in children as lasting for less than 3 weeks, subacute coughing lasting 3–8 weeks and chronic coughing persisting greater than 8 weeks [3]. These time periods have also been adopted by two Asian groups, the Japanese Respiratory and Chinese Thoracic Societies but there is no distinction between adults and children [4, 5]. Western guidelines emphasized the need to separate the two age groups [1, 2]. A recent systematic review and meta-analysis of chronic cough in China utilized the 4 week duration as the cut-off [6]. The ACCP guidelines state that for patients greater than 14 years of age the approach to evaluation and management is similar to their guidelines for the adult [7].

This chapter will discuss acute bronchitis in children since chronic bronchitis is a topic presented elsewhere. Since there is some ambiguity as to its duration, coughing between 2 and 8 weeks (subacute bronchitis) will also be mentioned.

2. Children are not little adults

Although anatomic differences are minimal between adults and those greater than 14 years old, there are important differences in infants and especially in neonates and need to be considered. Anatomic differences in airway morphology such as total surface area dimension to weight between neonates and adults result in a much higher vulnerability or susceptibility of the child’s airway surfaces to noxious or toxic insults, such as air pollution [8]. Children have a higher respiratory rate than adults and therefore inhale more air relative to their size than do adults. Additionally, they tend to spend more time outdoors, playing and being active. Therefore, they are exposed more often and to a greater degree to polluted outdoor air than adults. There is an association between particulate air pollution with acute bronchitis in children and rates of bronchitis decrease in areas in which the particulate concentration has declined [9]. This correlation has been further supported by a recent review of 34 studies, 16 of which were subjected to meta-analysis [10]. Another investigation indicated a possible role of low ambient temperature interacting with the PM_2.5 concentration and an increased risk for viral acute bronchitis [11]. Studies are in progress to examine the effects of indoor particulate matter in children 3–5 years of age [12]. The increased risk for acute viral bronchitis could be due to the damaged airway epithelium resulting from toxic air.

Additionally, there may be additional detrimental effects of poor air quality on the neonate’s immature immune system. Air pollution can enhance certain T helper subpopulations and dysregulate anti-viral immune responses [13]. It is well-established that exposure to passive smoking in the family home is a major risk factor for lower respiratory tract (LRT) infection (including bronchitis) for children. A meta-analysis of 60 studies confirmed this risk for those aged 2 years and less [14]. The neonate starts with an immature and therefore impaired immune system and then various early life exposures impact its subsequent immune function [15]. In developing countries factors such as malnutrition, preterm delivery, low birth weight, incomplete immunization and poor feeding practices all contribute to the increased risk for development of acute respiratory tract infection in children [16].

Finally, the diameter of the infant’s airways is much smaller than that of the adult’s. According to Poiseuille’s Law, resistance through a cylinder is inversely proportional to its radius to the fourth power (see Figure 1). If there is an increase by 1 mm in the bronchial epithelium due to mucus production, edema or swelling from inflammation (whether by viral infection or toxic air inhalation), the airway resistance in an adult airway may increase by three-fold compared with a 16-fold increase in an infant. Therefore, infants and young children will experience much more respiratory difficulty than older children or adults and are more prone to fatigue and subsequent respiratory failure from the increased work in breathing through a narrower airway. Additionally, the 75-fold decrease in cross-sectional area is more pronounced in an infant than in adult (a 44-fold decrease) resulting in an increased propensity to mucus plugs and airway obstruction.

Figure 1.

The effect of airway narrowing in adult and neonate ariways.

3. Acute bronchitis: etiology

The distinction between infections of the upper respiratory tract (URT) and lower respiratory tracts (LRT) such as bronchitis, bronchiolitis, and pneumonia can be difficult. “Acute bronchitis is a clinical diagnosis characterized by cough due to acute inflammation of the trachea and large airways without evidence of pneumonia. Pneumonia should be suspected in patients with tachypnea, tachycardia, dyspnea, or lung findings suggestive of pneumonia” [17]. In one review of 14 studies conducting in primary care settings, acute cough was mainly caused by URT infections (62%) followed by bronchitis (33%) [18]. Cough associated with acute respiratory tract infections in the ambulatory setting appears to resolve in 50% of children by 10 days and in 90% by 25 days in pooled results from five studies conducted in Western countries [19].

3.1 Viruses

Acute episodes of coughing are usually caused by respiratory viral infections with most commonly identified being rhinovirus, enterovirus, influenza A and B, parainfluenza, coronavirus, human metapneumovirus, and respiratory syncytial virus. Bacteria are detected in 1–10% of cases of acute bronchitis [17]. In contrast it should be noted that the etiology in developing countries is predominantly bacterial [16]. Although respiratory viruses can be the most common cause of acute bronchitis the precise organism is not usually identified because viral cultures and serologic testing are not routinely performed for acute bronchitis in children. However, the recent identification of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) has resulted in its rapid detection by home detection kits and confirmation by polymerase chain reaction (PCR)-based laboratory tests. The clinical presentation of COVID-19 can range from asymptomatic, to mild upper respiratory symptoms, acute bronchitis, severe pneumonia and death after multi-organ failure. The most common symptoms of COVID-19 infection in children are cough and fever [20]. Loss of taste or smell are noteworthy and somewhat specific. Other signs and symptoms include cough that becomes productive, chest pain, changes in the skin (such as discoloration areas on the feet or hands, sore throat, nausea with vomiting, abdominal pain or diarrhea; chills, muscle aches and pain, extreme fatigue, new severe headache, and new nasal congestions.

These infections are usually self-limiting and symptoms such as coughing are resolved after a couple weeks. It can be difficult to distinguish between acute viral bronchitis and the common cold or URT infection. “Besides cough, other signs and symptoms of acute bronchitis include sputum production, dyspnea, nasal congestion, headache, and fever…Patients may have substernal or chest wall pain when coughing. Fever is not a typical finding after the first few days…Production of sputum, even purulent, is common and does not correlate with bacterial infection” [17].

3.2 Bacterial and other non-viral infectious causes

Rare bacterial causes such as Bordetella pertussis, Mycoplasma pneumonia and Chlamydophila pneumonia are important to recognize since specific antibiotics are available and need to be started early to prevent or limit community spread. The presence of posttussive vomiting was found to be moderately sensitive (60%) and specific (66%) in diagnosing pertussis in children. In contrast, for adults both paroxysmal cough and absence of fever had high sensitivity (93.2% and 81.8%, respectively) but low specificity (20.6% and 18.8%). On the other hand, inspiratory whooping and posttussive emesis had low sensitivity (32.5% and 29.8%) but high specificity (77.7% and 79.5%) [21]. The presence of pertussis in over one-third of patients who are still coughing between 2 and 4 weeks [18] is noteworthy in view of evidence that treatment with appropriate antibiotics can limit the spread if given early. Indeed, the BTS guidelines state: “Much coughing in children lasting >3 weeks is related to transient viral or pertussis-like infections” [3]. Surveys of pertussis have emphasized the increased risk of pertussis in adolescents and adults (especially those aged greater than 50 years) in Europe and Asia [22] and in children in Africa [23] (despite high vaccination rates in some areas).

Infection with Mycoplasma pneumoniae and Chlamydophila pneumoniae are common in children aged 5 years or older [24]. In a review of 7 publications on Mycoplasma pneumonia in children, 91.4% had coughing and 94.2% with fever, but only 23.1% with dyspnea or difficulty breathing and 25.0% were wheezing [25]. The authors concluded their finding is “consistent with other studies that demonstrated no clinical or radiological features to identify Mycoplasma pneumonia.”

3.3 Foreign body

The possibility of an inhaled foreign body should always be considered in pediatrics, especially in children less than 3 years of age. Increased tendency for aspiration has been attributed to the child using their mouth to explore their world. They also have immature neuromuscular mechanisms to protect their airway as well as incoordination in swallowing. Additionally, there may be premature efforts by parents or other caretakers to start inappropriate solids or offering high-risk foods (such as peanuts) or having un-supervised mealtimes. Many times the aspiration may not be noticed and a detailed history will not reveal this possibility. A systematic review and meta-analysis of 7 studies specified 6 predictive variables: air trapping, unilateral reduced air entry, witnessed choking, wheezing and suspicious radiographic findings [26]. In a recent single-center study of 726 pediatric patients with confirmed foreign body aspiration coughing was present in 83.9% [27]. Another review of 15 studies (totaling 5606 patients) found no single finding had both positive and negative predictive values over 50%. The “classic triad” (history of an acute event of choking or coughing, wheezing, and unilateral decreased breath sounds) did have 90% specificity but only 35% sensitivity [28]. Obviously, removal of the foreign body will relieve the symptoms and prevent future damage. In some communities flexible bronchoscopy is readily available and should be performed. A review of 23 papers comprising 2588 cases indicated successful removal of the foreign body in 87.1% of cases [29]. When the presence of a foreign body is still uncertain, rigid bronchoscopy or computerized tomography (CT) are other options [30]. Both require general anesthesia and personnel experienced in detection and management of foreign body in young children.

3.4 Environmental factors

Exposure to irritants, odors, allergens, and extreme weather conditions such as cold and/or dry air can also cause acute cough. Not only can poor air quality result in an increased risk for microbial infections, but irritants (both indoors and outdoors) and cigarette smoke can directly affect the airway mucosal surfaces. A review of 7 studies also found adolescent use of e-cigarettes was associated with increased coughing [31]. Peripheral nerve fibers may be activated and mucus glands stimulated to produce mucus. These situations are speculated to result in “neurogenic inflammation of the cough reflex, which becomes hypersensitive,” [32] as well as bronchial inflammation with subsequent obstructed airways and stimulation of cough to expectorate the mucus containing the toxic substances and/or allergens. Some make the distinction between “specific acute coughing” which is a response to specific substances and “non-specific.” It is the latter which may eventually result in the diagnosis of bronchial asthma.

Childhood asthma can be particularly challenging to detect due to the young age and multiplicity of disease phenotypes. It can present as acute bronchitis or bronchiolitis and resolve as asthma symptoms are usually intermittent. The disease phenotypes are not fixed and may evolve as the child ages until one sees the typical asthma triad of “wheeze, shortness of breath and cough” [33]. Furthermore, their young age makes it difficult to conduct diagnostic tests such as measuring pulmonary function although there have been attempts at obtaining meaningful measurements easily and noninvasively. Other attempts to determine the role of various environmental allergens through in vitro or in vivo testing are not done at the initial presentation due to their need for subspecialty involvement and relatively invasiveness.

In summary, about 90% of cases of acute bronchitis will resolve without any acute intervention after 2 weeks since the main etiology are various respiratory viral infections. However, there may be familial factors such as a family history of asthma or other chronic lung disorders such as cystic fibrosis or bronhiectasis which indicate the need for closer evaluation for other underlying disease processes. Early detection is important since the acute episode may be the first indicating a chronic process. (See discussion on chronic bronchitis in children.) The presence of certain systemic and/or respiratory findings such as failure to thrive or clubbing may result in further evaluation such as chest roentgenogram and/or pulmonary function testing at earlier time periods [2, 3, 34]. These are referred to as “specific cough pointers” and listed in Table 1. Any previous episode of choking should prompt consideration for an inhaled foreign body and appropriate referral to a specialist. Finally, one needs to evaluate for any exposure to various environmental factors.

ISPAI [34]	ACCP [1]	ERS [2]
Systemic Redflags
Neonatal onset of cough
Digital clubbing	Digital clubbing	Digital clubbing
Failure to thrive	Growth failure	Failure to thrive
Use of medications/drugs
Palatal abnormalities
	Feeding difficulties	Feeding difficulties
	Neurodevelopmental abnormality	Neurodevelopmental abnormality
Fever
	Facial pain/purulent nasal discharge	Recurrent sinopulmonary infections
Pallor
Sweating
Dehydration
Findings suggestive of immunodeficiency		Immunodeficiency
	Recurrent pneumonia
	Recurrent infections
		Tuberculosis risk
Pulmonary Redflags
Chest pain	Chest pain	Chest pain
Daily moist or wet cough	Daily wet/productive cough
Hemoptysis	Hemoptysis	Haemoptysis
Abnormal cough characteristics
Tachycardia
	Cardiac abnormalities	Cardiac abnormalities
Hypoxia/cyanosis	Hypoxia/cyanosis
	Choked	History suggestive of inhaled foreign body
History of previous lung disease or predisposing causes	Previous history of chronic lung or esophageal disease
Dyspnea/tachypnea/respiratory distress	Dyspnea or tachypnea	Dyspnea
		Respiratory distress
	Exertional dyspnea	Exertional dyspnaea
Chest shape and chest wall deformities	Chest wall deformity	Chest wall deformity
	Hoarse voice/stridor
Adventitious lung sounds	Auscultatory findings abnormal	Auscultatory crackles
	Wheeze-monophonic
	Wheeze-polyphonic

Table 1.

The use of specific cough pointers by three professional organizations*suggesting further evaluation may be needed in children with acute bronchitis.

^*

ISPAC = Italian Society of Pediatric Allergy and Immunology [34]; ACCP = American College of Chest Physicians [1]; and ERS = European Respiratory Society [2].

4. Subacute bronchitis

When coughing continues longer than 2 weeks (but less than 8 weeks), it can be labeled as subacute bronchitis. A review of 14 studies conducted mainly in Western countries noted that subacute cough (that is, coughing persisting more than 3 weeks) is caused by recurrent respiratory tract infection (27.7%), asthma (50.4%) and pertussis (37.2%) [18]. The continued presence of viral respiratory infection is consistent with the observation that 10% of children will continue to cough after 25 days [18].

However several mechanisms for a prolonged post-infectious coughing have been postulated: (1) a continued inflammatory process as a result of the immune function to control the infection and (2) irritation caused by drainage of mucus in the nasopharynx or post-nasal drip (PND) [35]. The former can be seen as a similar process in which the inflammatory cells release mediators in response to inhaled allergens in allergic asthma. These mediators can effect nerve fibers, smooth muscles along bronchial airways, endothelial cells lining blood vessels, and/or goblet cells in airway mucus glands. A state of airway hyperreactivity (AHR) may the result of the inflammation, which can become chronic if there is continued exposure to the offending substance.

The BTS had designated the term of “postviral cough” as that cough originally starting with a viral infection of the URT but lasting greater than 3 weeks. “Recurrent cough” represent repeated episodes (at least two times per year) not associated with URT viral infection each one lasting greater than 7–14 days. If there is a clear precipitating trigger (such as exposure to fumes or cigarette smoke) then that cough is a “specific cough.” This is to distinguish from “non-specific isolated cough,” which typically is described as a persistent dry cough without any other respiratory symptom, no signs of chronic lung disease and a normal chest radiograph [3]. Some in this group may likely represent those with AHR; while others have asthma or cough-variant asthma.

An Australian study described children with a history of wet cough of greater than 3 weeks duration with a significant amount of neutrophils and pathogenic bacteria in their bronchoalveolar fluid (BAL) responding to a two-week treatment with antibiotics (amoxicillin-clavulanate acid) [36]. This condition which they termed protracted bacterial bronchitis (PBB) was redefined by the ERS to exclude the need to obtain BAL by three clinical criteria: “(1) presence of continuous chronic (>4 weeks’ duration) wet or productive cough; (2) absence of symptoms or signs (i.e., specific cough pointers) suggestive of other causes of wet or productive cough; and (3) cough resolved following a 2–4 week course of an appropriate oral antibiotic” [2] This definition has been adopted by the ACCP but with a qualifier that children with clinical PBB who also have BAL (or sputum) confirmation of pathogenic bacteria be termed “microbiologically based-PBB (PBB-micro) [1]. The initial description suggested that patients with cough continuing beyond 2 weeks can be further divided into those with a “wet” (69%) or “dry” sounding quality of their cough. Those with the former tend to indicate a specific etiology, the most common which is bacterial infection or PBB (45%) [37]. Other pathogens also included M. pneumoniae, B. pertussis, and tuberculosis. These findings have been confirmed by numerous investigators with a prevalence varying from 11% to 41% of pulmonary referrals [38]. The most common bacteria include Haemophilus influenzae (47–81%) followed by Streptococcus pneumoniae, and less commonly Moraxella catarrhalis [39]. It appears the presence of H. influenzae increases the risk for the development of bronchiectasis [40] as well as recurrent PBB (defined as greater than 3 episodes per year) [31]. PBB and bronchiectasis share many features with chronic suppurative lung disease and some have speculated that these three represent a spectrum of severity with a common underlying pathology with bacterial infection interacting with neutrophilic mediated airway inflammation [41].

5. Management

Although viral respiratory infections account for a majority of acute bronchitis cases, it is important to obtain a detailed clinical history to evaluate the role of various environmental factors such as exposure to tobacco smoke or other irritants (both indoor such as perfumes or wood stove burning and outdoors such as air pollution), allergens from pets, trees, grasses, or weeds, dust, or molds. It is therefore important to evaluate and eliminate these environmental exacerbating factors as much as possible. Also an episode of choking could suggest an inhaled or aspirated foreign body.

Much of the coughing from respiratory viral infections is resolved by 2–3 weeks. There should be some improvement in the second week. Coughing which is relentless and progressive with increased severity (either frequency or severity or both) should prompt further evaluation after 2 weeks. Evaluation for pertussis should be considered sooner when clinical history is suggestive. Specifically, post-tussive vomiting is indicative of pertussis in children. In adolescents and adults the presence of whooping or post-tussive vomiting should rule in a possible diagnosis of pertussis and absence of paroxysmal cough or presence of fever should rule it out. Detection by PCR appears to be the most useful. Appropriate antibiotics (that is, macrolide) are given for prophylaxis of household contacts or those exposed who are at high risk of severe illness (such as infants, immunocompromised individuals) but they do not shorten the duration of coughing or hospitalization rate [42]. Azithromycin and clarithromycin appear to be equally effective but the former may have less side effects and is given once a day for 5 days. If given very early (in the first 1–2 weeks) it the disease, it can slightly alter the clinical course but their main role is to reduce the period of infectivity. However since the early stages of pertussis can be difficult to distinguish from a simple head cold, this recommendation is difficult to carry out in practice other than in the situation when coughing starts after a known exposure” [3]. A Cochrane review did not indicate any effective treatment for pertussis cough [43] and the duration can be quite prolonged. The median duration in unimmunized children less than 6 years was 52 to 61 days 29 to 39 days for those who received the pertussis vaccine [44].

As mentioned earlier, the possibility of infection with other atypical bacteria such as Mycoplasma pneumonia and Chlamydia should also be considered with prolonged coughing. Screening for tuberculosis should be done in high risk patient populations as well as in areas where TB is prevalent. Establishing the presence of Mycoplasma or Chlamydia is more difficult since serological tests alone do not distinguish Mycoplasma infection from carriage [45]. It appears that detection by PCR can be useful [46]. Antibiotic treatment for these two organisms is controversial. A Cochrane review of 7 studies involving 1912 children concluded there was insufficient evidence to make any specific recommendations due to lack of high quality (double blinded, placebo controlled) studies although one controlled study indicated 100% of children treated with azithromycin had clinical resolution compared to 77% untreated children after 1 month of follow-up [47].

It is always difficult to decide whether the episode of acute bronchitis represent the first attack of bronchial asthma. Pulmonary function testing can be performed to detect those children with asthma. Spirometry is often available and can be reliably used in children aged greater than 6 years and in some younger if trained pediatric personnel are conducting the tests [1]. However, ACCP does note that neither spirometry nor CXR are sensitive (i.e., normal results do not imply absence of disease) but they are specific (i.e., abnormal results do indicate presence of some respiratory illness). However, a systematic review of the use of spirometry did not find any randomized controlled trials demonstrating its use in improved clinical outcomes in children [48]. Part of the problem is that tests showing AHR are sensitive but not specific for asthma. Children may develop temporary AHR and an asthma-like transient clinical syndrome due to post-infectious processes (such as following infections with respiratory syncytial virus or M pneumonia) and in association with upper respiratory allergies such as allergic rhinitis. There is no relation to the child’s post-infectious AHR and subsequent development of asthma or response to asthma medications (such as inhaled albuterol or salbutamol and inhaled corticosteroids). There is difficulty in making a firm diagnosis of asthma because while “almost all children with asthma have intermittent cough, wheeze and/or exercise-induced symptoms, only about a quarter of children with these symptoms have asthma” as cited by ACCP [1]. Another variable is the type of challenge used to measure AHR with some suggesting exercise-stress testing over methacholine inhalation as being more sensitive for asthma. Therefore, those children who have isolated chronic cough and no wheezing should be followed and monitored closely. A 10-year follow-up suggest up to 45% do develop asthma and AHR (by methacholine challenge) is a strong risk factor [49]. Some have labeled them as “cough-variant asthma” but others believe that this is a misnomer and represent a problem of over-diagnosis of asthma. The ERS does recognize three subgroups of asthmatic cough with classic asthma characterized by airflow variability and AHR and diagnosed with improvement in spirometry variables after bronchodilators. Cough variant asthma have cough as the sole symptom and is improved with bronchodilators. The third form is eosinophilic bronchitis [2].

Unfortunately examination for the presence of eosinophilia in the blood, BAL fluid, sputum or bronchial biopsy (which is helpful in diagnosing adult asthma) is not rewarding in children and is quite invasive or difficult to obtain. Although there is strong evidence that measurement of fractional exhaled nitric oxide (F_eNO) may indicate eosinophilic involvement in the lungs, there have been conflicting results on its utility in evaluating cough in children [2]. Part of the problem are the presence of variability among detection methods and the different and varied patient populations being studied. Therefore, both the ACCP and ERS concluded that there is no good study using F_eNO levels as a reliable diagnostic indicator for asthma and also as predictor for anti-inflammatory response in treatment [1, 2].

5.1 Treatment

Management of acute bronchitis mainly consists of supportive care and possibly treatment of the more bothersome symptoms. Most guidelines stress the “trivial and self-limiting problem” of acute cough but recognize it does result in the child’s discomfort and can cause in loss of sleep for entire family [35]. The problem is a general lack of good studies showing both efficacy and safety of currently available medications, both over-the-counter and prescription. Therefore, there is a “wait-and-see” strategy for acute bronchitis [18], especially if it occurs during the winter-time when there is high prevalence of viral URTI in the community and in otherwise healthy children.

5.2 Medications

A recent systemic review of 34 studies on the use of non-steroidal anti-inflammatory drugs (NSAIDs) in acute viral respiratory tract infections showed these medications were beneficial in relieving fever and sore throat but not cough [50]. Another review by Cochrane of 30 studies (children included in 9) on the use of antihistamine-decongestant-analgesic combinations indicate “no evidence of effectiveness in young children” but “some general benefits in adults and older children” [51].

Two recent randomized controlled pediatric trials with local herbal remedies such as a root extract from Pelargonium sidoides in Africa [52] and Jiuwei Zhuhuang powder consisting of nine herbs in China [53] indicated their use significantly decreased the cough frequency over placebo in the first study or decreased the cough duration by 1 day over an antihistamine (chlorphenamine)-decongestant (cowbenzor)-analgesic (paracetamol) in the second study. These studies represent a growing interest to use natural remedies for acute viral respiratory infections in view of their apparent safety and the current lack of any effective cough relievers [54]. A Cochrane review of honey concluded “honey probably relieves cough symptoms to a greater extent than no treatment, diphenhydramine, and placebo; but may make little or no difference compared to dextromethorphan. Honey probably reduces cough duration better than placebo and salbutamol. There was no strong evidence for or against using honey” [55].

Although dextromethorphan (which is a non-opioid synthetic derivative of morphine) has been shown in three placebo-controlled trials to decrease cough frequency when compared with placebo [56] there are potential side-effects and safety concerns regarding its use in pediatrics. At higher doses there are psychoactive effects and therefore a potential for abuse [57]. A review of hydrocodone/chorpheniramine also did not reveal any “robust efficacy data” in the relief of cough and respiratory symptoms associated with allergy or viral URIs in pediatrics [58]. Therefore, previous ACCP guidelines emphasized the lack of efficacy and potential morbidity and mortality of over-the-counter (OTC) cough medications in young children for cough [59]. Subsequently, the United States Federal Drug Administration (FDA) issued a warning and encouraged manufacturers to re-labeled these products “do not use in children under 4 years of age.” Later the FDA also limited prescription opioid cough and cold medications to those greater than 18 years of age.

The updated ACCP guidelines [1] state “other than honey…OTC cough medications have little, if any, benefit in the symptomatic control of acute cough in children but importantly, preparations containing anti-histamine and dextromethorphan were associated with adverse events. Thus, using OTC medications has to be balanced with [potential] adverse events…For children with acute cough, we suggest that the use of over the counter cough and cold medicines should not be prescribed until they have been shown to make cough less severe or resolve sooner…honey may offer more relief for cough symptoms than no treatment, diphenhydramine, or placebo, but it is not better than dextromethorphan…suggest avoiding codeine-containing medications because of the potential for serious side effects.” A recent Cochrane review indicated some general benefit in adults and older children with antihistamine-analgesic-decongestant combinations for the common cold but “these benefits must be weighed against the risk of adverse effects. There is no evidence of effectiveness in young children” [51].

The rationale behind the use of antihistamines is the possible role of allergy in acute bronchitis. The presence of mucus in the bronchial tubes may be difficult to expel due to the narrowed airway and the inadequacy of the cough reflex. Additionally, there may be production of mucus in the nasopharynx which descends through the pharynx causing persistent mechanical stimulation of the upper portion of the larynx [35]. The process could be triggered from atopic or allergic factors as well concomitant infection causing acute as well as chronic inflammation of the upper airways. Because of the multiple etiologies which can include not only various rhinitis and sinusitis phenotypes but also various anatomic abnormalities, chemical-induced rhinitis, etc., “a uniform definition of upper airway cough syndrome (UACS) with post-nasal drip (PND) is lacking across the United States, Europe, and Asia” [60]. Diagnosis is mainly clinical since radiographic studies such as conventional sinus radiograph or paranasal Water view or paranasal sinus CT are limited with low sensitivity and low specificity. Therefore, the ACCP, American Academy of Pediatrics, Infectious Diseases Society of America all do not recommend routine radiological assessment. Unfortunately there are no randomized control trials on therapies for UACS examining the effect on cough. One study on allergic rhinitis did find a significant decrease nasal symptoms and daytime cough (but not nighttime cough) using topical corticosteroids (mometasone furoate) [61]. If sinusitis is suspected, the recommended first-line therapy is antibiotics (amoxicillin or amoxicillin-clavulanate) for 7–10 days for acute (>10 days) and 20 days for chronic (>90 days) sinusitis [2].

There is no role for antibiotics in acute bronchitis (without concomitant sinusitis) since the etiology is not bacterial. However, there continues to be a tendency for physicians to prescribe amoxicillin, amoxicillin-clavulanate or azithromycin in almost 40% cases of acute bronchitis, laryngitis, and rhinopharyngitis [62]. It is difficult to determine whether they were seriously considering the possibility of pertussis or the atypical bacteria (i.e., Mycoplasma or Chlamycia) as mentioned above. Additionally, in contrast to the usual dry cough from infection by atypical bacteria, a wet cough may develop and persist for greater than 3 weeks raising the possibility of protracted bacterial bronchitis (PBB) [37]. Since part of the definition is the child’s response to 2–4 weeks of antibiotics the practitioner needs to critically evaluate and decide whether an empiric trial of antibiotics is needed after 2 weeks of coughing. ACCP guidelines do recommend that “children aged ≤ 14 years chronic (>4 weeks duration) wet or productive cough unrelated to an underlying disease and without any other specific cough pointers 2 weeks of antibiotics targeted to common respiratory bacteria (Streptococcus pneumonia, Haemophilus influenza, Moraxella catarrhalis) targeted to local antibiotic sensitivities” [1]. If there is a response within 2 weeks, then the diagnosis of PBB can be made. If there is no response after 2 weeks, an additional 2 weeks of antibiotic(s) should be done A recent randomized controlled trial indicated that an initial 4-week antibiotic course in suspected PBB led to a longer cough-free period than a 2 week duration [63]. ERS also agreed that a “trial of antibiotics is suggested in children with chronic wet cough with normal chest radiographs, normal spirometry and no warning signs” [2]. If there is no response after a total of 4 weeks of antibiotics, then further investigations such as flexible bronchoscopy with cultures and/or chest computerized tomography (CT) should be considered as further diagnostic procedures since the condition has now evolved into chronic bronchitis with coughing duration of greater than 4 weeks.

If a trial of asthma therapy is warranted in selected patients (see above discussion on Management), inhaled corticosteroids (ICS) are suggested. The ACCP recommends 400 mcg/day equivalent of budesonide or beclomethasone “as this dose is effective in the management of most childhood asthma and adverse events occur on higher doses” and reassess in 2 to 4 weeks. However, if there is a response, the child “does not necessarily have asthma and the child should be re-evaluated off asthma treatment as resolution of cough may occur with the period effect (spontaneous resolution or a transient effect responsive to ICS use” [1]. This is due to a Cochrane review that indicate no benefit from ICS in treatment with non-specific chronic cough related to asthma [64]. The ERS suggests that ICS may be less effective “since inflammation in cough-variant asthma and eosinophilic bronchitis is located in different parts of the airway from that seen in classic asthma, and may be drive by other pathways such as the innate immune system” [2]. Indeed, inhalation of bronchodilators (alone) or anticholinergics are not effective for the non-specific or asthmatic-like cough. Therefore, a trial of systemic anti-leukotriene medication was suggested for adults but the relatively high incidence (>10%) of mild and transient neuropsychiatric adverse side-effect preclude their empiric use in children. ACCP guidelines did mention older studies showing resolution of cough after 2 weeks of oral theophylline or inhaled mast cell stabilizers (cromoglycate or nedocromil). There was no mention of the role for combined low-dose ICS and long-acting beta 2 agonist but ERS noted a lack of any good studies examining their use in cough-variant asthma and asthmatic cough.

6. Conclusions

Acute and chronic bronchitis represent a spectrum of disease involving the lower airways. The most common etiology is a respiratory viral infection which usually causes short-lived coughing lasting less than 2–3 weeks in 90% of cases and resolves without any complications. The cough results from viral infection of epithelial cells and shedding of necrotic cells into the airway exposing sensory nerve endings. Attempts to control the infection involve the production of cytokines causing vascular leak, mucus secretion, and recruitment of inflammatory cells. These result in some blockage of the airway which may further invoke coughing to remove the mixture of secretions and mucus. Coughing resolves with control of the viral infection.

Some children may require a longer time to heal with bronchial epithelium regeneration and down-regulating the immune response. The injured epithelial surface may be at increased risk for bacterial superinfection, which will then require the use of antimicrobial medications. This process may be similar to viral infections of the upper airways producing croup which may then progress to bacterial tracheitis. Other children may have an initial infection with nonviral pathogens which will persist and result in prolonged coughing. Involvement of tuberculosis, mycoplasma and chlamydia has to be evaluated taking into account the surrounding community. Environmental factors such as exposure to cigarette smoke, perfumes, etc., need to be examined and managed accordingly. The possibility of an inhaled foreign body should always be considered.