Chronic Cough

Chronic Cough

27  Chronic Cough HENRY MILGROM • Cough may be classified as acute (lasting 8 weeks). Fortunately, in most cases, this presupposition is inaccurate...

643KB Sizes 0 Downloads 29 Views

27 

Chronic Cough HENRY MILGROM

• Cough may be classified as acute (lasting <3 weeks), subacute (lasting 3 to 8 weeks), or chronic (lasting >8 weeks).

Fortunately, in most cases, this presupposition is inaccurate, but a systematic approach to the diagnosis is necessary, and therapy, to be effective, may have to be directed simultaneously at more than one involved cough mechanism. Evidence-based algorithms to manage the chronic cough of children based on validated outcome measures and a priori definitions to designate resolution should be put to use.8,9 Child-specific cough management protocols are advocated in Australia, the USA and the UK.6

• The cause of chronic cough can be determined in most patients; specific therapy based on a systematic evaluation is usually successful.

Differential Diagnosis

KEY POINTS • Cough is an important defense mechanism. • Cough is a common manifestation of disease in childhood.

• Congenital anomalies and aspiration are relatively uncommon causes of chronic cough in children.

Introduction Cough is a widespread sign and symptom of diseases ranging from uncomplicated respiratory tract infections to serious illnesses affecting several organ systems. It is a source of discomfort for the young patient and anxiety for the parents.1,2 In the years 1995–1996, 24 million annual physician visits for cough took place in the USA, the largest number documented for a single symptom.3 Nearly half the patients were younger than 15 years old. In this young cohort, cough accounted for 8.5% of all medical appointments.3 Pediatric texts generally describe chronic cough as a condition that persists for more than 3 weeks. This observation suggests that chronic cough is likely to improve in time without treatment.4 A better informed classification by Irwin and colleagues divides cough into three categories: acute, lasting less than 3 weeks; subacute, lasting 3 to 8 weeks; and chronic, lasting more than 8 weeks.5 Irwin’s definition of chronic cough excludes most self-limiting cases. A chronic cough by these criteria often lasts much longer than 8 weeks and requires medical attention. Viral infections of the upper respiratory tract are the most common causes of acute cough. Typically, the symptoms resolve within 10 to 14 days.6 Patients with subacute cough most often have a history of recent upper respiratory tract infection or seasonal allergic rhinitis (e.g. postinfectious cough, bacterial sinusitis and asthma). Children with chronic or recurrent episodes of dry, nonproductive cough over several months, require careful and systematic evaluation for the presence of specific diagnostic indicators.7 They pose a perplexing problem in pediatric practice and call for a careful evaluation. Cough may be a manifestation of an underlying disorder that must be identified and treated. Many children with chronic cough have experienced repeated treatment failures, and the families have come to regard the condition as permanent and untreatable. 238

(Figure 27-1, Box 27-1)

The differential diagnosis of cough in childhood varies with the age of the patient, the duration, character and time of occurrence of the cough, associated signs and symptoms, and the patient’s exposure history. In the neonatal period, congenital abnormalities, especially pulmonary or cardiac, must be considered. Prematurity, especially in a patient who had required mechanical ventilation, may lead to bronchopulmonary dysplasia or the development of tracheal or bronchial stenosis. Vomiting and regurgitation may be the presenting signs and symptoms of gastroesophageal reflux (GER) or a tracheoesophageal fistula. Recurrent choking or cough associated with difficulty in sucking or swallowing suggests aspiration. Cough may occur in the course or following resolution of a respiratory infection. Attendance in daycare increases the risk of upper respiratory symptoms and infections in young children. In the toddler, foreign body aspiration and cystic fibrosis are added to the list of causes. A history of fever and/or presentation in winter suggests a viral etiology; seasonal occurrence suggests asthma or seasonal allergic rhinitis; year-round symptoms suggest perennial allergic rhinitis. Maternal smoking, in particular, appears to influence the development of respiratory symptoms in young children.10 In the older child, immune deficiency, tuberculosis and psychogenic cough enter into the differential diagnosis. Sinusitis, postnasal drip and GER may contribute to cough at any age. Cigarette smoking and psychogenic causes also require consideration among adolescents.11 A recent study showed that in otherwise healthy children with unexplained chronic cough, a significant proportion of the coughs was preceded by episodes of reflux. Most of these episodes were acidic in older children but not in infants12(Figure 27-3). Early evaluation and treatment of children with recurrent cough, sinusitis, foreign-body aspiration or GER are important to prevent bronchiectasis.13 How often do normal children cough? Accurate answers come from studies that used cough recorders. Cough frequency over 24 hours was 11.3, with a range of one to 34 in 41 children free from respiratory infection for at least 1 month. Only two children coughed at night.14 In children with chronic cough, the frequency was 65/day and in normal controls 10/day.15



27  Chronic Cough

239

History Physical examination Sputum examination

Specific findings

No

Abnormal Chest x-ray Obstruction reversibility

Spirogram Normal

Empiric nasal washes, nasal steroids, breathing exercises

Clinical response

Appropriate assessment

Inhaled corticosteroids, β-agonists Continue Tx

Cough persists

Yes Postnasal drip Rhinosinusitis

Nasal saline Nasal steroids

Wet cough

Antibiotics

Wheezing Cough variant asthma Eosinophilic bronchitis

Clinical response

Empiric inhaled corticosteroids and β-agonists or ipratropium bromide

Continue Tx

GERD

Cough persists Positive

Methacholine challenge

Inhaled corticosteroids, β-agonists

Infectious or postinfectious

Normal pH probe

Positive

H2 blocker, proton pump inhibitor

Normal Sinus CT

Positive

Nasal washes, nasal steroids, antibiotics

Aspiration syndromes

Normal Chest CT

Abnormal

Bronchoscopy Compression syndromes

Spirometry

Inhaled corticosteroids β-agonists

H2 blocker, proton pump inhibitor

Chest x-ray Cultures Serology ELISA PPD Gastric aspirate

Observe feeding UGI Chest MRI Fluoroscopy/swallowing study Chest CT pH probe Bronchoscopy

Chest x-ray UGI Chest CT Chest MRI Catheterization

Psychosocial evaluation Cough suppression Breathing exercises Bronchiectasis

Cardiac

Chest x-ray Sweat test High resolution chest CT UGI Immune work-up Ciliary biopsy Bronchoscopy

Chest x-ray ECG Echocardiogram Catheterization

Figure 27-1  Algorithm for the evaluation and treatment of chronic cough in childhood. CT – computed tomography, Tx – therapy, GERD – gastroesophageal reflux disease, ELISA – enzyme-linked immunosorbent assay, PPD – purified protein derivative, UGI – upper gastrointestinal series, MRI – magnetic resonance imaging, ECG – electrocardiogram.

240

SECTION E  Upper Airway Disease

BOX 27-1 DIFFERENTIAL DIAGNOSIS OF CHRONIC COUGH Congenital anomalies Connection of the airway to the esophagus Laryngeal cleft Tracheoesophageal fistula Laryngotracheomalacia Primary laryngotracheomalacia Laryngotracheomalacia secondary to vascular or other compression Bronchopulmonary foregut malformation Congenital mediastinal tumors Congenital heart disease with pulmonary congestion Chiari type I malformation Infectious or postinfectious cough Recurrent viral infection (infants and toddlers) Chlamydial infection (infants) Whooping cough-like syndrome Bordetella pertussis infection Chlamydia infection Mycoplasma infection Cystic fibrosis (infants and toddlers) Granulomatous infection Mycobacterial infection Fungal infection Suppurative lung disease (bronchiectasis and lung abscess) Cystic fibrosis Foreign body aspiration with secondary suppuration Ciliary dysfunction Immunodeficiency Primary immunodeficiency Secondary immunodeficiency (acquired immune deficiency syndrome)

Paranasal sinus infection Cough-variant asthma Rhinitis related Allergic rhinitis Rhinosinusitis Vasomotor rhinitis Postnasal drip Gastroesophageal reflux without aspiration Vocal cord dysfunction Aspiration (fluid material) Dyskinetic swallowing with aspiration General neurodevelopmental problems Möbius’ syndrome Chiari malformations Bottle-propping and bottle in bed (infant and toddlers) Gastroesophageal reflux Foreign body aspiration (solid material) Upper airway aspiration (tonsillar, pharyngeal, laryngeal) Tracheobronchial aspiration Esophageal foreign body with an obstruction or aspiration resulting from dysphagia Physical and chemical irritation Smoke from tobacco products (active and passive) Wood smoke from stoves and fireplaces Dry, dusty environment (hobbies and employment) Volatile chemicals (hobbies and employment) Dampness Mold Psychogenic cough Habit cough

Modified from Brown MA, Morgan WJ. Clinical assessment and diagnostic approach to common problems. In: Taussig LM, Landau LI, editors. Pediatric respiratory medicine. St Louis: Mosby; 1999.

Sound

Unfortunately, most studies rely on parents to give an account of their child’s cough, a method that has been shown to provide inaccurate information.16,17 When questionnaires administered to parents about their child’s coughing were compared to overnight recordings performed in 145 homes, the agreement was low.18

6.0 5.0

Air volume

50

(Figures 27-2 and 27-3) Cough serves as a protective mechanism to clear the respiratory tract and to defend it against the aspiration of noxious materials. While mechanical barriers limit the exposure of the respiratory tract to inhaled pathogens, the mucociliary apparatus and cough act to expel any organisms that may have bypassed the primary defenses. Two associated processes, bronchoconstriction and mucus secretion, add to its effectiveness. Recurrent partial collapse or incomplete inflation of the lungs and pneumonia associated with ineffective cough attest to its importance.19 Cough is executed as a complex reflex, an automatic or involuntary response to a stimulus, completed by the afferent and efferent pathways and a putative cough center in the brain, but also, at least in part, intensified or restrained under voluntary control. The main afferent pathways of cough originate in nerve receptors immediately beneath the respiratory epithelium in the larynx and the tracheobronchial tree, and in extrapulmonary

L/s

Pathophysiology

2.0 1.0

40

Flow rates

3.0

30

Subglottic pressure

20

cm H2O

4.0

10

0.1 second

0.0

0 1 2

3

Negative Minimal flow flow phase phase

Positive flow phase

Inspiratory Glottis phase closure

Expiratory phase (explosive)

Figure 27-2  Changes in flow rate, air volume, subglottic pressure and sound level generated during the act of coughing. (From Bianco S, Robuschi M. Mechanics of cough. In: Braga PC, Allegra L, editors. Cough. New York: Raven; 1989.)



27  Chronic Cough

241

≤2 years of age Patients with episodes of cough preceded by reflux detected by esophageal impedance (n = 83) 60%

40%

>2−<6 years of age 21.7%

78.3% 19.4%

80.6%

≥6 years of age

GER-related cough with esophageal pH 4−7

6.3%

93.8%

GER-related cough with esophageal pH <4 Figure 27-3  Proportion of children with cough preceded by reflux with pH 4–7 or <4, n = 8. The three small panels on the right present the data by age: <2 years (n = 15), >2–<6 years (n = 36), >6 years (n = 32). (From: Ghezzi M, Guida E, Ullmann N, Sacco O, Mattioli G, Jasonni V, Rossi GA, Silvestri M. Weakly acidic gastroesophageal refluxes are frequently triggers in young children with chronic cough. Pediatr Pulmonol 2013;48:295–302).

sites: the nose, the paranasal sinuses, the pharynx, ear canals and ear drums, the pleura, the stomach, the pericardium and the diaphragm. Nerve impulses from the tracheobronchial tree pass through the vagus, the principal afferent pathway. Cough may result from direct stimulation of this nerve.20 The trigeminal, glossopharyngeal and phrenic nerves conduct impulses from extrapulmonary sites.21 Axon reflexes traveling through branches of sensory end-organs may cause the release of neuropeptides and subsequent smooth muscle contraction, mucus secretion and epithelial injury. Thus, sensory signals taking part in cough may trigger or enhance bronchospasm. Reflexes regulate the parasympathetic nervous system, and chronic cough lowers the threshold for sensory signals. Efferent impulses of the cough reflex are transmitted to the respiratory musculature through the phrenic and other spinal motor nerves, and to the larynx through the recurrent laryngeal branches of the vagus. The vagus also provides efferent innervation to the tracheobronchial tree where its branches mediate bronchoconstriction.

Cough and Bronchospasm Cough and bronchospasm are two closely related reflexes that enhance one another, but neither depends on the other for its action.22 Cough clears the airways effectively only at high lung volumes; sufficient air velocity to shear mucus from bronchial walls can be achieved only down to the sixth or seventh generation of airway branching.23 Co-existing bronchoconstriction adds to the effectiveness of cough by extending peripherally the region of rapid and turbulent airflow. Challenge with either

methacholine or histamine provokes both cough and bronchoconstriction.24 However, the receptors for both reflexes are functionally distinct, and either response can arise independently. Challenge with hyperosmolar solutions causes both cough and bronchoconstriction, but hypo-osmolar solutions tend to bring about cough alone.25 Pretreatment divides induced cough from bronchoconstriction.26 When aerosolized water serves as the provoking agent, inhaled lidocaine blocks cough but not bronchoconstriction. When inhaled capsaicin is used to provoke cough, opiates administered systemically suppress cough whereas those administered by inhalation suppress bronchoconstriction.26 Bronchoconstriction, but not the urge to cough, can be blocked by pretreatment with intravenous atropine, consistent with the role of cholinergic pathways in the efferent limb of reflex bronchoconstriction. The mechanisms that trigger cough and bronchospasm following exercise or exposure to cold air appear to be different. Cough results mainly from excessive water loss, while bronchoconstriction follows airway rewarming.27 Cold, air-induced bronchoconstriction can be blocked by β-adrenergic agents, but cough cannot. Cough most often results from excitation of receptors concentrated in the larynx and proximal airways, while bronchoconstriction can be triggered from the lower airways as well. Finally, inflammatory changes in the airways may result in cough without simultaneously giving rise to bronchospasm.28

Cough-Variant Asthma Childhood asthma is a syndrome of inflammation in medium and small airways that gives rise to hyperresponsiveness and

242

SECTION E  Upper Airway Disease

constriction of the bronchial smooth muscle, edema and disruption of the mucosa, and obstruction of the airway lumen.29 Inflammation may lead to airway remodeling with proliferation of smooth muscle and deposition of matrix proteins. Coughvariant asthma is associated with the same disordered physiological processes and presenting signs, but overt wheezing is absent, and cough is the most discernible clinical sign. However, substantial evidence shows that awareness of symptoms by children with asthma is poor,30 and both children and their parents may be more aware of cough than of other symptoms that may be present as well. The diagnosis of asthma on the basis of cough alone accounts for the profusion of cases of cough-variant asthma that are open to doubt.31 In 1991, 10% of children with cough as the only symptom were diagnosed as having asthma; 2 years later, the figure had increased to 22.6%. Whereas in the past, cough may have been underrecognized as a sign of asthma, at present the opposite appears to be true.32,33 This is borne out by reports in which children with persistent nocturnal cough improved after 2 weeks of placebo therapy and received only modest additional benefit from a course of high-dose inhaled corticosteroids.34 Inhaled albuterol and beclomethasone in children with cough, but without wheezing, were no more effective than placebo in reducing cough frequency.35 Surprisingly, even the documentation of airway hyperreactivity did not predict a child’s response to these asthma medications. A study of nocturnal cough showed that in the absence of wheeze, shortness of breath or tightness of the chest, cough did not indicate hidden or atypical asthma in most children.36 Children under 4 years of age with frequent recurrent wheeze and a stringent index for the prediction of asthma at school age showed significantly higher median fractional exhaled nitric oxide (NO) levels (11.7 [11.85]) (median [interquartile range]) than children with recurrent cough but no history of wheeze (6.5 [5.5]; P < .001) and those with early recurrent wheeze and a loose index for the prediction of asthma at school age (6.4 [6.5]; P < .001). No difference in FeNO levels was found between children in the latter two groups (P = .91).37 A prospective study of infants followed up to age 11 years, showed that recurrent cough present early in life resolved in the majority of children. Children with recurrent cough but without wheeze did not have airway hyperresponsiveness or atopy, and significantly differed from those with classical asthma, with or without cough.38 Brooke and colleagues reassessed, during the early school years, a cohort of children identified as having recurrent cough in the preschool period. Seventy of 125 (56.0%; 95% CI 47.3–64.5%) were symptom-free at follow-up, 46 (36.8%; 95% CI 28.7–45.5%) continued to have recurrent cough in the absence of colds, and only nine (7.2%; 95% CI 3.6–12.8%) reported recent wheezing. The authors concluded that long-term recurrent cough in some children is consistent with the diagnosis of cough-variant asthma, but that few progress to develop asthma characterized by wheeze.39 Isolated cough is rarely due to asthma and often fails to respond to asthma medications.40 On the other hand, patients with a prolonged history of cough who respond to treatment with asthma medications or show evidence of bronchospasm or hyperresponsiveness without concurrent wheezing may be considered to have cough-variant asthma. Patients may be free of bronchoconstriction at the time of their evaluation. Their history of respiratory disease may be difficult to assess, while physical findings and routine pulmonary function tests may disclose no evidence of airway obstruction. In such cases,

evaluation of airway function by bronchial provocation with methacholine, histamine or exercise is recommended. In children too young to perform pulmonary function testing, the diagnosis of cough-variant asthma may be confirmed by the patient developing unequivocal evidence of reversible airways obstruction later in the clinical course and by the patient’s response to asthma therapy.

Cough During and After Respiratory Infection Children have an average of six to eight respiratory infections per year, a number that may be higher in those with siblings or in daycare. Repeated infections common in winter months may result in a chronic cough. Acute bronchitis usually follows the symptoms of upper respiratory illness. Cough associated with infection with respiratory syncytial virus (RSV), other respiratory viruses and cytomegalovirus, Mycoplasma pneumoniae, Chlamydia trachomatis, Ureoplasma urealyticum, Pneumocystis jiroveci (formerly carinii), Corynebacterium diphtheriae and Bordetella pertussis often lasts beyond the acute stage. Measles causes a cough with coryza, conjunctivitis and fever. In the immunized patient, atypical measles is more likely to cause cough or pneumonia than the characteristic rash. Persistent bacterial bronchitis (PBB) is an increasingly diagnosed form of chronic wet cough that occurs in children with a history of mild asthma or possibly misdiagnosed asthma.41 Some of the children have a history of invasive medical therapy (prolonged ventilation, cardiac surgery) and many have an underprivileged background. These children have a chronic wet productive cough with bacteria such as Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis persisting in the airways, and an associated neutrophilia. Spirometry and chest x-rays are typically normal. The cough responds to a course of antibiotic (e.g. amoxicillin-clavulanate for 2–4 weeks).42 Prolonged duration of cough and increased neutrophil counts are related to worse high-resolution computed tomography scan scores. A recent retrospective study identified a cohort of children with protracted bacterial bronchitis that for the most part had started in infancy.43 Almost three quarters of the children had an associated airway malacia. These children responded well to antibiotics, although a significant number relapsed and needed additional courses of treatment.43 A favorable response to a course of antibiotics confirms the diagnosis of PBB and further investigations may be unnecessary. Children who do not respond to treatment require investigation for specific causes of suppurative lung disease. This includes a sweat test and genotyping for cystic fibrosis, exhaled NO, evaluation of ciliary ultrastructure and beat frequency, white cell count, immunoglobulin levels and functional antibody studies, barium swallow, swallowing videofluorscopy and esophageal reflux studies.41 The pathogenesis of postinfectious cough is not known. Children with persistent postinfectious cough do not have airway eosinophilia typical of untreated asthma, but some manifest increased reactivity of the airways. These observations suggest that postinfectious cough has different pathophysiological features from asthma.44 The infection causing the cough, in most cases, remains unidentified. The diagnosis is clinical and one of exclusion. It should be considered in patients with normal chest x-rays and pulmonary function tests who cough only after respiratory tract infections. Postinfectious cough generally regresses over time, but it often recurs. Its resolution may

be accelerated by the administration of inhaled corticosteroids or ipratropium bromide.45 ACUTE VIRAL BRONCHIOLITIS Bronchiolitis occurs in epidemics during the winter months in temperate regions, and during the hottest months and the rainy season in tropical climates. Cough set off by microorganisms contributes to their spread and survival. RSV is the leading cause of epidemic bronchiolitis, accounting for over 40% of cases. Influenza, parainfluenza type 3 and adenovirus are responsible for many of the remaining cases. The human metapneumovirus and bocavirus also play a significant role.46 The risk of RSV illness in the first year of life is over 60%, and it will have infected nearly all children by the age of 2 years.47 RSV lower respiratory tract infections lead to 125,000 hospital admissions per year in the USA. Eighty percent occur in infants with a peak incidence at 2 to 8 months.48 RSV accounts for 25% of all acute hospitalizations in children younger than 5 years with chronic lung disease. Between 0.5% and 3.2% of children with RSV infection require hospitalization, and there are approximately 4500 deaths per year. Environmental risk factors for severe RSV infection include poverty, crowding, exposure to tobacco smoke and malnutrition. Older children and adults develop antibodies to RSV, but the immunity is incomplete, and re-infection may occur at any age. In these older patients, infection with RSV usually takes the form of an upper respiratory illness, often with bronchitis. There is a general consensus that following even mild RSV bronchiolitis, children are at increased risk for repeated bouts of respiratory symptoms during the first 3 years of life.49 Stein and colleagues reported a relationship between RSV infection and recurrent respiratory symptoms up to 6 years of age, but not to asthma after the of age 13 years.50 However, more recent evidence points to an association between severe RSV infection early in life and increased incidence of asthma and eczema later.51 Further, hospitalization for bronchiolitis in infancy is associated with an increased risk of asthma, and an increased use of asthma medication at 28 to 31 years of age.52 MYCOPLASMA PNEUMONIAE Most Mycoplasma pneumoniae infections in infants and young children are asymptomatic or are associated with upper respiratory symptoms only.53 However, it is the most frequent cause of pneumonia in children between 5 and 15 years of age,54 and a cause of bronchiolitis in all age groups. Mycoplasma pneumoniae pneumonia presents with a gradual onset of malaise, fever and headache. Cough begins several days after the onset of the illness and often persists for weeks. It may be productive of white or blood-tinged sputum. Physical findings include crackles, rhonchi and bronchial breath sounds. The incidence of wheezing with the acute infection has been reported to be 40%. X-ray findings, though not diagnostic, frequently show unilateral lower lobe involvement. The pattern is initially reticular and interstitial. Later, patchy segmental consolidation is seen. Hilar adenopathy and pleural effusions may be present. Ten percent of the children develop an exanthem and 36% have elevated hepatic transaminases. The diagnosis can be made by measuring specific IgM antibody. A rise in IgG antibody takes between 1 and 2 weeks post infection. Cold agglutinins are positive in about 40% to 60% of patients; however, the results are not specific. There is little evidence that treatment with antibiotics is helpful during the acute

27  Chronic Cough

243

illness; however, macrolide antibiotics may shorten the duration of fever and respiratory symptoms. Infection with mycoplasma may produce a long-term impairment in lung function even in asymptomatic children. Clinical reports, throat culture and serological studies, and animal models suggest a role for mycoplasma in airway hyperresponsiveness. In nonasthmatic subjects, significant response to bronchodilators has been noted 1 month after infection. More significantly, abnormal forced expiratory volume in 1 second (FEV1) and forced expiratory flow after 50% of the expired vital capacity have been noted up to as long as 3 years after initial infection.55 BORDETELLA PERTUSSIS (see Box 27-2) Before widespread vaccine coverage started in the late 1940s, there were as many as 270,000 cases of pertussis diagnosed in the USA per year, with as many as 10,000 deaths, predominantly among infants. Pertussis reached epidemic proportions every 2 to 5 years. Immunization with diphtheria–tetanus–pertussis (DTP) using whole Bordetella pertussis reduced the average incidence of pertussis in the USA from 157 per 100,000 population in the early 1940s to fewer than one in 1973. However, the cycles of outbreaks continued because neither infection nor immunization produces lifelong immunity to pertussis.56 Because of concerns over the safety of the DPT vaccine, beginning in the early 1990s, the USA started the transition from DPT to diphtheria–tetanus–acellular pertussis (DTaP) for the immunization of children. Pertussis is now resurgent, and many cases are occurring in vaccinated children and adolescents. In countries using acellular vaccines, waning immunity is at least part of the problem.57 It appears that vaccination rates in the young population are satisfactory, but the same is not true for older individuals, including health workers.58–60 In the years 2005–2010, the incidence of pertussis rose to between four and nine per 100,000.56 A study was conducted from 2006 to 2011 to assess the risk of pertussis in children relative to the time elapsed after the fifth dose of DTaP. This period included a large outbreak in 2010. DTaP was being used for all five recommended doses. Year on year after the fifth dose of DTaP there was a 42% increase in odds of acquiring pertussis.61 As many as 90% of nonimmune household contacts acquire the disease. Infection in immunized children and older persons is often mild. The burden of disease assessed by rates of complications and death remains greatest in the youngest patients, but there has been a recent resurgence of less severe pertussis

BOX 27-2 RISK FROM DISEASE VS RISK FROM DTaP PERTUSSIS Pneumonia: 1 in 8 Encephalitis: 1 in 20 Death: 1 in 1500 DTaP Continuous crying, then full recovery: 1 in 1000 Convulsions or shock, then full recovery: 1 in 14,000 Acute encephalopathy: 0–10.5 in 1,000,000 Death: None proven Source: http://www.cdc.gov/vaccines/vac-gen/6mishome.htm#risk

244

SECTION E  Upper Airway Disease

in adolescents and adults. These groups constitute a major source of disease transmission to younger children. Increased exposure to pertussis in the community, delay in identification and treatment, and high contact rates among children attending school or daycare contribute to the spread of the disease. It is important to note that pediatric healthcare workers are at particular risk for pertussis exposure, infection and subsequent disease transmission to susceptible patients.62 In 2011, Tdap vaccination coverage among health workers was only 26.9%.58 The widespread use of whole-cell pertussis vaccine in combination with diphtheria and tetanus toxoids (DTP), starting in the USA in the late 1940s, led to a historic low point of 1010 cases of pertussis in 1976. However, since the early 1980s, cases of pertussis have increased with cyclical peaks every 3 to 4 years. In 1996, the US Centers for Disease Control and Prevention reported 7796 cases of pertussis, almost half of whom were aged 10 years or older. In the same year, acellular pertussis vaccines were licensed and recommended for routine immunization of infants.3 The effectiveness of the complete vaccination series is 80% (95% CI 66–88%). Receiving fewer than three doses constitutes a significant risk factor (relative risk 5.1; 95% CI 3–8.6%).63 In the unvaccinated child, infection with Bordetella pertussis leads to a catarrhal phase lasting 1 to 2 weeks with rhinitis, conjunctivitis, low-grade fever and cough. B. pertussis infection causes infiltration of airway mucosa by lymphocytes and polymorphonuclear leukocytes, necrosis of the midzonal layers of the mucosa and injury to the ciliated epithelium of the respiratory tract. A stage of tracheobronchitis, lasting 1 to 6 weeks, ensues with episodes of paroxysmal cough that increase in number and severity. Repetitive forceful coughs during a single expiration are followed by an abrupt inspiration that produces the characteristic whoop. Many children experience post-tussive emesis. Fever is absent or minimal. Convalescence takes weeks to months. Pertussis is more severe in the first year of life. A clinical case is defined as an acute cough illness lasting a minimum of 14 days in a person with at least one pertussisassociated symptom (i.e. paroxysmal cough, post-tussive vomiting or inspiratory whoop) or 14 days of cough during an established outbreak. A confirmed case is a cough illness of any duration in a person from whom B. pertussis has been isolated, or that meets the clinical definition and is confirmed by polymerase chain reaction or an epidemiological connection to a laboratory-confirmed case.3 Although B. pertussis infection should be suspected in children with paroxysmal cough, other organisms, most notably adenovirus, parainfluenza viruses, RSV and mycoplasma, have been implicated.40 There is growing evidence that B. pertussis is an important cause of persistent cough in adolescents and adults. Pertussis has been implicated in 16% of cases of chronic cough of adults in Denmark. Susceptibility to infection with B. pertussis recurs several years after vaccination. Moreover, cases of laboratory proven reinfection have been reported.64 B. pertussis should be considered in patients with symptoms of typical or atypical whooping cough, irrespective of their vaccination status or past history of the disease.64 By demonstrating B. pertussis in an adult, one can reassure him/her that the symptoms will subside without the need for extensive evaluation and treatment, and recommend measures to protect others, especially unvaccinated infants.65 Droplet precautions are recommended for 5 days after initiation of effective therapy or until 3 weeks after the onset of paroxysms if appropriate antimicrobial therapy has

not been given. Erythromycin or clarithromycin eliminates pertussis from the nasopharynx in 3 to 4 days, decreasing the spread of the disease.66 Given within 14 days of onset, these antibiotics may abort pertussis. Once paroxysms of cough develop, antibiotics have little effect on the course of illness. An association between erythromycin and idiopathic hypertrophic pyloric stenosis has been reported in infants.67 There are no such reports for clarithromycin.68 In addition to maintaining high vaccination rates among preschool children, effort must be directed at the identification and treatment of pertussis cases to prevent further spread of the disease. Erythromycin (40–50 mg/kg per day orally in four divided doses, maximum 2 g/day) for 14 days is recommended for all close contacts irrespective of age or immunization status. Exposure of infants to children and adults with cough illnesses should be minimized. A major public health challenge at present is to address the illness in adolescents and adults. A rational strategy might be a universal booster vaccination for adolescents and a program targeted at those adults most likely to have contact with infants. CHLAMYDIA TRACHOMATIS Infants with C. trachomatis infection present with a highpitched, staccato, nonproductive cough and tachypnea without fever that begins around 4 weeks of age and lasts for several weeks, even after therapy with erythromycin.69 Concomitant conjunctivitis is a frequent finding. MYCOBACTERIUM TUBERCULOSIS Pediatric pulmonary tuberculosis remains a major cause of morbidity and mortality worldwide.70 From 1985 to 1992, the number of cases of childhood tuberculosis (TB) increased; however, between 1992 and 1998, the numbers declined substantially in all age groups. The incidence of TB among children is lower than among adults, and most of the pediatric morbidity and mortality occur in children younger than 5 years of age. In the USA, the groups with the highest rates include immigrants from Asia, Africa and Latin America, the homeless and residents of correctional facilities.71 Children contract TB from adults and adolescents; disease transmission among youngsters is most uncommon. When the tuberculin skin test converts to positive, most M. tuberculosis infections in children are asymptomatic. The radiographs at that time are usually negative, and the primary infection progresses slowly. Infection with M. tuberculosis that becomes symptomatic usually involves the hilar and mediastinal lymph nodes as well as lung parenchyma. Early manifestations become evident 1 to 6 months after initial infection. They include fever, weight loss, cough, night sweats and chills. Chest x-rays may show lymphadenopathy of the hilar and mediastinal nodes, involvement of a lung segment or lobe with atelectasis or infiltrate, cavitary lesions and miliary disease. Tuberculous meningitis may be an early finding. Later extrapulmonary manifestations may involve the middle ear, mastoid, bones, joints, skin, and kidneys.71 The recommended treatment regimen for TB disease consists of an initial 2-month phase of four drugs: isoniazid, rifampin, pyrazinamide and ethambutol, followed by a 4-month continuation phase of isoniazid and rifampin. Ethambutol is generally not used for young children whose visual acuity

cannot be monitored. Streptomycin may be substituted for ethambutol, but must be given by injection. Ethambutol (or streptomycin) can be discontinued when drug susceptibility results show the infecting organism to be fully drug-susceptible.71 Children from Asia or Africa where tuberculosis is endemic may have cough, often with hemoptysis, and without fever, as a result of an infestation with a fluke of the genus Paragonimus acquired by eating undercooked freshwater crab or crawfish.

Cough Associated with Allergic Rhinitis, Rhinosinusitis and/or Postnasal Drip Allergic rhinitis and rhinosinusitis (both described elsewhere in this text) are associated with cough that results from postnasal drip and irritation of the larynx. Chronic sinusitis may be an early manifestation of immunodeficiency or ciliary dysfunction. Irwin and colleagues identified postnasal drip as the most common cause of chronic cough among their patients.5 The diagnosis can be established by history. Mucoperiosteal changes on x-ray or sinus computed tomography (CT) of an atopic child in the absence of opacification or air-fluid levels and acute symptoms do not constitute an indication for treatment with antibiotics or sinus surgery. A most effective treatment is once or twice daily nasal irrigation with normal saline buffered by bicarbonate, followed by the instillation of a nasal corticosteroid spray.

Cough Associated with Compression Syndromes TRACHEOBRONCHOMALACIA Tracheo- or broncho-malacia is characterized by flaccidity or congenital absence of the cartilaginous rings supporting the trachea and/or the bronchi. Although most infants are asymptomatic, some present with cough, often described as brassy, paroxysmal dyspnea, wheezing and stridor.40 Chest x-rays frequently show recurrent ‘pneumonia’ that results from the collapse of segments of the airway during expiration. Increased secretions associated with respiratory infections precipitate symptoms. The caliber of the airways on chest x-ray varies from normal to markedly reduced depending on the phase of respiration. The appearance of pneumonia is most often caused by atelectasis, but secondary infection of the collapsed lung may occur. Prolongation of the expiratory phase and suprasternal and intercostal retractions are common. The diagnosis is established by observation of the collapse of tracheal or bronchial walls on fluoroscopy or bronchoscopy. Intrinsic airway stenosis or extrinsic compression exaggerates the manifestation of tracheomalacia. These complications must be considered during endoscopy. If associated bronchospasm is present, it must be treated aggressively. Although the symptoms usually subside by 12 to 18 months of age, some infants may require a trial of continuous positive airway pressure or mechanical ventilation. VASCULAR RINGS The trachea can become partially obstructed by a vascular abnormality involving a right aortic arch with left ligamentum

27  Chronic Cough

245

arteriosum or persistent ductus arteriosus, double aortic arch, anomalous innominate or left carotid artery. These abnormalities are generally referred to as vascular rings. Typical symptoms include inspiratory stridor, expiratory wheezing and a barking cough. Respiratory distress may be present, especially during feeding or when infection intervenes. Feeding difficulties may be present in the first few weeks of life. There may be recurrent pneumonia and atelectasis. The presence of vascular rings must be considered in any infant with stridor. The chest x-ray may show a right or an indeterminate aortic arch. Tracheal compression by an anomalous innominate artery causes a curvilinear indentation of the anterior trachea. While barium esophagrams may show characteristic indentations from various anomalies of the aortic arch, magnetic resonance imaging (MRI) with its multiplanar images has become the imaging procedure of choice at many institutions. Laryngotracheobronchoscopy is useful in excluding upper airway obstruction. Tracheal compression viewed endoscopically may be recognizable as a pulsatile, extrinsic mass. Vascular rings may be life-threatening, but with prompt recognition and surgical treatment, they are usually completely correctable.11,72 MEDIASTINAL MASSES Mediastinal masses may be present at birth. Children under 2 years are likely to present with respiratory symptoms including dyspnea, cough, stridor and chest pain. Additional signs and symptoms may include cyanosis, atelectasis, superior vena cava syndrome, Horner’s syndrome, dysphagia, spinal cord compression, intercostal nerve neuralgia, and cervical lymphadenopathy. These masses may be categorized as congenital or neoplastic. Most neoplastic tumors are malignant, and prompt diagnosis and treatment are required. In a large number of older children, the masses are asymptomatic and are recognized co-incidentally on chest x-rays. The asymptomatic masses are often benign. Chest x-rays provide information about location, size and presence or absence of calcifications. The barium swallow may be helpful in defining the anatomy. CT and MRI provide the most useful information for further diagnosis and treatment. Other helpful tests include percutaneous biopsy, bone marrow aspiration, urinary catecholamines and skeletal survey. Monoclonal antibodies have been used for diagnosis, assessment of response to therapy and monitoring for relapse.72 BRONCHIAL STENOSIS Bronchial stenosis is a fixed narrowing of the bronchus, usually not associated with other congenital malformations, although co-existing segmental bronchomalacia, most commonly of the left main bronchus, has been reported. In the past, tuberculosis was a common cause of bronchial stenosis. It can occur at any level along the bronchial tree, although it most commonly involves a main bronchus, just distal to the carina. The degree of stenosis is variable. Wheezing, both inspiratory and expiratory, is a typical presenting symptom. It may be associated with cough, dyspnea and stridor. Chest x-rays reveal recurrent atelectasis that may become secondarily infected. Hyperinflation is usually noted on the x-rays of patients with stenosis of the main bronchus. In patients with segmental bronchomalacia, the involved lung is usually hyperlucent. If the orifices of the upper lobes or right middle lobe are involved, there may be

246

SECTION E  Upper Airway Disease

an associated collapse. Recurrent consolidation or persistent collapse is a common radiological finding of stenosis of a lobar bronchus. Diagnosis is accomplished by endoscopy. Treatment varies with the severity of obstruction. In some cases, the administration of bronchodilators and chest physical therapy is sufficient; more severe cases may require positive pressure ventilation or surgery to remove the stenotic segment. Lobar resection may be necessary to control persistent infection.73 TRACHEAL STENOSIS Signs and symptoms of congenital tracheal stenosis include persistent cough and respiratory distress in the newborn period. Patients may have expiratory stridor and wheezing. History of feeding difficulties is common. Chest x-rays and fluoroscopy may reveal a missing segment of the trachea. Radiographs of the neck that are highly penetrated may show tracheal narrowing. In congenital tracheal stenosis there is intrinsic narrowing of the tracheal lumen caused by complete cartilaginous rings. The size of the lumen can be assessed by CT or MRI. The definitive diagnosis is made by endoscopy. The differential diagnosis includes extrinsic compression of the trachea by vascular rings or mediastinal masses. Tracheotomy may be necessary to maintain a patent airway. Endoscopic procedures can be used to treat thin tracheal webs and unilateral lesions. Conservative management of patients with mild symptoms should be attempted. Dilation of tracheal stenosis may provide a temporary solution until definitive surgical repair can be accomplished. Surgical treatment is associated with significant morbidity and mortality.73

Cough Associated with Aspiration Syndromes Aspiration pneumonia is a common disorder frequently mistaken for nonspecific respiratory infection, while aspiration bronchitis is often mistaken for asthma. In infants, these conditions are most commonly associated with the inhalation of milk as a result of one of three disorders: impairment of sucking or swallowing likely to be neurogenic in origin, GER or tracheoesophageal fistula. These are conditions that must not be overlooked. The initial step in diagnosis is to observe the child, while nursing, for difficulty with sucking or swallowing or for associated cough or choking. Gross structural abnormalities of the mouth, jaw or palate can be noted. Placing a finger in the baby’s mouth can assess the act of sucking. X-rays of children with aspiration bronchitis typically show perihilar thickening and increased bronchovascular markings, while those of children with aspiration pneumonia show patchy areas of uniform opacity that may have a segmental or lobar distribution. In infants, the posterior parts of the upper and lower lobes are most commonly involved, with the right side predominating. Fluoroscopy is used to evaluate the anatomy of the upper airway and esophagus and the swallowing function. Esophageal pH probe or impedance probe monitoring establishes the presence of reflux.74 Bronchoscopy and microscopic examination for lipid-laden macrophages substantiate the diagnosis of aspiration. Tracheoesophageal fistulas require prompt surgical repair. The management of a child with a swallowing disorder requires the assistance of a clinic that specializes in this problem.

Gastroesophageal Reflux (see Figure 27-3)

GER is a common cause of chronic cough in individuals of all ages and of apnea in infants, even without co-existing aspiration. Its most likely mode of action is through vagal stimulation, although aspiration must be considered. GER has been documented in about half of adults with chronic cough, and it commonly occurs in children.75 The respiratory manifestations of GER – cough, wheezing, sore throat, hoarseness, throat clearing, choking and throat irritation – often persist in the absence of more familiar symptoms such as heartburn and regurgitation.76 Proton pump inhibitors or H2 blockers effectively reduce the respiratory complications of GER. However, higher than standard doses may be necessary and therapy may need to be continued for several months before a therapeutic effect is achieved. Laparoscopic fundoplication has been performed safely, even in high-risk children.77

Foreign Body A foreign body may lodge in the hypopharynx, larynx, trachea, bronchus or esophagus. Aspiration of a foreign body into the airway typically causes stridor. It is a pediatric emergency requiring immediate management by a specialist, even though unsuspected bronchial foreign bodies may be present for a long time and lead to chronic bronchitis and bronchiectasis. Unrecognized esophageal foreign bodies resulting in tracheal compression have caused recurrent wheezing or cough without dysphagia for as long as a year. Cough, wheezing or dyspnea may date from the time of aspiration or may begin later, after edema and inflammation have set in and reflex bronchospasm has resulted. The majority of aspirated foreign bodies are foods such as peanuts or sunflower seeds, but a remarkable variety of objects has been removed at bronchoscopy. It is of note that peanuts release oils that irritate the bronchial mucosa, causing inflammation and edema. Other organic solids, such as beans, peas, corn or seeds, can absorb water and increase considerably in size. In one third of patients with foreign body aspiration, the actual event goes unobserved by caregivers.78 The diagnosis may be suspected on the basis of history and physical findings. Classical signs are wheezing, cough and decreased breath sounds. Use of a differential stethoscope may be helpful in detecting localized airway obstruction. The diagnosis is established by radiographic findings and ultimately by bronchoscopy. Chest x-rays show atelectasis in cases of complete obstruction of a bronchus. In cases of partial obstruction, the foreign body may act as a valve that allows air entry but impedes exhalation from a portion of a lung. Comparison of inspiratory and expiratory radiographs shows a hyperinflated obstructed portion in comparison to the unaffected lung following expiration. On decubitus radiographs and fluoroscopy, the dependent lung should show less inflation unless obstructive hyperinflation from the valve-like mechanism is present. Bronchoscopy provides decisive evidence for diagnosis and treatment. Rigid bronchoscopy is preferred because it allows for the removal of the foreign body at the time of diagnosis. Treatment with bronchodilators, postural drainage and chest physical therapy as an alternative to bronchoscopic removal of the foreign body is no longer recommended.



Cystic Fibrosis Cystic fibrosis is diagnosed with increasing frequency during neonatal screening. The presenting symptoms of this disease are cough, poor weight gain and abnormal stools. The earliest symptom is usually a loose cough. Most patients experience recurrent lower respiratory infection before 12 months of age, but the age of onset is variable. Purulent bronchitis may be associated with wheezing and cough, and the diagnosis of asthma is often made in error. Purulent chronic cough in children must always be regarded as a pathological finding.40

Allergic Bronchopulmonary Aspergillosis Timely diagnosis of allergic bronchopulmonary aspergillosis (ABPA) is important because untreated ABPA results in progressive, irreversible lung damage. ABPA is a disease differentiated by recurrent infiltrates on chest x-ray, markedly elevated serum immunoglobulin E (IgE), eosinophilia and underlying asthma. Clinically it is characterized by afebrile episodes of cough, sputum production, dyspnea and wheezing.

Hypersensitivity Lung Disease Hypersensitivity pneumonitis or extrinsic allergic alveolitis is a syndrome that results from sensitization to inhaled organic dusts, which in children are most often avian antigens. Bird fancier’s disease has been reported to occur in families. During acute attacks, patients suffer from both respiratory and systemic symptoms, including cough, dyspnea, temperature as high as 40°C, chills and myalgia.

Vocal Cord Dysfunction Vocal cord dysfunction (VCD) is a condition characterized by a paradoxical adduction of the vocal cords on inspiration that causes shortness of breath, cough and stridor.79 VCD in children commonly occurs during exertion and must be differentiated from exercise-induced bronchospasm (EIB). VCD has been documented in adolescents, usually female athletes.80 Among these patients, perfectionism, depression and anxiety are common. The chest x-rays in uncomplicated VCD are normal. Spirometry shows blunting or truncation of the inspiratory portion of the flow-volume curve. Because of the episodic nature of VCD, the flow rate patterns may vary, and during asymptomatic periods, normal flow-volume curves are likely to be found. It is possible to replicate symptoms and spirometric findings of VCD by exercise or inhalation challenge, but negative results do not rule out the diagnosis. Observation of the vocal cords of a patient experiencing either spontaneous or induced symptoms by flexible fiberoptic rhinolaryngoscopy documents the presence of VCD.79 The examination can be videotaped or photographed for the medical records. Complications are rare and discomfort is minimal. In VCD, the vocal cords adduct anteriorly from the vocal process, and the posterior glottic chink remains open. The adduction occurs during inspiration or in both the inspiratory and expiratory phases. The adduction of vocal cords with an open glottic chink in a symptomatic patient unequivocally establishes the diagnosis of VCD.

27  Chronic Cough

247

In the author’s experience, the most successful treatment of VCD is that derived from breathing exercises used for hyperfunctional voice disorders to decrease the laryngeal muscle tone. These techniques are likely to desensitize the cough pathways.79,81 In some extreme cases, hypnosis, biofeedback and psychotherapy have been used successfully. An approach reserved for acute attacks is the administration of a mixture of helium and oxygen. More aggressive therapies under study for patients with intractable, recurrent symptoms include injection of botulinum toxin directly into one vocal cord or sectioning of the laryngeal nerve.79,81

Psychogenic Cough Although it has been suggested that psychogenic cough typically ceases at night and has a barking or honking character, in actual fact, there are no distinguishing clinical features, and the diagnosis should be considered only after other possibilities have been excluded.45 In some cases, a complete evaluation may require an assessment of the psychosocial factors that influence the origin, progression, persistence and/or exacerbation of chronic cough. Some children derive secondary gain in the form of greater attention or emotional support from their parents. In others, trauma such as physical abuse or school phobia may cause a conversion syndrome. A psychological evaluation may be necessary to focus on specific detrimental effects of the cough, a disruptive process that may affect negatively a broad spectrum of social and interpersonal experiences. This may range from distress at school to exclusion from play, social functions or participation in sports. As in other chronic medical conditions, emotional responses to the symptom may need to be addressed. Depression and frustration are the most common adjustment reactions, but negative responses may range over the entire affective spectrum. Patients with psychogenic cough often believe that they have a serious chest problem. The diagnosis has been made in 3% to 10% of children with cough of unknown etiology that persists for more than 1 month. In 17 published reports, 149 of 153 patients were under 18 years of age. While wholly psychogenic cough is rare, children and/or parents may exaggerate some or all aspects of the cough. Occasionally it is difficult to reconcile the parents’ or child’s accounts with clinical findings. The parents may demand inappropriate treatment and may instill in the child the belief that he/she is physically disabled. When clinical findings differ from the history, confirmation of the cough by the use of a recording device and/or admission to the hospital for observation may be invaluable. The circumstances call for sympathy and understanding, and the doctor’s responsibility to the child must take precedence over the doctor-parent relationship. Habit cough, a diagnosis of exclusion, results from the lowering of the threshold for sensory signals in chronic nonproductive cough that may become self-perpetuating and persist even after the initial inciting reason is no longer present.

Evaluation Information about the history of onset, character of the cough (harsh, dry, productive, paroxysmal), triggers, time of occurrence and accompanying symptoms or sensations may offer clues about its etiology. A detailed health history must be obtained with attention to the neonatal period; feeding

248

SECTION E  Upper Airway Disease

problems; congenital malformations affecting the heart, great vessels, nasopharynx and upper respiratory tract, and gastrointestinal tract; respiratory infections; signs and symptoms of chronic illness; respiratory symptoms including those relating to the upper airway, such as postnasal drip or irritation, and lower respiratory tract, such as wheezing, dyspnea and exercise tolerance; heartburn; nocturnal symptoms; and environmental exposures, including cigarette smoke, at home, at school, at daycare, and at the homes of close playmates. The social history provides information about family or school problems that may contribute to psychogenic cough. The physical examination focuses on the head and neck and the respiratory and cardiovascular systems. Signs of allergic rhinitis, stridor, tachypnea, hyperinflation, wheezes, crackles, rhonchi (with special attention paid to unilateral or asymmetric findings), heart murmurs, gallops and congestive heart failure are sought. Eosinophils on the nasal smear suggest allergic rhinitis and neutrophils infectious sinusitis. Eosinophils in the sputum suggest asthma. Pulmonary function testing should be undertaken in any child capable of performing the necessary maneuvers. Generally, useful data include a complete blood count with differential, serum IgE, allergy skin tests, an examination of the vocal cords, chest and sinus x-rays and/or CT, bronchial challenge, and esophageal pH or impedance monitoring.82 Exhaled NO may help to identify toddlers with recurrent cough who will go on to develop asthma. Other laboratory tests based on clinical findings comprise specific studies recommended for the conditions discussed above. They include sputum culture, immunoglobulins, purified protein derivative (PPD), sweat test and ciliary biopsy. Bronchoscopy is rarely indicated. For dynamic evaluation of compression syndromes, flexible bronchoscopy provides the best detail, but if a foreign body aspiration is likely, rigid bronchoscopy should be used. Cough with hemoptysis is an indication for a chest x-ray, chest CT and bronchoscopy.

Environment It is important to obtain an environmental history of children with chronic cough because it may be possible to improve their surroundings. Environmental history for chronic cough should include exposure to cigarette smoke in all children, to aeroallergens, especially indoors, in older children, and dietary history in infants and toddlers. In utero exposure to mainstream smoke from the mother and even to environmental tobacco smoke changes fetal lung development and causes airflow obstruction and airway hyperresponsiveness. Children exposed to environmental tobacco smoke postnatally have more symptoms of cough, wheeze, respiratory illnesses, decreases in lung function and increases in airway responsiveness.83 A survey of respiratory symptoms in children aged 12 to 14 years was conducted throughout Great Britain as part of the International Study of Asthma and Allergies in Childhood (ISAAC). The response rate was 79.3%, and 25,393 children in 93 schools participated.84 Cough and phlegm were associated with active and passive smoking. Gas cooking was significantly associated with dry night cough. The prevalence of cough and phlegm tended to be higher in metropolitan areas; the opposite applied to asthma. Exposure to any passive smoking raised the odds ratio (OR) for night cough (OR = 1.8), snoring (OR = 1.4) and respiratory infections during the first 2 years of life (OR = 1.3). Respiratory

problems were more prevalent in homes with reported molds or dampness with adjusted OR ranging from 1.32 (95% CI 1.06–1.39) for bronchitis to 1.89 (95% CI 1.58–2.26) for cough.85 There is an association between coal fires and nocturnal cough.86

Treatment The goal of clinical evaluation of chronic cough is to identify its causes and to prescribe specific remedies such as modification of the child’s environment and treatment of postnasal drip or GER. Antiasthma drugs are not reliably effective in patients with chronic dry cough, nevertheless a 2- to 4-week course of a potent inhaled corticosteroid should be administered to children with prolonged cough without wheeze who have not already received such therapy, especially if they have obstructive pulmonary function tests or positive bronchial challenge results. Inhaled corticosteroids should be discontinued in children who have received an adequate trial and are continuing to cough, and whose pulmonary function tests are normal. Failure to improve after 4 weeks of inhaled corticosteroids and/or normal pulmonary function tests calls for consideration of alternative diagnoses and for proceeding with the clinical evaluation described above. New treatment should be directed at all conditions identified as potentially responsible for the patient’s cough and should include breathing exercises.79 Health information available on the Internet relating to treatment of cough is generally unreliable. A review of websites identified more incorrect than correct information, and only one of 19 received a high score.87 Parents may hold unrealistic expectations and may demand needless medications. In such cases, it is best to acknowledge the child’s discomfort, to give a realistic time course for resolution of symptoms and to promote active management with non-pharmacological treatments. Patient education fulfills an important role in the management of chronic cough. The patient and family who understand how individual mechanisms contribute to the cough and where each type of treatment fits, carry out their regimen with greater adherence and reduced anxiety. They cope more effectively with the symptoms, especially during periods of exacerbation. On rare occasions, it may be necessary to enlist the help of a psychotherapist to help the family accept the diagnosis and to adhere to therapy. Over-the-counter pediatric cough and cold medications are widely marketed and used despite lack of evidence of efficacy and numerous recent reports challenging their safety. Serious adverse effects have been associated with accidental overdose, inadvertent misuse and drug-drug or drug-host interactions in children given standard doses.88 An estimated 7091 children under 12 years are treated annually in the USA in emergency departments for adverse drug events attributable to cough and cold medications. Most visits (64%) are for children aged 2 to 5 years. Unsupervised ingestions account for 66% of estimated emergency department visits.89 Data obtained from 4267 children enrolled from 1999 to 2006 in the Slone Survey, a random digit-dial telephone survey of medication use by the US population, disclosed that in a given week, 10.1% of US children use a cough and cold medication. Exposure is highest to decongestants (6.3%; mostly pseudoephedrine) and first-generation antihistamines (6.3%; the most common were chlorpheniramine, diphenhydramine and brompheniramine), followed by antitussives (4.1%; mostly dextromethorphan) and expectorants (1.5%; almost exclusively guaifenesin). Multiple-ingredient



27  Chronic Cough

249

BOX 27-3  KEY FEATURES EVALUATION OF CHRONIC COUGH • Cough is a common manifestation of disease in childhood. • Cough is an important defense mechanism. • Cough functions as a complex neurological reflex. • Cough may be classified as acute (lasting <3 weeks), subacute (lasting 3–8 weeks) or chronic (lasting >8 weeks). • Persistent bacterial bronchitis (PBB) is characterized by a chronic wet productive cough, with bacteria such as Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis persisting in the airways and an associated neutrophilia. Spirometry and chest x-rays are typically normal. The cough typically responds to a course of antibiotics (e.g. amoxicillin-clavulanate for 2–4 weeks).42 • The cause of chronic cough can be determined in most patients; specific therapy based on a systematic evaluation is usually successful. • A chest radiograph should be obtained in children with chronic cough to rule out lower respiratory tract and cardiac pathology.

products accounted for 64.2% of all cough and cold medications used. Exposure to antitussives, decongestants and firstgeneration antihistamines was highest among 2- to 5-year olds (7.0%, 9.9% and 10.1%, respectively) followed by children younger than 2 years (5.9%, 9.4% and 7.6%, respectively).90 During 2004 to 2005, an estimated 1519 children under 2 years of age were treated in US emergency departments for adverse events associated with cough and cold medications. A review by the Food and Drug Administration (FDA) covering several decades identified 123 deaths related to the use of such products in children under 6 years of age.88,91 The infants ranged in age from 17 days to 10 months. Postmortem testing showed evidence of recent administration of pseudoephedrine, antihistamine, dextromethorphan and/or other cold-medication ingredients.92 On a positive note, pseudoephedrine use by children appears to be declining since the institution of the 2005 Combat Methamphetamine Epidemic Act.90 In the Slone survey conducted from 1999 to 2006, use in 2006 (2.9%) was significantly lower than in 1999–2005 (5.2%).

• Postnasal drip, acting alone or with other conditions, is the most common cause of chronic cough. • Asthma is very often associated with chronic cough, but few children with chronic cough develop asthma. • Cough-variant asthma is suggested by (1) airway obstruction and reversibility, (2) airway hyperresponsiveness and/or (3) clinical improvement after treatment with asthma medications. • Gastroesophageal reflux may cause or intensify chronic cough through a vagal reflex or as a result of aspiration of stomach contents. • Postinfectious cough resolves over time; the use of oral or inhaled corticosteroids or ipratropium bromide may shorten its duration. • Congenital anomalies and aspiration are relatively uncommon causes of chronic cough in children. • Bronchiectasis is a rare cause of chronic cough in children. • Psychogenic cough and habit cough are diagnoses of exclusion.

Conclusions Our goals are not merely to find effective therapies for chronic cough, but also to identify and eliminate factors that predispose children to this aggravating problem. In the meantime we must strive to limit harm, such as children’s exposure to tobacco smoke and families’ reliance on over-the-counter medications. In addition to pertussis, outbreaks of H. influenzae, mumps and measles have been linked in the USA to vaccine avoidance. We should continue to reassure parents and to encourage them to vaccinate not only their children but also themselves. Every healthcare visit should be viewed as an opportunity to review the patient’s immunization history and to ensure that everyone is fully vaccinated. The key features of chronic cough are summarized in Box 27-3. The complete reference list can be found on the companion Expert Consult website at http://www.expertconsult.inkling .com.

KEY REFERENCES 6. Chang AB, Robertson CF, Van Asperen PP, Glasgow NJ, Mellis CM, Masters IB, et al. A multicenter study on chronic cough in children: burden and etiologies based on a standardized management pathway. Chest 2012;142:943–50. 8. Chang AB, Robertson CF, van Asperen PP, Glasgow NJ, Masters IB, Teoh L, et al. A cough algorithm for chronic cough in children: a multicenter, randomized controlled study. Pediatrics 2013;131:e1576–83. 9. Newcombe PA, Sheffield JK, Chang AB. Parent cough-specific quality of life: development and validation of a short form. J Allergy Clin Immunol 2013;131:1069–74.

12. Ghezzi M, Guida E, Ullmann N, Sacco O, Mattioli G, Jasonni V, et al. Weakly acidic gastroesophageal refluxes are frequently triggers in young children with chronic cough. Pediatr Pulmonol 2013;48:295–302. 42. Stark P, Heenan R, Orsani F, Jachno K, Connell TG. Amoxycillin-clavulanate for chronic wet cough in children: cautious interpretation of study findings warranted. Thorax 2013;68: 296–7. 43. Kompare M, Weinberger M. Protracted bacterial bronchitis in young children: association with airway malacia. J Pediatr 2012;160: 88–92.

56. Cherry JD. Epidemic pertussis in 2012—the resurgence of a vaccine-preventable disease. N Engl J Med 2012;367:785–7. 58. Lu PJ, Graitcer SB, O’Halloran A, Liang JL. Tetanus, diphtheria and acellular pertussis (Tdap) vaccination among healthcare personnelUnited States, 2011. Vaccine 2014;32:572–8. 61. Klein NP, Bartlett J, Rowhani-Rahbar A, Fireman B, Baxter R. Waning protection after fifth dose of acellular pertussis vaccine in children. N Engl J Med 2012;367:1012–19. 89. Schaefer MK, Shehab N, Cohen AL, Budnitz DS. Adverse events from cough and cold medications in children. Pediatrics 2008;121:783–7.

27  Chronic Cough 249.e1

REFERENCES 1. Marchant JM, Newcombe PA, Juniper EF, Sheffield JK, Stathis SL, Chang AB. What is the burden of chronic cough for families? Chest 2008;134:303–9. 2. Newcombe PA, Sheffield JK, Juniper EF, Marchant JM, Halsted RA, Masters IB, et al. Development of a parent-proxy quality-of-life chronic cough-specific questionnaire: clinical impact vs psychometric evaluations. Chest 2008;133: 386–95. 3. From the Centers for Disease Control and Prevention. Pertussis–United States, 1997–2000. JAMA 2002;287:977–9. 4. Powell CV, Primhak RA. Stability of respiratory symptoms in unlabelled wheezy illness and nocturnal cough. Arch Dis Child 1996;75: 385–91. 5. Irwin RS, Madison JM. The diagnosis and treatment of cough. N Engl J Med 2000;343: 1715–21. 6. Chang AB, Robertson CF, Van Asperen PP, Glasgow NJ, Mellis CM, Masters IB, et al. A multicenter study on chronic cough in children: burden and etiologies based on a standardized management pathway. Chest 2012;142:943–50. 7. Irwin RS, Baumann MH, Bolser DC, Boulet LP, Braman SS, Brightling CE, et al. Diagnosis and management of cough executive summary: ACCP evidence-based clinical practice guidelines. Chest 2006;129(1 Suppl.):1S–23S. 8. Chang AB, Robertson CF, van Asperen PP, Glasgow NJ, Masters IB, Teoh L, et al. A cough algorithm for chronic cough in children: a multicenter, randomized controlled study. Pediatrics 2013;131:e1576–83. 9. Newcombe PA, Sheffield JK, Chang AB. Parent cough-specific quality of life: development and validation of a short form. J Allergy Clin Immunol 2013;131:1069–74. 10. Lister SM, Jorm LR. Parental smoking and respiratory illnesses in Australian children aged 0–4 years: ABS 1989–90 National Health Survey results. Aust N Z J Public Health 1998;22: 781–6. 11. Milgrom H, Wood RI, Ingram D. Respiratory conditions that mimic asthma. Immunol Allergy Clin North Am 1998;18:113–32. 12. Ghezzi M, Guida E, Ullmann N, Sacco O, Mattioli G, Jasonni V, et al. Weakly acidic gastroesophageal refluxes are frequently triggers in young children with chronic cough. Pediatr Pulmonol 2013;48:295–302. 13. Boren EJ, Teuber SS, Gershwin ME. A review of non-cystic fibrosis pediatric bronchiectasis. Clin Rev Allergy Immunol 2008;34:260–73. 14. Munyard P, Bush A. How much coughing is normal? Arch Dis Child 1996;74:531–4. 15. Chang AB, Asher MI. A review of cough in children. J Asthma 2001;38:299–309. 16. Falconer A, Oldman C, Helms P. Poor agreement between reported and recorded nocturnal cough in asthma. Pediatr Pulmonol 1993;15: 209–11. 17. Shann F. How often do children cough? Lancet 1996;348:699–700. 18. Dales RE, White J, Bhumgara C, McMullen E. Parental reporting of children’s coughing is biased. Eur J Epidemiol 1997;13:541–5. 19. Chang AB. Cough, cough receptors, and asthma in children. Pediatr Pulmonol 1999;28:59–70. 20. Helmers SL, Wheless JW, Frost M, Gates J, Levisohn P, Tardo C, et al. Vagus nerve stimulation therapy in pediatric patients with refrac-

tory epilepsy: retrospective study. J Child Neurol 2001;16:843–8. 21. Irwin RS, Rosen MJ, Braman SS. Cough. A comprehensive review. Arch Intern Med 1977; 137:1186–91. 22. Cough and wheeze in asthma: are they interdependent? Lancet 1988;1:447–8. 23. Leith DE. Cough. Phys Ther 1968;48:439–47. 24. Chausow AM, Banner AS. Comparison of the tussive effects of histamine and methacholine in humans. J Appl Physiol 1983;55:541–6. 25. Eschenbacher WL, Boushey HA, Sheppard D. Alteration in osmolarity of inhaled aerosols cause bronchoconstriction and cough, but absence of a permeant anion causes cough alone. Am Rev Respir Dis 1984;129:211–15. 26. Fuller RW, Karlsson JA, Choudry NB, Pride NB. Effect of inhaled and systemic opiates on responses to inhaled capsaicin in humans. J Appl Physiol 1988;65:1125–30. 27. McFadden ER Jr, Nelson JA, Skowronski ME, Lenner KA. Thermally induced asthma and airway drying. Am J Respir Crit Care Med 1999;160:221–6. 28. Chang AB, Harrhy VA, Simpson J, Masters IB, Gibson PG. Cough, airway inflammation, and mild asthma exacerbation. Arch Dis Child 2002;86:270–5. 29. Lemanske RF Jr. Inflammation in childhood asthma and other wheezing disorders. Pediatrics 2002;109(2 Suppl.):368–72. 30. Baker RR, Mishoe SC, Zaitoun FH, Arant CB, Lucas J, Rupp NT. Poor perception of airway obstruction in children with asthma. J Asthma 2000;37:613–24. 31. Kelly YJ, Brabin BJ, Milligan PJ, Reid JA, Heaf D, Pearson MG. Clinical significance of cough and wheeze in the diagnosis of asthma. Arch Dis Child 1996;75:489–93. 32. McKenzie S. Cough–but is it asthma? Arch Dis Child 1994;70:1–2. 33. Chang AB. Isolated cough: probably not asthma. Arch Dis Child 1999;80:211–13. 34. Davies MJ, Fuller P, Picciotto A, McKenzie SA. Persistent nocturnal cough: randomised controlled trial of high dose inhaled corticosteroid. Arch Dis Child 1999;81:38–44. 35. Chang AB, Powell CV. Non-specific cough in children: diagnosis and treatment. Hosp Med 1998;59:680–4. 36. Ninan TK, Macdonald L, Russell G. Persistent nocturnal cough in childhood: a population based study. Arch Dis Child 1995;73:403–7. 37. Moeller A, Diefenbacher C, Lehmann A, Rochat M, Brooks-Wildhaber J, Hall GL, et al. Exhaled nitric oxide distinguishes between subgroups of preschool children with respiratory symptoms. J Allergy Clin Immunol 2008;121: 705–9. 38. Wright AL, Holberg CJ, Morgan WJ, Taussig LM, Halonen M, Martinez FD. Recurrent cough in childhood and its relation to asthma. Am J Respir Crit Care Med 1996;153(4 Pt 1): 1259–65. 39. Brooke AM, Lambert PC, Burton PR, Clarke C, Luyt DK, Simpson H. Recurrent cough: natural history and significance in infancy and early childhood. Pediatr Pulmonol 1998;26:256–61. 40. Chang AB. Cough. Pediatr Clin North Am 2009;56:19–31, ix. 41. Shields MD, Doherty GM. Chronic cough in children. Paediatr Respir Rev 2013;14:100–5, quiz 6, 37–8.

42. Stark P, Heenan R, Orsani F, Jachno K, Connell TG. Amoxycillin-clavulanate for chronic wet cough in children: cautious interpretation of study findings warranted. Thorax 2013;68: 296–7. 43. Kompare M, Weinberger M. Protracted bacterial bronchitis in young children: association with airway malacia. J Pediatr 2012;160:88–92. 44. Zimmerman B, Silverman FS, Tarlo SM, Chapman KR, Kubay JM, Urch B. Induced sputum: comparison of postinfectious cough with allergic asthma in children. J Allergy Clin Immunol 2000;105:495–9. 45. French CL, Irwin RS, Curley FJ, Krikorian CJ. Impact of chronic cough on quality of life. Arch Intern Med 1998;158:1657–61. 46. Yanney M, Vyas H. The treatment of bronchiolitis. Arch Dis Child 2008;93:793–8. 47. Law BJ, Carbonell-Estrany X, Simoes EA. An update on respiratory syncytial virus epidemiology: a developed country perspective. Respir Med 2002;96(Suppl. B):S1–7. 48. Schlesinger C, Koss MN. Bronchiolitis: update 2001. Curr Opin Pulm Med 2002;8:112–16. 49. McBride JT, McConnochie KM. RSV, recurrent wheezing, and ribavirin. Pediatr Pulmonol 1998;25:145–6. 50. Stein MT, Harper G, Chen J. Persistent cough in an adolescent. J Dev Behav Pediatr 1999; 20:434–6, discussion 436–8. 51. Castro M, Schweiger T, Yin-Declue H, Ramkumar TP, Christie C, Zheng J, et al. Cytokine response after severe respiratory syncytial virus bronchiolitis in early life. J Allergy Clin Immunol 2008;122:726–33, e3. 52. Backman K, Piippo-Savolainen E, Ollikainen H, Koskela H, Korppi M. Increased asthma risk and impaired quality of life after bronchiolitis or pneumonia in infancy. Pediatr Pulmonol 2014;49:318–25. 53. Fernald GW, Collier AM, Clyde WA Jr. Respiratory infections due to Mycoplasma pneumoniae in infants and children. Pediatrics 1975;55: 327–35. 54. Murphy CG, van de Pol AC, Harper MB, Bachur RG. Clinical predictors of occult pneumonia in the febrile child. Acad Emerg Med 2007;14: 243–9. 55. Sabato AR, Martin AJ, Marmion BP, Kok TW, Cooper DM. Mycoplasma pneumoniae: acute illness, antibiotics, and subsequent pulmonary function. Arch Dis Child 1984;59:1034–7. 56. Cherry JD. Epidemic pertussis in 2012—the resurgence of a vaccine-preventable disease. N Engl J Med 2012;367:785–7. 57. Plotkin SA. The pertussis problem. Clin Infect Dis 2014;58:830–3. 58. Lu PJ, Graitcer SB, O’Halloran A, Liang JL. Tetanus, diphtheria and acellular pertussis (Tdap) vaccination among healthcare personnelUnited States, 2011. Vaccine 2014;32:572–8. 59. National and state vaccination coverage among adolescents aged 13–17 years–United States, 2012. MMWR Morb Mortal Wkly Rep 2013; 62:685–93. 60. Vaccination coverage among children in kindergarten – United States, 2012–13 school year. MMWR Morb Mortal Wkly Rep 2013;62: 607–12. 61. Klein NP, Bartlett J, Rowhani-Rahbar A, Fireman B, Baxter R. Waning protection after fifth dose of acellular pertussis vaccine in children. N Engl J Med 2012;367:1012–19.

249.e2 SECTION E 

Upper Airway Disease

62. Kuncio DE, Middleton M, Cooney MG, Ramos M, Coffin SE, Feemster KA. Health care worker exposures to pertussis: missed opportunities for prevention. Pediatrics 2014;133:15–21. 63. Khetsuriani N, Bisgard K, Prevots DR, Brennan M, Wharton M, Pandya S, et al. Pertussis outbreak in an elementary school with high vaccination coverage. Pediatr Infect Dis J 2001; 20:1108–12. 64. Versteegh FG, Schellekens JF, Nagelkerke AF, Roord JJ. Laboratory-confirmed reinfections with Bordetella pertussis. Acta Paediatr 2002; 91:95–7. 65. Birkebaek NH, Kristiansen M, Seefeldt T, Degn J, Moller A, Heron I, et al. Bordetella pertussis and chronic cough in adults. Clin Infect Dis 1999;29:1239–42. 66. Lebel MH, Mehra S. Efficacy and safety of clarithromycin versus erythromycin for the treatment of pertussis: a prospective, randomized, single blind trial. Pediatr Infect Dis J 2001;20: 1149–54. 67. Cooper WO, Griffin MR, Arbogast P, Hickson GB, Gautam S, Ray WA. Very early exposure to erythromycin and infantile hypertrophic pyloric stenosis. Arch Pediatr Adolesc Med 2002; 156:647–50. 68. Goldstein LH, Berlin M, Tsur L, Bortnik O, Binyamini L, Berkovitch M. The Safety of Macrolides During Lactation. Breastfeed Med 2009;4:197–200. 69. Chen CJ, Wu KG, Tang RB, Yuan HC, Soong WJ, Hwang BT. Characteristics of Chlamydia trachomatis infection in hospitalized infants with lower respiratory tract infection. J Microbiol Immunol Infect 2007;40:255–9. 70. Eamranond P, Jaramillo E. Tuberculosis in children: reassessing the need for improved diagnosis in global control strategies. Int J Tuberc Lung Dis 2001;5:594–603. 71. American Academy of Pediatrics. Tuberculosis. In: Pickering L, editor. Report of the Committee

on Infectious Diseases. Elk Grove Village, IL: 2003. 72. Andrews T, Myer C, Bailey W. Intrathoracic lesions involving the tracheobronchial tree. In: Myer C, Cotton R, Shott S, editors. The Pediatric Airway: An Interdisciplinary Approach. Philadelphia: JB Lippincott; 1995. 73. Oermann CM, Moore RH. Foolers: things that look like pneumonia in children. Semin Respir Infect 1996;11:204–13. 74. Condino AA, Sondheimer J, Pan Z, Gralla J, Perry D, O’Connor JA. Evaluation of gastroesophageal reflux in pediatric patients with asthma using impedance-pH monitoring. J Pediatr 2006;149:216–19. 75. McGeady S. GERD and airways disease in children and adolescents. In: Stein M, editor. Gastroesophageal Reflux Disease and Airway Disease. New York: Marcel Dekker; 1999. 76. Block BB, Brodsky L. Hoarseness in children: the role of laryngopharyngeal reflux. Int J Pediatr Otorhinolaryngol 2007;71:1361–9. 77. Rothenberg SS, Bratton D, Larsen G, Deterding R, Milgrom H, Brugman S, et al. Laparoscopic fundoplication to enhance pulmonary function in children with severe reactive airway disease and gastroesophageal reflux disease. Surg Endosc 1997;11:1088–90. 78. Cohen SR, Herbert WI, Lewis GB Jr, Geller KA. Foreign bodies in the airway. Five-year retrospective study with special reference to management. Ann Otol Rhinol Laryngol 1980;89 (5 Pt 1):437–42. 79. Marcinow AM, Thompson J, Chiang T, Forrest LA, deSilva BW. Paradoxical vocal fold motion disorder in the elite athlete: experience at a large division I university. Laryngoscope 2014;124: 1425–30. 80. Landwehr LP, Wood RP 2nd, Blager FB, Milgrom H. Vocal cord dysfunction mimicking exerciseinduced bronchospasm in adolescents. Pediatrics 1996;98:971–4.

81. Chung KF, Chang AB. Therapy for cough: active agents. Pulm Pharmacol Ther 2002;15:335–8. 82. Pattenden S, Antova T, Neuberger M, Nikiforov B, De Sario M, Grize L, et al. Parental smoking and children’s respiratory health: independent effects of prenatal and postnatal exposure. Tob Control 2006;15:294–301. 83. Joad JP. Smoking and pediatric respiratory health. Clin Chest Med 2000;21:37–46. 84. Burr ML, Anderson HR, Austin JB, Harkins LS, Kaur B, Strachan DP, et al. Respiratory symptoms and home environment in children: a national survey. Thorax 1999;54:27–32. 85. Dales RE, Zwanenburg H, Burnett R, Franklin CA. Respiratory health effects of home dampness and molds among Canadian children. Am J Epidemiol 1991;134:196–203. 86. Strachan DP, Elton RA. Relationship between respiratory morbidity in children and the home environment. Fam Pract 1986;3:137–42. 87. Pandolfini C, Impicciatore P, Bonati M. Parents on the web: risks for quality management of cough in children. Pediatrics 2000;105:e1. 88. Sharfstein JM, North M, Serwint JR. Over the counter but no longer under the radar–pediatric cough and cold medications. N Engl J Med 2007;357:2321–4. 89. Schaefer MK, Shehab N, Cohen AL, Budnitz DS. Adverse events from cough and cold medications in children. Pediatrics 2008;121:783–7. 90. Vernacchio L, Kelly JP, Kaufman DW, Mitchell AA. Pseudoephedrine use among US children, 1999–2006: results from the Slone survey. Pediatrics 2008;122:1299–304. 91. FDA halts sales of some anti-vomiting suppositories … and are cough medications effective in children? Child Health Alert 2007;25:1–2. 92. Rimsza ME, Newberry S. Unexpected infant deaths associated with use of cough and cold medications. Pediatrics 2008;122:e318–22.