Contemporary Topics in Pediatric Pulmonology for the Primary Care Clinician

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Contemporary Topics in Pediatric Pulmonology for the Primary Care Clinician Gary A. Mueller, MD,a,b Stephen Wolf, MD,b Elizabeth Bacon, DO,b Shalini Forbis, MD, MPH,a Leora Langdon, RN, CPNP,b and Charlotte Lemming, MSW, LISW-Sb

Disorders of the respiratory system are commonly encountered in the primary care setting. The presentations are myriad and this review will discuss some of the more intriguing or vexing disorders that the clinician must evaluate and treat. Among these are dyspnea, chronic cough, chest pain, wheezing, and asthma. Dyspnea and chest pain have a spectrum ranging from benign to serious, and the ability to effectively form a differential diagnosis is critical for reassurance and treatment, along with decisions on when to refer for specialist evaluation. Chronic cough is one of the more common reasons for primary care office visits, and once again, a proper differential diagnosis is necessary to assist the clinician in formulating an appropriate treatment plan. Infant wheezing creates much anxiety for parents and accounts for a large number of office

visits and hospital admissions. Common diagnoses and evaluation strategies of early childhood wheezing are reviewed. Asthma is one of the most common chronic diseases of children and adults. The epidemiology, diagnosis, evaluation, treatment, and the patient/parent education process will be reviewed. A relatively new topic for primary care clinicians is cystic fibrosis newborn screening. The rationale, methods, outcomes, and implications will be reviewed. This screening program may present some challenges for clinicians caring for newborns, and an understanding of the screening process will help the clinician communicate effectively with parents of the patient.

Cystic Fibrosis and the Evolution of CF Newborn Screening

In addition, the American College of Medical Genetics (ACMG), upon the request of the Maternal and Child Health Bureau, convened an expert panel to evaluate conditions that should be included on newborn screening panels. Cystic fibrosis (CF) was one of the 29 conditions originally listed on this panel. CF differs somewhat from other disorders in conventional newborn screening for two reasons: it incorporates DNA testing into part of the primary test algorithm and a missed diagnosis will not result in a devastating neurologic problem, imminent pain, or early death. Serum immunoreactive trypsinogen (IRT) is the only digestive enzyme produced to originate solely from the pancreas. Confirmatory research in Australia, France, and Colorado validated the use of IRT from a Guthrie card or dried blood dot as an initial screening test.2 Three decades of subsequent research has added strong evidence regarding the benefits of early diagnosis for patients with cystic fibrosis. Newborn screening programs for cystic fibrosis have grown rapidly and a variety of different testing methods and evaluation systems have been implemented, but all screening algorithms begin with IRT and use a sweat chloride

ewborn screening is a highly successful and essential public health endeavor that began in the 1960s. It is responsible for developing, implementing, and overseeing policies and procedures for identifying newborns with congenital disorders, such as PKU and congenital hypothyroidism, to enable timely intervention to improve neurologic outcomes. This program includes a system of education, screening, follow-up, diagnosis, management, and evaluation. Conditions that are determined suitable for newborn screening follow Wilson and Jungnerdefined criteria.1 These include the capacity to detect the condition at an early stage of the disease, the availability of an effective treatment, and other factors.

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From the aDepartment of Pediatrics, Boonshoft School of Medicine, Wright State University, Dayton, OH; and bDepartment of Pulmonary Medicine, Dayton Children's Hospital, Dayton, OH. Curr Probl Pediatr Adolesc Health Care 2013;43:130-156 1538-5442/$ - see front matter & 2013 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.cppeds.2013.05.001

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test for making the diagnosis of CF. Like most screening tests, none of these methods currently achieves 100% sensitivity. Sensitivity varies depending on the screening algorithm used, the performance of laboratory assays, the cutoff point assigned to the screening assay, and the prevalence in the population tested. The diagnosis of CF is made by measuring sweat chloride concentration. However, this testing is not amenable to mass screening. In the early 1970s, it was noted that newborns with CF were born with elevated serum levels of the pancreatic enzyme trypsinogen. Then, in 1979, IRT use was reported as an indirect marker for identifying CF in newborns.2 Colorado initiated an IRT/IRT-based CF newborn screening program in 1982. Initial protocols required a second blood sample when an initial IRT was elevated and this delayed subsequent sweat testing and diagnosis. With the development of DNA diagnostic tests for the most common mutations in the CFTR gene, an alternate testing algorithm was developed. This removed the need for the second blood draw, diminished time to diagnosis, and improved screening. The second algorithm is known as IRT/DNA and was proposed by the state of Wisconsin. The drawback of this two-tier protocol is the potential for unwanted carrier detection and inability to test for all known mutations in a costeffective manner. Wisconsin used the IRT/DNA test and tested for the delta F508 mutation alone. The delta F508 mutation accounts for 67% of all abnormal alleles and 85% of all CF patients have at least one delta F508 mutation. In 1985, Wisconsin performed a randomized, blinded prospective study looking at CF newborn screening using IRT alone or a two-tiered IRT/DNA test. Half of the newborns were assigned to an early diagnosis group. Using the IRT-alone protocol, newborns with an IRT of 4180 ng/ml (99.8th percentile) were contacted by their primary care provider and at approximately 6 weeks of age a sweat test was obtained at one of the State's CF centers. A CF diagnosis was confirmed if the chloride level was 460 mmol/L. The other half of newborns whose IRT was 4100 ng/ml samples were analyzed for the presence of the delta F508 CFTR mutation. Those patients who were heterozygous or homozygous for delta F508 were contacted by the primary care clinician and a sweat test was performed. This study concluded that the IRT/DNA approach to CF newborn screening decreases the number of false-positive subjects contacted, without a significant increase in cost.3

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However, CF genotype is highly variable depending on ethnicity and geographic origin. Of all CF patients, 15% do not have the delta F508 mutation. By comparison, more than 90% of alleles in the Danish CF population are delta F508. An additional panel of four CFTR mutations, W1282X, N1303K, 3849 þ 10 kb C to T, and G542X, accounts for 97% of alleles in Ashkenazi Jews. However, only 25% of Puerto Rican mutations are identified with a panel of the16 most common mutations. In Massachusetts, delta F508 accounts for about 62% of CF alleles. Using this information, Massachusetts implemented a multipleCFTR-mutation testing showing improved sensitivity to about 95%. Increased sensitivity from multiple mutation panels also resulted in 26% more carrier identification in Massachusetts.4 Each state directs its own newborn screening policy. Therefore, each state determines which CF screening algorithm it will use. As with all NBS programs, a balance must be struck between sensitivity, specificity, and clinical utility in determining which algorithm to use in CF NBS. Currently all 50 states in the United States have adopted newborn screening protocols for cystic fibrosis.

Benefit of CF Newborn Screening Newborn screening programs for cystic fibrosis were introduced with the expectation that diagnosis soon after birth would allow treatment to be initiated in CF clinics before the development of significant malnutrition or lung disease. The implicit assumption was that early detection and treatment would lead to better clinical outcomes. The most obvious benefit from NBS for CF has been improved nutritional status.5 The Wisconsin CF Neonatal Screening Project designed a randomized clinical trial to assess the benefits and risks of early diagnosis through screening.6 They studied two cohorts, an early diagnosis screened cohort and a standard diagnosis control group, from 1985 through a 13-year follow-up. Despite similar nutritional therapy and the inherently better pancreatic status of the control group, analysis of nutritional outcomes revealed significantly greater growth associated with early diagnosis. Additionally, the results showed that severe malnutrition persists after delayed diagnosis of CF and that catch-up may not be possible.6 A study from Australia found the same type of results in 2011.7 Martin et al.8 compared the US and Australian Cystic Fibrosis Registries

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looking for the impact of newborn screening using comparison of demographics, clinical practice, and outcome measures such as differences in pulmonary function and growth. The results showed a significant difference from those diagnosed by NBS. Australian children had significantly greater mean height and weight percentiles than US children. Mean FEV1 was similar in the two countries. The conclusion from this study was children diagnosed with CF after newborn screening benefited from better lung function and BMI than those diagnosed clinically.8

Differences in Newborn Screening Algorithms IRT/IRT is the simplest and most cost effective of CF newborn screening modalities. Elevated serum trypsinogen levels at birth are screened for, with the cutoff for a positive value being above the 90–99.5th percentile of a birth cohort. Usually this is about 100 ng/ml IRT but may need to be adjusted for the population screened. Specimens showing elevated levels at birth are re-tested at 2 weeks of age. The positive value is then adjusted for age, usually the 95th–97th percentile, as a decline in IRT is usually seen with age.5 This method has the advantage of being a single biochemical method and lacks the need for genetic reporting or counseling. However, setting cutoff values for particular populations can be difficult. Also, immunoreactive trypsinogen (IRT) values remain fairly stable until about 2 weeks of age and then decrease. In the majority of patients with CF, this value will remain elevated for at least 1 year. Low-birthweight infants and ill infants also can have elevated IRT values possibly due to increased stress at birth, immaturity, or other illness in these infants. Other variations in IRT have been noted between reagent lots, in different seasons (significantly lower in summer than winter), and in different ethnic groups (African-American higher than Caucasians). Due to these noted variations, some laboratories have begun using floating cutoff values calculated daily. Advantages of this model include simplicity of one marker used, avoidance of carrier detection and subsequent need for genetic counseling. Disadvantages are difficulties in setting cutoff values, requirement of second blood specimen, and occurrence of false-positive results due to stressed premature infants and African-American newborns.5 IRT/DNA protocols screen for elevated IRT using a cutoff value of 1–5% of the highest samples in a birth cohort are then submitted for DNA analysis.5 At a

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minimum, a 25-mutation panel for CFTR is recommended by the ACMG. Infants found to have one or two mutations are considered as positive for NBS and referred for sweat chloride testing. In the US, 90% of newborns evaluated for CF are screened using IRT/DNA protocols.7 Specimens found to have extremely high IRT with no mutations may also be referred for sweat testing. Use of DNA analysis in the second tier of screening necessitates the selection of mutations in the CFTR gene for testing. A decision can be made to test for only the delta F508 mutation, for delta F508 and multiple mutations associated with severe disease, or for a panel of multiple mutations that includes some variants associated with mild or variable phenotypes. The frequency of delta F508 in the community will help determine the usefulness of a single mutation assay in the second tier of the screen. As discussed, earlier in Massachusetts, the use of a multiple mutation panel, rather than just a single panel for delta F508, increased the detection of affected infants by 50% and reduced the false-negative rate fourfold; although it also increased detection of carriers by 43%.5 Challenges reported in choosing multiple mutation panels include reagent availability, genotype variations seen in communities, and genotype–phenotype relationships (mild vs. severe). The IRT/IRT/DNA model requires programs to collect a second specimen and ideally have the ability to link these two specimens. In this model, the IRT cutoff value is lowered to improve sensitivity and the second IRT is generally only performed in a subset of initial specimens. This method depends on the ability to have accurate record linkage and reliable demographic information. Typically the second IRT is set around the highest 5–10% of initial IRT levels. Second elevated IRT results are then referred for mutation analysis. If the second specimen is not received, screening can be completed by performing DNA analysis on the initial specimen. This method identifies fewer CF heterozygote carrier infants. Finally, the IRT/DNA/Expanded Genetic Analysis (EGA) model is similar to the IRT/DNA model where two CF-causing mutations are identified but differ in the approach when single mutations are detected. When single mutations are identified in the EGA program, the sample is further tested for the presence of any additional CFTR mutations.5 Current EGA methods are able to detect nearly all types of mutations including novel variants that, in some cases, may result in disease. However, additional mutations that do not cause CF disease or are of unknown clinical significance are also

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detected, and should not be reported. In California, which has the largest program using this method, sweat chloride testing is only performed when two CFTR mutations are identified. An advantage of this method is that the sequencing step lowers the number of confirmatory sweat chloride tests compared to the IRT/DNA method. Disadvantages include higher laboratory costs and potential delays in diagnosis because of the sequencing step. Another major disadvantage is the detection of newborns carrying second CFTR mutations of unknown clinical significance. These infants with CRMS, CFTR-related metabolic syndrome, will enter prolonged follow-up protocols, are at risk for unnecessary clinical management, and may possibly never develop CF. This uncertainty created with the diagnosis of CRMS may cause anxiety in families.

performing the test. Collection from two sites on the body reduces the likelihood of insufficient sampling. Positive sweat chloride testing results are values of 460 mEQ/L and diagnostic of CF. Negative sweat chloride test results are values o30 mEQ/L for infants less than 6 weeks of age. Borderline sweat chloride results are values between 30 and 59 mEQ/L. The diagnosis of CF is not always straightforward. The sweat chloride test remains the gold standard for CF diagnosis but does not always give a definitive result. Genotype analysis also does not always provide clarity. More than 2000 mutations have been identified in the CFTR gene, not all which result in CF. Harmful mutations in the gene can present from sinusitis in adulthood to severe lung, pancreatic, and liver disease in infants.

CF Newborn Screening Diagnostic Dilemmas

Borderline Sweat Tests

If an infant has an elevated immunoreactive trypsiIn infants with a positive NBS, a diagnosis of CF can nogen (IRT) and/or CF mutation then a sweat chloride be made if the sweat chloride value is 460 mEQ/L. CF test is performed. The protocol for scheduling the is very unlikely in infants with sweat chloride valueparent and patient, and further CF newborn screening s o30 mEQ/L. Infants with a positive CF NBS and education process, is determined by each state. Consweat chloride values in the intermediate range, 30– firmatory sweat chloride testing is the gold standard for 59 mEQ/L, should undergo at least a CFTR gene diagnosis and should be conducted on all infants with a mutation assessment if this is not included in the positive NBS result, including those with two mutations NBS.2 In the presence of two CF-causing mutations, a 5 detected. A positive screen result is not a diagnosis and diagnosis of CF can be made. Maternal DNA should be analyzed if necessary to detershould always be confirmed by a mine whether the two mutations diagnostic test for CF. In fact, approximately 90% of positive NBS do not A positive screen result is are present on the chromosome2 in a cis or trans relationship. have CF. Additionally, as it is a screening test, there will be a very not a diagnosis and should Infants with intermediate sweat always be confirmed by a chloride values and no or one low occurrence of false negatives. Thus, in the correct clinical context, a CF-causing mutation cannot be diagnostic test for CF. sweat chloride test should still be diagnosed definitively with CF. performed despite a negative CF These infants are at an increased NBS. Sweat chloride testing should always be performed risk for CF, as demonstrated by the abnormal NBS and at a laboratory affiliated with a CF Foundation accredited increased sweat chloride value, and should be followed care center, where testing can be coordinated with up. Clinical manifestations of CF can appear in the first appropriate genetic counseling and clinical follow-up. few weeks of life and therefore a clinical assessment, Performing sweat chloride testing in newborns including nutritional status and growth and respiratory presents unique challenges. Sweat testing should not disease, should be performed at a CF care center by be performed in newborns less than 48 h of age. 2 months of age. The sweat test should be repeated at Performing the sweat chloride test before the newborn age 2–6 months. If the sweat chloride levels remain in is 2 weeks of age and/or less than 2 kg has been an intermediate range, 40–59 mEQ/L, for infants aged associated with higher incidence of inadequate sam6 months and older, the child should continue to be 6 pling. When inadequate sweat volume is obtained, the monitored every 6–12 months with clinical evaluations, repeat sweat testing, and other testing as appropriate.2 In sweat chloride test should be repeated. Sweat collecthe presence of one CF-causing mutation and clinical tion and analysis should follow CLSI document C34 findings suggestive of CFTR dysfunction, and the laboratory should have adequate experience in Curr Probl PediatrAdolesc Health Care, July 2013

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bronchiectasis, pancreatitis, etc., a diagnosis of CFTRrelated metabolic syndrome, CRMS, can be made.

CRMS (CFTR-related Metabolic Syndrome) Individuals identified by NBS are diagnosed with CF if they have an elevated sweat chloride level or if they have inherited two known disease-causing mutations in the CFTR gene. However, not all CFTR mutations are known to be disease causing.9 The term CFTR-related metabolic syndrome or CRMS is used to describe infants identified by high IRT on NBS who have sweat chloride values o60 mEQ/L and up to two CFTR mutations, at least one of which is not clearly categorized as a “CFcausing mutation” and thus do not meet CF Foundation guidelines for the diagnosis of CF. In most cases infants found to have high IRTs on NBS undergo an initial sweat test by 2–4 weeks of age at an accredited laboratory and most will also have had some CFTR mutation testing as part of the NBS. It is recommended that infants with initial sweat chloride values in the intermediate range (30–59 mEQ/L) have a repeat sweat test by 2 months of age, which may confirm the intermediate value or demonstrate resolution into the normal, o30 mEQ/L, or abnormal 460 mEQ/ L, range. Infants with persistent intermediate sweat tests should have CFTR DNA analysis, access to genetic counseling, and an evaluation by a CF specialist. These infants should also undergo a third sweat test at 6 months of age and be monitored by their primary care clinician and a CF clinician, as these repeated sweat tests may not provide clear diagnostic information. After complete assessment, healthy infants with elevated IRT should be considered to have CRMS if they have either: (1) Intermediate sweat chloride concentrations on at least two occasions and fewer than two CFcausing CFTR mutations or (2) A normal sweat chloride and two CFTR mutations, of which no more than one is known to be CF-causing.9 In the United States, 8% (N ¼ 114) of CF patients diagnosed in 2011 have cystic fibrosis-related metabolic syndrome. Overall 1095 individuals were diagnosed with CF by NBS. Infants with CRMS should be monitored routinely as they are at an increased risk for developing CF-like symptoms and because evolving signs and symptoms, new information about disease-

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causing CFTR mutations, or change in sweat chloride concentrations may ultimately lead to a diagnosis of CF. When a child is diagnosed with CRMS, a potentially difficult situation is created for the family. Care should be given to first to do no harm as many of these patients will live a long and healthy life with low risk of ever developing signs or symptoms of CF. However, because preventive care is preferred over symptomatic care, these individuals should not be lost to follow-up.

CF Newborn Screening Psychosocial Aspects The newborn screening process is a significant enhancement to the medical care of those with cystic fibrosis although it has brought about new trials and tribulations for families and the cystic fibrosis center medical team (i.e. physicians, nurse practitioners, nurses, social workers, dieticians, respiratory therapists, pharmacists, psychologists, and physical therapists). The new parent is informed that their infant tested as positive in a screen that requires further medical intervention. The method by which the primary care clinician informs parents about the abnormal screening represents a central factor in the parent's level of uncertainty and distress during the waiting period.10 Paramount in this process is communication to families by a CF clinician specialist as soon as possible to answer questions and alleviate fears. The second is the ability to schedule the sweat test in a timely manner. Information given to them prior to the test and on that day is also crucial in their ability to cope.10 Higher incidences of depressive symptoms are reported prior to diagnostic confirmation via the sweat test and on average does not decrease until 6 months from the first positive sweat test.8,10 The initial studies on newborn screening did not show significantly higher stress scores over the traditionally diagnosed CF families, however, they did have a higher frequency of “at-risk scores.”11 The earlier the diagnosis can be made after notification of a positive NBS, the more confidence the parents have in the medical profession and lessen their anxiety.12 This anxiety can be more intense and prolonged with the children that fall into the category of CRMS. Prior to new born screening, parents sought answers from clinicians regarding their child's slow rate of growth or chronic coughing. The relationship between the family and the medical staff began often with the

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goal of treatment answers and collaboration. With newborn screening, the initial contact, made as a result of a test, may begin with shock. A goal for the cystic fibrosis center medical team will be to provide support and guidance for their psychosocial challenges and concerns that accompany living with a chronic illness. Parents often experience high levels of emotional stress. They begin to worry and may have guilt about “giving the child CF.” They often search for answers on the internet and in the community. They begin to question relatives and seek answers to who may also carry the gene. Anxious feelings may arise about the child's symptoms, which creates a hypervigilent state of worry for the parent.13 The earlier the clinician can provide the diagnosis is consistently associated with less negative feelings and more confidence in the doctors and medical team.14 The opposite results are seen when there is a prolonged diagnostic period. Parental anger and anxiety increase along with mistrust of the medical profession.8,14 Newborn screening for CF represents a challenge for the healthcare system. However, the benefits of improved short- and long-term outcomes are becoming more apparent.4,7,8 Early diagnosis, before structural damage occurs, is making a difference. The primary care clinician aids in this process by seeing that a positive NBS is promptly referred to the nearest CF treatment center, and is supportive of the family with appropriate medical information before diagnosis confirmation. The early diagnosis of CF by NBS has introduced a new psychosocial dynamic for the clinician. When handled correctly, parental confidence and hope can be improved compared to the pre-NBS era.

Chronic Cough in Infants, Children, and Adolescents Cough is the most common symptom of respiratory disease and overall the most common presenting symptom in the pediatric age group.15 Although cough may be a symptom of respiratory disease, it is very important to remember that cough itself is a normal protective reflex. As such it is an integral part of the intrinsic lung defenses and an essential component of airway clearance and thus lung health. The cough reflex originates with cough receptors that are widely distributed in the respiratory tract, but it is important to note that cough receptors are only present in areas innervated by the afferent vagus nerve. The

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location of the receptors involved in the initiation of the cough reflex is important in the evaluation and management of chronic cough. Although cough is a reflex, it is important to remember that there is cortical modulation of this reflex. Thus, unlike other reflexes, cough is both voluntarily and involuntarily regulated and as a result cough can be voluntarily initiated or suppressed. Most cough in children is related to a previous viral upper respiratory infection and is self-limited, typically lasting for 1–3 weeks before resolving. It has been shown that 35–40% of school-aged children still cough 10 days after the onset of a viral upper respiratory and 10% will still have a cough after 25 days.16 In addition, since it is a protective reflex, some cough in healthy children is to be expected and accepted as normal. It has been found that otherwise healthy school-aged children can experience cough up to 10 times/day.17 Thus, what is considered to be a “normal” cough, what is expected following viral upper respiratory infection, and what is considered to be “chronic” may overlap. There is no exact definition of chronic cough in children but, in general, it is usually defined as a daily cough of greater than 4 weeks in duration. This definition of chronic cough as cough lasting for greater than 4 weeks is in part due to the natural course of viral upper respiratory infections but it also due to both the social burden associated with chronic cough and also with the intention of reducing long-term complications related to the underlying cause.15 Cough arises as a symptom from many underlying disorders and common causes of cough in adults should not be extrapolated to children. Consideration must be given to specific conditions associated with chronic cough in children and adolescents including asthma, disorders of the upper airway, cystic fibrosis, infection such as pertussis, abnormalities of the airways including tracheomalacia and bronchomalacia, protracted bacterial bronchitis, bronchiectasis, gastroesophageal reflux, swallowing dysfunction, foreign body aspiration, interstitial lung disease, and because the cough reflex can be cortically modulated, the habit cough syndrome is very common particularly in older children and adolescents. Of course, treatment of the cough must be based on the underlying etiology. The majority of children with chronic cough can easily be managed by primary care practitioners. Only 17.6% of children in a recent cohort of children with chronic cough had an etiology (bronchiectasis, cystic fibrosis, tracheomalacia, or aspiration lung disease) that is generally diagnosed and managed by pediatric pulmonologists.15

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Evaluation The evaluation of chronic cough begins with the characteristics of the cough, the history, and physical exam. Characteristics of the cough may suggest the underlying etiology. These characteristics include, but are not limited to, brassy or barky, dry or wet, and paroxysmal, and nocturnal. If it is brassy or barky in nature, one may consider in infants tracheomalacia or other airway abnormalities, while in adolescence habit cough must be given consideration. If wet or productive then sinusitis, persistent bacterial bronchitis, cystic fibrosis, or other causes of bronchiectasis must be considered. If the cough is dry then asthma or the rare interstitial lung diseases must be considered in any age group. Should the cough be paroxysmal in nature then pertussis or pertussis-like syndromes must be considered. A nocturnal cough is often associated with asthma or post-nasal drip while the hallmark of habit cough is that it ceases at night. Finally, an early morning cough associated with awakening may point to a problem with impaired airway clearance such as persistent bacterial bronchitis, cystic fibrosis, and other causes of bronchiectasis. The physical exam may point to a specific underlying disorder. The physical exam of the head and neck may reveal a transverse nasal crease, allergic shiners, boggy nasal mucosa, polyps, post-nasal drip, or cobblestoning of the posterior pharynx. Evaluation for the chest may show hyperinflation, wheezes, crackles, or stridor. Examination of the extremities may reveal digital clubbing. However, many times the physical examination is normal. A chest x-ray is indicated for all children and adolescents with a chronic cough. Spirometry is recommended in children who are able to perform the test usually beginning at age 5. An obstructive pattern associated with demonstration of a reversible obstruction following a bronchodilator (412% improvement in forced expiratory volume in 1 s or FEV1) is helpful in suggesting asthma as a cause of the cough. A restrictive pattern on spirometry manifested by a decreased forced vital capacity (FVC) or increased FEV1/FVC ratio may suggest other etiologies of the cough such as interstitial lung disease. A therapeutic or empiric trial of antibiotics for a wet cough for suspected sinusitis or protracted/persistent bronchitis is often used and may be warranted.18 A similar therapeutic trial of oral steroids may be used for a dry cough should history and physical exam point to asthma as the suspected cause.18 However, if a

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therapeutic trial of medication is initiated, either with antibiotics or steroids, then a specific plan for the length of therapy must be determined as well as a follow-up visit to document the response to the medication trial. If there is no response then further evaluation is indicated. However, for both sinusitis and protracted or persistent bacterial bronchitis, a cough may recur after initial clearing and a prolonged course of antibiotics may be required.19,20

Common Causes Asthma Children with asthma may present with cough as part of their presentation but most commonly children with asthma present with both cough and wheezing. However, because of the very high prevalence of asthma, the presence of an isolated cough in any child should warrant consideration of asthma as the underlying cause, especially if the cough is worse with activity, occurs at night while asleep, or is worse with viral upper respiratory infections. The absence of wheezing on exam does not exclude the diagnosis, while the presence of a bronchodilator response on spirometry may be quite helpful. Asthma is a disease characterized by increased airway reactivity resulting in reversible airway obstruction. This airway obstruction is composed of varying amounts of bronchial smooth muscle spasm that is responsive to β-2 adrenergic agonists; and mucosal edema and secretions that are responsive to corticosteroids. Thus, if asthma is suspected, an empiric therapeutic trial of steroids and inhaled β agonist is recommended. In most children, the bronchodilator can be delivered via metered dose inhaler with the aid of a spacer. The steroid trial can be in the form of Prednisone 2 mg/kg/day given orally in divided doses twice daily for 7 days. Alternatively a moderate dose of inhaled corticosteroids (200–400 mg/ day of fluticasone, 440–800 mg/day of budesonide, or equivalent) with the use of a spacer can be employed.18 Response to the inhaled corticosteroids can be delayed for as long as up to 4 weeks, so in many instances the trial of oral steroids is preferred by clinicians and parents. Follow-up is essential to document response and to discontinue medications in patients in whom the cough does not respond.

Disorders of the Upper Airway Cough due to disorders of the nose and sinuses, although quite common in adults, is infrequently seen in infants,

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children, and adolescents. The upper airway proximal to the larynx is not innervated by the vagus nerve and cough receptors begin in the larynx, so increased nasal secretions from allergic rhinitis, chronic rhinitis, sinusitis, or in younger children, adenoiditis cannot stimulate cough directly but must reach the larynx to cause cough. Thus the cough associated with nasal or upper airway disorders is many times wet because it is caused by the clearing of secretions that reach the larynx. In addition, such a cough will accompany other poorly controlled nasal symptoms such as nasal congestion, rhinitis, or sneezing and may be more pronounced when lying supine. The physical exam may be helpful if cobblestoning of the posterior pharynx is present or if frank post-nasal drip is visualized. Treatment is directed at the underlying cause of the rhinitis. If sinusitis is suspected then an empiric therapeutic trial of antibiotics may be indicated without obtaining sinus x-rays because the test has a very low specificity.20 In addition, abnormal sinus x-rays in asymptomatic children and in children with uncomplicated viral upper respiratory infections are quite common.20

Cystic Fibrosis There is considerable variability in the mutations of the Cystic Fibrosis Transmembrane Regulator Gene (CFTR), now numbering more than 1900, and these mutations result in an altered and variable function of the chloride channel. This results in the potential for a wide range of clinical presentations that can range from the classical cystic fibrosis with malabsorption, failure to thrive, and chronic lung disease to less common isolated aspermia and congenital absence of the vas deferens in males. As a result it is not uncommon for CF patients in adolescence and early adulthood to present to their primary clinician with isolated persistent cough.21 In addition, many of these CF variants may not be identified in newborn screening programs. Thus cystic fibrosis should be considered as a cause of chronic cough in older children and adolescents even in the absence of other signs and symptoms. This is particularly true if the cough persists despite aggressive treatment of suspected underlying asthma. The diagnosis of cystic fibrosis is made by performing a sweat chloride measurement.

Pertussis In the light of numerous recent outbreaks, pertussis is becoming an increasingly important consideration in persistent cough. Although usually associated with other symptoms such as fever, pertussis can present

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as a persistent cough especially in the presence of previous antibiotics and vaccinations.22 In addition, pertussis should be suspected even if a child has been fully immunized because partial vaccine failure can occur.23 The cough of pertussis is characteristically paroxysmal or spasmodic and classically occurs during the second or paroxysmal phase approximately 2 weeks into the illness. There may be an isolated cough or a series of repetitive hacking spells of cough in a single expiration. The cough may be severe enough to be associated with post-tussive gagging or emesis. The classical whoop following a coughing paroxysm is more common in infants but many times will be absent. Diagnosis is made by identifying the pertussis antigen through a polymerase chain reaction performed on nasopharyngeal secretions obtained using a nasal swab. Establishing a diagnosis is most important to prevent its spread. Treatment with new macrolide antibiotics, such as clarithromycin or azithromycin, demonstrate efficacy comparable to erythromycin but with fewer gastrointestinal side effects and are the preferred antibiotics of choice. The cough associated with pertussis can be prolonged and is often referred to as the “100-day cough.” Treatment of the cough after the appropriate course of antibiotics can also be quite difficult. Anticholinergic agents such as ipratropium bromide may be considered.24

Airway Malacia Chronic cough has also been well described in airway malacia. Although primarily associated with symptoms in infants, the presentation of cough due to airway malacia may not be present until later in childhood.25 Cough resulting from airway malacia occurs from the increased intrathoracic pressure during cough causing the anterior and posterior walls to collapse causing irritation and additional stimulation of the cough receptors in that location and the resulting characteristic brassy or barky cough. In addition, poor airway clearance of mucous due to collapse of the airway during expiration can occur resulting in retained secretions that act as an ongoing stimulus for cough. Related to the poor airway clearance associated with airway malacia is the clinical entity of protracted bacterial bronchitis. Infants with protracted bacterial bronchitis, of which 74% had demonstrated airway malacia, presented with a persistent productive cough and associated neutrophilia and high colony counts of Streptococcus pneumonia, Haemophilus influenza, or Moraxella catarrhalis

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from bronchoalveolar lavage.26 As mentioned previously, cough associated with protracted bacterial bronchitis responds to appropriate antibiotics but may require a prolonged course, repeated courses, or even maintenance or prophylactic antibiotics.

Bronchiectasis

Bronchiectasis, in the absence of cystic fibrosis, is also a consideration in chronic cough. The cough can be isolated or associated with wheezing, and is usually wet in nature. As a result bronchiectasis should also be considered if the cough persists despite aggressive treatment of suspected underlying asthma. It must also be considered if there is a past history of a severe respiratory infection or ongoing failure to thrive. Chest x-ray may reveal the presence of bronchiectasis but sensitivity is lacking, thus High-Resolution Computerized Tomography (HRCT) of the chest may be required.

Habit Cough As previously mentioned, there is cortical modulation of the cough reflex so cough can be initiated and suppressed voluntarily. The habit cough presents with a very characteristic harsh, tracheal, barking, or honking cough which is repetitive and extremely irritating to the parents, fellow students, teachers, and healthcare clinicians but many times not to the child. The major characteristics of this cough are its absence while asleep and many times the cough will clear if the child is distracted. Of course, diagnostic workup for this cough should be minimized. Habit cough can often be diagnosed based on its distinctive clinical characteristics. Treatment of the habit cough may be frustrating for the clinician and parent and very time consuming. Various approaches including reassurance and distraction, self-hypnosis, and biofeedback have been advocated.27,28 Suggestion therapy, which has been reported to result in the complete cessation of symptoms in 15 min, perhaps is the most effective.29 Suggestion therapy utilizes a “distractor” such as sipping on warm water, a throat lozenge, or lollipop along with strong verbal reinforcement that this will stop the cough. It can be implemented in the office but in order to be successful the patient and the parents must be committed to this therapy.

Gastroesophageal Reflux There are several mechanisms by which gastroesophageal reflux disease (GERD) may trigger cough,

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directly through the stimulation of laryngeal cough receptors or due to gross or microaspiration and indirectly through vagal-mediated neural reflexes that produce cough in response to distal esophageal reflux. Gastroesophageal reflux can also occur as a direct result of coughing due to the associated increase in both intrathoracic and intra-abdominal pressures during a cough. Thus, it can be very difficult to differentiate cause and effect with gastroesophageal reflux. The overall prevalence of gastroesophageal reflux (GER) in the pediatric age group is quite high. Gastroesophageal reflux occurs in half of infants under the age of 3 months, reaches a peak at 4 months of age, and then decreases to about 5% by 1 year of age.104 While GERD is a frequent cause of chronic cough in adults, it is infrequently the cause of isolated cough in children.30 A meta-analysis has not documented the efficacy of therapy for GERD in treating chronic cough in children.31 In addition, the response of cough to anti-reflux therapy can take up to 8–12 weeks in adults but unfortunately there are no data regarding the time for resolution of the cough in children with reflux therapy.30 Finally, no randomized controlled study has been conducted on the use of proton pump inhibitors for the treatment of cough in children.30

Aspiration Lung Disease Feeding and swallowing disorders in children are prevalent and often complex and multifactorial in nature.32 Oropharyngeal aspiration (OPA) and swallowing dysfunction present with a variety of signs and symptoms including cough. Cough is rarely an isolated symptom but is rather associated with other symptoms such as wheezing, wet voice, noisy or wet breathing, choking, gagging, and recurrent pneumonia. Cough associated with a wet voice is the most frequent clinical marker in OPA.32 Evaluation of suspected OPA may include a referral to a speech pathologist or feeding specialist, modified barium swallow or video fluoroscopic swallow study, flexible endoscopic evaluation of swallowing, nuclear studies such as salivagram, bronchoscopy, and gastrointestinal studies.33 In infants and children with foreign body aspiration, cough is a common symptom. Decreased breath sounds and wheezing are also common. The clinical presentation of foreign body aspiration is a sudden onset of cough. However, chronic cough can be the presenting symptom in a previously missed inhalation of a foreign body.34 A normal chest x-ray does not exclude foreign body aspiration and either a specific medical history or

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an asymmetric or changing physical exam may suggest additional evaluation. This consists of either inspiratory or expiratory chest x-rays or bilateral decubitus films looking for hyperinflation. Flexible fiberoptic bronchoscopy may also be helpful. However, if the index of suspicion is quite high, a rigid bronchoscopy is indicated so that diagnosis and removal of the foreign body can be accomplished during the same procedure. Diagnosis is essential to prevent long-term morbidity. Long-term complications such as bronchiectasis from undiagnosed foreign body were found in 60% of children who were diagnosed 30 days after inhalation.35

Interstitial Lung Disease A dry, nonproductive cough can be the presenting symptom of interstitial lung disease (ILD) in children. ILD is rare when compared to other forms of pediatric lung disease and may be caused by a diverse diseases such as infections, inhalation injury, auto immune disorders, sarcoidosis, pulmonary hemorrhage syndromes, structural lung disease such as lymphangiectasia, and metabolic disease, all of which are beyond the scope of this paper but are reviewed elsewhere.36 The dry, nonproductive cough is usually seen in conjunction with other symptoms such as a dyspnea on exertion, tachypnea, hypoxemia, and fatigue. Common physical findings in children and adolescents include cyanosis, clubbing, crackles, and increased work of breathing manifested by inspiratory retractions. However, the physical exam may be normal, particularly early on in the disease process. Hypoxemia is common, especially with exercise. Spirometry usually demonstrates a restrictive pattern with a decrease in forced vital capacity. Typical chest x-ray abnormalities include parenchymal densities that are either reticular nodular or ground glass in appearance. High-Resolution Computerized Tomography (HRCT) of the chest is more sensitive in detecting the distribution and pattern of disease. If interstitial lung disease is suspected, a referral to a Pediatric Pulmonologist for further evaluation is warranted.

Dyspnea in Children and Adolescents In general, the term dyspnea refers to the sensation of feeling short of breath or the uncomfortable feeling of breathlessness. Unlike physical signs found in underlying cardiopulmonary disease, dyspnea is a perception or sensation. It is a very complex symptom that involves both physiological and psychological factors. The

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sensation of dyspnea can reflect altered pulmonary mechanics associated with pulmonary disease, occur with acute hypoxemia, hypercapnia or acidosis, and can be influenced by or even caused by cognitive or psychological factors. Dyspnea can occur as a result of deconditioning, obesity, underlying airway disease, parenchymal and interstitial lung disease, respiratory muscle abnormalities, metabolic or blood gas abnormalities, cardiac disease, chest wall deformities, and anemia. Dyspnea at rest by itself is an infrequent complaint in children and adolescents; however, dyspnea with exercise or exertion is quite common. Presenting complaints may vary from parents of younger children who feel their child “cannot keep up with their friends” or “must sit down to rest” to adolescents who complain of “shortness of breath even with simple exercise” or “they can't seem to get a deep enough breath in.” Dyspnea out of proportion to the amount of exercise may be an early manifestation of an underlying cardiopulmonary process. When one goes from a state of rest to a state of exercise both oxygen consumption and carbon dioxide formation increase causing an increase in alveolar ventilation. A linear relationship exists between oxygen consumption and ventilation. This increase in alveolar ventilation is achieved by both increases in tidal volume at low to moderate workloads and with increases in respiratory rate at increasing levels of exercise. However, during this expected increase in ventilation, if there is underlying pulmonary disease associated with an increase in mechanical load, then there will be a rapid mismatch or disassociation between the respiratory drive and the amount of work that is achieved. This disassociation results in the sensation or perception of dyspnea. Thus, if underlying conditions exist, dyspnea occurs out of proportion to the amount of exercise and thus may be an early manifestation of an underlying cardiopulmonary process. In the evaluation of dyspnea, it is important to remember that other factors can influence the sensation of feeling short of breath. The perception of dyspnea is strongly influenced by behavioral and cognitive factors. These psychological factors may influence the sensation of dyspnea or may even create the sensation itself. Feelings of anger or depression can intensify the perception of dyspnea and in panic or hyperventilation attacks the perception is experienced without any underlying physiologic abnormalities. The sensation of dyspnea is stronger in patients with higher scores for anxiety and has been reported in patients with anxiety disorders with no underlying cardiopulmonary disease.37,38

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It is also important to remember that the perception of dyspnea may be diminished in children with underlying chronic cardiopulmonary disease because they adapt to the perception of dyspnea and as a result may under report symptoms. This diminished perception of dyspnea is seen in patients with near fatal asthma.39

Physical Findings Abnormal physical findings associated with dyspnea may be absent at the time of physical exam. However, findings consistent with increased work of breathing such as inspiratory retractions, an active expiratory phase, use of accessory muscle, and nasal flaring may be present. Auscultation may reveal normal or diminished breath sounds, inspiratory stridor, expiratory wheezing and crackles. If present, the character of associated stridor or wheezing may be helpful. Lowpitched inspiratory stridor is usually associated with supraglottic obstruction while high-pitched stridor is usually associated with laryngeal or subglottic narrowing. Monophonic expiratory wheezing occurs with obstruction of a single intrathoracic airway, while polyphonic wheezing indicates diffuse small airway involvement. Hypoxemia may be absent at rest but demonstrated with minimal exertion.

if exercise-induced asthma or bronchospasm is considered or a complete exercise test to maximal exertion measuring VO2 max, anaerobic threshold, oxygen pulse, Ve/VO2, and the heart rate–work ratio if one is considering cardiac abnormalities or deconditioning as the cause of the exercise-induced dyspnea. If anemia is suspected then a CBC to check Hgb/Hct is warranted. If underlying interstitial lung disease is suspected a High-Resolution Computed Tomography (HRCT) of the chest may be considered. Finally, if underlying cardiac disease is suspected, a baseline EKG and echocardiogram may be warranted and a referral to a Pediatric Cardiologist for further workup should be considered.

Common Causes Deconditioning

Sedentary behaviors in children and adolescents are far too common and are not only linked to concerns for obesity, cardiovascular disease, type II diabetes, and skeletal health, but also lead to deconditioning. Sedentariness resulting in deconditioning and places a greater number of otherwise healthy children at risk for exercise intolerance and exercise-induced dyspnea than any other disorder presented in this review. The presence of deconditioning may also be a factor in the dyspnea associated with other underlying Additional Testing cardiopulmonary conditions as the cycle of dyspnea, reduced activity, The workup and evaluation of The workup and evaluation deconditioning, and then increasexercise-induced dyspnea should be ing dyspnea is commonly associthorough and succinct so as to of exercise-induced ated with cardiopulmonary or quickly rule out or identify the presdyspnea should be other chronic illnesses. ence or absence of any underlying thorough and succinct so as Obtaining an accurate and cardiopulmonary disease. Then an underlying cognitive or psychological to quickly rule out or identify thorough history regarding the component should be considered the presence or absence of patient's physical activity is essential in the evaluation of early in the diagnostic process. any underlying dyspnea because sedentary In addition to a thorough history cardiopulmonary disease. behaviors leading to decondiand physical exam, the basic workup tioning are frequently involved. of dyspnea should include a baseline The rates of obesity in chilchest x-ray, pulmonary function tests dren and adolescents have dramatically increased over to include at least pre- and post-bronchodilator spirothe past 25 years and exercise-induced dyspnea is very metry and, if available, lung volumes and diffusing common in obese children. If one extrapolates findings capacity. The evaluation of exercise-induced dyspnea in obese, middle-aged adults to children and adolesmay also require a formal exercise test to reproduce the cents, in an epidemiologic study 80% of obese adults symptoms, provide an opportunity to observe the reported dyspnea after climbing two flights of stairs.40 reported symptoms, and also measure the cardiopulmonary physiology associated with the dyspnea. This There are several reasons for exercise-induced dyspincludes a 6-min exercise-induced bronchospasm test, nea in obese children. First, deconditioning is an

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important factor. Aerobic capacity and cardiopulmonary fitness in most instances will be decreased in obese children. Second, there is an impairment of pulmonary mechanics associated with diminished lung volumes and a decrease in chest wall compliance due to the excess weight. This imposes an increased mechanical load on the respiratory system. Third, the additional metabolic cost and increased energy demands needed to move the excess body weight is a factor.41 Fourth, it has been demonstrated that obese subjects perceive a greater degree of dyspnea in response to exercise than non-obese subjects do.42 Finally, as with other chronic illness and sedentary behavior, the cycle of dyspnea, reduced activity, deconditioning, and then increasing dyspnea is commonly associated with obesity. It is important to remember, however, that obese patients can have other underlying factors that may be contributing to the exercise-induced dyspnea and these need to be considered.

Exercise-induced Asthma/Exercise-induced Bronchospasm Strenuous exercise may induce airway obstruction through bronchoconstriction. Many terms for this bronchoconstriction have been used including exerciseinduced bronchospasm (EIB) or exercise-induced asthma (EIA). Exercise-induced bronchospasm (EIB) is used to describe the bronchoconstriction associated with exercise in patients with persistent asthma and in those with allergic rhinitis. Exercise-induced asthma (EIA) is used to describe the bronchoconstriction associated with exercise in otherwise normal individuals who do not have underlying persistent asthma or allergic rhinitis. Bronchoconstriction with exercise has been seen in up to 90% of individuals with persistent asthma, up to 40% of individuals with allergic rhinitis, and in 10–13% of the general population.43 In patients with EIA, the diagnosis is often based on self-reported symptoms without objective lung function tests. It is important to remember that self-reporting of symptoms consistent with exercise-induced asthma is many times unreliable and the correlation with subsequent exercise testing is poor in school-aged children and also in elite athletes.44 In addition, perception of dyspnea may be diminished in children with underlying chronic cardiopulmonary disease.39 These children adapt to the perception of dyspnea, therefore, there is a poor correlation in patients with underlying asthma between the degree of airway obstruction and the perception of dyspnea. As a

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result symptoms associated with bronchoconstriction during exercise may be unrecognized or over-reported. In many instances, the presence or absence of either EIA or EIB cannot be accurately determined on the basis of the symptoms alone. Symptoms usually occur between 5 and 10 min into exercise and may be more prominent after the end of activity. They range from mild dyspnea alone to accompanying cough, wheezing, and perhaps significant shortness of breath. Treatment for exercise-induced bronchospasm associated with underlying persistent asthma begins with optimizing control of the underlying airway inflammation. Exacerbation of exercise-induced bronchospasm (EIB) may be an indication of inadequate control of the underlying persistent asthma and step-up therapy should be considered. Treatment and prevention of the bronchoconstriction associated with both EIB and EIA is most effective using a short-acting beta agonist (SABA) such as albuterol. The effectiveness of SABAs is optimal if they are used 20 min before anticipated exercise. Montelukast also prevents EIB/EIA in some patients.45 However, Montelukast had no benefit in the treatment of asthma-like symptoms or increased airway responsiveness in elite athletes.46 A warm-up period has been suggested as helpful. The use of a warm-up period to prevent EIB/EIA is based on the existence of a refractory period of 1–3 h following an episode of exercise-induced bronchoconstriction during which additional exercise will not cause significant bronchospasm. Therefore, if a warm-up period is recommended the warm up must be substantial (at least 5–10 min of enhanced activity). While this type of warm-up period is not practical in most activities, it may be considered in specific situations such a before competitive sports. Inhaled corticosteroids have no beneficial effect in preventing bronchospasm associated with exercise other than in controlling the baseline airway inflammation associated with persistent asthma and should not be used prior to exercise. Also, Long-Acting Bronchodilators (LABA) are not approved for use in the United States for the prevention of exercise-induced bronchoconstriction, either EIA/EIB. However, in Europe formoterol, because of its rapid onset of action, has been demonstrated to be effective for up to 8 h in blocking exercise-induced bronchoconstriction.47 Due to limited access to testing facilities in many communities and also because of the expense involved, a therapeutic trial of β-2-agonist is warranted. Of 141

course, close follow-up is indicated to document the presence or absence of a response. If there is no improvement in reported symptoms then a formal 6-min exercise-induced test is warranted. A positive exercise-induced bronchospasm test is considered to be the reproduction of symptoms in association with a decrease in the FEV1 of 12% from baseline.

Vocal Cord Dysfunction Vocal cord dysfunction (VCD) is a frequent cause of exercise-induced dyspnea and is frequently misdiagnosed as exercise-induced asthma. It was initially described in 1983 in patients presenting as asthma and was characterized by the paradoxical and inappropriate adduction of vocal cords during inspiration.48 This adduction of the vocal cords produces increased airway resistance, subsequent increased work of breathing, and the perception of dyspnea. It is associated with inspiratory stridor, which is frequently mistaken as wheezing by patients and parents. The presentation can also be very dramatic. It usually occurs during periods of maximum exercise but can occur spontaneously unassociated with exercise.49 VCD is most commonly seen in otherwise healthy adolescents and is more common in females. VCD is also frequently seen in competitive and elite athletes.50 In addition, VCD is seen in children with persistent asthma. In these patients VCD will make symptom recognition and the management of the underlying asthma much more difficult. VCD is an involuntary and functional disorder and has been described as psychogenic and associated with underlying stress, anxiety, or other underlying psychopathology.51 However, VCD can occur after viral upper respiratory infections and thyroid surgery. Thus VCD as a function of altered autonomic imbalance has been suggested.52 VCD has also been associated with gastroesophageal reflux.53 The diagnosis of VCD can be based on visualization of the abnormal adduction of the cords following an exercise challenge or in many instances demonstration of the flattening of the inspiratory portion of the flow– volume loop when the patient is symptomatic. Management of VCD includes patient education, reassurance, speech therapy, and consideration for psychological counseling in some cases. Speech therapy techniques employ breathing exercises, including either diaphragmatic breathing or pursed lip breathing, which involve the relaxation of the larynx with conscious activation of the diaphragm. These breathing exercises

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are intended to provide relief of acute symptoms and to control symptoms when they occur but they do require practice and repetition on the part of the patient. The long-term outcome of vocal cord dysfunction is excellent as spontaneous resolution is common.49

Interstitial Lung Disease Exercise-induced dyspnea may also be the presenting symptom of interstitial lung disease (ILD) in children. Dyspnea with exertion is usually seen in conjunction with other symptoms such as a nonproductive cough, tachypnea, hypoxemia, and fatigue, and the presentation may be acute or insidious. Dyspnea is initially first seen with exercise and subsequently at rest in a child with underlying ILD.

Cardiac Abnormalities Most significant congenital heart diseases are identified early in infancy and are not a concern in the older child or adolescent who presents with exercise-induced dyspnea. However, most patients with congenital heart disease, such as Tetralogy of Fallot, or those who have undergone surgical repair, such as the Fontan procedure, will experience some degree of exercise-induced dyspnea. Therefore, should patients with known congenital heart disease experience increased dyspnea associated with exercise, they must have reevaluation of their cardiac status. In children without previously identified congenital heart disease, other cardiac abnormalities that may cause exercise-induced dyspnea are extremely rare. Supraventricular tachycardia (SVT) or other arrhythmias, myocarditis, hypertrophic cardiomyopathy, or congenital coronary artery anomalies can be considered. In these situations poor cardiac output caused by arrhythmias and subsequent lack of adequate O2 delivery during exercise leads to the sensation of dyspnea. Obtaining an accurate and thorough history regarding the presence of associated symptoms of dizziness, syncope, palpitations, or chest pain associated with exercise is important in determining possible cardiac involvement with the symptom of exercise-induced dyspnea. Additional workup including EKG and Echocardiogram may be warranted. Referral to a pediatric cardiologist may be appropriate if there is suspicion of an underlying cardiac abnormality.

Pectus Excavatum Chest wall deformities such as pectus excavatum are common. Pectus excavatum occurs in an estimated one

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in 300–400 births, with male predominance. In most instances, the existence of the deformity creates significant cosmetic concerns and may cause significant psychosocial issues. Cosmetic repair is the most frequent reason for surgical correction. The most commonly reported symptom among patients with pectus excavatum, other than cosmetic, is exertional dyspnea. Several indices are used to grade the severity of pectus excavatum, but the Haller index is a well-established and commonly referenced scale.54 The Haller index is obtained through the use of a chest CT scan and is derived by dividing the transverse diameter of the chest by the anterior–posterior diameter, measured from the inner aspect of the sternum to the anterior aspect of the vertebral body. An index greater than 2.5 is considered significant and an index greater than 3.2 is considered severe and is often used as a criterion for surgical candidacy. However a Haller index greater than 3.2 is not always indicative of underlying cardiopulmonary restrictions. Deconditioning, which may in part be due to an underlying psychosocial issue associated with the cosmetic impact, is the most common cause of exertional dyspnea associated with pectus excavatum. It has been demonstrated that patients with pectus excavatum have a lower level of aerobic fitness when compared to controls.55 In addition, exertional dyspnea may be caused by a restrictive ventilatory defect caused by the deformity. The deformity in pectus excavatum reduces the intrathoracic volume thus resulting in a restrictive ventilatory defect with reductions in both total lung capacity and vital capacity. This restriction is usually mild but may be more pronounced with more severe defects. The restrictive defect and abnormal chest wall mechanics lead to increased work of breathing, further contributing to the diminished exercise capacity observed in some patients. However, data are conflicting on the effect of the underlying restrictive defect on exercise. In addition, a meta-analysis that examined the effects of surgical repair on pulmonary function in pectus excavatum patients showed pulmonary function did not significantly improve after surgical repair.56 Exertional dyspnea in pectus deformities may have a cardiac basis because the deformity may cause a diminished or reduced stroke volume that becomes exaggerated with exercise leading to early dyspnea with exercise. In contrast to pulmonary function, a meta-analysis found that cardiovascular function significantly and clinically improved after surgical repair of the pectus excavatum.57

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If a patient with a significant pectus excavatum presents with exercise-induced dyspnea, pulmonary function testing is recommended. These include lung volumes to assess the degree of restriction and a full exercise test to maximal exertion measuring VO2 max, anaerobic threshold, oxygen pulse, Ve/VO2, and the heart rate–work ratio.

Anemia Anemia if present, from whatever cause, can cause exercise-induced dyspnea by diminishing the oxygen carrying capacity of the blood and subsequently diminishing the amount of oxygen that can be delivered to tissues and exercising muscles. This is associated with an accelerated rise of lactic acid by the skeletal muscles early on during exercise, imposing an additional respiratory stimulus and creating and heightening the sensation of dyspnea. The extent of the exercise intolerance is related to the severity of the anemia.58 Many children who have mild anemia, with a hemoglobin level in the range of 10–12 g/dl, are unaffected at low and moderate exercise intensities. They are able to compensate with increased cardiac output. However, children or adolescents with mild anemia may experience dyspnea sooner than anticipated with maximal exercise. On the other hand, in patients with moderate to severe anemia, exerciseinduced dyspnea will occur after very mild exertion.

Chest Pain in Children and Adolescents Chest pain is a very common symptom resulting in scheduled and unscheduled office visits to the primary care clinician's office. Though it may cause considerable anxiety for the patient and parents, the cause is typically benign and the challenge is often to sort out serious from benign etiologies, and then treat and reassure appropriately. There are a number of good indepth reviews on chest pain.59–61 This brief review will not describe each cause of childhood chest pain in detail. Rather, a general clinical understanding of chest pain will be described, along with recommendations regarding when to refer patients for specialist evaluation. A thorough history and physical exam can usually distinguish patients who can be managed by reassurance from those who require intervention. Laboratory testing is needed in only a select small number of patients.62

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TABLE 1. Non-cardiac causes of chest pain Though the prevalence is not well known, peak presentation is at 12–14 years of age. There is no Idiopathic gender predilection, though psychosomatic causes tend Musculoskeletal to cluster in females. Age is an important demographic, Muscle strain, trauma Costochondritis as children younger than 12 years are more likely to have Tietze's syndrome organic disease.62,63 Chest pain will present as either Slipping rib syndrome acute or chronic. In a report of 407 children with chest Precordial catch syndrome Breast development pain presenting to an emergency department, acute pain Infection (e.g. herpes zoster) (lasting for less than 48 h) occurred in 43% and chronic 63 Psychogenic (more than 6 months) in 7%. By contrast, in a study of Vocal cord dysfunction 100 adolescents with chest pain in a general pediatric Anxiety office, pain of greater than 6 months duration was seen in Panic disorder 36%.64 The anxiety families experience often is an Conversion reaction extension of what they experience in adults. In a series Pulmonary of studies, 56% of family members expected a cardiac Pneumonia Exercise-induced asthma cause while the rate is probably no more than 6%.64–66 In Pneumothorax a recent prospective study of chest pain presenting to a Pulmonary embolism pediatric cardiology department, only 1.2% (out of a Sickle cell acute chest syndrome total of 406 patients) had cardiac pathology.60 Gastrointestinal The presentation of chest pain can be broadly divided Gastroesophageal reflux disease Peptic ulcer disease into cardiac and non-cardiac, and this is often the Foreign body delineation that most concerns parents and clinicians. Esophageal spasm (“nutcracker esophagus”) There is a wide variation regarding causes of chest pain Cholecystitis Subphrenic inflammation among studies. However, the general frequency reported, from most common to least, is idiopathic, Miscellaneous Drug abuse (e.g. cocaine) musculoskeletal, psychogenic, breast pain, respiratory, Intrathoracic malignancy gastrointestinal, cardiac, and miscellaneous. Cardiac Spinal cord nerve root compression and non-cardiac causes of chest pain are summarized in Tables 1 and 2. prompt attention. A family history of premature ischemic The history and physical exam will typically suggest heart disease, sudden death, arrhythmia, and cardiomyif a condition is benign, and guide further investigation opathy should be ascertained. A psychosocial history is if necessary. As mentioned, age is one factor. The particularly important. Is the child under any family or onset and duration of pain may suggest chest wall is school demands? Is there bullying at school? Does the involved or not. Transient, sharp, and brief twinges of patient have a “type A” personality, placing a lot of pain could be due to precordial catch (apical) or slipped pressure on herself? Is there a family history of chest rib syndrome (lower anterior costal margin).67,68 pain, anxiety, or depression? Of course, psychosocial Crushing chest pain with radiation lasting minutes disturbances are common in organic disease, but in the may be cardiogenic or esophageal in origin. Benign face of an otherwise normal history and physical exam it pain tends to have a sudden onset at rest, lasting can be very instructive. Drug use history, prescription seconds to minutes, sharp in character, and often and illicit, is necessary. localized to the chest wall.61 The Physical exam should first focus absence of crushing poorly localized on growth and vital signs. Poor pain, with no radiation, no nausea or growth indicates probable chronic sweating, and not associated with Chest pain with syncope disease. The physical exam is exertion is reassuring and reasonably and chest pain that awak- normal in 37–60% of cases.63,64,69 excludes disease-causing myocardial ens a child from sleep are Examination of the pertinent sysischemia. Chest pain with syncope and chest serious warning signs war- tems: respiratory, cardiac, gastropain that awakens a child from sleep ranting prompt attention. intestinal, and chest wall should be routine. are serious warning signs warranting

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TABLE 2. Cardiac causes of chest pain

Decreased myocardial oxygenation Cardiomyopathy Left ventricular outflow obstruction (e.g. aortic stenosis) Idiopathic hypertrophic cardiomyopathy Arrhythmias Coronary artery abnormalities Anomalous left coronary artery Kawasaki's disease Inflammatory Pericarditis Myocarditis Miscellaneous Mitral valve prolapse Aortic dissection Pulmonary hypertension Drug abuse (e.g. cocaine and methamphetamines)

The slipping rib syndrome may not be found unless the “hooking maneuver” is performed, particularly on those with brief, sharp pain during movement.68 The exam is performed with the patient lying on his unaffected side, while the clinician hooks their fingers under the lower costal margin of the other, affected, side and pulls anteriorly. A positive result reproduces the patient's pain and causes a palpable “click” or “pop.” Slipping rib syndrome is produced by impingement of an intercostal nerve between two costal cartilages, secondary to the subluxation of an interchondral articulation. The first seven ribs are firmly linked to the sternum by sternocostal joints. The 8th, 9th, and 10th ribs are attached by interchondral weak joints. The 11th and 12th ribs, when present, are “floating ribs” with no anterior connection to the sternum and are not involved in this syndrome. According to the original mechanical description, one of the lower three ribs connecting to the sternum slips behind the rib above it and produces pain.68 The condition usually just requires reassurance, time, and possibly NSAID medication. However, if it does not resolve, then local anesthesia in the form of a nerve block injection is typically curative. Observation of the behavior of the parent and child in the office provides useful information. Chest pain that is chronic and associated with recurrent multiple somatic complaints may be psychogenic. Medical tests are unnecessary in most cases, and, of course, chosen to assist the history and physical when organic pathology is suspected.62,63,65,69,70 Balancing this fact is the potential utility in obtaining basic screening tests if it will relieve anxiety in the parent

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and patient, when reassurance is not enough to relieve anxiety. In one prospective study, using a basic algorithm in a pediatric cardiology practice, an ECG was performed on all patients with chest pain, finding an abnormality in 20 out of 406 patients.60 Using that algorithm, a normal ECG, history, exam, and nonexertional chest pain make cardiac pathology very unlikely. Chest radiographs are not usually helpful in the face of normal history and exam. Exertional chest pain may place exercise-induced asthma into the differential diagnosis, particularly when cardiac pathology is unlikely. The only prospective study on the topic reported that of 88 otherwise healthy patients who underwent a formal exercise study, 54% had a positive response for exercise-induced asthma (EIA) defined as a 15% drop in FEV1.71 The mean age of the patients was 12 years, and the pain was mid-sternal. Of interest, not all patients responded to albuterol in reversing the drop in FEV1. This is in stark contrast to an earlier study of 147 patients that reported a 9.5% incidence of EIA with an exercise study.72 In cases diagnosed as idiopathic, there may be occult gastrointestinal disease. In a study of 16 patients with controlled asthma and chest pain greater than 2 months duration, 11 had esophagitis on endoscopy and seven met the GERD criteria by pH probe.73 Nine of the 16 patients responded to medical therapy. Thus, persistently worrisome pain despite an entirely normal evaluation may benefit from gastrointestinal consultation. Though cardiac disease is an uncommon cause of pediatric chest pain, prompt diagnosis is required. Indications for referral to a pediatric cardiologist are listed in Table 3.

Recurrent Wheezing in Infants and Young Children Recurrent wheezing is common in children. While asthma is a common cause of childhood wheezing, there are other etiologies that must be considered in TABLE 3. Indications for referral of pediatric chest pain to a cardiologist

Abnormal cardiovascular exam Exertional chest pain Syncope or near syncope (particularly with exercise) Palpitations Crushing apical chest pain with radiation to back, arm, or neck History of structural heart disease or pulmonary hypertension Abnormal ECG Family history of arrhythmia, sudden death, early coronary artery disease History of Kawasaki disease

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infants and young children including congenital malformations, inflammatory processes, foreign body aspiration, aspiration syndromes, and transient wheezing of childhood. Congenital malformations such as tracheobronchial tree malformations and vascular compression can cause wheezing in children. If wheezing is monophonic, it likely originates from more central airways. Tracheomalacia is an abnormal collapse of the trachea due to localized or generalized weakness of the tracheal wall. Tracheomalacia can occur as an isolated event. However, it is often associated with other congenital anomalies including tracheoesophageal fistula, posterior laryngeal clefts, and esophageal atresia.74 Clinical manifestations of tracheomalacia include wheezing, a “honking” cough, airway obstruction with expiratory stridor, and occasionally “dying spells” with cyanosis. These symptoms usually present during the immediate neonatal period and worsen over the first few months of life. In most children, the symptoms slowly resolve over time as the trachea grows and strengthens. Bronchial wall abnormalities such as bronchomalacia or bronchial stenosis may also present with wheezing, unresponsive to corticosteroids, recurrent infections, or stridor. Both tracheomalacia and bronchial wall malformations can be diagnosed with endoscopy. Vascular rings and slings are other rare congenital malformations that can present with wheezing unresponsive to steroids. In addition to respiratory symptoms, infants with vascular rings or slings sometimes have choking or dysphagia. These malformations, including right-sided aortic arch, double aortic arch, and pulmonary artery sling, cause extrinsic compression of the airway. A barium swallow study can help diagnose a vascular ring because the esophagus will be indented posteriorly. Echocardiography, CT, and MRI angiography are also employed for evaluation of vascular rings and slings.75 Right-sided aortic arch rarely requires treatment unless there is a complete vascular ring. The complete ring may be divided, usually with the division of the ligamentum arteriosum. A double aortic arch causes concentric compression by surrounding the trachea. In this case, the least dominant of the arches is divided. A pulmonary artery sling compresses the right main bronchus. A pulmonary artery sling requires division and reimplantation into the main pulmonary artery trunk. There is a very high association with pulmonary artery slings and congenital tracheal stenosis due to complete tracheal rings being present. Thus, if a pulmonary artery sling is

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present, further airway evaluation should be performed for complete tracheal rings. Inflammatory processes such as bronchiolitis and cystic fibrosis also need to be considered in children with wheezing. Bronchiolitis is a lower respiratory tract infection of the peripheral airways that primarily affects young infants. In classic bronchiolitis, nasal congestion and cough precede the abrupt onset of lower respiratory infections by 2–3 days.76 Fever may be present early and may be absent by the time respiratory distress develops. Infants can have tachypnea, tachycardia, retractions, and cyanosis. Wheezes with or without crackles are heard on auscultation. Hypoxemia is common due to ventilation–perfusion mismatch. Most infants recover in 5–7 days. Infants with a history of chronic lung disease or congenital heart disease are at greater risk for severe symptoms. Bronchiolitis is most commonly caused by respiratory syncytial virus (RSV). Picornaviruses (rhinovirus and enteroviruses) also can cause bronchiolitis and have been associated with significant wheezing. Parainfluenza types 1, 2, and 3; influenza B; adenovirus 1, 2, and 5; human metapneumovirus; and in older children, Mycoplasma pneumonia also cause bronchiolitis.77,78 The diagnosis of bronchiolitis is based on clinical presentation. Laboratory testing with nasopharyngeal aspiration for viruses can also support the diagnosis. Chest x-ray for a child with bronchiolitis demonstrates hyperinflation, flattening of the diaphragms, peribronchial infiltrates, and patchy atelectasis. Cystic fibrosis (CF) also needs to be considered in a child who presents with recurrent respiratory infections and wheezing. While newborn screening now occurs nationwide in the United States, it is important to remember that this test is only a screen and if clinical suspicion is present, a sweat test in an accredited laboratory should be performed. When the onset of wheezing is sudden, foreign body aspiration should be considered. This is most commonly seen in children between 1 and 4 years of age. The aspiration episode is frequently not recognized or may be forgotten if the symptoms take several days to develop. Symptoms can be acute or chronic depending on the size of the foreign body aspirated and its location in the airway. The sudden onset of wheezing, cough, and respiratory distress especially with asymmetric breath sounds is the classic presentation of foreign body aspiration. Careful comparison of air exchange between symmetric parts of the lung is important and the child should be examined repeatedly to determine

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Finally, transient wheezing of childhood needs to be whether the foreign body may be moving around the considered in young children with recurrent wheezing. airway. Any foreign body that is thought to be lodged in Approximately 40% of children will have at least one the mainstem bronchus or trachea is considered a medical episode of wheezing. However, 60% of children who emergency because if it is coughed upward in the trachea, wheeze within the first 3 years of life will have it could lodge underneath the vocal cords and cause total resolution of wheezing by 6 years of age.83 This is airway obstruction. End-inspiratory and end-expiratory anteroposterior and lateral chest x-rays can help evaluate referred to as transient early wheezing. Children with for foreign body aspiration. The radiographs should be transient early wheezing tend to wheeze with lower carefully evaluated for local atelectasis, local hyperinflarespiratory tract infections. There is often no family tion, and visible foreign bodies. In young children, endhistory of asthma or allergen sensitization. expiratory films are often difficult, so decubitus films may provide additional Asthma in Children information. Normal chest radiographs do not rule out foreign bodies, so when Normal chest radiographs and Adolescents there is a history suggestive for foreign do not rule out foreign Childhood asthma continues to body aspiration, bronchoscopy should be a significant disease, with a bodies, so when there is be performed. While either flexible or prevalence that has increased from a history suggestive for rigid bronchoscopy can be used to 8.7% to 9.6% during the 2000s.84 foreign body aspiration, diagnose a foreign body, rigid bronchoPediatric asthma accounts for a scopy is the preferred technique as it bronchoscopy should be significant proportion of morbidity allows for removal of the object.79 accounting for 155,000 hospital performed. Aspiration syndromes also need to admissions and 593,000 emerbe considered when a child presents gency department visits in with recurrent wheezing. Aspiration can occur “from 2006.85 However, recent data suggest that asthma care above” in which the child aspirates when swallowing or increasingly is being managed in an ambulatory care “from below” which is related to gastroesophageal setting. This is reflected in the increased numbers of visits reflux. Acute aspiration can cause mucosal edema, to physician offices coupled with slight decreases in visits bronchorrhea, and airway obstruction which progresses to emergency departments for pediatric asthma care.85 This to acute pneumonitis and possibly respiratory failure. trend places an increased burden on primary care clinicians Chronic aspiration leads to an inflammatory state that to be able to diagnose and treat asthma and provide asthma can eventually result in chronic lung disease. Chronic education (Table 4). aspiration needs to be considered in premature infants Asthma is a multifactorial disease. The National and children with complex medical conditions includAsthma Education and Prevention Program (NAEPP) ing gastroesophageal reflux, neurologic injuries, expert panel report 3 was released in 2007 and defines chronic respiratory disease, neuromuscular disorders, asthma as “a common chronic disorder of the airways and abnormal connections between the airway and gastrointestinal tract.80 Chronic aspiration of gastric TABLE 4. Overview of asthma care contents does occur, and there is a relationship between Diagnosis GER and chronic respiratory symptoms including History and physical exam wheezing, chronic cough, nocturnal cough, apnea, and Testing recurrent respiratory infections.81,82 Evaluation for Pulmonary function testing Chest radiograph aspiration can include a video swallow study and/or functional endoscopic evaluation of swallow. An upper Initial Assessment Severity assessment GI or esophagram is helpful to define the upper Appropriate medication choice gastrointestinal anatomy. Impedance probe monitoring Ongoing reassessment: every 1–6 months, as needed is useful to evaluate for gastroesophageal reflux. EndosAssess chronic asthma control copy helps to detect structural abnormalities that can Assess symptoms cause aspiration. An MRI of the brain may also be Spirometry, exhaled nitric oxide Adjust medications needed to evaluate for neurologic causes of dysphagia Asthma education (Table 6) such as an Arnold–Chiari malformation.

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that is complex and characterized by variable and recurring symptoms, airflow obstruction, bronchial hyperresponsiveness, and underlying inflammation.”86 The interplay of these elements lead to asthma symptomatology and are also targeted by asthma therapies.

Initial Diagnosis Asthma diagnosis requires a detailed history, a focused physical examination, and spirometry when appropriate. The history should elicit prior episodes of wheezing. This is important because asthma is a chronic disease and therefore is typically not diagnosed with the first episode of wheezing. A diagnosis of asthma should be made with caution in infants and toddlers who may have had episodes of wheezing that are only associated with viral upper respiratory tract infections. Although estimates vary, at least 20% of young children who wheeze with RSV will go on to develop asthma.87 Family history can also be of assistance in children who wheeze as well as a history of other atopic conditions including atopic dermatitis and allergic rhinitis. For the history of present illness, questions should include assessing for symptoms such as cough (worse at night), wheezing, difficulty breathing, and/or chest tightness. Another critical component of the history is to assess the occurrence of symptoms with exercise or play and to assess how often rescue medications such as albuterol is given for these symptoms. Frequency and severity of symptoms should be elicited to assist in determining severity. These questions will assist the clinician in determining the severity of asthma. The physical examination for asthma is a focused exam. Critical elements include assessing upper airways, including nares and oropharynx, and assessment of the chest wall, particularly assessing chest wall movement and auscultation of the heart and lungs as well as skin exam. A normal lung exam does not rule out asthma. In fact, many children will not wheeze unless they develop an exacerbation. In addition, some children will have cough-variant asthma, which is indicated by coughing rather than wheezing with exacerbations. A trial of a short-acting bronchodilator with an improvement in the cough can help ascertain this variant. Pulmonary function testing is useful as well. Abnormal findings on lung exam may include a prolonged expiratory phase of respiration, wheezing, or decreased air movement. If, based on the history and physical examination, a diagnosis of asthma is

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uncertain, consider other potential diagnoses. Examples include upper airway disease (allergic rhinitis and sinusitis), upper and central airway obstruction (foreign body, vocal cord dysfunction, and laryngotracheomalacia), small airway obstruction (viral bronchiolitis, cystic fibrosis, and laryngotracheomalacia), and others (gastroesophageal reflux). The diagnosis of asthma in young children is often made on a clinical basis. A chest x-ray should be considered for children with a first episode of wheezing, focal wheezing, fever, and for children who do not respond to bronchodilators in an acute setting. For older children in whom a diagnosis of asthma is being considered, the National Asthma Education and Prevention Program (NAEPP) expert panel report 3 recommends utilization of office spirometry or pulmonary function testing to demonstrate the degree of obstruction and to assess reversibility in children aged five and older. Once diagnosis of asthma is established, the severity of asthma is determined. The severity of asthma will assist the clinician in determining an appropriate asthma treatment regimen. Asthma severity is classified as intermittent, mild persistent, moderate persistent, and severe persistent. Determination of severity is made based upon the assessment of impairment and risk. Impairment assessments include symptom occurrence, nighttime awakenings, use of short-acting beta-2 adrenergic agonists for symptoms (SABA), interference with activities, and lung function (for children able to complete testing). Risk assessment entails the assessment of need for systemic oral corticosteroids (such as prednisolone, prednisone, and dexamethasone) over the past year and consideration of hospitalizations and intensive care admissions (Table 5). Initial severity assessment should then drive medication choices.

Intermittent Asthma Patients with intermittent asthma have symptoms less frequently than 2 days/week, use SABA less than two times a week, and have zero nighttime awakenings over the course of a month. Additionally they should have none or only one exacerbation that requires treatment with an oral corticosteroid annually. Patients who fall into this category only require treatment with a short-acting β-2 agonist inhaler.

Mild Persistent Asthma These patients have symptoms at least two times/ week but not as often as daily (similar frequency for SABA use). Nighttime awakenings should be limited

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TABLE 5. Severity assessment of asthma

Intermittent

Mild persistent

Moderate persistent

Severe persistent

Impairment Symptoms Nighttime awakenings SABA use Normal activity limitations

2 days/week* None 2 days/week* None

42 days/week 1–2 x/month 42 days/week Minor limitations

Daily 3–4 x/month Daily Somewhat limited

Throughout day Weekly Throughout day Extremely limited

Risk assessment Exacerbations (require oral corticosteroids)

0–1 time/year

2 exacerbations/6 months, 4/year, and risk for persistent asthma.* Consider severity of and interval between exacerbations.

*Adapted from NAEPP.

to two times/month and they should not have more than minor activity limitations. All patients with all severities of persistent asthma combined will have two or more exacerbations requiring oral corticosteroids (OCS) in 6 months or four in 1 year that were longer than 1 day in duration. Clinicians should also consider the severity of exacerbations as part of severity assessment (requirement for hospitalization and ICU admission). Patients with mild persistent asthma will be started at “step two” treatment according to National Asthma Education and Prevention Program (NAEPP) expert panel report 3. The preferred choice is to start a low-dose inhaled corticosteroid (ICS) but alternatives that could be considered include montelukast.

Moderate Persistent Asthma In this severity classification, patients have symptoms daily and therefore may require SABA daily. They typically will have nighttime awakenings due to asthma symptoms (i.e. cough) three to four times in a month and have some degree of activity limitation. Primary care clinicians are urged by the NAEPP to consider referral to a specialist for management of these patients due to studies documenting improved outcomes with subspecialty care for patients with moderate to severe asthma.86 These patients should be started with step three or four medications. Step three medications are medium-dose inhaled corticosteroids. There are many choices within this category and practitioners should be comfortable with a few alternatives in their practice. Additionally there are both inhaled as well as nebulized alternatives in this category. Consideration of family pressures and needs may assist clinicians in determining which form of medication to utilize. Research has demonstrated that ICS medication can be utilized effectively with infants and toddlers if medication is disbursed with a valved holding chamber and with appropriate education.88,89

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Step four treatment of moderate persistent asthma consists of use of a medium-dose ICS with the addition of either a long-acting beta-2 agonist (LABA) or montelukast. Clinicians should be aware of black box warnings for LABAs and should be prepared to discuss this with parents to avoid parent noncompliance due to medication safety concerns. Deciding whether a patient should be started at step three or step four requires clinical judgment and is based on patient severity characteristics of the asthma.

Severe Persistent Asthma Patients with severe persistent asthma have symptoms of asthma throughout the day (and therefore may be using albuterol multiple times on a daily basis) and have nighttime symptoms more often than once a week. In addition, these patients experience severe limitations in daily activities. Simple daily activities may lead to symptomatology such as cough or wheezing. Clinicians should be aware that for some patients with moderate or severe asthma, they may have experienced this severity of symptoms for many years and therefore may not even be aware of the level of limitation of activities. Obtaining spirometry upon initial diagnosis can assist clinicians in identifying “poor perceivers” of their asthma symptoms and lead to appropriate medication choices as well as referral to subspecialists as needed. Spirometry is preferred over peak flow alone.86

Ongoing Asthma Care Children with asthma require ongoing care and continual reassessment. In addition, the treatment of asthma is complicated by the fact that impairment (daytime and nighttime symptoms and activity limitation) can vary during the year (i.e. with seasons or specific allergens) and then can also change over the

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course of life. For example, with adolescence, some children may see asthma severity change over time. These factors necessitate the ongoing monitoring of children with asthma by primary care clinicians. Components of ongoing care include the assessment of disease control, adjustment of medications as needed, consideration of factors that may worsen asthma, and ongoing patient and family education. Ongoing assessments will determine the level of control of chronic symptoms.86 Asthma control will be assessed as being well controlled, not well controlled, or poorly controlled. Children who are well controlled will have symptoms less frequently than 2 days/week and need their SABA less than two times/week. Nighttime awakenings due to cough should be less than once/ month and should have no interference with normal activities. Due to the seasonal variation in asthma symptomatology for some patients, do not decrease medications until these patients have maintained “wellcontrolled asthma” for 1 year. Consider discussing this with parents early on to decrease the likelihood of families discontinuing medications because the patient is not having problems. Well-controlled patients (if ≥3 months) can be seen every 6 months.86 “Not well controlled” asthma patients have symptoms more than 2 days/week (or multiple times on 2 or less days/week) and may need to step up their level of medications. For example, a patient on a low-dose inhaled corticosteroid may need to be placed on a medium-dose inhaled corticosteroid. These patients will need to be seen on a more frequent basis until their asthma has been well controlled for at least 3 months. Other considerations in determining the frequency of follow-up visits for asthma may include the need for ongoing education, assessment of inhaler technique, or a family or patient who may need more frequent followup to assist in maintaining preventive therapies. Patients with poorly controlled asthma are having asthma symptoms such as cough or wheeze throughout the day and this will manifest itself as severe activity limitation. These children will typically be utilizing a SABA inhaler multiple times/day. However, there may be occasions where a child who is a “poor perceiver” may not recognize his/her asthma symptoms. These patients are having three or more asthma exacerbations in a year that require oral steroids for treatment. Strongly consider referral to a specialist for these patients. Another consideration for clinicians when approaching patients with asthma is exercise-induced bronchospasm. As many as 50% of asthma patients will also

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experience symptoms with exercise.90 If, with history, it is not obvious whether exercise induces asthma symptoms, ordering lung function testing with exercise may be indicated. Typically, patients will complete preexercise function testing, then complete testing after running on a treadmill, and finally receive a dose of SABA and complete a third round of testing. This should clarify clinical questions about exercise-induced asthma symptoms. For patients with exercise-induced asthma, initiating use of SABA inhaler 15–20 min prior to exercise can decrease the occurrence of symptoms with exercise. Other considerations include increasing controller medications such as increasing the ICS dose or adding either a leukotriene modifier or a long-acting β-2 agonist to the current daily medication regimen. Achieving “well-controlled” asthma for athletes can assist in allowing them to participate fully in physical activities such as gym class and sports. Other factors that influence asthma control need to be considered when working with patients and families to achieve asthma control. Key among these factors includes assessment for allergic rhinitis. For patients who also have allergic rhinitis, it is helpful to complete allergy testing so that parents will be aware of specific allergens. For some allergens, avoidance may be possible and for others, such as dust or mold, there may be opportunities for mitigation of these factors. Another comorbid condition that may worsen asthma symptoms is gastroesophageal reflux (GER), which is present in approximately 20% of asthma patients.91 Assessing the poorly controlled patient for GER, and treating or referring to a specialist for treatment can improve outcomes. Clinicians should ascertain environmental tobacco smoke exposure (ETS) for children with asthma. For those children with ETS, assessment of adults for willingness to consider smoking cessation is the first step. Provide information on the effects of ETS on asthma and information on where a parent can access more information or support.

Pulmonary Function Testing Objective measures of lung function are desirable for the child and adolescent with persistent asthma. Peak flow measurement once was considered the standard of care for all patients old enough to complete this maneuver accurately. Peak flows cannot be utilized for asthma diagnosis but can be utilized for monitoring of asthma symptoms. Current standards for peak flow monitoring require determining the individual patient's personal best peak flow to use for determining when Curr Probl Pediatr Adolesc Health Care, July 2013

is trying to determine whether or not the patient has lung function is worsening. This creates an inherent asthma, ordering PFTs with bronchodilator response flaw for patients who have not achieved well-controlled can assist the clinician in making a diagnosis. Followasthma. In addition, achieving accurate peak flow up PFTs could then be ordered without bronchodilareadings is highly dependent on technique and effort. tors. Another benefit of PFTs that have been completed It is possible for a patient to utilize the tongue and cheek in a pediatric center is that specialists will read and to create an artificially normal or elevated reading. interpret these results that can be of assistance for those Despite these limitations, peak flows can play a role in who may not comfortable with the subtleties of ongoing asthma care. One particular instance would be interpretation of pediatric test results. for those patients who have been identified as poor perceivers of their asthma symptoms or for patients who have severe exacerbations and do not perceive sympExhaled Nitric Oxide Testing toms until late in the course of the exacerbation. If utilizing peak flow meters, it is incumbent on the Exhaled nitric oxide is a newer test that is being clinician to learn proper techniques and provide proper utilized for diagnosis and assessing the effectiveness of instruction periodically to the child and parents. inhaled corticosteroid therapy for patients with asthma Complete pulmonary function testing (PFT) is typically (both pediatric and adult). Exhaled nitric oxide is a completed at a pulmonary function lab. For children, if it product of eosinophilic inflammation, and along with is not a pediatric facility, the clinician will need to non-eosinophilic inflammation, is seen in asthma. ascertain that the accessible lab carries appropriate equipInhaled corticosteroid therapy decreases eosinophilic ment for children such as pediatric mouthpieces and that inflammation. Exhaled nitric oxide is being utilized to staff have experience and are comfortable instructing assess response to inhaled corticosteroid (ICS) therapy. children and obtaining valid results in children. Children However, this modality should be utilized with a aged seven and older should be able to complete testing. degree of caution. Two recent meta-analyses docuChildren between 5 and 7 years may or may not be able mented that utilization of this test to guide therapy, to properly complete testing. when compared with current standard care for pediaOffice-based spirometry can also be set up and trics, leads to increased doses of ICS therapy but has performed. Spirometry is the assessment of flow and not demonstrated clinical effectiveness in decreasing volume, a portion of which is independent of the effort of asthma exacerbations.93,94 More research is needed to the patient, as long as a reasonable effort is performed. determine the role of this test in monitoring and This is a test that most children aged seven and older adjusting asthma therapy before it can be utilized in (without cognitive delays) should be able to complete a primary care clinical setting. when administered by a trained staff member who is able to adequately coach children. Spirometry can be used for diagnosis of asthma and as a follow-up tool to assess Patient and Family Education chronic level of control and lung function. It also will require the Asthma, as a chronic disease, physician to be comfortable with requires patient education. Studies interpreting the results of the test Studies document decreased document decreased hospitalizahospitalizations and emer- tions and emergency department (FEV1).92 Spirometry assesses a number of gency department visits for visits for children with asthma 95,96 elements of function. Elements children with asthma who who receive asthma education. that are vital to asthma include Important considerations when receive asthma education. FEV1, FEV1/FVC, and FEF25– educating patients and families 75. Typically, when first ordering include consideration of the literacy PFTs for patients with asthma, skills of population. Over 40% of patients will also utilize a short-acting bronchodilator adult Americans read at either basic or below basic (SABA) and then repeat the test. This serves to assess levels.97 Use of medical or technical terminology can the degree of bronchodilator response in children. further hinder understanding and retention of materials. Testing can be ordered with or without SABA. For a Often, due to time constraints in the office, large new patient or one in whom the primary care clinician volumes of information are presented in conjunction

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with written materials. Basic tenets of patient education include using plain language, providing three main points of information at a given visit, and assessing for understanding.98 Plain language is defined as “living room language” or language that the average adult can understand the first time they hear it. Healthcare clinicians understand this to mean avoidance of medical terminology. This is one aspect of plain language. Other types of words to consider include concept terms (i.e. intake), category terms (i.e. adverse), and value terms (i.e. adequate). For more information and more examples, go to the National Patient Safety Foundation's website and look for information on health literacy and the “ASK ME 3” initiative.99 Another element of patient education is assessing for understanding. This is the concept of providing educational information verbally and then assessing if the information was correctly heard and understood. Typically, it is important to emphasize to the family and patient that the clinician is assessing that needed information has been provided rather than that the parent is being tested. For adults with learning disabilities or limited literacy skills, being “tested” could be considered to be threatening or shame-inducing so sensitivity to this process is critically important. The clinician starts by stating the information, then asks the parent pretend that the clinician is the other parent/ caregiver and pretend to provide them with the information or “teach back.” This provides the clinician with an opportunity to assess how much information was retained and how accurately it was retained. The clinician can then review any information as needed and correct any misunderstandings. Utilizing plain language and proper verbal communication techniques should be accompanied by written materials that can be read by the majority of patients. Finding handouts written at a 4th-grade reading level would reach the majority of patients who have some reading skills. Other options are utilizing handouts that are plain language friendly. These documents are typically written at a 7th-grade reading level.

Elements of Asthma Education The National Asthma Education and Prevention Program (NAEPP) expert panel report 3 provides guidance on elements of asthma education that are considered important to review and reinforce with families (Table 6). These topics include basic facts

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TABLE 6. Components of asthma education

Basic facts about asthma What is asthma control and current level of control Roles of medications Reinforce skills (i.e. inhaler technique) Identifying and responding to asthma symptoms When and where to seek care

about asthma: what is asthma control and what is the current level of control, what are the roles of medications, reinforce skills (i.e. inhaler technique), identifying and responding to different level of symptoms, when and where to seek care and environmental triggers and how to address them. Written asthma management plans have been recommended as a part of asthma management and asthma education for many years. These documents, when provided in a methodical manner with appropriate education on the use of plans can improve outcomes for children with asthma such as by decreasing hospitalizations and by improving adherence to medical therapy.100–102 Written asthma management plans (WAMPs) are written documents that typically are divided into three zones based on asthma symptomatology, typically utilizing the “stop light” analogy, green zone, yellow zone, and red zone. WAMPS are tools for parents and caregivers to utilize at home to assist in making asthma treatment decisions. These written documents allow clinicians to complete treatment information for each of the three zones. Selection of a WAMP for utilization in a clinical setting is critical. Readily available plans are written at many different levels of readability (the grade level of a written document).103 Therefore, selection of a WAMP for utilization in clinical practice requires evaluation of the WAMP and how it will meet the needs and reading ability of the intended patient population. It is important that these documents be provided to families along with education on utilization of these plans. Utilizing teach back (described in earlier paragraph) is an effective strategy to assess that the parent understands the information given to him/her. Written asthma management plans should be provided to patients with asthma upon initiating therapy (even SABA inhaler therapy for mild intermittent asthma), whenever a medication change or adjustment is made, and annually as part of standard asthma education protocol. When the annual WAMP is provided, this is an opportunity for the clinician to provide reinforcement of asthma education specific to identifying asthma symptoms and responding appropriately by

Curr Probl Pediatr Adolesc Health Care, July 2013

utilizing the guidance provided by completed written asthma management plan. Childhood asthma continues to be a common chronic health condition among children. Primary care clinicians should be prepared to diagnose asthma, determine its severity, and then appropriately start medications. Due to the chronicity and variability of this disease over the life course, continual reassessment of asthma control with adjustment of medication therapy is required. Finally, it is important for asthma patients and their families to receive ongoing asthma education to assist families in achieving optimal outcomes for children with asthma.86

7.

8.

9.

10.

Conclusion This has been a broad overview of commonly presenting respiratory chief complaints to the primary care clinician. A large number of maladies form the differential diagnoses of these common reasons for primary care office visits. The history and physical exam will narrow the differential diagnosis and guide evaluation, and ultimately, the treatment. Reassurance can be provided for the benign disorders, and decisions for further testing or subspecialist referral must be effectively made for the suspected non-benign disorders. The primary care clinician will also frequently encounter chronic asthma and positive cystic fibrosis newborn screening results and a firm grasp of the evidencebased approach to these disorders is necessary for effective management and patient counseling.

11. 12.

13.

14.

15. 16.

17. 18.

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