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Original Research: COUGH |

Associated Factors in Children With Chronic Cough FREE TO VIEW

Vikram Khoshoo, MD, PhD; Dean Edell, MD, MPH, FCCP; Sopan Mohnot; Robert Haydel, Jr, MD; Emilio Saturno, MD; Aaron Kobernick, MD, MPH
Author and Funding Information

Affiliations: From the West Jefferson Medical Center (Drs. Khoshoo, Edell, Haydel, and Saturno), New Orleans, LA; Tulane University (Ms. Mohnot), New Orleans, LA; and Tulane University Medical Center (Dr. Kobernick), New Orleans, LA.

Correspondence to: Vikram Khoshoo, MD, PhD, Pediatric Specialty Center, West Jefferson Medical Center, 1111 Medical Center Blvd, South 650, Marrero, LA 70072; e-mail: vkhoshoo@sbcglobal.net


This article was presented in part at the Annual Conference of American College of Chest Physicians, Chicago, IL, October 24, 2007.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.xhtml).


© 2009 American College of Chest Physicians


Chest. 2009;136(3):811-815. doi:10.1378/chest.09-0649
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Published online

Background:  Children presenting with chronic cough are common to the primary care physicians, but data on the etiology are scant.

Methods:  We evaluated 40 children (age range, 5 to 12 years) with chronic cough (> 8 weeks duration) with no obvious cause who were referred by their primary care physicians. All patients underwent an extensive multispecialty workup that included pulmonary, GI, allergy, immunology, and otorhinolaryngology testing. Response to treatment was quantified pretreatment and 8 weeks after treatment by using a visual analog scale.

Results:  Positive diagnostic test results were noted for gastroesophageal reflux disease (27.5%), allergy (22.5%), asthma (12.5%), infection (5%), aspiration (2.5%), and multiple etiologies (20%). Appropriate treatment for these factors resulted in a significant improvement in cough.

Conclusion:  Reflux, allergy, and asthma accounted for > 80% of the likely etiologic factors of chronic cough in children and responded to a¡ppropriate treatment.

Chronic cough is estimated to affect 7 to 10% of children.1 Chronic cough has been associated with a variety of illnesses, including asthma, gastroesophageal reflux disease, allergic rhinitis, postviral illness, bronchiectasis, and passive smoking.26 In many cases, the etiology of chronic cough is clearly declared in a patient's history or on physical examination findings. In other cases, however, the diagnosis remains clinically challenging. Practice guidelines released by the American College of Chest Physicians in 2006, offered advice to the primary care physicians encountering chronic cough, but levels of evidence were generally based on expert opinion only7 because there are limited data describing the etiology of chronic cough in children.8 Discerning the most common causes of chronic cough is valuable information for the primary care physicians both to direct empiric therapy and to guide referrals efficiently.7,9,10 In this first study of its kind, we comprehensively evaluated children with chronic cough by using a multispecialty workup.

Patients

Children with a cough duration of > 8 weeks were referred to the Pediatric Specialty Center at West Jefferson Medical Center and underwent the workup. They were all from the same geographic area. Patients were evaluated by and workup was directed by the same pulmonologist, gastroenterologist, allergist, immunologist, and otorhinolaryngologist. For inclusion in the study, the children had to have been born full term, be neurodevelopmentally appropriate for age, with no direct or indirect cigarette smoke exposure, no history of a febrile or respiratory illness, and no underlying cardiac illness. Children already carrying a diagnosis of asthma, reactive airway disease, or cystic fibrosis were not included. Only those children who could cooperate in pulmonary function testing and methacholine challenge testing were included in the study. The protocol was approved by the institutional review board, and consent was obtained from all patients.

Workup

This was a prospective study performed with consecutively selected patients over a period of 4 years. The standard workup for all patients included chest radiography, bronchoscopy (for anatomy, and bronchial wash for bacterial culture and lipid-laden macrophages), pulmonary function testing with methacholine challenge tests (for bronchial hyperreactivity, especially in the absence of wheezing to make a diagnosis of cough-variant asthma), sweat chloride testing, extended (20 to 24 h) esophageal pH/impedance monitoring, allergy skin testing, and measuring of Ig levels (IgA, IgE, IgM, and IgG subclasses). In select cases, esophagogastroduodenoscopy (for anatomy, esophagitis, and eosinophilia), barium swallow/esophagogram (for anatomy, swallowing function, and aspiration), antibodies to childhood vaccines, CT scans of the paranasal sinuses, CT scans of the chest, skin tests for tuberculosis, and α1-antitrypsin phenotypes were performed. An ear, nose, and throat evaluation including laryngoscopy was also performed in select cases for all but those children who tested positive for allergy. For the extended pH study monitoring, the position of the distal probe was confirmed radiologically in the distal esophagus about 2.5 cm proximal to the lower esophageal sphincter. The study finding was regarded as being abnormal if the pH in the distal esophagus was < 4 for > 5% of the duration. For the bronchial provocation test, methacholine was administered by using the five-breath dosimeter method, in which concentrations of 0.025, 0.25, 2.5, 10, and 25 mg/mL were given to the patients.11,12 After a baseline spirometry test was performed, patients were instructed to inhale from the nebulizer for five slow inhalations. The FEV1 was measured about 1 min after the fifth inhalation. If the FEV1 fell < 20% from the baseline, the procedure was continued by using the next higher dosage; however, if it fell ≥ 20% from the baseline, testing was discontinued. The results were interpreted by analyzing the changes in the FEV1. A negative methacholine challenge result indicated that the patient was not responsive to the provocative concentration of > 10 to 25 mg/mL; a positive methacholine challenge result was identified as a provocative concentration of < 10 mg/mL, causing a fall in FEV1 of > 20% from the baseline.

Skin tests for specific allergens were considered positive if they produced a wheal response of at least 3 mm greater than the negative control after 15 min of application.13,14 The diagnosis of asthma was established if episodic symptoms of airflow obstruction or airflow hyperresponsiveness were present, if airflow obstruction was at least partially reversible (as measured by spirometry), and if alternative diagnoses were excluded. Reversibility was determined by an increase in FEV1 of > 12% from the baseline measure after inhalation of a short-acting β2-agonist.15

Treatment

The associated factors identified were treated with a uniform protocol, as follows: (1) gastroesophageal reflux disease was treated with a combination of a proton pump inhibitor (esomeprazole, 20 mg two times a day) along with a prokinetic agent (metoclopramide, 0.15 mg/kg per dose tid), and diet changes were also recommended; (2) allergy was treated with a combination of an antihistamine (cetirizine, 10 mg/d) along with a leukotriene modifier (montelukast, 5 mg/d), allergen avoidance was recommended, nasal symptoms were treated with a nasal corticosteroid (mometasone, one to two sprays one to two times a day); (3) asthma was treated with a combination of an inhaled corticosteroid (fluticasone, 100 to 250 μg) and a long-acting β2-agonist (salmeterol, 50 μg) given two times a day with or without a leukotriene modifier, acute symptoms were treated with a nebulized short-acting β2-agonist (levalbuterol, 1.25 mg three to four times a day); (4) infection was treated with IV vancomycin, 10 mg/kg per dose every 6 h; (5) aspiration was treated with thickened feeds and speech/occupational therapy; (6) patients with a negative workup were administered antiasthma medications, antiallergy medications, antibiotics, decongestants, and cough suppressants; and (7) some patients also received additional treatment with guaifenesin. A few patients in the asthma and allergy groups received an initial 5-day course of methylprednisolone (1 to 2 mg/kg/d).

Assessment of Cough

Cough was quantified by using a visual analog scale that ranged from 0 to 100. The two extremes were “no cough at all” and “coughing all the time.” The parents assigned the scores. Scores were based on the symptoms over the past 1 week, and were scored at first visit and after 8 weeks of treatment. The patients served as their own control subjects, and comparisons were made using a paired t test. The scale was adapted from Irwin et al.16

Forty consecutive children (mean age, 7.8 years; age range, 5 to 12 years; 17 were female, and 23 were male) fulfilling all entry criteria were included in the study. The duration of cough ranged from 8 to 36 weeks (mean [± SD] duration, 18 ± 6 weeks). The associated factors are listed in Table 1. One or more associated and potentially causative factors were identified in 90% of children. The single most common factor associated with chronic cough by itself was gastroesophageal reflux disease (27.5%). Allergy was the most prevalent cause by itself and concomitantly with another factor (42.5%) followed by reflux (32.5%). Overall, in 82.5% of children, asthma, allergy, or reflux were likely causes of cough. Two children (5%) had bronchial wash cultures that were positive for Streptococcus pneumoniae. In four children (10%), the results of all tests performed were normal, and habitual cough was suspected.

Table Graphic Jump Location
Table 1 Associated Factors in Children With Chronic Cough and Their Response to Treatment

Values are given as No. (%) or mean ± SD.

*Based on a 0-to-100 visual analog scale.

†Both had S pneumoniae.

‡Not significant (p > 0.05), the remaining values are statistically significant (p < 0.05).

Further, of the 17 patients with allergy, upper airways cough syndrome was diagnosed in 11 patients, based on an ear, nose, and throat evaluation with or without radiology. No significant correlation of any particular associated factor was seen with the age of the patient. The two children with infection had the shortest duration of symptoms at 8.5 weeks.

Twenty-three of the 40 patients had a nocturnal cough at least 2 days a week. Nocturnal cough was more common in the allergy and asthma groups (16 of 22 patients) than in the reflux groups (4 of 13 patients). Overall, only 4 of 40 patients had a productive cough.

Children with a positive diagnostic test result were treated as described above. After 8 weeks of treatment, patients in all categories showed a significant improvement (p < 0.05) in cough except those who did not have any identifiable associated factor.

This is the first study to comprehensively evaluate children with chronic cough and without a selective workup. Our study suggests that among children with chronic cough (ie, cough of > 8 weeks duration), the most common likely causative factors were allergy, reflux, and asthma. Most children with allergy were found to have upper airway cough syndrome (previously designated as postnasal drip syndrome). Nocturnal cough was more common in the asthma and allergy groups compared with the reflux group, but, as reported before,17 neither the character nor the timing of cough are good predictors of the cause. The second part of the study involved assessing the response to treatment to help establish the role of the associated factors as the etiology of chronic cough. We used a scoring system for quantifying cough by using a visual analog scale. This has been used effectively by several investigators in the past.16 There was a significant improvement in the cough scores after 8 weeks of standardized treatment in all groups.

Chronic cough is a common presenting complaint to primary care physicians, yet data evaluating the etiology of chronic cough are scant. It is essential to know the common etiologies of chronic cough in order to establish an appropriate differential diagnosis and to make treatment and referral decisions. With this heightened awareness about the potential causative factors, the primary care physicians can direct history taking, physical examinations, investigations, and treatment more efficiently. In selected cases, empiric treatment with acid-suppressing agents, oral and nasal antiallergy medications, and/or inhaled corticosteroids may seem justified and worth considering, especially where subspecialty services are not readily available. Through a preintervention/postintervention model and by using the patients as their own control subjects, the data from our study have indeed shown significant reduction in cough and hence efficacy for the treatments administered. The strongest evidence for treatment efficacy will ultimately come from carefully designed double-blind, placebo-controlled studies.

There are a few caveats to our study. One may express concern about the relatively small number of patients in our study. Every patient underwent all major diagnostic tests. The workup was not selective. This is a strength. It would have been easier to include a much larger number of patients with a selective workup. That approach would not be scientifically rigorous.

Excluding children with a preceding febrile or acute respiratory illness would have excluded children with chronic cough occurring after a viral respiratory illness, an important cause of persistent cough. Similarly, our data probably underestimate the contribution of asthma toward chronic cough because patients with obvious wheezing would have been already given a diagnosis and treated by their primary care physicians, and thus excluded from the study. In addition, the prevalence of cough-variant asthma may seem higher among our population because these children would not have presented with wheezing but would have been given a diagnosis only after a positive methacholine challenge test result, as was done after the referral.

Our results are very different from those of Marchant et al,18 who found infection-related etiologies to be predominant in their population. There are several reasons for these differences. In their study, Marchant et al18 defined chronic cough as a cough of > 3 weeks duration. The American College of Chest Physicians guidelines7 recommend a 4-week duration as the cutoff for chronic cough. These guidelines were authored by investigators from Dr. Marchant's group. This 4-week cutoff for children is arbitrary and in sharp contrast to the 8-week cutoff recommended for use in adults, also by the American College of Chest Physicians.19

The reasons for the difference in the definition for pediatrics and adults are not clear. We interviewed 22 pediatric pulmonologists in the United States to get a consensus for what they believed should be the right cutoff for duration of cough to define chronic cough in children. The unanimous verdict was a duration of at least 8 weeks. Two major reasons for using the 8-week cutoff were presented by these experts. First, the 8-week cutoff in children would conform to the general definition of chronic cough in adults as well as to the American College of Chest Physicians guidelines.19 Second, it was believed that postinfectious cough could last for up to 8 weeks and needed to be excluded from the definition, as has been done for the adult guidelines.20 Cough lasting 3 to 8 weeks is termed subacute cough and encompasses the bulk of the postinfectious etiologies. Therefore, using the cutoff of 3 weeks in the definition of chronic cough it is not surprising that the study by Marchant et al18 found infection-related etiologies to be predominant. In our study, we used the 8-week cutoff for chronic cough, and, as expected, noninfectious causes were predominant. Our results are quite in line with adult studies of chronic cough in which an 8-week cutoff has been used. The patients in the study by Marchant et al18 were also younger than those in our study, and it is possible that infection by itself may be more common in younger children.

Another reason for the differences in the results between our study and that of the study by Marchant et al18 is that they performed a selective workup and we performed a more comprehensive workup in all patients (eg, extended esophageal pH monitoring was performed in only one-third of the patients in the study by Marchant et al18 but in 100% of the patients in our study). It is then no surprise that the prevalence of gastroesophageal reflux was higher in our patients. Moreover, the inclusion and exclusion criteria in our study were designed more to discern the possible etiologies in what we believed would represent “nonobvious” causes from the perspective of a primary care physician and yet conform to what the experts believed would be a clinically relevant definition of chronic cough (ie, a cough duration of > 8 weeks). To get a true perspective of the etiology of chronic cough, we believed that, irrespective of the differences in our results, it was important for the general practitioners to understand the definition of chronic cough used by different studies and the population that has been studied. After all, the important issue is to eliminate ambiguity and help the primary care physician to develop protocols and practice guidelines for effectively dealing with this common problem. Based on current recommendations of the American College of Chest Physicians,7 it would seem to the primary care physicians that treatment with antibiotics would be the preferred empiric treatment of chronic cough in children. This approach is problematic.

Based on our data, it seems that we may have to rethink the current recommendations. The next step would be to design and evaluate intervention studies in children with chronic cough to develop cost-effective practice guidelines for primary care physicians.

Author contributions: Drs. Khoshoo, Edell, Haydel, and Saturno conceived the study, developed the protocol, and managed the patients. Ms. Mohnot and Dr. Kobernick contributed to the data analysis. Dr. Khoshoo wrote the first draft.

Financial/nonfinancial disclosures: The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Dockery DW, Gold DR, Rotnitsky A, et al. Effects of age, sex and race on prevalence of respiratory symptoms among children. Am Rev Respir Dis. 1989;139:A23
 
Wubbel C, Faro A. Chronic cough in children. Pediatr Case Rev. 2003;3:95-104. [PubMed] [CrossRef]
 
Chang AB, Asher MI. A review of cough in children. J Asthma. 2001;38:299-309. [PubMed]
 
Marchant JM, Masters IB, Taylor SM, et al. Utility of signs and symptoms of chronic cough in predicting specific cause in children. Thorax. 2006;61:694-698. [PubMed]
 
Schwartz J. Air pollution and children's health. Pediatrics. 2004;113suppl:1037-1043. [PubMed]
 
Weinberger M, Abu-Hasan M. Pseudo-asthma: when cough, wheezing, and dyspnea are not asthma. Pediatrics. 2007;120:855-864. [PubMed]
 
Chang AB, Glomb WB. Evidence based clinical guidelines for evaluating chronic cough in pediatrics: ACCP evidence-based clinical practice guidelines. Chest. 2006;129:260-283
 
Luyt DK, Burton PR, Simpson H. Epidemiological study of wheeze, doctor diagnosed asthma, and cough in preschool children in Leicestershire. BMJ. 1993;306:1386-1390. [PubMed]
 
Bush A. Paediatric problems of cough. Pulm Pharmacol Ther. 2002;15:309-315. [PubMed]
 
Chang AB, Powell CV. Non-specific cough in children: diagnosis and treatment. Hosp Med. 1998;59:680-684. [PubMed]
 
Law KW, Ng KK, Yuen KN, et al. Detecting asthma and bronchial hyper responsiveness in children. Hong Kong Med J. 2000;6:99-104. [PubMed]
 
American Thoracic Society Guidelines for methacholine and exercise challenge testing. Am J Respir Crit Care Med. 2000;161:309-329. [PubMed]
 
Wallace DV, Bahna SL, Goldstein S, et al. American Academy of Allergy, Asthma and Immunology Work Group Report: allergy diagnosis in clinical practice. J Am Coll Immunol. 2007;120:967-969
 
Bernstein IL, Li JT, Bernstein DI, et al. Allergy diagnostic testing: an updated practice parameter. Ann Allergy Asthma Immunol. 2008;100suppl:S1-S148
 
National Asthma Education and Prevention Program (NAEPP) Expert panel report 2: guidelines for a diagnosis and management of asthma. 1997; Bethesda, MD National Institutes of Health
 
Irwin RS, Zawacki JK, Wilson MM, et al. Chronic cough due to gastroesophageal disease. Chest. 2002;121:1132-1140. [PubMed]
 
Mello C, Irwin R, Curley F. Predictive values of character, timing and complications of chronic cough in diagnosing its cause. Arch Intern Med. 1996;156:997-1003. [PubMed]
 
Marchant JM, Masters B, Taylor SM, et al. Evaluation and outcome of young children with chronic cough. Chest. 2006;129:1132-1141. [PubMed]
 
Irwin RS. Introduction to the diagnosis and management of cough: ACCP evidence-based clinical practice guidelines. Chest. 2006;129:25S-27S. [PubMed]
 
Bramann SS. Postinfectious cough: ACCP evidence-based clinical practice guidelines. Chest. 2006;129suppl:S138-S146
 

Figures

Tables

Table Graphic Jump Location
Table 1 Associated Factors in Children With Chronic Cough and Their Response to Treatment

Values are given as No. (%) or mean ± SD.

*Based on a 0-to-100 visual analog scale.

†Both had S pneumoniae.

‡Not significant (p > 0.05), the remaining values are statistically significant (p < 0.05).

References

Dockery DW, Gold DR, Rotnitsky A, et al. Effects of age, sex and race on prevalence of respiratory symptoms among children. Am Rev Respir Dis. 1989;139:A23
 
Wubbel C, Faro A. Chronic cough in children. Pediatr Case Rev. 2003;3:95-104. [PubMed] [CrossRef]
 
Chang AB, Asher MI. A review of cough in children. J Asthma. 2001;38:299-309. [PubMed]
 
Marchant JM, Masters IB, Taylor SM, et al. Utility of signs and symptoms of chronic cough in predicting specific cause in children. Thorax. 2006;61:694-698. [PubMed]
 
Schwartz J. Air pollution and children's health. Pediatrics. 2004;113suppl:1037-1043. [PubMed]
 
Weinberger M, Abu-Hasan M. Pseudo-asthma: when cough, wheezing, and dyspnea are not asthma. Pediatrics. 2007;120:855-864. [PubMed]
 
Chang AB, Glomb WB. Evidence based clinical guidelines for evaluating chronic cough in pediatrics: ACCP evidence-based clinical practice guidelines. Chest. 2006;129:260-283
 
Luyt DK, Burton PR, Simpson H. Epidemiological study of wheeze, doctor diagnosed asthma, and cough in preschool children in Leicestershire. BMJ. 1993;306:1386-1390. [PubMed]
 
Bush A. Paediatric problems of cough. Pulm Pharmacol Ther. 2002;15:309-315. [PubMed]
 
Chang AB, Powell CV. Non-specific cough in children: diagnosis and treatment. Hosp Med. 1998;59:680-684. [PubMed]
 
Law KW, Ng KK, Yuen KN, et al. Detecting asthma and bronchial hyper responsiveness in children. Hong Kong Med J. 2000;6:99-104. [PubMed]
 
American Thoracic Society Guidelines for methacholine and exercise challenge testing. Am J Respir Crit Care Med. 2000;161:309-329. [PubMed]
 
Wallace DV, Bahna SL, Goldstein S, et al. American Academy of Allergy, Asthma and Immunology Work Group Report: allergy diagnosis in clinical practice. J Am Coll Immunol. 2007;120:967-969
 
Bernstein IL, Li JT, Bernstein DI, et al. Allergy diagnostic testing: an updated practice parameter. Ann Allergy Asthma Immunol. 2008;100suppl:S1-S148
 
National Asthma Education and Prevention Program (NAEPP) Expert panel report 2: guidelines for a diagnosis and management of asthma. 1997; Bethesda, MD National Institutes of Health
 
Irwin RS, Zawacki JK, Wilson MM, et al. Chronic cough due to gastroesophageal disease. Chest. 2002;121:1132-1140. [PubMed]
 
Mello C, Irwin R, Curley F. Predictive values of character, timing and complications of chronic cough in diagnosing its cause. Arch Intern Med. 1996;156:997-1003. [PubMed]
 
Marchant JM, Masters B, Taylor SM, et al. Evaluation and outcome of young children with chronic cough. Chest. 2006;129:1132-1141. [PubMed]
 
Irwin RS. Introduction to the diagnosis and management of cough: ACCP evidence-based clinical practice guidelines. Chest. 2006;129:25S-27S. [PubMed]
 
Bramann SS. Postinfectious cough: ACCP evidence-based clinical practice guidelines. Chest. 2006;129suppl:S138-S146
 
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