CHEST
Original Research SIGNS AND SYMPTOMS OF CHEST DISEASE
Children With Chronic Nonspecific Isolated Cough Ozlem Yilmaz, MD; Arzu Bakirtas, MD; Hacer Ilbilge Ertoy Karagol, MD; Erdem Topal, MD; and Ipek Turktas, MD
Background: This study observed children with chronic nonspecific isolated cough (NIC) to investigate clinical differences between children whose symptoms resolved spontaneously and those who eventually developed asthma and then explored the differences among the children who eventually developed asthma in terms of their time of response to a trial of inhaled corticosteroid (ICS). Methods: Children with chronic NIC were managed either with a wait-and-review approach or with a 2-week trial with 400 mg/d inhaled budesonide according to the preference of their parents. Responses were monitored with a validated cough score. Treatment was prolonged to 8 weeks in the case of partial responders. All children were followed up at 3-month intervals. Results: A total of 109 children (median [interquartile range] age, 5 [3.5-9] years; cough duration, [8-16] weeks]) were followed for a mean (⫾ SD) time of 21(⫾ 5) months. Cough did not recur in 71% (spontaneous resolution) but relapsed in 28% of the children who later responded to ICS treatment again (asthma). Aeroallergen sensitization (relative risk, 2.86; 95% CI, 1.17-6.99) and previous history of chronic cough (relative risk, 2.68; 95% CI, 1.10-6.49) increased the risk of asthma. Cough duration, the cough score, the family history of asthma, and serum eosinophilia were not found discriminative for the final diagnosis. There were no differences among children who eventually developed asthma and responded to either the 2-week or 8-week trial in terms of the study parameters. Conclusions: Chronic NIC does not recur in the majority of children. Initial response to the ICS trial may be misleading but the trial may be preferred for children who have atopic sensitization, a previous history of chronic cough, or both. CHEST 2014; 145(6):1279–1285 Abbreviations: CVA 5 cough variant asthma; ICS 5 inhaled corticosteroid; NIC 5 nonspecific isolated cough
is one of the most common reasons for preCough sentation to a doctor. Nonspecific isolated cough 1-4
(NIC) is a common category of chronic cough, especially in children.5,6 Evidence suggests that only a minority of children with chronic NIC have asthma.5-10 A trial of inhaled corticosteroid (ICS) treatment is gen-
Manuscript received October 2, 2013; revision accepted December 28, 2013; originally published Online First January 30, 2014. Affiliations: From the Department of Pediatric Allergy and Asthma, School of Medicine, Gazi University, Ankara, Turkey. Funding/Support: The authors have reported to CHEST that no funding was received for this study. Correspondence to: Ozlem Yilmaz, MD, Department of Pediatric Allergy and Asthma, School of Medicine, Gazi University, Besevler, Ankara, Turkey 06510; e-mail: [email protected] © 2014 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.13-2348 journal.publications.chestnet.org
erally recommended for children with chronic NIC who have persistent symptoms. However, chronic cough guidelines in children emphasize that the response to ICS treatment may be a period effect rather than an indication for a diagnosis of asthma. Therefore, an early relapse of cough that again responds to ICS treatment may represent a diagnosis of asthma.5,6 Nevertheless, it is difficult to decide on the final diagnosis without a follow-up. Many previous research studies have focused on the evaluation and outcome of chronic cough.1,2,4 There are studies in the past that have examined cough in terms of “recurrent cough,” “persistent cough,” “night cough,” or “persistent nocturnal cough” in children.10-14 However, there are limited data available about chronic NIC. The primary aim of this study was to observe children with chronic NIC and to investigate clinical differences between children whose symptoms resolved CHEST / 145 / 6 / JUNE 2014
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spontaneously and those who eventually developed asthma. As a secondary aim, we examined the differences among children who eventually developed asthma in terms of their time of response to ICS treatment.
Materials and Methods Children aged , 18 years with chronic cough lasting ⱖ 4 weeks who were referred to the Department of Pediatric Allergy and Asthma at our hospital were screened for inclusion in the study. All children were evaluated by at least two allergists for specific cough pointers and characteristic cough patterns using a form we designed according to the recommendations in the guidelines.5,6 A chest radiograph and a pulmonary function test with bronchodilator responsiveness (for children old enough to conduct the maneuvers) were performed in all participants. Children with a specific cough pointer, characteristic cough pattern, and wet cough or with an abnormality in the chest radiograph or pulmonary function test were excluded from the study. Children with a previous diagnosis of a chronic respiratory disorder, those who had been on ICS or leukotriene receptor antagonist or bronchodilator treatment, or those using angiotensin-converting enzyme inhibitors were also excluded from the study. All other children with dry chronic cough and a normal physical examination were included in the study. Laboratory Investigations and Child Management Chest radiographs were taken in posteroanterior and lateral positions and reported by the radiology department. Pulmonary function tests were performed with a daily calibrated spirometer (Vmax 20C; SensorMedics, CareFusion Corp) in accordance with the American Thoracic Society Guidelines.15,16 We used the Knudson reference set for spirometry prediction. Age, sex, height, weight, and ethnicity were entered before each measurement. All children were white. Atopy was determined with a panel of skin prick tests that included house dust mites, pollens, alternaria, animal dander, latex, and histamine (10 mg/mL histamine phosphate) as positive controls and 0.9% sterile saline as negative controls. The skin prick test was considered positive if the mean wheal diameter was ⱖ 3 mm than the negative control. The serum eosinophil count was determined with an automatic complete blood count analyzer. The Gazi University Hospital ethics committee approved the study, and written informed consent was obtained from all children and/or their parents (project approval No. 293). Definitions were as follows: • Chronic cough: cough lasting ⱖ 4 weeks.6 • Specific cough pointers: Any auscultatory abnormality, classic cough characteristics, cardiac abnormalities, chest pain, chest wall deformity, daily moist or productive cough for . 3 months, digital clubbing, dyspnea, exertional dyspnea, failure to thrive, feeding difficulties, hemoptysis, immune deficiency, neurodevelopmental abnormality, recurrent pneumonia, wheeze, allergic rhinitis/postnasal drip, atopic eczema, passive smoking, symptoms of gastroesophageal reflux.5,6 • Characteristic cough patterns: Barking or brassy cough, cough productive of casts, honking cough, paroxysmal (with/ without whoop), staccato cough.5,6 • Nonspecific isolated dry cough: Persistent dry cough lasting ⱖ 4 weeks with no other respiratory symptoms.5,6 • Cough score: A validated verbal category cough scale scoring daytime plus nighttime cough scores.17 1280
• Daytime score: 0 5 no cough; 1 5 cough for one or two short periods only; 2 5 cough for more than two short periods; 3 5 frequent coughing but does not interfere with school or other activities; 4 5 frequent coughing which interferes with school or other activities; and 5 5 cannot perform most usual activities due to severe coughing. • Nighttime score: 0 5 no cough at night; 1 5 cough on waking or on going to sleep only; 2 5 awoken once or awoken early due to coughing; 3 5 frequent waking due to coughing; 4 5 frequent coughs most of the night; and 5 5 distressing cough. • Complete cough resolution (complete response): Improvement of ⱖ 75% or total resolution according to the recorded cough score for ⱖ 3 consecutive days.18-20 • Partial cough resolution (partial response): Improvement of 25% to 75% according to the basal cough score. • Nonresolution of cough (no response): Improvement of ⱕ 25% according to the basal cough score. • Chest radiograph abnormality: Any abnormality (other than peribronchial thickening) as interpreted by a radiologist. • Spirometry abnormality: As determined by the American Thoracic Society and European Respiratory Society Criteria with predicted values used.15,16 FEV1 , 80, FEV1/FVC , 80, FEF25-75 , 70% predicted and ⱖ 12% or 200 mL increase in FEV1 20 min after 400 mg of salbutamol inhalation were considered a spirometry abnormality. • Serum eosinophilia: ⱖ4% eosinophils in the complete blood count. • Classic asthma: Recurrent episodes of wheeze, dyspnea, or both that respond to inhaled b2-agonist, or bronchodilator responsiveness documented on spirometry (ⱖ 12% change in FEV1% predicted after 400 mg of salbutamol). • Cough variant asthma (CVA): Nonspecific chronic dry cough that resolves completely with ICS treatment 400 mg/d budesonide or equivalent within a 2-week to 8-week period and relapses after stopping treatment, and then again responds to the same treatment. • Relapse: A new chronic cough period or a cough with a wheezing after complete response to either ICS treatment of 2 or 8 weeks or after a wait-and-review period. All children were managed according to Figure 1. To ensure effective delivery of the inhaled treatment, parents of each child were trained by the same inhalation technician in a standard manner. All patients were followed up and their cough diary entries were reviewed by the same physician (O. Y.). Parents recorded daytime and nighttime cough scores according to the verbal descriptions detailed in the definitions given previously. This is a validated verbal category score that has been previously used in chronic cough studies in children.17,20,21 Parents filled in the cough diary daily during coughing periods lasting ⱖ 4 weeks. Response to treatment was evaluated according to the mean cough score. The treatment of children who were partially responsive to the 2-week treatment with ICS was prolonged to 8 weeks with the same dose of the drug. A plan to consult with other departments (pediatric pulmonology, cardiology, immunology, gastroenterology, and ear, nose, and throat) was made in the case of children who were nonresponsive to the 2-week treatment or partially responsive to the 8-week ICS treatment to ensure a differential diagnosis. All children were examined at 3-month intervals for any recurrence of cough. Children were admitted to the outpatient clinic for reevaluation any time they had symptoms. Statistical Analysis Statistical analysis was performed using the Statistical Package for Social Sciences 16.0 software (IBM). Descriptive analysis was Original Research
used for the characterization of patients. Data that had a normal distribution were described by using mean ⫾ SD values; median and interquartile ranges (IQRs) were used otherwise. The Pearson x2 test or Fisher exact test was used to compare categorical variables between the groups. The unpaired Student t test was used for two-group comparisons of normally distributed data, and the Mann-Whitney U test was used for nonparametric data. For the multivariate analysis, possible factors were entered into the logistic regression analysis to determine independent predictors. A two-sided value of P , .05 was considered statistically significant.
Results One hundred nineteen children with nonspecific cough lasting ⱖ 4 weeks participated in the study (Fig 2). Seven children did not attend to the clinic after initial evaluation (either wait and review or 2-week trial of ICS). Three children were not available for the followups at 3-month intervals after completion of initial trial of ICS treatment. Those 10 children were, therefore, excluded from the study. One hundred nine children were included in the final analysis. Fifty-seven of these children (52%) were male. The median age was 5 years (25th-75th percentile, 3.5-9 years). Median cough duration was 12 weeks (25th-75th percentile, 8-16 weeks). Of 109 patients, 26% had a cough period between 4 and 8 weeks, and 74% described a cough
period lasting ⱖ 8 weeks. All patients were followed up for at least 1 year. Mean (⫾ SD) follow-up time was 21 months (⫾ 5 months). Thirty-nine children could perform a spirometry test on recruitment. Nine were in the relapsing group. In the follow-up, six more children in the relapsing group could perform spirometry. None of the 15 children had reversibility on follow-up. Spontaneous Resolution and Asthma Frequency We determined the frequency of spontaneous resolution and asthma among children with chronic NIC. Of 109 patients, chronic cough did not recur in 77 during the follow-up period (71%, spontaneous resolution). Thirty-one patients (28%) relapsed within a median of 6 weeks (25th-75th percentile, 4-16 weeks). Twenty-one of the relapsed patients received a diagnosis of classic asthma (relapsed with wheezing) and 10 of them received a diagnosis of CVA (relapsed with chronic cough: five children had six episodes of chronic cough; one child had four episodes, three children had seven episodes, and one child had 10 recurrent episodes of chronic cough that responded to ICS trials). Differences Between Spontaneous Resolution and Asthma We evaluated the differences between children with chronic NIC that resolved spontaneously and those with chronic NIC who eventually developed asthma. There were no significant differences between children with chronic NIC that resolved spontaneously and those with chronic NIC who eventually developed asthma (classic asthma, CVA, or both) in terms of the duration of cough at admission (P 5 .28), the cough score (P 5 .12), the family history of asthma (P 5 .42), and the presence of eosinophilia (P 5 .19) (Table 1). Atopic sensitization to aeroallergens (P 5 .01) and previous history of chronic cough (P 5 .01) were found more frequently in children with chronic NIC who eventually developed asthma than in children in whom the condition resolved spontaneously. Logistic regression analysis revealed that atopic sensitization to aeroallergens and previous history of chronic cough increased the risk of having asthma by 2.86 (95% CI, 1.17-6.99) and 2.68 (95% CI, 1.10-6.49), respectively. Differences in Treatment Response Duration
Figure 1. Management of chronic nonspecific isolated cough. The solid arrow represents first chronic cough episode; the dashed arrow represents relapse during follow-up. ICS 5 inhaled corticosteroid; SABA 5 short-acting b2-agonist. journal.publications.chestnet.org
Regarding management and differences in terms of the duration of the response to treatment, 86 patients (79%) preferred a trial of treatment and 23 patients (21%) preferred a wait-and-review approach. All children in the wait-and-review group (n 5 23) improved within 2 weeks, and there was no relapse except in one case that was diagnosed as having classic asthma. In the wait-and-review group, nine children (39%) had CHEST / 145 / 6 / JUNE 2014
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Figure 2. Flowchart of patients with chronic cough. Numbers on the left and right sides indicate children with chronic cough duration of 4 to 8 wk and ⱖ 8 wk, respectively. GERD 5 gastroesophageal reflux disease. See Figure 1 legend for expansion of other abbreviation.
a family history of asthma, five (22%) had atopic sensitization to aeroallergens, and six (26%) had a previous history of chronic cough. Preferring therapy was significantly more frequent in children with a cough duration of ⱖ 8 weeks compared with those with a duration of 4 to 8 weeks (P 5 .03). Of 86 patients who received ICS, 28% were treated for a period of 2 weeks. In 72% of the patients who received ICS, treatment was prolonged to 8 weeks due to a partial response. There was one patient who did not improve on the ICS treatment of 8 weeks and was diagnosed with gastroesophageal reflux disease. This patient responded to proton pump inhibitor treatment. A comparison between the children with chronic NIC who eventually developed asthma in terms of time to response to the initial ICS 1282
treatment (2 weeks vs 8 weeks) revealed no significant differences (Table 2).
Discussion This was a real-time observational study that specifically evaluated children with chronic NIC according to the recommendations of two major cough guidelines for children.5,6 Chronic NIC in almost threequarters of the children resolved spontaneously and did not recur for at least 1 year. Chronic NIC in , 30% of the children turned out to be asthma in the follow-up. The duration of the cough, the cough score, a family history of asthma, and serum eosinophilia were not Original Research
Table 1—Comparison of Children With Chronic NIC Considering the Final Diagnosis (n 5 108) Spontaneous Remission (n 5 77) Asthma (n 5 31)
Characteristics Duration of cough, median (25th-75th percentile), wk Cough score, median (25th-75th percentile), wk Previous history of chronic cough Family history of asthma Serum eosinophilia Atopic sensitization
10 (8-12)
12 (6-16)
4 (4-5)
4 (3-6)
23 (30)
17 (55)a
26 (34) 7 (9) 20 (26)
13 (42) 6 (19) 16 (52)a
Data are given as No. (%) unless otherwise indicated. One patient who had a diagnosis of gastroesophageal reflux disease was excluded. NIC 5 nonspecific isolated cough. aP , .05 compared with children with spontaneous remission.
different in the children with chronic NIC that resolved spontaneously and those with chronic NIC who eventually developed asthma. On the other hand, a previous history of chronic cough and atopic sensitization were significantly more frequent in children with asthma compared with children with spontaneous resolution. Unfortunately, we could not find any discriminative factors among the children with chronic NIC who eventually developed asthma in terms of the time to response to ICS treatment. Previous studies have reported that children with chronic NIC tend to improve with time and that chronic NIC does not recur in the majority.8,14,22 However, a small sample may deteriorate and develop bronchial hyperreactivity and wheezing.23,24 A careful follow-up of all patients with chronic NIC is, therefore, important, not only to avoid mislabeling children as having asthma but also to avoid delaying the diagnosis of children with chronic NIC who eventually developed Table 2—Comparison of Children With Chronic NIC Who Eventually Developed Asthma Considering the Initial Response to ICS (n 5 30) Characteristics Time to relapse, mean ⫾ SD, wk Duration of cough, median (25th-75th percentile), wk Cough score, mean ⫾ SD Previous history of chronic cough Family history of asthma Serum eosinophilia Atopic sensitization
2-wk Treatment (n 5 8) 14.1 ⫾ 12.3 12 (8.5-23)
8-wk Treatment (n 5 22) 10.5 ⫾ 9.6 12 (6-16)
P Value .39 .47
3.8 ⫾ 1.3
4.9 ⫾ 1.9
.20
6 (75)
11 (50)
.40
4 (50)
8 (36)
.67
2 (25) 6 (75)
4 (18) 9 (41)
.64 .21
Data are given as No. (%) unless otherwise indicated.ICS 5 inhaled corticosteroid. See Table 1 for expansion of other abbreviation. journal.publications.chestnet.org
asthma. In this study, the same physician followed up on the children with chronic NIC for almost 2 years. We observed that chronic NIC did not recur, even in 65% of the children who seemed responsive to the initial ICS treatment (56 of 86). Therefore, the initial response to the ICS treatment was misleading in almost two-thirds of children as a clue for diagnosis. This phenomenon, known as the “period effect,” has previously been well documented in randomized, placebocontrolled studies that report improvement in the placebo group.9,10 A randomized study design for a trial of ICS or a wait-and-see approach and then performing a crossover would have been better. However, our intention was to observe what happened in daily practice. We discussed the options with parents, and which group the children would be treated in was based on parental preference in accordance with the recommendations of the cough guidelines. We found that atopic sensitization to aeroallergens and a previous history of chronic cough increased the risk of having asthma nearly three times in children with chronic NIC. An association between personal/ family history of atopy with chronic/recurring/nocturnal cough was reported in previous studies in which atopy was determined using questionnaires.8,12,13,25 On the other hand, the present study found that a previous history of chronic cough was a risk factor for asthma in children with chronic NIC. Although this has not been reported in other studies, it is not an unexpected finding because recurrent symptoms are among the main features of asthma. The cough guidelines recommend an ICS trial in children with chronic NIC for a defined period of time and with clear-cut outcomes to diagnose asthma. The guidelines suggest a trial ranging from at least 2 to 3 weeks to 8 to 12 weeks, after which the response to the ICS trial should be evaluated.5,6 The definitive period of time after which the response should be determined is not clear. Thus, the duration of the ICS trial was prolonged to 8 weeks in children who showed partial response to the 2-week treatment in this study. The authors aimed to find differences between the responders to a 2-week trial and those who required a longer treatment period (8 weeks) among children who eventually developed asthma. We saw in this study that almost two-thirds of the children who eventually developed asthma were partially responsive to a 2-week treatment with ICS but showed a complete response when their treatment was prolonged to 8 weeks (22 of 30). On the other hand, the cough did not relapse in almost two-thirds of the children whose treatments were prolonged to 8 weeks (40 of 62). Therefore, the disadvantages of taking on an early and perhaps unnecessary further investigation of the chronic cough with the 2-week trial and the disadvantages of the 8-week trial period, with the unnecessary prolongation of the CHEST / 145 / 6 / JUNE 2014
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ICS treatment, seem to be the same. Also, if we had not discussed the options with the parents and instead recommended an observation period of 2 weeks to all the children as a mode of initial management, we could have prevented a further 16 unnecessary ICS treatments, which made up one-fifth of the children who resolved spontaneously. Additionally, a higher percentage of spontaneous resolution was seen in the children for whom the wait-and-review approach was chosen. These children had a shorter period of chronic cough (4-8 weeks). Therefore, a better definition of chronic cough would be ⱖ 8 weeks, a period that would allow the spontaneous resolution of postviral cough. In this study, the authors used a validated cough score for reporting cough, which was a method that was different from previous questionnaire-based studies using recalled data.11,12,26 This has the potential of increasing the accuracy of collected data because it was seen that the questions on the symptoms of cough were likely to be poorly recollected and unreliably reported by parents.17,22 Additionally, the children were managed and followed by a single allergist at regular intervals, and the average follow-up period was almost 2 years. There were limitations in this study. We could not use objective methods for recording coughs, such as a cough meter or a video recording system because these were both costly and impractical for long-term observation. The number of children who could perform spirometry on recruitment and follow-up were small, which was limiting in terms of the diagnosis of asthma. Also, a bronchial challenge test was not performed to confirm diagnosis of cough-variant asthma in children who relapsed with chronic cough and responded to ICS treatment again. On the other hand, although we cannot be sure, we think that complete response to ICS treatment each time the chronic cough episodes recur (minimum, four; maximum, 10 episodes) decreases the probability of viral respiratory tract infections in these children. The number of children who eventually developed asthma was small, which might have caused a type 2 error for comparisons within this group. In addition, parameters such as viral respiratory pathogens, exhaled nitric oxide, and sputum eosinophilia that could help in understanding the pathophysiology, response to treatment, and the prognosis of children with chronic NIC were not investigated in this study. Following up on the development of asthma in a healthy atopic control group for the same period would have been much more useful in terms of revealing the specific risk of atopy in the case of chronic NIC. Nonetheless, the results in the current study may be thought of as preliminary research that might suggest the benefit of further investigation with more patients in different settings. 1284
In conclusion, chronic NIC does not recur in the majority of children. Initial responses to the ICS trial may be misleading. A careful follow-up of these children is important so that they are not overdiagnosed with asthma and also in terms of correctly identifying the ones who eventually develop asthma. A wait-andreview approach of at least 2 weeks may be considered initial management for all children with chronic NIC. A trial with ICS may be preferred for children who have atopic sensitization, a previous history of chronic cough, or both.
Acknowledgments Author contributions: Dr Yilmaz had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis, including and especially any adverse effects. Dr Yilmaz: contributed to the preparation, writing, and revision of the manuscript; participated in the development of the protocol; and had primary responsibility for assessment of participants in the study center. Prof Bakirtas: contributed to the preparation, writing, and revision of the manuscript and had primary responsibility for protocol development and outcome assessment. Dr Ertoy Karagol: contributed to the development of the protocol, had responsibility for assessment of participants in the study center, and revision of the manuscript. Dr Topal: contributed to the development of the protocol, had responsibility for assessment of participants in the study center, and revision of the manuscript. Prof Turktas: contributed to the writing, revision, and supervision of the manuscript. Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Other contributions: We thank all of the children and their parents who participated in this study.
References 1. Cornford CS, Morgan M, Ridsdale L. Why do mothers consult when their children cough? Fam Pract. 1993;10(2):193-196. 2. Leonardi GS, Houthuijs D, Nikiforov B, et al. Respiratory symptoms, bronchitis and asthma in children of Central and Eastern Europe. Eur Respir J. 2002;20(4):890-898. 3. French CL, Irwin RS, Curley FJ, Krikorian CJ. Impact of chronic cough on quality of life. Arch Intern Med. 1998; 158(15):1657-1661. 4. Marchant JM, Masters IB, Taylor SM, Cox NC, Seymour GJ, Chang AB. Evaluation and outcome of young children with chronic cough. Chest. 2006;129(5):1132-1141. 5. Shields MD, Bush A, Everard ML, McKenzie S, Primhak R; British Thoracic Society Cough Guideline Group. BTS guidelines: recommendations for the assessment and management of cough in children. Thorax. 2008;63(suppl 3):iii1-iii15. 6. Chang AB, Glomb WB. Guidelines for evaluating chronic cough in pediatrics: ACCP evidence-based clinical practice guidelines. Chest. 2006;129(1_suppl):260S-283S. 7. McKenzie S. Cough—but is it asthma? Arch Dis Child. 1994; 70(1):1-2. 8. Powell CV, Primhak RA. Stability of respiratory symptoms in unlabelled wheezy illness and nocturnal cough. Arch Dis Child. 1996;75(5):385-391. Original Research
9. Chang AB, Phelan PD, Carlin JB, Sawyer SM, Robertson CF. A randomised, placebo controlled trial of inhaled salbutamol and beclomethasone for recurrent cough. Arch Dis Child. 1998;79(1):6-11. 10. Davies MJ, Fuller P, Picciotto A, McKenzie SA. Persistent nocturnal cough: randomised controlled trial of high dose inhaled corticosteroid. Arch Dis Child. 1999;81(1):38-44. 11. Ninan TK, Macdonald L, Russell G. Persistent nocturnal cough in childhood: a population based study. Arch Dis Child. 1995;73(5):403-407. 12. Spelman R. Two-year follow up of the management of chronic or recurrent cough in children according to an asthma protocol. Br J Gen Pract. 1991;41(351):406-409. 13. Wright AL, Holberg CJ, Morgan WJ, Taussig LM, Halonen M, Martinez FD. Recurrent cough in childhood and its relation to asthma. Am J Respir Crit Care Med. 1996;153(4 pt 1): 1259-1265. 14. Brooke AM, Lambert PC, Burton PR, Clarke C, Luyt DK, Simpson H. Night cough in a population-based sample of children: characteristics, relation to symptoms and associations with measures of asthma severity. Eur Respir J. 1996;9(1): 65-71. 15. Standardization of Spirometry, 1994 Update. American Thoracic Society. Am J Respir Crit Care Med. 1995;152(3):1107-1136. 16. Miller MR, Hankinson J, Brusasco V, et al; ATS/ERS Task Force. Standardisation of spirometry. Eur Respir J. 2005; 26(2):319-338. 17. Chang AB, Newman RG, Carlin JB, Phelan PD, Robertson CF. Subjective scoring of cough in children: parent-completed
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vs child-completed diary cards vs an objective method. Eur Respir J. 1998;11(2):462-466. Marchant JM, Masters IB, Taylor SM, Chang AB. Utility of signs and symptoms of chronic cough in predicting specific cause in children. Thorax. 2006;61(8):694-698. Chang AB, Landau LI, Van Asperen PP, et al; Thoracic Society of Australia and New Zealand. Cough in children: definitions and clinical evaluation. Med J Aust. 2006;184(8): 398-403. Chang AB, Robertson CF, van Asperen PP, et al. Can a management pathway for chronic cough in children improve clinical outcomes: protocol for a multicentre evaluation. Trials. 2010;11:103. Chang AB, Robertson CF, van Asperen PP, et al. A cough algorithm for chronic cough in children: a multicenter, randomized controlled study. Pediatrics. 2013;131(5):e1576-e1583. Chang AB. Cough, cough receptors, and asthma in children. Pediatr Pulmonol. 1999;28(1):59-70. Koh YY, Jeong JH, Park Y, Kim CK. Development of wheezing in patients with cough variant asthma during an increase in airway responsiveness. Eur Respir J. 1999;14(2):302-308. Cloutier MM, Loughlin GM. Chronic cough in children: a manifestation of airway hyperreactivity. Pediatrics. 1981;67(1): 6-12. Lewis H. Chronic cough: is it asthma? Arch Dis Child. 1999; 80(6):582. Kelly YJ, Brabin BJ, Milligan PJ, Reid JA, Heaf D, Pearson MG. Clinical significance of cough and wheeze in the diagnosis of asthma. Arch Dis Child. 1996;75(6):489-493.
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Original Research SIGNS AND SYMPTOMS OF CHEST DISEASE
Children With Chronic Nonspecific Isolated Cough Ozlem Yilmaz, MD; Arzu Bakirtas, MD; Hacer Ilbilge Ertoy Karagol, MD; Erdem Topal, MD; and Ipek Turktas, MD
Background: This study observed children with chronic nonspecific isolated cough (NIC) to investigate clinical differences between children whose symptoms resolved spontaneously and those who eventually developed asthma and then explored the differences among the children who eventually developed asthma in terms of their time of response to a trial of inhaled corticosteroid (ICS). Methods: Children with chronic NIC were managed either with a wait-and-review approach or with a 2-week trial with 400 mg/d inhaled budesonide according to the preference of their parents. Responses were monitored with a validated cough score. Treatment was prolonged to 8 weeks in the case of partial responders. All children were followed up at 3-month intervals. Results: A total of 109 children (median [interquartile range] age, 5 [3.5-9] years; cough duration, [8-16] weeks]) were followed for a mean (⫾ SD) time of 21(⫾ 5) months. Cough did not recur in 71% (spontaneous resolution) but relapsed in 28% of the children who later responded to ICS treatment again (asthma). Aeroallergen sensitization (relative risk, 2.86; 95% CI, 1.17-6.99) and previous history of chronic cough (relative risk, 2.68; 95% CI, 1.10-6.49) increased the risk of asthma. Cough duration, the cough score, the family history of asthma, and serum eosinophilia were not found discriminative for the final diagnosis. There were no differences among children who eventually developed asthma and responded to either the 2-week or 8-week trial in terms of the study parameters. Conclusions: Chronic NIC does not recur in the majority of children. Initial response to the ICS trial may be misleading but the trial may be preferred for children who have atopic sensitization, a previous history of chronic cough, or both. CHEST 2014; 145(6):1279–1285 Abbreviations: CVA 5 cough variant asthma; ICS 5 inhaled corticosteroid; NIC 5 nonspecific isolated cough
is one of the most common reasons for preCough sentation to a doctor. Nonspecific isolated cough 1-4
(NIC) is a common category of chronic cough, especially in children.5,6 Evidence suggests that only a minority of children with chronic NIC have asthma.5-10 A trial of inhaled corticosteroid (ICS) treatment is gen-
Manuscript received October 2, 2013; revision accepted December 28, 2013; originally published Online First January 30, 2014. Affiliations: From the Department of Pediatric Allergy and Asthma, School of Medicine, Gazi University, Ankara, Turkey. Funding/Support: The authors have reported to CHEST that no funding was received for this study. Correspondence to: Ozlem Yilmaz, MD, Department of Pediatric Allergy and Asthma, School of Medicine, Gazi University, Besevler, Ankara, Turkey 06510; e-mail: [email protected] © 2014 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.13-2348 journal.publications.chestnet.org
erally recommended for children with chronic NIC who have persistent symptoms. However, chronic cough guidelines in children emphasize that the response to ICS treatment may be a period effect rather than an indication for a diagnosis of asthma. Therefore, an early relapse of cough that again responds to ICS treatment may represent a diagnosis of asthma.5,6 Nevertheless, it is difficult to decide on the final diagnosis without a follow-up. Many previous research studies have focused on the evaluation and outcome of chronic cough.1,2,4 There are studies in the past that have examined cough in terms of “recurrent cough,” “persistent cough,” “night cough,” or “persistent nocturnal cough” in children.10-14 However, there are limited data available about chronic NIC. The primary aim of this study was to observe children with chronic NIC and to investigate clinical differences between children whose symptoms resolved CHEST / 145 / 6 / JUNE 2014
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spontaneously and those who eventually developed asthma. As a secondary aim, we examined the differences among children who eventually developed asthma in terms of their time of response to ICS treatment.
Materials and Methods Children aged , 18 years with chronic cough lasting ⱖ 4 weeks who were referred to the Department of Pediatric Allergy and Asthma at our hospital were screened for inclusion in the study. All children were evaluated by at least two allergists for specific cough pointers and characteristic cough patterns using a form we designed according to the recommendations in the guidelines.5,6 A chest radiograph and a pulmonary function test with bronchodilator responsiveness (for children old enough to conduct the maneuvers) were performed in all participants. Children with a specific cough pointer, characteristic cough pattern, and wet cough or with an abnormality in the chest radiograph or pulmonary function test were excluded from the study. Children with a previous diagnosis of a chronic respiratory disorder, those who had been on ICS or leukotriene receptor antagonist or bronchodilator treatment, or those using angiotensin-converting enzyme inhibitors were also excluded from the study. All other children with dry chronic cough and a normal physical examination were included in the study. Laboratory Investigations and Child Management Chest radiographs were taken in posteroanterior and lateral positions and reported by the radiology department. Pulmonary function tests were performed with a daily calibrated spirometer (Vmax 20C; SensorMedics, CareFusion Corp) in accordance with the American Thoracic Society Guidelines.15,16 We used the Knudson reference set for spirometry prediction. Age, sex, height, weight, and ethnicity were entered before each measurement. All children were white. Atopy was determined with a panel of skin prick tests that included house dust mites, pollens, alternaria, animal dander, latex, and histamine (10 mg/mL histamine phosphate) as positive controls and 0.9% sterile saline as negative controls. The skin prick test was considered positive if the mean wheal diameter was ⱖ 3 mm than the negative control. The serum eosinophil count was determined with an automatic complete blood count analyzer. The Gazi University Hospital ethics committee approved the study, and written informed consent was obtained from all children and/or their parents (project approval No. 293). Definitions were as follows: • Chronic cough: cough lasting ⱖ 4 weeks.6 • Specific cough pointers: Any auscultatory abnormality, classic cough characteristics, cardiac abnormalities, chest pain, chest wall deformity, daily moist or productive cough for . 3 months, digital clubbing, dyspnea, exertional dyspnea, failure to thrive, feeding difficulties, hemoptysis, immune deficiency, neurodevelopmental abnormality, recurrent pneumonia, wheeze, allergic rhinitis/postnasal drip, atopic eczema, passive smoking, symptoms of gastroesophageal reflux.5,6 • Characteristic cough patterns: Barking or brassy cough, cough productive of casts, honking cough, paroxysmal (with/ without whoop), staccato cough.5,6 • Nonspecific isolated dry cough: Persistent dry cough lasting ⱖ 4 weeks with no other respiratory symptoms.5,6 • Cough score: A validated verbal category cough scale scoring daytime plus nighttime cough scores.17 1280
• Daytime score: 0 5 no cough; 1 5 cough for one or two short periods only; 2 5 cough for more than two short periods; 3 5 frequent coughing but does not interfere with school or other activities; 4 5 frequent coughing which interferes with school or other activities; and 5 5 cannot perform most usual activities due to severe coughing. • Nighttime score: 0 5 no cough at night; 1 5 cough on waking or on going to sleep only; 2 5 awoken once or awoken early due to coughing; 3 5 frequent waking due to coughing; 4 5 frequent coughs most of the night; and 5 5 distressing cough. • Complete cough resolution (complete response): Improvement of ⱖ 75% or total resolution according to the recorded cough score for ⱖ 3 consecutive days.18-20 • Partial cough resolution (partial response): Improvement of 25% to 75% according to the basal cough score. • Nonresolution of cough (no response): Improvement of ⱕ 25% according to the basal cough score. • Chest radiograph abnormality: Any abnormality (other than peribronchial thickening) as interpreted by a radiologist. • Spirometry abnormality: As determined by the American Thoracic Society and European Respiratory Society Criteria with predicted values used.15,16 FEV1 , 80, FEV1/FVC , 80, FEF25-75 , 70% predicted and ⱖ 12% or 200 mL increase in FEV1 20 min after 400 mg of salbutamol inhalation were considered a spirometry abnormality. • Serum eosinophilia: ⱖ4% eosinophils in the complete blood count. • Classic asthma: Recurrent episodes of wheeze, dyspnea, or both that respond to inhaled b2-agonist, or bronchodilator responsiveness documented on spirometry (ⱖ 12% change in FEV1% predicted after 400 mg of salbutamol). • Cough variant asthma (CVA): Nonspecific chronic dry cough that resolves completely with ICS treatment 400 mg/d budesonide or equivalent within a 2-week to 8-week period and relapses after stopping treatment, and then again responds to the same treatment. • Relapse: A new chronic cough period or a cough with a wheezing after complete response to either ICS treatment of 2 or 8 weeks or after a wait-and-review period. All children were managed according to Figure 1. To ensure effective delivery of the inhaled treatment, parents of each child were trained by the same inhalation technician in a standard manner. All patients were followed up and their cough diary entries were reviewed by the same physician (O. Y.). Parents recorded daytime and nighttime cough scores according to the verbal descriptions detailed in the definitions given previously. This is a validated verbal category score that has been previously used in chronic cough studies in children.17,20,21 Parents filled in the cough diary daily during coughing periods lasting ⱖ 4 weeks. Response to treatment was evaluated according to the mean cough score. The treatment of children who were partially responsive to the 2-week treatment with ICS was prolonged to 8 weeks with the same dose of the drug. A plan to consult with other departments (pediatric pulmonology, cardiology, immunology, gastroenterology, and ear, nose, and throat) was made in the case of children who were nonresponsive to the 2-week treatment or partially responsive to the 8-week ICS treatment to ensure a differential diagnosis. All children were examined at 3-month intervals for any recurrence of cough. Children were admitted to the outpatient clinic for reevaluation any time they had symptoms. Statistical Analysis Statistical analysis was performed using the Statistical Package for Social Sciences 16.0 software (IBM). Descriptive analysis was Original Research
used for the characterization of patients. Data that had a normal distribution were described by using mean ⫾ SD values; median and interquartile ranges (IQRs) were used otherwise. The Pearson x2 test or Fisher exact test was used to compare categorical variables between the groups. The unpaired Student t test was used for two-group comparisons of normally distributed data, and the Mann-Whitney U test was used for nonparametric data. For the multivariate analysis, possible factors were entered into the logistic regression analysis to determine independent predictors. A two-sided value of P , .05 was considered statistically significant.
Results One hundred nineteen children with nonspecific cough lasting ⱖ 4 weeks participated in the study (Fig 2). Seven children did not attend to the clinic after initial evaluation (either wait and review or 2-week trial of ICS). Three children were not available for the followups at 3-month intervals after completion of initial trial of ICS treatment. Those 10 children were, therefore, excluded from the study. One hundred nine children were included in the final analysis. Fifty-seven of these children (52%) were male. The median age was 5 years (25th-75th percentile, 3.5-9 years). Median cough duration was 12 weeks (25th-75th percentile, 8-16 weeks). Of 109 patients, 26% had a cough period between 4 and 8 weeks, and 74% described a cough
period lasting ⱖ 8 weeks. All patients were followed up for at least 1 year. Mean (⫾ SD) follow-up time was 21 months (⫾ 5 months). Thirty-nine children could perform a spirometry test on recruitment. Nine were in the relapsing group. In the follow-up, six more children in the relapsing group could perform spirometry. None of the 15 children had reversibility on follow-up. Spontaneous Resolution and Asthma Frequency We determined the frequency of spontaneous resolution and asthma among children with chronic NIC. Of 109 patients, chronic cough did not recur in 77 during the follow-up period (71%, spontaneous resolution). Thirty-one patients (28%) relapsed within a median of 6 weeks (25th-75th percentile, 4-16 weeks). Twenty-one of the relapsed patients received a diagnosis of classic asthma (relapsed with wheezing) and 10 of them received a diagnosis of CVA (relapsed with chronic cough: five children had six episodes of chronic cough; one child had four episodes, three children had seven episodes, and one child had 10 recurrent episodes of chronic cough that responded to ICS trials). Differences Between Spontaneous Resolution and Asthma We evaluated the differences between children with chronic NIC that resolved spontaneously and those with chronic NIC who eventually developed asthma. There were no significant differences between children with chronic NIC that resolved spontaneously and those with chronic NIC who eventually developed asthma (classic asthma, CVA, or both) in terms of the duration of cough at admission (P 5 .28), the cough score (P 5 .12), the family history of asthma (P 5 .42), and the presence of eosinophilia (P 5 .19) (Table 1). Atopic sensitization to aeroallergens (P 5 .01) and previous history of chronic cough (P 5 .01) were found more frequently in children with chronic NIC who eventually developed asthma than in children in whom the condition resolved spontaneously. Logistic regression analysis revealed that atopic sensitization to aeroallergens and previous history of chronic cough increased the risk of having asthma by 2.86 (95% CI, 1.17-6.99) and 2.68 (95% CI, 1.10-6.49), respectively. Differences in Treatment Response Duration
Figure 1. Management of chronic nonspecific isolated cough. The solid arrow represents first chronic cough episode; the dashed arrow represents relapse during follow-up. ICS 5 inhaled corticosteroid; SABA 5 short-acting b2-agonist. journal.publications.chestnet.org
Regarding management and differences in terms of the duration of the response to treatment, 86 patients (79%) preferred a trial of treatment and 23 patients (21%) preferred a wait-and-review approach. All children in the wait-and-review group (n 5 23) improved within 2 weeks, and there was no relapse except in one case that was diagnosed as having classic asthma. In the wait-and-review group, nine children (39%) had CHEST / 145 / 6 / JUNE 2014
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Figure 2. Flowchart of patients with chronic cough. Numbers on the left and right sides indicate children with chronic cough duration of 4 to 8 wk and ⱖ 8 wk, respectively. GERD 5 gastroesophageal reflux disease. See Figure 1 legend for expansion of other abbreviation.
a family history of asthma, five (22%) had atopic sensitization to aeroallergens, and six (26%) had a previous history of chronic cough. Preferring therapy was significantly more frequent in children with a cough duration of ⱖ 8 weeks compared with those with a duration of 4 to 8 weeks (P 5 .03). Of 86 patients who received ICS, 28% were treated for a period of 2 weeks. In 72% of the patients who received ICS, treatment was prolonged to 8 weeks due to a partial response. There was one patient who did not improve on the ICS treatment of 8 weeks and was diagnosed with gastroesophageal reflux disease. This patient responded to proton pump inhibitor treatment. A comparison between the children with chronic NIC who eventually developed asthma in terms of time to response to the initial ICS 1282
treatment (2 weeks vs 8 weeks) revealed no significant differences (Table 2).
Discussion This was a real-time observational study that specifically evaluated children with chronic NIC according to the recommendations of two major cough guidelines for children.5,6 Chronic NIC in almost threequarters of the children resolved spontaneously and did not recur for at least 1 year. Chronic NIC in , 30% of the children turned out to be asthma in the follow-up. The duration of the cough, the cough score, a family history of asthma, and serum eosinophilia were not Original Research
Table 1—Comparison of Children With Chronic NIC Considering the Final Diagnosis (n 5 108) Spontaneous Remission (n 5 77) Asthma (n 5 31)
Characteristics Duration of cough, median (25th-75th percentile), wk Cough score, median (25th-75th percentile), wk Previous history of chronic cough Family history of asthma Serum eosinophilia Atopic sensitization
10 (8-12)
12 (6-16)
4 (4-5)
4 (3-6)
23 (30)
17 (55)a
26 (34) 7 (9) 20 (26)
13 (42) 6 (19) 16 (52)a
Data are given as No. (%) unless otherwise indicated. One patient who had a diagnosis of gastroesophageal reflux disease was excluded. NIC 5 nonspecific isolated cough. aP , .05 compared with children with spontaneous remission.
different in the children with chronic NIC that resolved spontaneously and those with chronic NIC who eventually developed asthma. On the other hand, a previous history of chronic cough and atopic sensitization were significantly more frequent in children with asthma compared with children with spontaneous resolution. Unfortunately, we could not find any discriminative factors among the children with chronic NIC who eventually developed asthma in terms of the time to response to ICS treatment. Previous studies have reported that children with chronic NIC tend to improve with time and that chronic NIC does not recur in the majority.8,14,22 However, a small sample may deteriorate and develop bronchial hyperreactivity and wheezing.23,24 A careful follow-up of all patients with chronic NIC is, therefore, important, not only to avoid mislabeling children as having asthma but also to avoid delaying the diagnosis of children with chronic NIC who eventually developed Table 2—Comparison of Children With Chronic NIC Who Eventually Developed Asthma Considering the Initial Response to ICS (n 5 30) Characteristics Time to relapse, mean ⫾ SD, wk Duration of cough, median (25th-75th percentile), wk Cough score, mean ⫾ SD Previous history of chronic cough Family history of asthma Serum eosinophilia Atopic sensitization
2-wk Treatment (n 5 8) 14.1 ⫾ 12.3 12 (8.5-23)
8-wk Treatment (n 5 22) 10.5 ⫾ 9.6 12 (6-16)
P Value .39 .47
3.8 ⫾ 1.3
4.9 ⫾ 1.9
.20
6 (75)
11 (50)
.40
4 (50)
8 (36)
.67
2 (25) 6 (75)
4 (18) 9 (41)
.64 .21
Data are given as No. (%) unless otherwise indicated.ICS 5 inhaled corticosteroid. See Table 1 for expansion of other abbreviation. journal.publications.chestnet.org
asthma. In this study, the same physician followed up on the children with chronic NIC for almost 2 years. We observed that chronic NIC did not recur, even in 65% of the children who seemed responsive to the initial ICS treatment (56 of 86). Therefore, the initial response to the ICS treatment was misleading in almost two-thirds of children as a clue for diagnosis. This phenomenon, known as the “period effect,” has previously been well documented in randomized, placebocontrolled studies that report improvement in the placebo group.9,10 A randomized study design for a trial of ICS or a wait-and-see approach and then performing a crossover would have been better. However, our intention was to observe what happened in daily practice. We discussed the options with parents, and which group the children would be treated in was based on parental preference in accordance with the recommendations of the cough guidelines. We found that atopic sensitization to aeroallergens and a previous history of chronic cough increased the risk of having asthma nearly three times in children with chronic NIC. An association between personal/ family history of atopy with chronic/recurring/nocturnal cough was reported in previous studies in which atopy was determined using questionnaires.8,12,13,25 On the other hand, the present study found that a previous history of chronic cough was a risk factor for asthma in children with chronic NIC. Although this has not been reported in other studies, it is not an unexpected finding because recurrent symptoms are among the main features of asthma. The cough guidelines recommend an ICS trial in children with chronic NIC for a defined period of time and with clear-cut outcomes to diagnose asthma. The guidelines suggest a trial ranging from at least 2 to 3 weeks to 8 to 12 weeks, after which the response to the ICS trial should be evaluated.5,6 The definitive period of time after which the response should be determined is not clear. Thus, the duration of the ICS trial was prolonged to 8 weeks in children who showed partial response to the 2-week treatment in this study. The authors aimed to find differences between the responders to a 2-week trial and those who required a longer treatment period (8 weeks) among children who eventually developed asthma. We saw in this study that almost two-thirds of the children who eventually developed asthma were partially responsive to a 2-week treatment with ICS but showed a complete response when their treatment was prolonged to 8 weeks (22 of 30). On the other hand, the cough did not relapse in almost two-thirds of the children whose treatments were prolonged to 8 weeks (40 of 62). Therefore, the disadvantages of taking on an early and perhaps unnecessary further investigation of the chronic cough with the 2-week trial and the disadvantages of the 8-week trial period, with the unnecessary prolongation of the CHEST / 145 / 6 / JUNE 2014
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ICS treatment, seem to be the same. Also, if we had not discussed the options with the parents and instead recommended an observation period of 2 weeks to all the children as a mode of initial management, we could have prevented a further 16 unnecessary ICS treatments, which made up one-fifth of the children who resolved spontaneously. Additionally, a higher percentage of spontaneous resolution was seen in the children for whom the wait-and-review approach was chosen. These children had a shorter period of chronic cough (4-8 weeks). Therefore, a better definition of chronic cough would be ⱖ 8 weeks, a period that would allow the spontaneous resolution of postviral cough. In this study, the authors used a validated cough score for reporting cough, which was a method that was different from previous questionnaire-based studies using recalled data.11,12,26 This has the potential of increasing the accuracy of collected data because it was seen that the questions on the symptoms of cough were likely to be poorly recollected and unreliably reported by parents.17,22 Additionally, the children were managed and followed by a single allergist at regular intervals, and the average follow-up period was almost 2 years. There were limitations in this study. We could not use objective methods for recording coughs, such as a cough meter or a video recording system because these were both costly and impractical for long-term observation. The number of children who could perform spirometry on recruitment and follow-up were small, which was limiting in terms of the diagnosis of asthma. Also, a bronchial challenge test was not performed to confirm diagnosis of cough-variant asthma in children who relapsed with chronic cough and responded to ICS treatment again. On the other hand, although we cannot be sure, we think that complete response to ICS treatment each time the chronic cough episodes recur (minimum, four; maximum, 10 episodes) decreases the probability of viral respiratory tract infections in these children. The number of children who eventually developed asthma was small, which might have caused a type 2 error for comparisons within this group. In addition, parameters such as viral respiratory pathogens, exhaled nitric oxide, and sputum eosinophilia that could help in understanding the pathophysiology, response to treatment, and the prognosis of children with chronic NIC were not investigated in this study. Following up on the development of asthma in a healthy atopic control group for the same period would have been much more useful in terms of revealing the specific risk of atopy in the case of chronic NIC. Nonetheless, the results in the current study may be thought of as preliminary research that might suggest the benefit of further investigation with more patients in different settings. 1284
In conclusion, chronic NIC does not recur in the majority of children. Initial responses to the ICS trial may be misleading. A careful follow-up of these children is important so that they are not overdiagnosed with asthma and also in terms of correctly identifying the ones who eventually develop asthma. A wait-andreview approach of at least 2 weeks may be considered initial management for all children with chronic NIC. A trial with ICS may be preferred for children who have atopic sensitization, a previous history of chronic cough, or both.
Acknowledgments Author contributions: Dr Yilmaz had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis, including and especially any adverse effects. Dr Yilmaz: contributed to the preparation, writing, and revision of the manuscript; participated in the development of the protocol; and had primary responsibility for assessment of participants in the study center. Prof Bakirtas: contributed to the preparation, writing, and revision of the manuscript and had primary responsibility for protocol development and outcome assessment. Dr Ertoy Karagol: contributed to the development of the protocol, had responsibility for assessment of participants in the study center, and revision of the manuscript. Dr Topal: contributed to the development of the protocol, had responsibility for assessment of participants in the study center, and revision of the manuscript. Prof Turktas: contributed to the writing, revision, and supervision of the manuscript. Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Other contributions: We thank all of the children and their parents who participated in this study.
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