Original Research

SIGNS AND SYMPTOMS OF CHEST DISEASE

journal.publications.chestnet.org CHEST / 145 / 6 / JUNE 2014 1279
CHEST
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 treat-
ment may represent a diagnosis of asthma.
5,6
Never-
theless, it is difcult to decide on the nal 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
C
ough is one of the most common reasons for pre-
sentation to a doctor.
1-4
Nonspecic isolated cough
(NIC) is a common category of chronic cough, espe-
cially in children.
5,6
Evidence suggests that only a
minor ity of children with chronic NIC have asthma.
5-10

A trial of inhaled corticosteroid (ICS) treatment is gen-
Background: This study observed children with chronic nonspecic isolated cough (NIC) to inves-
tigate clinical differences between children whose symptoms resolved spontaneously and those
who eventually developed asthma and then explored the differences among the children who even-
tually 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 m g/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 nal 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 nonspecic isolated cough
Children With Chronic Non specic
Isolated Cough
Ozlem Yilmaz , MD ; Arzu Bakirtas , MD ; Hacer Ilbilge Ertoy Karagol , MD ; Erdem Topal , MD ;
and Ipek Turktas , MD
Manuscript received October 2, 2013; revision accepted
December 28, 2013; originally published Online First January 30,
2014.
Afliations: 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: drozlemyilmaz09@gmail.com
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
Downloaded From: http://journal.publications.chestnet.org/ by M Darwich on 10/13/2014
1280 Original Research
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): Improve-
ment of 75% or total resolution according to the recorded
cough score for 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 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
FEV
1
, 80, FEV
1
/FVC , 80,
FEF
25-75
, 70% predicted and 12% or 200 mL increase in
FEV
1
20 min after 400 m g of salbutamol inhalation were
considered a spirometry abnormality.
Serum eosinophilia: 4% eosinophils in the complete blood
count.
Classic asthma: Recurrent episodes of wheeze, dyspnea, or
both that respond to inhaled b
2
-agonist, or bronchodilator
responsiveness documented on spirometry ( 12% change
in FEV
1
% predicted after 400 m g of salbutamol).
Cough variant asthma (CVA): Nonspecic chronic dry cough
that resolves completely with ICS treatment 400 m g/d budes-
onide 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 man-
ner. 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 denitions given previously. This is a
validated verbal category score that has been previously used in
chronic cough studies in children.
17,20,21
Parents lled in the cough
diary daily during coughing periods lasting 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 respon-
sive to the 8-week ICS treatment to ensure a differential diagnosis.
All children were examined at 3-month intervals for any recur-
rence 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
spontaneously and those who eventually developed
asthma. As a secondary aim, we examined the differ-
ences 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 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 specic
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 broncho-
dilator responsiveness (for children old enough to conduct the
maneuvers) were performed in all participants. Children with a
specic cough pointer, characteristic cough pattern, and wet cough
or with an abnormality in the chest radiograph or pulmonary func-
tion 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 treat-
ment, 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 chil-
dren 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 con-
trols and 0.9% sterile saline as negative controls. The skin prick test
was considered positive if the mean wheal diameter was 3 mm
than the negative control. The serum eosinophil count was deter-
mined with an automatic complete blood count analyzer.
The Gazi University Hospital ethics committee approved the
study, and written informed consent was obtained from all chil-
dren and/or their parents (project approval No. 293).
Denitions were as follows:
Chronic cough: cough lasting 4 weeks.
6

Specic 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 difculties, hemoptysis, immune
deciency, neurodevelopmental abnormality, recurrent pneu-
monia, wheeze, allergic rhinitis/postnasal drip, atopic eczema,
passive smoking, symptoms of gastroesophageal reux.
5,6

Characteristic cough patterns: Barking or brassy cough,
cough productive of casts, honking cough, paroxysmal (with/
without whoop), staccato cough.
5,6

Nonspecic isolated dry cough: Persistent dry cough lasting
4 weeks with no other respiratory symptoms.
5,6

Cough score: A validated verbal category cough scale scoring
daytime plus nighttime cough scores.
17

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journal.publications.chestnet.org CHEST / 145 / 6 / JUNE 2014 1281
period lasting 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 chil-
dren 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 res-
olution and asthma among children with chronic NIC.
Of 109 patients, chronic cough did not recur in 77
dur ing the follow-up period (71%, spontaneous reso-
lution). 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 diag-
nosis of classic asthma (relapsed with wheezing) and
10 of them received a diagnosis of CVA (relapsed with
chronic cough: ve children had six episodes of chronic
cough; one child had four episodes, three children had
seven episodes, and one child had 10 recurrent epi-
sodes 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 signicant differences between chil-
dren 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 pre-
vious 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 regres-
sion analy sis 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
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 chil-
dren 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
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
x
2
test or Fisher exact test was used to compare categorical vari-
ables 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 logis-
tic regression analysis to determine independent predictors. A
two-sided value of P , .05 was considered statistically signicant.
Results
One hundred nineteen children with nonspecic
cough lasting 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 follow-
ups at 3-month intervals after completion of initial
trial of ICS treatment. Those 10 children were, there-
fore, excluded from the study. One hundred nine chil-
dren were included in the nal 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
Figure 1. Management of chronic nonspecic isolated cough.
The solid arrow represents rst chronic cough episode; the dashed
arrow represents relapse during follow-up. ICS 5 inhaled cortico-
steroid; SABA 5 short-acting b
2
-agonist.
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1282 Original Research
treatment (2 weeks vs 8 weeks) revealed no signi-
cant differences ( Table 2 ).
Discussion
This was a real-time observational study that specif-
ically evaluated children with chronic NIC according
to the recommendations of two major cough guide-
lines for children.
5,6
Chronic NIC in almost three-
quarters 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
a family history of asthma, ve (22%) had atopic sensi-
tization to aeroallergens, and six (26%) had a previous
history of chronic cough. Preferring therapy was sig-
nicantly more frequent in children with a cough dura-
tion of 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 treat-
ment of 8 weeks and was diagnosed with gastroesoph-
ageal reux 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
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 8 wk, respectively. GERD 5 gastroesophageal reux
disease. See Figure 1 legend for expansion of other abbreviation.
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journal.publications.chestnet.org CHEST / 145 / 6 / JUNE 2014 1283
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 ini-
tial 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 previ-
ously been well documented in randomized, placebo-
controlled 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 perform-
ing a crossover would have been better. However, our
intention was to observe what happened in daily prac-
tice. We discussed the options with parents, and which
group the children would be treated in was based on
parental preference in accordance with the recommen-
dations 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/noctur-
nal 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 pre-
vious 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 nding 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 denitive
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 nd 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 unnec-
essary 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
different in the children with chronic NIC that resolved
spontaneously and those with chronic NIC who even-
tually developed asthma. On the other hand, a previous
history of chronic cough and atopic sensitization were
signicantly more frequent in children with asthma
compared with children with spontaneous resolution.
Unfortunately, we could not nd 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, impor-
tant, not only to avoid mislabeling children as having
asthma but also to avoid delaying the diagnosis of chil-
dren with chronic NIC who eventually developed
Table 1 Comparison of Children With Chronic NIC
Considering the Final Diagnosis (n 5 108)
Characteristics
Spontaneous
Remission (n 5 77) Asthma (n 5 31)
Duration of cough, median
(25th-75th percentile), wk
10 (8-12) 12 (6-16)
Cough score, median
(25th-75th percentile), wk
4 (4-5) 4 (3-6)
Previous history of chronic
cough
23 (30) 17 (55)
a

Family history of asthma 26 (34) 13 (42)
Serum eosinophilia 7 (9) 6 (19)
Atopic sensitization 20 (26) 16 (52)
a

Data are given as No. (%) unless otherwise indicated. One patient
who had a diagnosis of gastroesophageal reux disease was excluded.
NIC 5 nonspecic isolated cough.

a
P , .05 compared with children with spontaneous remission.
Table 2 Comparison of Children With Chronic NIC
Who Eventually Developed Asthma Considering the
Initial Response to ICS (n 5 30)
Characteristics
2-wk Treatment
(n 5 8)
8-wk Treatment
(n 5 22) P Value
Time to relapse,
mean SD, wk
14.1 12.3 10.5 9.6 .39
Duration of cough,
median
(25th-75th
percentile), wk
12 (8.5-23) 12 (6-16) .47
Cough score,
mean SD
3.8 1.3 4.9 1.9 .20
Previous history of
chronic cough
6 (75) 11 (50) .40
Family history of
asthma
4 (50) 8 (36) .67
Serum eosinophilia 2 (25) 4 (18) .64
Atopic sensitization 6 (75) 9 (41) .21
Data are given as No. (%) unless otherwise indicated.ICS 5 inhaled
corticosteroid. See Table 1 for expansion of other abbreviation.
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1284 Original Research
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 chil-
dren 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-and-
review approach of at least 2 weeks may be consid-
ered 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 revi-
sion of the manuscript and had primary responsibility for protocol
development and outcome assessment.
Dr Ertoy Karagol: contributed to the development of the proto-
col, 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/nonnancial disclosures: The authors have reported
to CHEST that no potential conicts of interest exist with any
companies/organizations whose products or services may be dis-
cussed in this article.
Other contributions: We thank all of the children and their par-
ents who participated in this study.
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