Download Airway Inflammation as an Assessment of Chronic Nonproductive

Airway Inflammation as an Assessment
of Chronic Nonproductive Cough*
Sang Yeub Lee, MD†; Jae Youn Cho, MD; Jae Jeong Shim, MD;
Han Kyeom Kim, MD; Kyung Ho Kang, MD, FCCP; Se Hwa Yoo, MD; and
Kwang Ho In, MD
Objectives: The possibility that a bronchial inflammatory process could be involved with a chronic
nonproductive cough without other potential causes such as postnasal drip syndrome, bronchial
asthma, gastroesophageal reflux, chronic bronchitis, bronchiectasis, or the use of angiotensinconverting enzyme inhibitors has not been clearly described. We investigated the possibility that
a chronic nonproductive cough without other potential causes is associated with airway inflammation, and if this is so, what the relationship might be between this inflammation and the
possible etiology of the cough.
Subjects: Twenty-five adults with chronic nonproductive cough as an isolated symptom over a
3-week period, and 5 healthy control subjects were studied.
Measurements and results: Clinical assessments, cough scores, methacholine challenges, allergy
skin prick tests, and bronchoscopies for bronchial biopsies were performed. In the bronchial
biopsies, the patients were divided into the following two subgroups: 21 patients who were
infiltrated with eosinophils vs the healthy control group (median, 12.0 vs 0.0 cells/mm2,
respectively; p < 0.01); and 4 patients who were infiltrated with lymphocytes vs the healthy
control group (median, 84.5 vs 22.0 cells/mm2, respectively; p < 0.01). With the methacholine
challenge test, 5 of the 21 eosinophil-infiltrated patients received diagnoses of cough-variant
asthma, and the other 16 patients received diagnoses of eosinophilic bronchitis. In the lymphocyte-infiltrated group, all four patients received diagnoses of lymphocytic bronchitis.
Conclusions: These results suggest that a chronic nonproductive cough as an isolated symptom is
associated with airway inflammation due to eosinophil and lymphocyte infiltration. The causes of
the chronic nonproductive cough were eosinophilic bronchitis, cough-variant asthma, and
lymphocytic bronchitis.
(CHEST 2001; 120:1114 –1120)
Key words: airway inflammation; cough; cough-variant asthma; eosinophilic bronchitis; lymphocytic bronchitis
Abbreviations: PC20 ⫽ provocative concentration of methacholine causing a 20% fall in FEV1; PEF ⫽ peak expiratory
flow
cough is defined as a cough persisting for
C athronic
least 3 weeks. Its pathophysiology is still
1
poorly understood. Systemic evaluation of the potential causes of chronic cough based on the locations of
afferent limbs of the cough reflex has shown that
*From the Pulmonary Division (Dr. Lee), the Department of
Internal Medicine, College of Medicine, Konkuk University,
Chungju, Korea; Korea University (Drs. Cho, Shim, Kang, Yoo,
and In), Seoul, Korea; and the Department of Pathology (Dr.
Kim), College of Medicine, Korea University, Seoul, Korea.
†Dr. Lee is currently at the Department of Internal Medicine,
Pulmonary Division, Pundang CHA General Hospital, College of
Medicine, Pochon CHA University, Kyonggi-do, Korea.
This study was supported by Brain Korea 21.
Manuscript received October 17, 2000; revision accepted April 6,
2001.
Correspondence to: Kwang Ho In, MD, The Pulmonary Division,
The Department of Internal Medicine, Korea University Anam
Hospital 126 –1, 5Ka, Anam-Dong, Sungbuk-Ku, Seoul, Korea,
136 – 075; e-mail: [email protected]
postnasal drip syndrome, gastroesophageal reflux,
and asthma are the main etiologies of persistent
cough. The so-called “cough-variant asthma” is also a
well-known cause of cough,2 and nonasthmatic eosinophilic bronchitis, a less common etiology, also
has been described.3,4
Asthma is associated with airway inflammation.
Boulet and colleagues5 reported that the chronic
cough observed in nonasthmatic subjects, which was
caused by postnasal drip syndrome and gastroesophageal reflux, is also associated with airway inflammation. However, the possibility that a bronchial inflammatory process may be involved in a chronic
nonproductive cough without the other potential
causes of postnasal drip syndrome, bronchial asthma,
gastroesophageal reflux, chronic bronchitis, bronchiectasis, or the use of angiotensin-converting enzyme
inhibitors has not been clearly described.
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Clinical Investigations
We investigated the possibility that a chronic
nonproductive cough without other potential causes
is associated with airway inflammation, and if this is
so, what the relationship might be between this
inflammation and the possible etiology of the cough.
Materials and Methods
Patients
Twenty-five patients, 10 men and 15 women who were 20 to 64
years of age (mean, 39.8 year), who were referred to the Korea
University Hospital for persistent dry cough of more than 3
weeks’ duration were studied. The inclusion criteria included a
normal pulmonary function test result, a normal chest examination and radiograph, and nonsmoking status. Exclusion criteria
included postnasal drip syndrome, gastroesophageal reflux, the
use of a medication known to induce chronic cough (eg, angiotensin-converting inhibitor or ␤-blockers), evidence of a respiratory tract infection in the previous 8 weeks, or a history of asthma,
chronic bronchitis, or any other chest or systemic diseases.
Postnasal drip syndrome was considered as an etiology if the
patients experienced the sensation of “having something drip
down into their throat” and/or had to clear their throat frequently, or if a physical examination of the pharynx revealed
secretions or a cobblestone mucosa, with or without signs of
chronic sinusitis on the sinus radiograph, as suggested by a
thickening of the sinus mucosa.
Gastroesophageal reflux was considered if the 24-h measurement of the esophageal pH was positive. Coughers were compared with a group of healthy control subjects (three men and
two women; mean age, 57.2 years). The control subjects were
nonsmokers and had normal chest radiograph results, normal
airway reactivity, and normal results of pulmonary function
testing. They had no current respiratory symptoms, were nonatopic, and had had no respiratory tract infection within the
previous month. No control subjects were receiving any medications. The study protocol was approved by the ethics committee
of Korea University College of Medicine, and written informed
consent was obtained from all patients and control subjects.
Procedures
All patients and control subjects were given a thorough
evaluation, which included the subjective measurement of cough
severity, methacholine challenge, allergy skin prick tests, and
fiberoptic bronchoscopy for bronchial biopsies, in order to
evaluate airway inflammation. The severity of the cough was
rated using the cough score (Table 1).6
The methacholine challenge was performed using the following method. Acetyl methacholine chloride (Sigma; St. Louis,
Table 1—Cough Verbal Category Descriptive Scores
Score
Symptom Description
0
1
2
3
4
5
No cough
Cough for one or two short periods only
Cough for ⬎ 2 short periods
Frequent coughing but does not interfere with activities
Frequent coughing that interferes with activities
Cannot perform most usual activities due to severe coughing
MO) was diluted with normal saline solution and was divided into
nine concentrated solutions ranging from 0.075 to 25 mg/mL.
Each concentrated methacholine solution was inhaled five times
through a nebulizer (DeVilbiss Pulmo-aide Compressor/Nebulizer; SM Instruments; Doylestown, PA) and a dosimeter (MicroDosimeter; Sunrise Medical; Carlsbad, CA). FEV1 was measured
after each inhalation, and the provocative concentration of
methacholine resulting in a 20% fall in FEV1 from the baseline
measurement (PC20) was subsequently calculated from a logresponse curve using linear interpolation. A positive airway
hyperresponsiveness was defined when the PC20 was ⬍ 8 mg/
mL.
Allergy skin prick tests were performed with a solution (Bencard; Brentford, UK) of 55 common allergen extracts. The sizes
of the wheal and the area of erythema were measured with a skin
test reaction gauge (Bencard) 15 min after the skin prick. A
negative result on the test indicated that there was no reaction
induced by an allergen but that there was a normal reaction to the
controlled histamine solution. A score of 1⫹ was given to areas of
erythema of ⬍ 21 mm, and a score of 2⫹ was given for areas of
erythema of ⬎ 21 mm, with the ratio of the wheal size of ⬍ 1
compared to that induced by the histamine-controlled solution.
The ratios between 1 and 2 were given a score of 3⫹. Ratios
between 2 and 3 were given a 4⫹. Scores of ⬎ 2⫹ were
designated as atopic.
A bronchoscopic biopsy was performed under local anesthesia
with 2% lidocaine spray using flexible bronchoscopy (model BF
1T30; Olympus; Tokyo, Japan). The oxygen saturation and pulse
rate were checked by pulse oximetry during the procedure. From
the carina of the second and third segment of the right bronchus,
three or four pieces of tissue were obtained, were fixed with 10%
formalin, were embedded on paraffin, were sliced at a 6-␮m
thickness, were stained with hematoxylin-eosin, and were examined under a light microscope.
Assessment of Airway Inflammation
Inflammatory cell counts and basement membrane thickness
were measured from the histologic sections. To avoid observer
bias, all microscopic slides were coded prior to analysis by one
pathologist and were analyzed blindly, in terms of the patients’
clinical data. Inflammatory cell counts were calculated manually
from the light microscopy using a graticule (eyepiece micrometer;
Olympus) at ⫻200 magnification. The cell counts were measured as
the mean number of cells per square millimeter (ie, 1 mm2)
measured at three different sections. Differential counts of lymphocytes, basophils, eosinophils, plasma cells, and so forth were
performed. Only the surface of the connective tissue was considered, excluding both smooth muscle cells and mucus glands. Cell
differentiation was based on the type of nuclei and granules
inside the cells. The cells were counted only if the nuclei were
observed. The thickness of the basement membrane was assessed
on three sections stained with hematoxylin-eosin and was measured from the base of the bronchial epithelium to the outer limit
of the reticular lamina of the basement membrane using a
micrometer at ⫻400 magnification. The final result was the mean
of all measurements obtained for each biopsy specimen.
Statistical Analysis
All statistical analyses were performed using statistical software
(SAS, version 6.12; SAS Institute; Cary, NC). The results were
expressed as the mean values of FEV1, FVC, peak expiratory flow
(PEF), and the thickness of the basement membranes, and as the
median and range for cell counts from biopsy specimens. The
Wilcoxon two-sample test was used to compare the mean values
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Table 2—Clinical Characteristics of Patients*
Characteristics
Patients (n ⫽ 25)
Mean age, yr
Sex
Male
Female
Cough score
3
4
5
Symptom duration, mo
FEV1, % predicted
FVC, % predicted
PEF, % predicted
Provocation‡
With
Without
Atopy
With
Without
39.8 ⫾ 12.0
10
15
12
9
4
2–6†
104 ⫾ 15.8
88.2 ⫾ 12.0
102.3 ⫾ 17.7
5
20
Figure 1. The eosinophil-infiltrated group. The bronchial mucosa shows eosinophil infiltration predominantly in the subepithelial connective tissue. Epithelial denudation and basement
membrane thickening are also noted (hematoxylin-eosin, original
⫻400).
5
20
*Values given as mean ⫾ SD, unless otherwise indicated.
†Most frequent duration.
‡Methacholine challenge.
1.77, 3.67, and 5.88 mg/mL. Five patients had
positive results to the allergy skin prick tests.
between groups of patients. Cell differential counts in bronchial
biopsy specimens were compared using the Kruskal-Wallis test.
Results
Patient Characteristics
The patient pool consisted of 10 men and 15
women, ranging in age from 20 to 64 years (Table 2).
The mean (⫾ SD) baseline daily cough scores were
3.68 ⫾ 0.75. The duration of the cough symptoms of
the patients ranged from 3 weeks to ⬎ 10 years, with
2 to 6 months being considered the most prevalent
duration (10 patients; 40%) (Table 3). The mean
values for FEV1, FVC, and PEF (% predicted) of the
patients were 104 ⫾ 15.8, 88.2 ⫾ 12.0, and
102.3 ⫾ 17.7, respectively.
Among the 25 patients, 5 had positive results for
the methacholine challenge (PC20, ⬍ 8 mg/mL). The
PC20 values for the five patients were 0.94, 1.53,
Assessment of Airway Inflammation
The patients were divided into an eosinophilinfiltrated group and a lymphocyte-infiltrated group
(Fig 1, 2). The eosinophil-infiltrated group was
considered to have ⬎ 3% occupancy of all cells,4
irrespective of other inflammatory cell counts. The
lymphocyte-infiltrated group was considered to have
more than twice the number of lymphocytes of the
control group (Fig 3) or to have ⬎ 60% occupancy
without increasing the numbers of other inflammatory cells. The eosinophil-infiltrated group consisted
of 21 patients with a median eosinophil count of 12.0
cells/mm2, while the median eosinophil count of the
Table 3—Number of Patients According to Duration of
Cough
Duration
No.
%
⬍ 1 mo
1–2 mo
2–3 mo
3–6 mo
6 mo–1 yr
1–5 yr
5–10 yr
⬎ 10 yr
2
2
4
6
3
2
4
2
8
8
16
24
12
8
16
8
Figure 2. The lymphocyte-infiltrated group. The bronchial
mucosa shows lymphocyte infiltration predominantly in the
subepithelial connective tissue and basement membrane thickening (hematoxylin-eosin, original ⫻400).
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Clinical Investigations
patients and 2 of 5 cough-variant asthma patients
had atopy. The lymphocytic bronchitis patients did not
have atopy.
Discussion
Figure 3. The healthy control group. The bronchial mucosa
shows no definite inflammatory cell infiltration and basement
membrane thickening (hematoxylin-eosin, original ⫻400).
control group was 0.0 cells/mm2 (p ⬍ 0.01). The
lymphocyte-infiltrated group consisted of four patients whose median eosinophil count was 84.5 cells/
mm2, in contrast with the 22.0 cells/mm2 of the
control group (p ⬍ 0.01) (Table 4). Significantly, the
mean thickness of the basement membrane of 25
patients was 14.20 ⫾ 5.19 ␮m, which is thicker than
that of the control group (mean, 3.50 ⫾ 1.37 ␮m)
(p ⬍ 0.01).
Etiologic Diagnosis
The causes of chronic nonproductive cough in the
patients were inferred from the methacholine challenge results and the pathologic findings. Five of 21
patients of the eosinophil-infiltrated group could receive diagnoses of cough-variant asthma due to positive
results to the methacholine challenge. However, 16
patients with negative results to the methacholine
challenge could receive diagnoses of eosinophilic bronchitis. All four patients in the lymphocyte-infiltrated
group were shown to have negative results for the
methacholine challenge and manifested lymphocytic
bronchitis (Fig 4). Three of 16 eosinophilic bronchitis
Two studies4,5 indicate that chronic cough is associated with airway inflammation. It is not clear how
the airway inflammation affects the cough reflex and
airway responsiveness, yet the hypothesis that epithelial cell damage could lead to an increased cough
reflex is highly supported.5 Denudation of the sensory nerve endings by epithelial damage due to the
inflammation may result in an increased cough reflex
to exogenous or endogenous factors. Epithelial damage along with inflammatory cell infiltration have
been observed in patients with chronic cough. This is
supported by studies7–9 showing that steroids assist
in healing the damaged epithelial cells by suppressing the infiltration of inflammatory cells, and that
they also participate in regenerating the destroyed
cilia, which results in a reduction of coughing.
Therefore, the pathogenesis of chronic cough can be
summarized as the damage of epithelial cells due to
airway inflammation.
In this study, an increase in inflammatory cell
infiltration and a thickening of the basement membrane in the patient group were found, in contrast
with the control group. Mostly, the inflammatory
cells were either eosinophils or lymphocytes. Typically, no significant differences were observed between the patient and control groups in the number
of inflammatory cells, with the exceptions of the
number of eosinophils and lymphocytes. Therefore,
we evaluated the patient group according to the
number of eosinophils and lymphocytes. First, we
defined the patients with increased eosinophils, as
compared with the number of eosinophils in the
healthy control group, to be an eosinophil-infiltrated
group. Then, we defined the patients with increased
lymphocytes, as compared with the number of lymphocytes in the healthy control group, to be a
Table 4 —Cell Counts per Square Millimeter of Surface in Bronchial Biopsy Specimens in Each Group According to
Dominant Cell Infiltration*
Cells
Eosinophil-Infiltrated
(n ⫽ 21)
Lymphocyte-Infiltrated
(n ⫽ 4)
Control Subjects
(n ⫽ 5)
Monocytes/macrophages
Lymphocytes
Eosinophils
Neutrophils
Plasmacytes
13.0 (8.0–25.5)
242.0 (165.5–810.5)
12.0† (5.5–174.5)
39.0 (19.5–52.0)
6.0 (0.0–14.0)
5.0 (4.0–8.25)
84.5† (55.0–113.2)
1.0 (0.25–1.0)
17.5 (11.0–42.0)
1.0 (0.0–2.0)
8.0 (3.0–8.5)
22.0 (11.5–38.5)
0.0 (0.0–1.0)
27.0 (21.5–29.0)
0.0 (0.0–1.0)
*Values given as median (range).
†Statistically significant (p ⬍ 0.01).
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Figure 4. Flow chart of the study analysis.
lymphocyte-infiltrated group. On the basis of inflammatory cell infiltration of the bronchial mucosa and
the results of the methacholine challenge, we were
able to consider the causes of chronic nonproductive
cough in the patients as cough-variant asthma, eosinophilic bronchitis, or bronchitis with lymphocyte
infiltration. For the investigation of bronchitis with
lymphocyte infiltration in this study, we think that a
term such as lymphocytic bronchitis perhaps would
be a useful label during further investigation of this
type of airway inflammation.
Our data suggest that the assessment of airway
inflammation is an important addition for the investigation of chronic nonproductive cough.4 We chose
to assess airway inflammation with bronchoscopic
biopsies instead of sputum induction, since it is
difficult to obtain successful results with the sputum
induction method in patients with dry cough. Although bronchoscopic biopsies are invasive, we believe that this method is more precise for the
assessment of airway inflammation.
Cough-variant asthma was first named by
Glauser10 in 1972 and is defined as a condition of
nonsmoking patients who have coughed for at least 3
weeks without other symptoms but who have normal
results of physical examinations, normal or almost
normal spirometry values, and positive results of
bronchial provocation testing.2,10 –13
It was reported that cough-variant asthma could
reach up to 29% of all patients with chronic cough and
up to 7 to 11% of all asthma patients.13,14 However,
many cases were overlooked without being diagnosed.
Therefore, patients with a nonspecific chronic cough,
such as a nocturnal dry cough or aggravated cough after
exercise and exposure to cold air, and with an atopic
allergy history, either family or individual, must be
suspected.2,11,13,14 In this study, 40% (two of five
patients) of cough-variant asthma patients showed
atopy, which was not significantly different from the 25
to 35% seen in cases of classic asthma.
Eosinophilic bronchitis was suggested by Gibson
et al3 in 1989 and was defined as an eosinophilic
airway inflammation with chronic cough as an isolated symptom with normal spirometry values and
normal methacholine airway responsiveness. It is a
new disease that does not have the diurnal variability of PEF or airway responsiveness to histamine,
adenosine 5⬘-monophosphate, and methacholine. No
specific association between airway inflammation and
airway hyperresponsiveness was inferred in cases of
eosinophilic bronchitis.15 Its pathogenesis is not yet
clear. However, it was suggested that airway inflammation by eosinophils and mast cells might be associated with the cough and heightened airway responsiveness but were not sufficient for the development
of the wheeze, airway hyperresponsiveness, or airway
obstruction that is characteristic of asthma.15
We measured eosinophilic airway inflammation in
patients with eosinophilic bronchitis and coughvariant asthma. There tend to be more eosinophils in
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Clinical Investigations
patients with cough-variant asthma than in those
with eosinophilic bronchitis. However, due to the
small number of patients in the study, any statistically significant conclusions could not be made.
Further investigations on the relationship between
the eosinophilic bronchitis and cough-variant asthma
are needed.
To our knowledge, there have not been any large
studies performed regarding the association with
atopy, and nothing has yet been proven. This study
demonstrated the relevance of atopy to be 18.8% (ie,
3 of 16 patients).
Compared with previous studies, the results of this
study suggested that eosinophilic bronchitis may be
the causative disease of a chronic nonproductive
cough15 and for the first time provided histopathologic evidence to that end. Furthermore, in this
study, 16 patients demonstrated signs of eosinophilic
bronchitis, which is three times the rate in coughvariant asthma patients (5 patients). These results indicate that there are more cases of undiagnosed eosinophilic bronchitis because cough-variant asthma
has been linked to chronic cough in only 29% of the
reported cases. Therefore, more interest and effort
are crucial in diagnosing unrecognized eosinophilic
bronchitis.
Patients with lymphocytic bronchitis were identified by their morphologic features. The patients with
this disease may have other specific diseases that the
authors could not diagnose, or it may truly be a
whole new disease. However, there was no evidence
of other possible diseases to account for the finding.
Also, Boulet and colleagues5 reported an increase in
lymphocytic infiltration in the bronchial tissues of
patients with chronic nonproductive cough without
any definitive causes. This issue should be investigated in future studies. Until then, we think that a
term such as lymphocytic bronchitis would be a
useful label.
The specific cause of lymphocytic bronchitis was
not identified but was considered to be a nonspecific
inflammatory reaction. In the lungs, lymphocytes,
along with macrophages, play an important role in
the inflammatory and immune reactions. The macrophage, as a phagocytic cell, is not antigen-specific.
The lymphocyte represents a significant refinement
in the inflammatory response (ie, antigen specificity
and discrimination of the self and other). In other
words, lymphocytes produce a defense mechanism
against the invasion of antigens and microorganisms
by antibody production, cytotoxic activity, or cytokine production.16,17 These lymphocytes are activated in particular when foreign antigens overwhelm
mucociliary escalators, macrophages, and neutrophil
defenses.18 The patients with lymphocytic bronchitis
did not have any specific history of exposure or any
occupational history. But since the lung is stimulated
by a large number of foreign infectious and noninfectious antigens on the tide of airflow, it would
be very difficult to actually find specific causative
antigens.
The clinical features of lymphocytic bronchitis
such as severity of cough and duration of symptoms
did not differ from those of eosinophilic bronchitis.
However, the lymphocytic bronchitis patients did
not have atopy. Oral prednisolone, 30 mg once a day
for 2 weeks, was prescribed to each patient with
lymphocytic bronchitis. The cough score was measured before and after the treatment. Three of four
patients had improved symptoms (change in cough
scores: 3 to 0; 4 to 1; and 3 to 1), but one patient had
no improvement (change in cough score, 4 to 3). The
effects of steroid therapy need further study such as
with a placebo-controlled study.
As mentioned above, chronic cough is the result of
epithelial damage due to inflammatory cell infiltration. However, the role of lymphocytes in epithelial
damage is controversial19 and requires further investigation.
Conclusion
Chronic nonproductive cough as an isolated symptom without other potential causes, such as postnasal
drip syndrome, bronchial asthma, gastroesophageal
reflux, chronic bronchitis, bronchiectasis, or the use
of angiotensin-converting enzyme inhibitors, is associated with airway inflammation by the infiltration of
inflammatory cells that are composed mainly of
eosinophils and lymphocytes. The causes are eosinophilic bronchitis, cough-variant asthma, and lymphocytic bronchitis (in order of frequency). Airway
inflammation has a useful role in the assessment of
chronic nonproductive cough.
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