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Cough Medicine

Background: Chronic dry cough without dyspnea and wheezing is a well-known condition that is considered to be clinically overrepresented in women. The etiology and morphology remain unknown in many cases despite thorough investigations.

Design: To examine inflammatory cells and the lymphocyte profile in the lower airways and blood in women with chronic cough of unknown etiology.

Setting: University hospital department of respiratory medicine.

Participants: Twenty-five otherwise healthy women with idiopathic cough and 11 age-matched healthy control women, all nonatopic nonsmokers.

Measurements: In order to characterize the cough, a careful standardized interview of the patients was made. Lung functions were tested. Cells were collected by BAL and analyzed for differential cell counts separate in the bronchial (first) wash and in the pooled peripheral washes (BAL fluid). The lymphocyte profile in BAL fluid and blood was characterized by dual-color flow cytometry.

Results: Eleven female patients formed a specific group with a history of a dry, nonproductive cough that always started in connection with an airway infection coinciding with menopause. Neither exercise, climate, nor seasonal change influenced the cough. BAL fluid contained an increased number of T (CD3+) lymphocytes: median. Seventy-three percent of T lymphocytes were T-helper lymphocytes (CD4+). A median of 57% of the BAL fluid T cells expressed HLA-DR activation marker compared with a median of 20% in the control subjects and in the other 14 included patients with chronic cough but with minor expectoration periodically (p < 0.001 and p < 0.0001, respectively). No differences between the groups were found in the blood.

Conclusions: HLA-DR-activated CD4+ lymphocytic airway inflammation with a low number of eosinophils was identified in a group of nonsmoking, nonatopic otherwise healthy women patients with dry cough of life-long character. The disease appeared exclusively in connection to menopause.

Key words: airway inflammation; autoimmunity; BAL; chronic bronchitis; dry nonproductive cough; female sex; menopause; nonsmokers; T-helper lymphocytes; women

Abbreviations: CD3+ = T lymphocyte; CD4+ = T-helper lymphocyte; CD8+ = T-cytotoxic lymphocyte; HLA = human leukocyte antigen; HRT = hormone replacement therapy; NS = not significant; PEF = peak expiratory

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Cough is the most common symptom in respiratory diseases, and the cause of cough can be identified in almost all patients. Occasionally, the diagnosis of the underlying disease must be preceded by a very thorough medical and clinical investigation, including anatomic and comprehensive diagnostic protocols. (1,2) Many studies (3-8) have been designed to find the etiology of a cough, but a specific cause may not be identified in all patients. Isolated chronic cough is usually associated with cough variant asthma, (9) gastroesophageal reflux, (10) and postnasal drip syndrome.

Despite the widespread use of bronchoscopy with BAL in studies of asthma and bronchitis as well as in respiratory medicine in general, (11) the method is considered to have limited value in determining the cause of isolated chronic cough. (12) Studies of inflammatory cells from the lower airways collected by BAL are still sparse in the context of "idiopathic" chronic cough. Boulet at al (13) found evidence of airway inflammation, particularly an increased number of mononuclear cells, in BAL fluid from 19 nonasthmatic patients with chronic dry cough. The lymphocyte subsets and subpopulation were not analyzed in that study. Eosinophilic bronchitis without clear signs of asthma has been demonstrated in a number of patients with chronic nonproductive cough. (14) In an article by Lee et al (15) 4 of 25 patients with dry cough received a diagnosis of lymphocytic bronchitis based on bronchial biopsies; unfortunately, neither sex, age, atopy, nor duration of cough was reported.

One clinical impression supported by the literature is that chronic cough develops in women more than in men. (2,7,8,16) Sen and Walsh (8) found that although > 70% of subjects undergoing bronchoscopy were men, there was a predominance of women among those admitted due to cough of unknown etiology.

In our outpatient department, we have noticed a group of middle-aged and elderly women with long-lasting dry cough that was resistant to all kinds of therapy. The cough was usually very troublesome, often causing disability and impaired quality of life. The aim of the present study was to characterize this specific group of female coughers with regard to a possible inflammatory process in the lower airways, assessed by BAL.

MATERIALS AND METHODS

Subjects

All patients who were admitted to the Department of Respiratory Medicine at Huddinge University Hospital because of chronic cough during a period of 2 consecutive years were considered for inclusion in the study. All coughers who, according to their referrals, had normal chest radiographic findings and were nonsmokers were selected for an interview carried out using a questionnaire at the clinic. Criteria for inclusion were cough for > 1 year without a history of dyspnea or wheezing in otherwise healthy, nonatopic, nonsmoking individuals who had no history of lung disease, gastroesophageal reflux, postnasal drip, or other serious diseases, and no use of drugs that may cause cough. Only patients with normal chest and sinus radiographic findings and normal routine blood test results including differential cell count, C-reactive protein, serum electrophoresis, and angiotensin-converting enzyme were accepted. Additional inclusion criteria were that the cause of the cough was unknown and that common therapy for asthma and cough, including corticosteroids, had failed. Ex-smokers were included if they had quit smoking > 10 years prior to the study and if they had been smoking for < 10 years. Allergy was excluded in all patients by skin-prick testing with common aeroallergens and total IgE in blood. Cough characteristics were analyzed separately.

Eleven healthy, nonatopic, lifelong nonsmoking women of similar ages as the patients were recruited from the hospital staff and served as control subjects. None of the control subjects was receiving regular treatment with medicines or hormone replacement. Two women in the control group regarded themselves as exposed to environmental tobacco smoke as adults (at home). Control subjects were investigated in accordance with the routines of newly admitted patients and they underwent physiologic examination, chest radiography, and routine blood tests including IgE. Lung function was measured in the control subjects by peak expiratory flow (PEF), and a value > 80% of the predicted was required for inclusion. (17)

During the 2 years of the study, 5 men (mean age, 59 years; range, 59 to 60 years) and 25 women (mean age, 58 years; range, 38 to 76 years) with therapy-resistant cough for > 1 year fulfilled the inclusion criteria. Since we have identified this condition as a problem found mainly in women, we chose to present only the data from the 25 female patients and the female control subjects. All participants gave informed consent, and the study was approved by the Ethics Committee at Huddinge University Hospital.

Study Design

In order to characterize the cough, one of the authors (E.M.) conducted a careful, standardized interview with all participants. The questions included the presence of expectoration, influence of irritating agents, exercise, climate, diurnal and seasonal variations, the occurrence of airway infections, the effect of previous treatment including corticosteroids, and whether hormone replacement therapy (HRT) had been administered and, if so, if it influenced the cough. The time relationship between the start of the cough and the onset of menopause (definite amenorrhea) or perimenopause (the period of hormone imbalance because of the decreasing production of female sexual hormones, age 43 to 64 years) was noted. (18)

Eleven women had dry, irritating cough without any expectoration, the "dry cough group," and 14 women had cough with some expectoration, the "productive cough group." Two "dry coughers" were treated with inhaled steroids on a regular basis (despite the lack of effect) at the time of the study. This medication was withdrawn 1 week prior to the study. Otherwise, the patients were currently not treated with any drugs, including HRT.

All patients and control subjects underwent bronchoscopy with BAL. Spirometry was performed in the patients, and PEF measurements were obtained in the control subjects. All the patients and six of the control subjects underwent a bronchial histamine challenge. Gastroscopy, diurnal esophageal pH measurement, CT of thorax, and specific blood tests were carried out in the patients when indicated from a clinical point of view.

Bronchoscopy and BAL

After premedication with 4 to 8 mg oxycodon and 0.2 to 0.4 mg scopolamine-hydrobromide subcutaneously, a fiberoptic bronchoscope (Olympus IT 20 D; Olympus Corporation of America; New Hyde Park, NY) was inserted via the nasal route and wedged at segmental or subsegmental level in the right middle lobe. Lignocaine was used for topical anesthesia. Six portions of 25 mL 0.9% saline solution (37[degrees]C) were instilled and gently aspirated in a siliconized plastic bottle kept on ice. The first fraction (bronchial wash) was analyzed separately for differential cell count and bacteria growth. Fractions 2 to 6 were pooled (BAL fluid) and analyzed for differential cell count and the subsets and subpopulation of lymphocytes. Bronchoscopies and BAL were performed identically and by the same examiner (E.M.) in all patients and control subjects.

Cell Analysis

Differential cell count was performed as previously described. (19) The frequency of T lymphocytes (CD3+), T-helper lymphocytes (CD4+), T-cytotoxic lymphocytes (CD8+), and activated T lymphocytes HLA-D[R.sup.+] was assessed in BAL fluid and blood by dual-color flow cytometry (FACScan; Becton Dickinson; Franklin Lakes, NJ). (19) A minimum of 10,000 cells was acquired and analyzed using software (Lysis II; Becton Dickinson). The lymphocyte gating to determinate the lymphocyte populations in BAL fluid and blood was made using forward- and side-scatter parameters and was controlled by using a combination of anti-CD45/CD14 monoclonal antibodies and CD3+ stained cells. The cells in BAL fluid and blood were stained according to identical protocols.

Lung Function

Spirometry was performed with a wedge spirometer (Vitalograph; Buckingham, UK) according to the American Thoracic Society recommendations. (20) Bronchial histamine provocation was also performed as was described by Cockcroft at al. (21) Airway resistance was measured in a constant-volume body plethysmograph (2000 TB; Cardio-Pulmonary Instruments; Houston, TX). The subjects inhaled increased concentration of histamine chloride, starting at 0.063 mg/mL up to 64 mg/mL as maximal concentration, each step representing a doubling of the previous concentration. The provocation was stopped if airway resistance increased by 100%, or if stipulated highest histamine concentration (64 mg/mL) was reached, or if the challenge induced symptoms that made further histamine inhalations impossible. The outcome of histamine challenge was compared to the reference values of the clinic.

Statistical Analysis

Results are presented as median (25 to 75th percentiles) if not otherwise stated. Comparisons between the groups were assessed by the Kruskal-Wallis test followed by the Mann-Whitney U test when appropriate; p values < 0.05 were considered significant.

RESULTS

Subjects

In the dry cough group, nine patients (82%) were lifelong nonsmokers and two patients were ex-smokers who had quit 16 years and 11 years prior to the study, respectively (Table 1). Nine women (82%) regarded themselves as exposed to environmental tobacco smoke as adults, either at home and/or at the workplace (Table 1). In all women, chronic cough had started in connection with an airway infection 1 to 2 years before or after the onset of menopause/ perimenopause, except for one woman in whom the cough commenced many years after menopause (Table 1). The cough occurred mostly in daytime, and the attacks were usually induced by irritating stimuli and did not stop as long as exposure continued. In some patients, cough was induced by dry air, whereas exercise, weather changes, and seasonal changes had no influence on the cough. HRT had no beneficial effect; in some women, cough was worsened by HRT.

In the productive cough group, 11 women (79%) were lifelong nonsmokers (Table 1). Cough and expectoration appeared mostly during the winter, and these women complained about recurrent, long-lasting airway infections. The condition corresponded to the clinical definition of chronic mucoid bronchitis: cough most days over 3 months in the last 2 consecutive years. The cough started in connection with an airway infection in some but not all women with productive cough. No time relationship between the start of cough and menopause was observed in this group, and the cough started before the age of 40 years, ie, in fertile age in 43% of these women (Table 1). The patients in this group were not sensitive to inhalation of irritating agents, and neither exercise nor cold air induced cough.

Lung Function and Bronchial Responsiveness

Lung function is shown in Table 1. In most patients, bronchial challenges were difficult because of the cough. In the dry cough group, histamine challenge was interrupted in 7 of 11 women because of increasing troublesome cough and hoarseness. Two women inhaled the stipulated maximal concentration (64 mg/mL) without significant change in FE[V.sub.1]. Decrease in FE[V.sub.1] > 20% occurred in two women at concentrations of 1 mg/mL and 2 mg/mL histamine chloride, respectively.

In the group with expectoration, 7 of 14 women could not conclude the histamine challenge due to intensive cough. Six women inhaled stipulated maximal histamine concentration (64 mg/mL) causing a fall in FE[V.sub.1] of 2 to 9% compared with the prechallenge value. The challenge was interrupted in one woman at 19% fall in FE[V.sub.1] at a histamine concentration of 2 mg/mL. Histamine provocation was performed in six control women. Maximal histamine concentration (64 mg/mL) yielded a < 5% fall in FE[V.sub.1].

Differential Cell Count

In the bronchial wash (first BAL fraction), the patients with dry cough had a higher proportion of lymphocytes than the patients with productive cough (p = 0.003). Patients with productive cough had significantly elevated neutrophils in the bronchial wash compared with the control subjects (p = 0.01) and the dry cough group (p = 0.009; Table 2).

In the BAL fluid (pooled washes 2 to 6), the proportion of lymphocytes was higher in the patients with dry cough and in the control subjects than in the patients with productive cough (p = 0.003 and p = 0.021, respectively; Table 2). The proportion of BAL fluid neutrophils in the productive cough group was higher than in the control subjects (p = 0.038) and the dry cough group (p = 0.009; Table 2).

There were no differences between the groups in the number of macrophages and eosinophils either in the bronchial wash or in the BAL fluid. In the dry group, no BAL fluid eosinophils were found in nine women. The remaining two women had 1% and 2% eosinophils, respectively. Three women with productive cough had 1 to 2% eosinophils, and 11 women had no eosinophils in the BAL fluid. Three of the control subjects had 1% BAL fluid eosinophils, while the other eight patients had none.

Lymphocyte Subsets in BAL Fluid

In the dry cough group, 57% of the BAL fluid T cells (CD3+) expressed HLA-DR, which should be compared with 20% in the other two groups (p < 0.001 and p < 0.0001, respectively; Table 3). There were no significant differences between the patients with dry cough and the control subjects regarding the proportions of T (CD3+), T helper (CD4+), and T cytotoxic (CDS+) [Table 3] lymphocytes.

In the women with productive cough, CD4+ lymphocytes were significantly lower (p < 0.001) and CD8+ lymphocytes were significantly higher (p = 0.005) compared with the control subjects and compared with the patients with dry cough (p < 0.0001 and p = 0.007, respectively; Table 3). The proportion of T lymphocytes (CD3+) was significantly lower in the patients with productive cough than in the patients with dry cough (p = 0.004; Table 3). In the productive cough group, 25% of the BAL fluid T cells expressed neither a CD4 nor a CD8 marker, whereas the corresponding values in the dry cough group and the control subjects were 9% and 13%, respectively (Table 3).

Absolute Cell Numbers in BAL Fluid

The BAL fluid of the women with dry cough contained significantly more lymphocytes, CD3+, and CD4+ than BAL fluid from the control subjects and the group with productive cough (Table 4). The patients with productive cough had significantly more granulocytes than the other two groups (Table 4).

Lymphocyte Subsets in the Blood

No differences were found between the three groups. HLA-DR expression on blood CD3+ lymphocytes was 12% (8 to 12) in women with dry cough, 7% (3 to 11) in women with productive cough, and 9% (6 to 12) in the control subjects (not significant [NS]).

DISCUSSION

In this study, we analyzed nonsmoking women with cough without known cause (idiopathic cough): one group with dry, nonproductive cough, and one group with productive cough. In women with dry cough, we found an airway inflammatory reaction dominated by lymphocytes; in women with productive cough, an airway inflammation dominated by neutrophils. In women with dry cough, the inflammatory reaction was characterized by activated T helper lymphocytes and the absence of eosinophils. Neither were eosinophils found in the women with productive cough, and T cells were dominated by cytotoxic CD8 phenotype lymphocytes. No signs of ongoing systemic inflammation were found in the blood in either group. Our material supports that chronic cough of unknown origin is a problem with a clear female dominance.

The patients in this study were highly selected by inclusion criteria. Only patients in whom the etiology of the cough was unknown and in whom, despite thorough investigations, no underlying diseases or cause of the cough could be identified were included. Long-lasting postinfectious cough was unlikely in these women since cough duration of > 1 year was required for inclusion. Because of the strict inclusion and exclusion criteria, there were only a limited number of patients during the period of 2 years. Cough characteristics were explored by a careful interview, and the coughers were separated into two groups: one group with patients who had never experienced increased airway secretion or productive cough, and one group with patients who had expectoration at least occasionally.

Dry Cough Group

It was recognized that only women had therapy-resistant isolated dry cough. The five men who fulfilled the inclusion criteria had cough with expectoration (data not shown).

Despite the absence of dyspnea and wheeze in the women with dry cough, asthma would be the most plausible diagnosis for the condition of chronic cough and lymphocytic airway inflammation, especially in those patients with proven increased airway responsiveness. The most important argument that the dry coughers, who were not treated with corticosteroids, did not have asthma was the absence of eosinophils in the airways, assessed by BAL. (22) The fact that attempts to treat the cough with corticosteroids had failed also supports the conclusion that the dry cough was not asthma. Another finding supporting different pathophysiologic mechanisms in asthma and in our patients was the different macroscopic appearance of the airway mucous membrane. In the patients with dry cough, the airway mucosa was atrophic with a conspicuously rich, slender vascular network and without any secretion, ie, quite opposite to the asthmatic airway inflammation which is characterized by a swollen, hyperemic, edematous mucous membrane with plenty of secretion. Another asthma characteristic, increased bronchial responsiveness, was found in only a few patients and was by itself not an indication of asthma. It has been demonstrated that bronchial challenges are of low discriminatory value in patients with chronic cough. (3,23,24)

Autoimmune diseases with pulmonary manifestations such as rheumatoid arthritis, connective tissue disorders, and primary biliary cirrhosis were unlikely to be the cause of cough because no clinical or laboratory signs of such diseases were found. (25-28) The dry, atrophic airway mucous membrane indicated the possibility of Sjogren syndrome, an autoimmune disease mostly affecting women. In Sj6gren syndrome, infiltration of the bronchial mucosa by CD4+ lymphocytes has been observed. However, alveolitis and bronchiolitis dominated by CD8+ lymphocytes, neutrophils, and/or activated macrophages have also been described in Sjogren syndrome. (29-32) Furthermore, the diagnostic characteristics of Sjogren syndrome, xerostomia and xerophthalmia, were not present in our patients. Other conditions associated with lymphocytic airway inflammation such as sarcoidosis were excluded by normal chest radiographs, normal levels of angiotensin-converting enzyme and calcium in the blood, and normal CT findings in some selective cases.

In the dry coughers, there was a clear connection between the first appearance of cough and an airway infection coinciding with perimenopanse in otherwise healthy women. In the women in whom dry cough started at < 40 years of age, one woman underwent an oophorectomy 2 years prior to the study at the age of 36 years, and the other woman < 40 years of age had symptoms indicating early perimenopanse. We have described an accumulation of CD4+ lymphocytes and elevated CD4/CD8 ratio in BAL fluid in healthy, postmenopausal women, a finding that was not observed in men. (19) Our hypothesis is that enhanced capacity in T helper lymphocyte function in women due to menopause may lead to exaggerated reactions to otherwise "normal" exposures, such as infections. Moreover, such exaggerated reactions may lead to negative consequences, possibly due to immune senescence, which has already started at the age of menopause. (18,33) Interestingly, in the women with dry cough, there was a high prevalence of fertility aberrations, such as involuntary childlessness, spontaneous miscarriage, dysmenorrhea, history of irregular menstruation, and ectopic pregnancy. No such abnormalities were noticed in the healthy control subjects, and only rarely in the women with productive cough (data not shown). Although speculative, it could be hypothesized that women exhibiting some dysfunction in fertility are predisposed to acquire the specific chronic airway inflammation with dry cough in the case of an airway infection that coincides with the hormonal and immunologic changes at menopause.

The high prevalence of exposure to environmental tobacco smoke in adulthood in the women with dry cough but not in the women with chronic bronchitis was unexpected. Exposure to environmental tobacco smoke in adulthood was found as a predisposing factor for the development of asthma and other airway diseases, particularly in combination with occupational exposure to irritants. (34,35)

Productive Cough Group

Both the clinical feature and the cell findings in the airways corresponded in this group of patients to what is commonly diagnosed as chronic bronchitis. What is noteworthy about this group is that the chronic bronchitis developed in lifelong nonsmokers and in women. Studies on chronic bronchitis have been performed on current smokers or on ex-smokers who had recently stopped smoking, and most studies have been conducted on male subjects. The women with productive cough were, in our material, not only nonsmokers, but were also not more exposed to environmental tobacco smoke than healthy women in general. In contrast to the women with dry cough, there was no connection between cough debut and menopause in the women with productive cough; the disease developed during adult life, irrespective of the actual state of fertility or menopause. There was a tendency toward a low number of lymphocytes in general and T helper lymphocytes in particular in the airways of the women in whom chronic bronchitis developed. This finding needs further examination. Although we did not particularly search for infections in this group, we had no indication of ongoing airway infection at the time of the study. These patients were probably exposed to occupational irritants and chemicals to a higher extent than the control subjects working in the hospital.

In conclusion, we have described a noneosinophilic inflammatory airway process dominated by activated T helper lymphocytes in menopausal women with isolated, chronic dry cough. The dry cough seemed to develop in connection with an infection at the time of menopause. Dysfunction in fertility might be a predisposing factor as well as exposure to environmental tobacco smoke in adulthood. Identification of a group with chronic productive cough indicates that chronic bronchitis may also be a problem in women who have never smoked.

Table 1--Demographic Data for Women *

                                                            Productive
             Variables                     Dry Cough           Cough

Participants, No.                         11                14
Mean age (range), yr                      58 (38-74)        56 (38-76)
Never-smokers                              9 (82)           11
Passive smoking ([dagger])                 9 (82)            5
                                       ([double dagger])
Cough duration, yr                         8 (5-18)          8 (4-12)
Mean age at cough start (range), yr       49 (37-61)        48 (32-69)
  Fertile ([section]), No.                 0                 6
  Perimenopause ([parallel]), No.          9                 6
  Postmenopause ([paragraph]), No.         2                 2
FE[V.sub.1] % of predicted               106 (79-118)       96 (90-101)
FE[V.sub.1]/FEV                           79 (73-83)        83 (75-89)
PEF % of predicted                            --                --

             Variables                 Control Subjects

Participants, No.                         11
Mean age (range), yr                      50 (39-62)
Never-smokers                             11 (100)
Passive smoking ([dagger])                 2 (18)

Cough duration, yr
Mean age at cough start (range), yr
  Fertile ([section]), No.
  Perimenopause ([parallel]), No.
  Postmenopause ([paragraph]), No.
FE[V.sub.1] % of predicted
FE[V.sub.1]/FEV
PEF % of predicted                           > 80

* Data are shown as median (25%-75%) percentiles or (25-75th)
percentiles or No. (%) unless otherwise indicated.

([dagger]) Exposed as an adult.

([double dagger]) p < 0.05 by Fisher exact test.

([section]) Fertile indicates all women < 43 years old who were
supposed to be fertile.

([parallel]) Perimenopause indicates women with perimenopausal
symptoms. Of these, all but one of the women were > 43 years old. One
woman, 37 years old, had nonregular menstrual periods and symptoms that
were considered to be related to the menopause.

([paragraph]) Postmenopause indicates all women with definite
amenorrhea. In this group, one woman, 38 years old, was included who
underwent oophorectomy at the age of 36 years.

Table 2--Differential Cell Counts *

                                      Bronchial (First) Wash

                                                    Neutrophil
Variables                          Lymphocytes     Granulocytes

Dry cough                            5 (6-17)       11 (8-27)
Productive cough                     2 (2-8)        54 (18-77)
Control                              2 (3-13)       12 (7-26)
p Values
  Dry cough vs control                  NS              NS
  Productive cough vs control           NS            0.01
  Dry cough vs productive cough     p = 0.003         0.009

                                                    Peripheral
                                                   Wash (Pooled
                                    Bronchial      Fractions 2
                                   (First) Wash       to 6)

Variables                          Macrophages     Lymphocytes

Dry cough                           73 (63-82)      25 (11-38)
Productive cough                    44 (25-81)       7 (2-13)
Control                             71 (49-84)      17 (8-23)
p Values
  Dry cough vs control                  NS              NS
  Productive cough vs control           NS          p = 0.021
  Dry cough vs productive cough         NS          p = 0.003

                                     Peripheral Wash (Pooled
                                        Fractions 2 to 6)

                                    Neutrophil
Variables                          Granulocytes    Macrophages

Dry cough                            1 (0-2)        72 (62-88)
Productive cough                     4 (1-21)       83 (59-91)
Control                              1 (0-2)        81 (74-89)
p Values
  Dry cough vs control                  NS              NS
  Productive cough vs control       p = 0.038           NS
  Dry cough vs productive cough     p = 0.009           NS

* Data are expressed as % of total cell number, median (25-75th)
percentiles. Comparisons were made by the Kruskal-Wallis test combined
with the Mann-Whitney U test when appropriate.

Table 3--T Lymphocytes in BAL Fluid (Pooled Peripheral Fractions 2 to
6) *

Variables                            CD3+         CD4+         CD8+

Dry cough                         92 (84-95)   73 (69-83)   15 (9-21)
Productive cough                  76 (73-88)   41 (33-54)   27 (16-37)
Control                           86 (80-90)   72 (59-74)   16 (12-17)
p Values ([dagger])
  Dry cough vs control                NS           NS           NS
  Productive cough vs control         NS        < 0.001       0.005
  Dry cough vs productive cough     0.004       < 0.0001      0.007

                                   Activated T
                                   Lymphocytes        CD4 + CD8+
Variables                         HLA-D[R.sup.+]   ([double dagger])

Dry cough                           57 (38-60)        91 (81-99)
Productive cough                    20 (15-26)        75 (60-81)
Control                             20 (15-30)        87 (71-89)
p Values ([dagger])
  Dry cough vs control               < 0.001              NS
  Productive cough vs control           NS              0.048
  Dry cough vs productive cough      < 0.0001           0.003

* Data are expressed as % of total cell number, median (25-75th)
percentiles.

([dagger]) p Values Mann-Whitney U test.

([double dagger]) Percentage of lymphocytes expressing CD4 and/or CD8
markers.

Table 4--Absolute Cell Numbers: BAL Fluid Analysis (Pooled Peripheral
Fractions 2 to 6) *

                                      Volume,        Cell Concentration
Variables                                mL                per mL

Dry cough                           78 (58-90)        0.08 (0.07-0.16)
Productive cough                    71 (62-89)        0.08 (0.04-0.14)
Control                             90 (84-100)       0.06 (0.02-0.08)
p Value ([dagger])
  Dry cough vs control                  0.04                0.02
  Productive cough vs control           0.03                 NS
  Dry cough vs productive cough          NS                  NS

                                                         Neutrophil
Variables                            All Cells          Granulocytes

Dry cough                          5.7 (4.1-11.3)     0.03 (0.0-0.07)
Productive cough                   7.1 (3.7-14.2)     0.3 (0.04-1.2)
Control                            4.7 (1.8-7.6)      0.06 (0.02-0.09)
p Value ([dagger])
  Dry cough vs control                   NS                  NS
  Productive cough vs control            NS                 0.02
  Dry cough vs productive cough          NS                 0.01

Variables                           Lymphocytes             CD3+

Dry cough                          1.1 (0.5-0.0)       1.2 (0.4-3.1)
Productive cough                   0.5 (0.2-0.6)       0.4 (0.2-0.5)
Control                            0.5 (0.3-0.7)       0.3 (0.25-0.6)
p Value ([dagger])
  Dry cough vs control                  0.03                0.02
  Productive cough vs control            NS                  NS
  Dry cough vs productive cough         0.02               0.007

Variables                               CD4+                CD8+

Dry cough                         0.9 (0.3-2.5)       0.15 (0.04-0.5)
Productive cough                  0.15 (0.07-0.25)    0.09 (0.06-0.18)
Control                           0.2 (0.15-0.3)      0.05 (0.04-0.1)
p Value ([dagger])
  Dry cough vs control                 0.02                  NS
  Productive cough vs control            NS                  NS
  Dry cough vs productive cough        0.0007                NS

* Data are presented as absolute No. x [10.sup.6], median (25-75th)
percentiles.

([dagger]) Mann-Whitney U test.

* From the National Institute of Environmental Medicine, Division of Lung and Allergy Research (Drs. Mund and Larsson), Karolinska Institutet, Stockholm; Division of Clinical Immunology and Pathology, Departments of Immunology, Microbiology and Pathology, Karolinska Hospital Huddinge (Dr. Christensson), Huddinge; and Division of Respiratory Medicine (Dr. Gronneberg), Karolinska Hospital, Stockholm Sweden.

This study was supported by funds from The Swedish Heart Lung Foundation and by grants from Fisons.

REFERENCES

(1) Poe RH, Harder RV, Israel RH, et al. Chronic persistent cough: experience in diagnosis and outcome using an anatomic diagnostic protocol. Chest 1989; 95:723-728

(2) McGarvy LPA, Heaney LG, Lawson JT, et al. Evaluation and outcome of patients with chronic non-productive cough using a comprehensive diagnostic protocol. Thorax 1998; 53:738-743

(3) Irwin RS, Madison JM. The persistently troublesome cough. Am J Respir Crit Care Med 2002; 165:1469-1474

(4) Puolijoki H, Lahdensuo A. Causes of prolonged cough in patient referred to a chest clinic. Ann Meal 1989; 21:425-427

(5) Ing AJ, Breslin BX. The patients with chronic cough. Med J Aust 1997; 166:491-496

(6) McGarvy LPA, Forshythe P, Heaney LG, at al. Bronchoalveolar lavage findings in patients with chronic nonproductive cough. Eur Respir J 1999; 13:59-65

(7) Kardos P, Gebhardt T. Chronic persistent coughs in general practice: diagnosis and therapy in 329 patients over the course of 2 years. Pneumology 1996; 50:437-441

(8) Sen RP, Walsh TE. Fiberoptic bronchoscopy for refractory cough. Chest 1991; 99:33-35

(9) Jonson D, Osborn LM. Cough variant asthma: a review of clinical literature. J Asthma 1991; 28:85-90

(10) Irwin RS, Zawacki JK, Wilson MM, et al. Chronic cough due to gastroesophageal reflux disease: failure to resolve despite total/near-total elimination of esophageal acid. Chest 2002; 121:1132-1140

(11) Investigative use of bronchoscopy, lavage and bronchial biopsies in asthma and other airway diseases: workshop summary and guidelines. Eur Respir J 1992; 5:115-121

(12) Poe RH, Harder RV, Israel RH, et al. Chronic cough: bronchoscopy or pulmonary function testing? Am Rev Respir Dis 1982; 126:160-162

(13) Boulet LP, Milot J, Boutet M, et al. Airway inflammation in nonasthmatic subjects with chronic cough. Am J Respir Crit Care Med 1994; 149:482-489

(14) Brightling CE, Ward R, Gob KL, et al. Eosinophilic bronchitis is an important cause of chronic cough. Am J Respir Crit Care Med 1999; 160:406-410

(15) Lee SY, Cho JY, Shim JJ, et al. Airway inflammation as an assessment of chronic nonproductive cough. Chest 2001; 120:1114-1120

(16) French CT, Fletcher KE, Irwin RS. Gender differences in health-related quality of life in patients complaining of chronic cough. Chest 2004; 125:482-488

(17) Hedenstrom H, Malmberg P, Agarwal K. Reference values for lung function tests in females: regression equations with smoking variables. Bull Eur Physiopathol Respir 1985; 21: 551-557

(18) Wise PM, Krajnak KM, Kashon ML. Menopause: the aging of multiple pacemakers. Science 1996; 273:67-70

(19) Mund E, Christenson B, Larsson K, et al. Gender dependent differences in physiological ageing in the immune system of lower airways in healthy non-smoking volunteers: study of the lymphocyte subsets in the bronchoalveolar lavage fluid and blood. Thorax 2001; 56:450-455

(20) Gardner RM. Standardization of spirometry: a summary of recommendations from the American Thoracic Society; the 1987 update. Ann Intern Med 1988; 108:217-220

(21) Cockcroft DW, Killian DN, Mellon JA, et al. Bronchial reactivity to inhaled histamine: a method and clinical survey. Clin Allergy 1977; 7:235-240

(22) Jeffery PK. Comparison of the structural and inflammatory features of COPD and asthma: Gilles F Filley Lecture. Chest 2000; 117(suppl 1):251S-260S

(23) Smith L, McFadden ER Jr. Bronchial hyperreactivity revisited. Ann Allergy Asthma Immunol 1995; 74:454-469

(24) Cain H. Bronchoprovocation testing. Clin Chest Med 2001; 22:651-659

(25) Birring SS, Brightling CE, Symon FA, et al. Idiopathic chronic cough: association with organ specific autoimmune disease and bronchoalveolar lymphocytosis. Thorax 2003; 58:1066-1070

(26) Wallaert B, Dugas M, Dansin E, et al. Subclinical alveolitis in immunological systemic disorders: transition between health and disease? Eur Respir J 1990; 3:1206-1216

(27) Fartoul TI, Cano-Valle F, Oliva E, et al. Follicular bronchiolitis in association with connective tissue disease. Lung 1985; 163:305-314

(28) Chatte G, Streichenberger N, Boillot O, et al. Lymphocytic bronchitis/bronchiolitis in patient with primary biliary cirrhosis. Eur Respir J 1995; 8:176-179

(29) Lahdensuo A, Korpela M. Pulmonary findings in patients with primary Sjogren's syndrome. Chest 1995; 108:316-319

(30) Popp W, Ritschka L, Scherak O, et al. Bronchoalveolar lavage in rheumatoid arthritis and secondary Sjogren's syndrome. Lung 1990; 168:221-231

(31) Gudbjornsson B, Hallgren L, Nettelbladt O, et al. Phenotypic and functional activation of alveolar macrophages, T lymphocytes and NK cells in patients with systemic sclerosis and primary Sjogren's syndrome. Ann Rheum Dis 1994; 53:574-579

(32) Papiris SA, Saetta M, Turato G, et al. CD4 positive T-lymphocytes infiltrate the bronchial mucosa of patients with Sjogren's syndrome. Am J Respir Crit Care Med 1997; 156:637-641

(33) Mund, E. Gender differences in immunity over human lifespan. In: Buist S, Mapp CE, eds. Respiratory diseases in women. Eur Respir Mon 2003; 25:26-38

(34) Leuenberger P, Schwartz J, Ackerman-Liebrich U, et al. Passive smoking exposure in adults and chronic respiratory symptoms (SALPALDIA Study). Am J Respir Crit Care Med 1994; 149:1400-1406

(35) Tredaniel J, Boffetta P, Saracci R, et al. Exposure to environmental tobacco smoke and adult non-neoplastic respiratory diseases. Eur Respir J 1994; 7:173-185

Manuscript received March 19, 2004; revision accepted November 3, 2004.

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

Correspondence to: Ester Mund, MD, The National Institute of Environmental Medicine, Division of Lung and Allergy Research, Karolinska Institutet, SE-171 77, Stockholm, Sweden; e-mail: em.mund@stockholm.mail.telia.com

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