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Noneosinophilic CD4 Lymphocytic Airway Inflammation in Menopausal Women With Chronic Dry Cough*

Posted on: Wednesday, 18 May 2005, 03:00 CDT

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. (CHEST 2005; 127:1714-1721)

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 flow

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 studies3-8 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 al13 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 Walsh8 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 radiographie 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 (37C) were instilled and gently aspirated in a siliconized plastic bott\le 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-DR+ 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.

Table 1-Demographic Data for Women*

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 FEV^sub 1^. Decrease in FEV^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 FEV^sub 1^ of 2 to 9% compared with the prechallenge value. The challenge was interrupted in one woman at 19% fall in FEV^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 FEV^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).

Table 2-Differential Cell Counts*

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 (CD8+) [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).

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

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 an\d 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

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

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 Sjgren syndrome, an autoimmune disease mostly affecting women. In Sjgren 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 Sjgren syndrome.29-32 Furthermore, the diagnostic characteristics of Sjgren 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 diy coughers, there was a clear connection between the first appearance of cough and an airway infection coinciding with perimenopause 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 perimenopause. 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 immunologie 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.

* 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. Grnneberg), Karolinska Hospital, Stockholm, Sweden. This study was supported by funds from The Swedish Heart Lung Foundation and by grants from Fisons.

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Ester Mund, MD; Birger Christensson, MD, PhD; Reidar Grnneberg, MD, PhD; and Kjell Larsson, MD, PhD, FCCP

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.chesrjournal. 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

Copyright American College of Chest Physicians May 2005

Source: Chest

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