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(Chest. 2006;130:362-370.)
© 2006 American College of Chest Physicians

Interpreting the Histopathology of Chronic Cough*

A Prospective, Controlled, Comparative Study

Richard S. Irwin, MD, FCCP; Robert Ownbey, MD; Philip T. Cagle, MD; Stephen Baker, MScPH and Armando E. Fraire, MD

* From the Division of Pulmonary, Allergy, and Critical Care Medicine (Dr. Irwin), and Department of Pathology (Drs. Fraire and Ownbey), Information Services, and Cell Biology (Dr. Baker), University of Massachusetts Medical School, Worcester, MA; and the Methodist Hospital, Houston, TX and Weill Medical College (Dr. Cagle), Cornell University, New York, NY.

Correspondence to: Richard S. Irwin, MD, FCCP, University of Massachusetts Medical School, Division of Pulmonary, Allergy, and Critical Care Medicine, 55 Lake Ave North, Worcester, MA 01655; e-mail: irwinr{at}ummhc.org

Abstract

Hypothesis: Trauma from chronic coughing produces airway inflammation similar to diseases causing cough.

Design: Prospective, cross-sectional, controlled, clinicopathologic correlation study in four groups: group 1, cough from intrapulmonary diseases; group 2, cough from extrapulmonary diseases; group 3, cough that was unexplained; and group 4, nonsmoking, asymptomatic control subjects.

Methods: Patients with chronic cough underwent a standardized workup including endobronchial biopsies before treatment. Causes were determined by a favorable response to therapy. Bronchial biopsy samples from control subjects were obtained from surgical specimens.

Results: There were 24 adult subjects (13 women and 11 men) with mean cough duration of 8.6 ± 7.4 years (± SD). Thirteen patients had cough due to a specific disease: intrapulmonary diseases in 5 patients, and extrapulmonary diseases in 8 patients. Eleven patients had unexplained cough. Compared to control subjects, there was minimal-to-moderate chronic inflammation in all coughers (p ≤ 0.0004), in group 1 (p ≤ 0.039), group 2 (p = 0.061), and group 3 (p ≤ 0.025) diseases that were not correlated with cough duration. There was no difference in type of inflammation, cough duration, or smoking history between groups, nor were there histologic differences between subjects with explained causes of cough compared with unexplained cough.

Conclusions: Our findings suggest that airway inflammation associated with chronic cough, assessed on morphologic appearance and inflammatory cell counting in hematoxylin-eosin–prepared samples, may be due to the trauma of coughing, and the inflammation may be similar to that seen with diseases putatively thought to cause chronic cough. Investigators must be cautious when attributing pathogenic importance to observed inflammatory changes in airways of coughing subjects.

Key Words: airway inflammation and cough • airway inflammation due to coughing • histopathology of chronic cough

Cough is a common manifestation of respiratory disease. Moreover, it is known to be the most frequent complaint for which patients seek medical care in the United States and Australia.12 While much has been learned about the diagnosis and treatment of cough,3 relatively little is known about its pathogenesis. Beginning with the description of nonasthmatic eosinophilic bronchitis by Gibson and colleagues4 in 1989, an increasing amount of attention has been devoted to assessing the cytologic and histologic pathology associated with cough and especially the role of inflammation and mediators of inflammation in predicting the cause of cough and its pathogenesis, and its response to therapy.

With respect to etiology, the literature to date on airway inflammation and cough has revealed the following: (1) eosinophilic inflammation has been primarily found in cough due to nonasthmatic eosinophilic bronchitis (unexplained, drug-induced, type I hypersensitivity),56789 classical asthma,610 and cough-variant asthma,11 but also in some patients with gastroesophageal reflux disease (GERD)12; and (2) inflammation consisting of lymphocytes and metachromatic cells (mast cells) associated with epithelial denudation has been found in a variety of diseases such as upper airway cough syndrome (previously referred to as postnasal drip syndrome [PNDS]13), GERD, and unexplained cough (previously referred to as idiopathic cough14).151617181920 Even though similar lymphocytic and mast-cell inflammation has been observed in extrapulmonary and pulmonary disorders of known etiology as well as unexplained cough, Lee et al17 suggested that unexplained chronic nonproductive cough be referred to as lymphocytic bronchitis, implying that lymphocytic bronchitis is the cause of the cough. Birring et al18 suggested that the mast cell, through the release of mediators, may be involved in the pathogenesis of the unexplained cough; while Gibson19 speculated that the mast cell may be involved in the pathogenesis of all coughs. While all previous authors have suggested or implied that the observed inflammatory changes in the airways of coughing subjects were directly or indirectly involved in the pathogenesis of cough, Boulet et al15 and McGarvey et al,12 in discussing their findings, considered the possibility that the inflammatory changes might have been due to trauma from coughing itself.

Because the act of coughing has been associated with profound, serious, devastating, and potentially life-threatening physical complications due to the physiologic changes that occur during coughing,21 we hypothesized that the trauma from coughing itself can produce inflammatory changes in the airways similar to changes due to diseases causing chronic cough, and that these traumatic changes do not necessarily provide clues to the identity of the underlying disease causing chronic cough. To help clarify the cause-and-effect relationship between chronic cough and airway inflammation, we performed a prospective, comparative, histopathologic analysis of respiratory mucosa of patients with chronic cough due to known intrapulmonary (group 1) and known extrapulmonary diseases (group 2), patients whose cough was unexplained (group 3), and nonsmoking, asymptomatic control subjects with solitary pulmonary nodules with histologically normal airways (group 4).

Materials and Methods

Definitions and Source of Pathologic Material
Based on the best available evidence,1322 the sites of origin for the stimulus to cough in intrapulmonary and extrapulmonary conditions were classified according to the following construct: the stimulus for coughing in extrapulmonary conditions is thought to arise outside of the lower respiratory tract, while the stimulus for provoking coughing in intrapulmonary conditions is thought to arise within the lower respiratory tract (ie, below the vocal cords). A convenience sample of consecutive and unselected patients prospectively evaluated for their complaint of chronic cough (> 8 weeks in duration) served as our study subjects. They were evaluated in standard fashion according to a previously published and validated evidence-based protocol.23 The definitive cause of cough was determined based on a favorable response to specific therapy according to previously published guidelines.24 When there was a favorable response to specific therapy, upper airway cough syndrome13 (previously referred to as PNDS), angiotensin converting enzyme inhibitor (ACEI)-induced cough, and GERD without typical changes consistent with gastrolaryngopharyngeal irritation or aspiration (eg, abnormal chest radiograph findings and/or localized lower airway inflammatory changes on bronchoscopy)22 were considered to be extrapulmonary causes of chronic cough. In this context, when patients responded to antireflux medical therapy, GERD was thought to be caused by irritation of the esophageal-bronchial cough reflex. The cough associated with ACEIs was categorized as an extrapulmonary cause because it has been typically described as a throat-tickling sensation and it has not been associated with bronchial hyperresponsiveness or inflammation of the lower respiratory tract.25 When there was a favorable response to specific therapy, asthma, environmental irritant bronchitis, and infectious bronchiolitis were considered to be intrapulmonary causes of chronic cough. When there was a favorable response to specific therapy simultaneously directed against extrapulmonary and intrapulmonary conditions in the same patients, these patients, for histopathologic comparison purposes, were categorized with the intrapulmonary subjects (group 1). When patients did not improve with specific therapy, unexplained14 (previously referred to as idiopathic) chronic cough was diagnosed by exclusion. Institution Review Board approval was obtained prior to initiating this study, and subjects gave informed written consent prior to being enrolled in this study.

As part of the diagnostic protocol, patients underwent flexible bronchoscopy while symptomatic and before a final diagnosis was made and before treatment had been begun. During bronchoscopy, bronchial wall biopsy samples were obtained from central airways that included carinae between segmental and subsegmental airways (eg, airway generations 4 and 5). With the exception of mild edema, there were no other obvious inflammatory lesions grossly seen during the endoscopic examination in any of the subjects as long as cough was not provoked during bronchoscopy. However, if the patients coughed during the procedure, immediately after coughing ceased the mucosa of the vocal cords (Fig 1 ) or lower airways was consistently observed to become red and swollen, changes interpreted as being consistent with transient passive congestion of the airways due to the act of coughing. Lung specimens from four nonsmoking asymptomatic patients without cough who had undergone wedge or lobar resections for solitary pulmonary nodules (benign chondroid hamartoma in two patients and non-small cell carcinoma in two patients) provided control material. Only the airways proximal to the solitary pulmonary nodules and from airway generations 4 and 5 were analyzed.


Figure 1
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  		Figure 1. Endoscopic views of supraglottic and glottic structures just before and immediately after an approximate 5-s paroxysm of spontaneous coughing in a patient being evaluated for chronic cough of 5 years in duration. Before the coughing episode, mucosal surfaces were normal. Immediately after coughing, mucosal surfaces appear red and swollen. Because the coughing paroxysm occurred spontaneously and was not provoked by the instillation of fluid or trauma from the endoscope or regurgitation or vomiting, the changes noted were thought to be caused by the act of coughing itself and most likely represent venous congestion. Reprinted from The American Journal of Medicine, 111 (8A), Richard S. Irwin, Cynthia T. French, Cough and Gastroesophageal Reflux: Identifying Cough and Assessing the Efficacy of Cough-Modifying Agents, 48S, 2001, with permission from Excerpta Medica, Inc.

 
The bronchoscopic tissue samples were all formalin fixed, paraffin embedded, cut at 5 µm with a standard microtome, and stained with hematoxylin-eosin according to standard procedures. Two pathologists (R.O. and A.E.F.), blinded to any clinical information regarding the subjects including cause and category of cough except for knowing that they had a chronic cough, jointly examined the glass slide tissue samples using a two-headed microscope (Olympus BH-2; Olympus America, Inc; Lake Success, NY). Examined parameters included the evaluation of acute and chronic inflammation in the subepithelial zone, bronchial epithelial denudation, goblet-cell metaplasia, squamous metaplasia, basement membrane thickness, eosinophils, lymphocytes, plasma cells, neutrophils, and mast cells. Basement membrane thickening, extent of epithelial denudation (in terms of percentage of denudation) and squamous and goblet-cell metaplasia were assessed at 100 x magnification. Basement membranes were considered thickened when they were > 8.0 µm. The type and degree of chronic inflammation (lymphocytes, plasma cells) were assessed by counting the number of cells per 200 x field using an eyepiece grid. At this magnification, each box of the grid measured 0.027 mm2. The determined value was then used to calculate the number of inflammatory cells per millimeter squared. The presence of neutrophils was regarded as evidence of acute inflammation. However, because neutrophils were quite rare, their numbers were assessed in terms of present (yes) or absent (no). Eosinophils and mast cells were also rare (but not as rare as neutrophils), and their numbers were determined on the basis of cells per high-power field (400 x magnification). Mast cells were quantified through enhancement with immunostaining with mast-cell tryptase.26

Statistical Analysis
Differences between diagnostic groups on continuous and ordinal variables were evaluated by the Kruskal-Wallis analysis of variance by rank.27 If the main effect was significant, pairwise comparisons between groups were evaluated by Mann-Whitney U tests27 with a Sidak adjustment to the p values to compensate for the additive effect on type I error due to multiple comparisons.2829 For categorical variables, overall significance among the three groups was evaluated by the Fisher-Freeman-Halton Exact Test.30 If there were significant effects, pairwise comparisons were made by Fisher Exact Test27 with a Bonferroni adjustment31 to the p value to compensate for multiple comparisons. A p value ≤ 0.05 was considered significant.

Results

Comparison of the Clinical Characteristics of the Four Study Groups
Twenty-four subjects (13 woman and 11 men) with mean age of 51.6 ± 11.9 years (± SD) were referred for evaluation of chronic cough of 8.6 ± 7.4 years in duration. While 8 of 24 patients (33%) were prior smokers (ie, they had not smoked for at least 10 years), 16 of 24 patients were never-smokers. Based on a favorable response to specific therapy, a definitive, specific cause of cough was determined in 13 of 24 patients (54%). In 5 of 13 patients, the causes consisted of intrapulmonary conditions (group 1) that included asthma, infectious bronchiolitis, environmental irritant bronchitis; in 8 of 13 patients, the causes consisted of extrapulmonary conditions (group 2) that included upper airway cough syndrome, GERD, and ACEI-induced cough. Based on an unfavorable response to specific therapy directed against the pretreatment putative causes of chronic cough, 11 of 24 patients (46%) were determined to have an unexplained cough (group 3). Four asymptomatic never-smokers with intrapulmonary pathology localized to their solitary pulmonary nodules served as control subjects (group 4). Demographic and clinical data for groups 1 to 4 are summarized in Table 1 . Prior to institution of therapy, all subjects had normal spirometry findings and negative methacholine inhalational challenge results, except for the three asthmatics in group 1 who had normal baseline spirometry findings and positive methacholine inhalational challenge results.


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  		Table 1. Demographic and Clinical Characteristics of Three Groups of Coughers and Control Subjects

 
Compared to control subjects, the entire cohort of coughers (p < 0.0001) and group 1 (p = 0.061), group 2 (p = 0.033), and group 3 (p = 0.022) subjects differed only with respect to the presence and duration of cough. There was no difference in age, gender distribution, or smoking. Compared to each other, there was no difference in cough duration, age, gender distribution, or smoking among groups 1 to 3.

Comparison of the Histopathologic Changes of the Four Study Groups
Table 2 summarizes the histopathologic changes observed in groups 1 to 4. In the surgically resected control specimens (group 4), there were no pathologic changes. Specifically, there was no inflammation or denudation of the mucosa in group 4 control subjects (Fig 2 ).


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  		Table 2. Histopathologic Characteristics of Three Groups of Coughers and Control Subjects*

 

Figure 2
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  		Figure 2. A representative histopathologic section of surgically resected lung tissue from a group 4, control, nonsmoking, asymptomatic patient. The airway is normal without any evidence of inflammation or denudation of the mucosa. This airway was proximal to the benign chondroid hamartoma that had been removed (hematoxylin-eosin, original x 400).

 
The entire cohort of chronic coughers, however, had evidence of histopathologic changes. Biopsy specimens from 23 of 24 subjects contained denuded epithelium ranging from 10 to 100% of cells; 4 of 24 subjects showed some degree of goblet-cell metaplasia composing 10 to 40% of the intact epithelium. Squamous metaplasia was seen in 7 of 24 biopsy specimens and made up 10 to 100% of the epithelium present. Basement membrane thickening was present in 5 of 24 biopsy specimens. Rare eosinophils were seen in only 4 of the 24 coughing subjects (16.6%) [1 subject in group 1, 1 subject in group 2, and 2 subjects in group 3; Fig 3 ]. None of the biopsy specimens showed evidence of acute inflammation (neutrophils), while all demonstrated some degree of chronic inflammation composed of lymphocytic or lymphoplasmacytic infiltration. The degree of chronic inflammation ranged from 1.8 to 18.2 cells per square millimeter. The epithelium was denuded in 68.75 ± 32.78% of sections, and there were 4.17 ± 10.60 goblet metaplastic cells, and 17.92 ± 33.23 squamous metaplastic cells per 100 x magnification. In addition, there were 3.76 ± 4.28 mast cells per 400 x magnification. Compared to control subjects, there were significantly more mast cells (p < 0.0001), inflammatory cells (p < 0.0001) primarily composed of lymphocytes, and denuded epithelium (p < 0.0004) in the entire cohort of coughers. However, there was no difference in goblet-cell or squamous metaplasia or basement membrane thickening.


Figure 3
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  		Figure 3. Representative histopathologic sections of tissue obtained at bronchoscopy from coughers in groups 1 to 3 showing similar findings. Top, A: Group 1 patient with cough due to the intrapulmonary condition, chronic bronchitis due to an environmental irritant; shown is a greatly denuded respiratory epithelium and a prominent basement membrane (arrow) [hematoxylin-eosin, original x 200]. Center, B: Group 2 patient with cough due to the extrapulmonary condition, GERD; shown is an intact respiratory epithelium, focal goblet-cell metaplasia, and a focus of moderate chronic inflammation, mostly lymphocytes (arrow) [hematoxylin-eosin, original x 400]. Bottom, C: Group 3 patient with unexplained cough; shown is an intact respiratory epithelium and a conglomeration of chronic inflammatory cells, mostly lymphocytes in the mid-center field (arrow) [hematoxylin-eosin, original x 400].

 
Compared to control subjects, group 1 subjects had more mast cells (p = 0.061), inflammatory cells per square millimeter and per 200 x magnification (p = 0.061), but not denuded epithelium (p = 0.172); group 2 had more mast cells (p = 0.039), inflammatory cells per square millimeter and per 200 x magnification (p = 0.032), and denuded epithelium (p = 0.031); and group 3 had more mast cells (p = 0.025), inflammatory cells per square millimeter and per 200 x magnification (p = 0.021), and denuded epithelium (p = 0.021). However, there was no difference in goblet-cell or squamous metaplasia, basement membrane thickening, or eosinophils. Compared to each other, there was no difference in the type of inflammation; however, the intrapulmonary group (group 1), on average, had more chronic inflammation then the extrapulmonary group (group 2) [p = 0.024].

Comparison of the Clinical and Histopathologic Characteristics of Cough Due to Known Conditions and Unexplained Cough
When the data of the known causes (group 1 and 2) of chronic cough were combined and compared to the unexplained group (group 3), there were no clinical or demographic (Table 1) or histopathologic differences (Table 2).

Discussion

From this prospective, cross-sectional, controlled study, two major findings emerged regarding the histopathologic changes, assessed on morphologic appearance and inflammatory cell counting in hematoxylin-eosin–prepared samples, in airway mucosa in patients with chronic cough. First, all subjects with chronic cough, no matter what the etiology, had some evidence of significant chronic airway inflammation on histopathologic examination of their airways compared with control subjects. Second, the type of chronic airway inflammation observed in subjects with chronic cough was similar in subjects with known intrapulmonary causes compared with known extrapulmonary causes of chronic cough and in subjects with known causes compared with subjects with unexplained cough.

Interpretation of Findings
While it is possible that the observed chronic inflammatory changes were providing some clue to the specific pathogenesis of chronic cough in our subjects that future studies will uncover, the indistinguishable findings between our varied groups of chronic coughers and the absence of any evidence of chronic inflammation in the noncoughing control group suggest that the act of coughing itself may be responsible for the denudation and other histopathologic findings. While the denudation may be due to artifact and caused by the biopsy forceps, the other histopathologic changes cannot be explained as artifactual. It is also possible that the high degree of denudation in all groups is a reflection of epithelial fragility. Because our airway inflammatory findings are similar to those that have been reported by multiple investigators151617181920 in subjects with chronic cough due to noneosinophilic diseases, our interpretation is also reconcilable with the findings of these other reports. Because we did not use immunohistochemistry to assist in identifying lymphocytes, it is possible that the degree of lymphocytosis in our coughing subjects was underestimated. However, mast cells were quantified through enhancement with immunohistochemistry. While subjects in group 2 had more mast cells and lymphocytes compared to group 1 (Table 2), the cause of this difference is unclear.

While our findings are similar to the greatest majority of other studies that have reported airway inflammatory changes in chronic coughers, a recent study by Niimi et al32 has shown a predominant neutrophilic inflammatory response in patients with chronic cough due to a variety of nonasthmatic conditions, as well as asthma. They did not appear to have assessed for lymphocytic inflammation. While it is not clear why there was a difference in neutrophilic inflammation observed in our study and that of Niimi et al,32 we assessed for neutrophilic inflammation and did not find it. We were not surprised by the absence of neutrophils in our subjects because the presence of neutrophilic inflammation reflects an acute inflammatory process and our subjects had a chronic and unchanged cough for years.

The literature21 on the physical events that can occur during the act of coughing and the complications that these changes can cause support the suggestion that trauma from the act of coughing itself can produce the inflammatory changes observed. For example, vigorous coughing can generate intrathoracic pressures up to 300 mm Hg, from 1 to 25 J of energy, expiratory velocities up to 28,000 cm/s or 500 miles per hour (ie, 85% of the speed of sound), and systolic BPs up to 140 mm Hg. Pressures, energy, and velocities of these magnitudes allow coughing to be an effective means of providing cardiopulmonary resuscitation and an effective defense mechanism. However, they have also been associated with a variety of profound physical and psychosocial adverse occurrences. A wide spectrum of respiratory complications has been reported21 that includes lower and upper airway trauma associated with severe compression of airways and violent undulations of laryngeal structures.33 Even without violent swings in pressure, there is good theoretical reason to presume that the high expiratory velocities of air known to occur during coughing can exert frictional stress on mucosal walls that may cause airway inflammation.34

There are other sources of literature that also support our contention that mechanical trauma from physical events similar to those induced by coughing can cause inflammation. For example, Lim and Wagner,35 in a rat model, showed that airway pressure (compressive stress) or stretch36 induced by the application of positive end-expiratory pressure can lead to increased airway inflammation, and a critical level of positive end-expiratory pressure was needed to provoke the response. Multiple studies3738 have suggested that the mechanical trauma of the upper airway in subjects with obstructive sleep apnea caused by dramatic pharyngeal pressure swings and violent muscle contractions against an occluded airway has the potential to cause structural damage to nerves and muscle fibers as well as inflammation within the pharyngeal tissues.

Potential Study Limitations
In this study, the known causes of chronic cough in our subjects were established on the basis of a favorable response to specific therapy. In addition, prior to performing the study, it was decided to further categorize the known causes of chronic cough into presumed extrapulmonary and intrapulmonary sites of stimulation, based on the best available pathogenic evidence132225 to facilitate comparative analyses of data. Although the diagnoses of upper airway cough syndrome (previously referred to as PNDS), GERD, and ACEI-induced cough in our subjects were considered extrapulmonary causes of cough, it is possible that future studies will show that our experimental categorization is not entirely accurate. However, even if this occurs, we believe that the clinical and research implications of our findings, summarized below, will remain valid because there was no difference in the type of inflammation between any of the groups of chronic coughers. For example, the type of inflammation was similar not only between extrapulmonary, intrapulmonary, and unexplained groups but also between explained coughers (groups 1 and 2 combined) and unexplained coughers. Although our study was not designed to assess repeat bronchial biopsies when cough disappeared, we speculate that the results of such an analysis would not alter the interpretation of our findings. If repeat biopsies showed that the inflammation abated or disappeared as cough disappeared, this would support a trauma interpretation. If the inflammation remained unchanged as cough disappeared, this would argue against the inflammation being the cause of the chronic cough in our subjects. Alternatively, such an analysis also may not alter the interpretation of our findings because it is possible that all coughing is associated with a final common pathway of inflammation, irrespective of etiology.

Clinical and Research Implications
Our findings suggest that airway inflammation associated with chronic cough may be due to the trauma of coughing itself. Because the histopathologic changes associated with coughing, assessed on morphologic appearance and inflammatory cell counting in hematoxylin-eosin–prepared samples, may not necessarily be a clue to the underlying cause of chronic cough, investigators must be cautious when imputing pathogenetic importance to observed inflammatory changes in airways of coughing subjects. In this regard, our study does not support the conclusions of others that chronic lymphocytic inflammatory airway changes, all by themselves, support the diagnosis of a specific diagnosis such as unexplained cough.17

Footnotes

Abbreviations: ACEI = angiotensin converting enzyme inhibitor; GERD = gastroesophageal reflux disease; PNDS = postnasal drip syndrome

This work was presented in part and published in abstract form at the XXIV Congress of the International Academy of Pathology, Amsterdam, The Netherlands, October 5–10, 2002 [Histopathology 2002; 4(s)AO.06.290:29]

None of the authors have any personal or financial conflicts of interest to disclose.

Dr. Irwin had nothing to do with the selection of reviewers, the review process, the decision to accept or invite the editorial that discusses this work. All of this was done without Dr. Irwin’s knowledge.

Received for publication September 1, 2005. Accepted for publication February 9, 2006.

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