CHEST. 2003;123(3) 

In This Article

The Cough Reflex and the "Healthy Smoker"

The human cough reflex is a vital protective and defensive reflex, and its integrity is important to protect the organism from irreparable harm.[1] It is therefore disappointing that our knowledge of the reflex, particularly the central control mechanisms, is scanty and that what little knowledge we do have is largely extrapolated from animal studies. This may explain the lack of effective antitussive agents in patients with a persistent cough. The only effective cough suppressant under these circumstances is morphine and it needs to be given in sedative doses, which has little clinical utility. A possible explanation for the difficulty in suppressing cough in humans is that the reflex is robust and highly conserved to protect the organism. There are circumstances in which the cough reflex is so sensitive that it interferes with quality of life, has adverse health effects, and needs to be suppressed. Many of these circumstances are associated with underlying conditions such as asthma, gastroesophageal reflux, and rhinitis, and in a small proportion there is no identifiable association.[2] An understanding of the pathophysiology of the coordination of the reflex in the medulla will fast track the development of effective antitussive agents. The cough reflex is also subject to voluntary control, and this raises the possibility of psychogenic influences. There may be constitutive factors that determine the sensitivity of our cough reflex, similar to bronchial hyperresponsiveness, although this has not been adequately addressed because of the varying methodology for cough challenge studies. It has been suggested that the cough reflex is more sensitive in women, but at least one study[3] found no difference between men and women.

The cough-sensitive nerves in the respiratory tract are the thin, myelinated, rapidly adapting pulmonary stretch receptors (RARs), and the nonmyelinated bronchial C-fibers, which are located throughout the tracheobronchial tree. These are subserved by the vagus nerve.[4] No specific cough receptor has yet been identified. There is controversy about whether the bronchial C-fibers have a central inhibitory or stimulatory effect.[4,5] However, recent evidence has suggested a stimulatory effect.[6] The nonmyelinated parenchymal pulmonary C-fibers appear to have an inhibitory effect on the cough reflex.[4] Much of the data in humans has come from cough challenge studies and the effects of protussive and antitussive agents. The standard protussive agents or cough stimulants used in cough challenge tests in adults include capsaicin, citric acid chloride-deficient solutions, distilled water, and hypertonic saline solution. Additional agents that are protussive are bradykinin and prostaglandins. Capsaicin appears to stimulate the nonmyelinated C-fibers, and chloride-deficient solutions stimulate the RARs. A vanilloid (capsaicin) receptor also has been identified in the human respiratory tract, the teleologic advantage of which is unclear.[7] Studies[8] in guinea pig cough models have suggested that capsaicin probably acts by stimulating pH receptors in the airways. The question often posed is whether cough challenges in the laboratory have any clinical relevance. Many studies have demonstrated an enhanced cough reflex sensitivity in patients with a range of clinical disorders that are associated with cough.[3]

The article in the current issue of CHEST by Dicpinigaitis (see page 685) represents an effort to understand the mechanism of cough in smokers. It is based on two smaller studies that observed a diminished cough reflex sensitivity in asymptomatic smokers. Capsaicin was used as the stimulant in this study, which examined the cough reflex sensitivity in relatively young, asymptomatic smokers. The particular strengths of this study are its gender specificity and the meticulous attention to standardization of the capsaicin cough challenge procedures. A weakness is that historical control subjects were used in the study. The author correctly points out why methodology is vital in cough challenge studies. We are not informed whether subjects were told to refrain from, for example, smoking or caffeine on the day of the cough challenges, the time of day of the challenge procedures, and how the coughs were counted. Several studies have addressed the factors that influence the cough challenge results, such as voluntary suppression of cough, the dose of the stimulant, and cigarette smoking preceding the challenge. It was therefore important that the control subjects should have been contemporaneous. For example, historical control subjects for methacholine bronchial challenge testing when testing mechanisms or new agents in asthma would not be acceptable. It is important that cough challenge procedures are also well-standardized so that observations in different laboratories that advance our knowledge about cough can be confirmed.

Notwithstanding these limitations, the study confirmed that cough reflex sensitivity to capsaicin is diminished in healthy smokers compared to healthy nonsmokers. We would naturally assume that cigarette smoke exposure should sensitize the cough reflex. The time before the last cigarette could have possibly influenced the results, but one cannot escape the systematic decrease in sensitivity in the smokers. The author proposes the following hypotheses to explain the observation: (1) nicotine-induced inhibition of C-fibers, but nicotine has been shown to stimulate cough in humans; and (2) mucus secretion may provide a barrier to tussive stimuli in cigarette smoke, but secretions in the airways are known cough stimulants. I think the most likely explanation proposed by the author is that long-term smokers may have been selected out by virtue of their constitutively diminished cough reflex sensitivity. It may also explain why individuals are able to tolerate cigarette smoke and then get addicted. Others may have an enhanced reflex sensitivity and are therefore unable to tolerate the acute effects of smoke and do not take up the habit. This raises once again the concept of the healthy smoker.[9] A systematic review of cross-sectional epidemiologic studies of spirometric lung function showed consistently that healthy (ie, asymptomatic) smokers had higher lung function values than did their nonsmoking counterparts. This may also be explained by a similar hypothesis that subjects with higher lung volumes are more likely to tolerate the acute effects of cigarette smoke and then go on to become long-term smokers. The missing piece in this intriguing puzzle is what determines the adverse effects of smoking that are observed in only about 20% of long-term smokers.

There is no doubt about the epidemiologic and clinical evidence that smokers have a chronic cough, and we need to explain this in the context of the observations by Dicpinigaitis. A proportion of long-term smokers will develop mucus hypersecretion (ie, chronic bronchitis), which is a stimulus for the RARs.[4] Long-term cigarette smoking causes neutrophilic inflammation in vulnerable smokers that sensitizes cough-sensitive nerves by the release of sensory neuropeptides and the direct stimulation of the nerves/receptors. In addition, emphysematous damage to the parenchyma may damage the inhibitory parenchymal pulmonary C-fibers. While cough and bronchoconstriction exist as independent reflexes, bronchoconstriction induced by cigarette smoke also may stimulate cough. This presupposes that smokers with a chronic cough have a sensitized cough reflex in response to conventional cough challenge testing. Surprisingly, this has not been well-studied, as most cough challenge studies exclude smokers.

Many more resources must be devoted to cough research so that we can, in particular, decipher the black box that controls the cough reflex. The observation in the current study suggests that there is a lot more to be learned from cough challenge testing in humans and about the influence of factors such as smoking. Definitive studies that investigate the cough reflex in smokers with and without COPD and/or symptomatic cough compared to control subjects will help us to understand the reflex and the effects of cigarette smoke on the cough reflex. This also may shed some light on why some smokers are predisposed to lung disease from smoking. Meticulous attention to detail and standardized challenge procedures, such as those defined for bronchial challenge testing, is critical to make these observations more meaningful.

Umesh G. Lalloo, MBChB, MD, FCCP, Durban, South Africa

Dr. Lalloo is acting head of the Department of Medicine, at the Nelson R. Mandela School of Medicine, University of Natal. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: permissions@chestnet.org).

Correspondence to: Umesh G. Lalloo, MBChB, MD, FCCP, Respiratory Unit, Department of Medicine, Nelson R. Mandela School of Medicine, Faculty of Health Sciences, University of Natal, Private Bag 7, Congella 4013, Durban, South Africa; E-mail: Lalloo@nu.ac.za.

  1. Lalloo UG, Barnes PJ, Chung KF. Pathophysiology and clinical presentations of cough. J Allergy Clin Immunol 1996; 98:S91-S96

  2. Irwin RS, Boulet L-P, Cloutier MM et al. Managing cough as a defense mechanism and as a symptom: a consensus panel report of the American College of Chest Physicians. Chest 1998; 114(suppl):133S-181S.

  3. Choudry NB, Fuller RW. Sensitivity of the cough reflex in patients with chronic cough. Eur Respir J 1992; 5:296-300

  4. Widdicombe JG. Neurophysiology of the cough reflex. Eur Respir J 1995; 8:1193-1202

  5. Karlsson JA, Sant'Ambrogio G, Widdicombe J. Afferent neural pathways in cough and reflex bronchoconstriction. J Appl Physiol 1998; 65:1007-1023

  6. Karlsson JA. The role of capsaicin-sensitive C-fibre afferent nerves in the cough reflex. Pulm Pharmacol 1996; 9:315-321

  7. Szallasi A. Vanilloid (capsaicin) receptors in health and disease. Am J Clin Pathol 2002; 118:110-121

  8. Lalloo UG, Fox AJ, Belvisi MG, et al. Capsazepine inhibits cough induced by capsaicin and citric acid but not by hypertonic saline in guinea pigs. J Appl Physiol 1995; 79: 1082-1087

  9. Becklake MR, Lalloo U. The "healthy smoker": a phenomenon of health selection? Respiration 1990; 57:137-144