UPPER AIRWAY INFLAMMATION IN OBSTRUCTIVE SLEEP APNEA

To the Editor :

I read with great interest the recent article by Dr. Kimoff and colleagues and the accompanying editorial by Dr. Svanborg on upper airway sensory nerve dysfunction in patients with obstructive sleep apnea syndrome (OSAS). Despite the descriptive nature of their study, Dr. Kimoff and colleagues (1) speculated without corroboration, and Dr. Svanborg concurred (2), that upper airway mucosal inflammation in OSAS could underlie, in part, this process particularly because it was partially reversible after nasal continuous positive airway pressure (nCPAP) therapy.

To this end, using distinct histological parameters and surrogate biomarkers in nasal lavage fluid and exhaled oral and nasal breath, including leukocytes, pentane, and nitric oxide, we have previously established that nasal and oropharyngeal mucosal inflammation is indeed present in patients with OSAS (3-7). Importantly, we found that immunoreactive neutral endopeptidase 24.11, a ubiquitous ectopeptidase that cleaves and inactivates proinflammatory neuropeptides and peptides, such as substance P, vasoactive intestinal peptide, and bradykinin in the upper airway mucosa, is decreased in the uvula epithelium of patients with OSAS. This, in turn, may amplify upper airway inflammation evoked by these peptides. Collectively, these data suggest that snoring-related mechanical trauma to the soft palate and uvula is not the sole factor underlying upper airway inflammation in OSAS, because the nasal mucosa is not subjected to repeated snoring-induced injury. In fact, this notion raises an intriguing possibility that nasal airway sensation is impaired in patients with OSAS and could be used as a relatively simple, noninvasive, objective, and reproducible means to gauge upper airway dysfunction in OSAS before and after nCPAP therapy. Importantly, topical antiinflammatory drugs, including recombinant human neutral endopeptidase 24.11, could also be considered as an adjunct to nCPAP therapy in these patients.

The University of Illinois at Chicago, Colleges of  Medicine and Pharmacy, Chicago, Illinois

1. Kimoff RJ, Sforza E, Champagne V, Ofiara L, Gendron D. Upper airway sensation in snoring and obstructive sleep apnea. Am J Respir Crit Care Med 2001; 164: 250-255 [Abstract/Free Full Text].

2. Svanborg E. Upper airway nerve lesions in obstructive sleep apnea. Am J Respir Crit Care Med 2001; 164: 187-189 [Free Full Text].

3. Rubinstein I. Nasal inflammation is present in patients with obstructive sleep apnea. Laryngoscope 1995; 105: 175-177 [Medline].

4. Müns G, Rubinstein I, Singer P. Phagocytosis and oxidative burst of granulocytes in the upper respiratory tract in chronic and acute inflammation. J Otolaryngol 1995; 24: 105-110 [Medline].

5. Sekosan M, Zakkar M, Wenig B, Olopade CO, Rubinstein I. Inflammation in the uvula mucosa of patients with obstructive sleep apnea. Laryngoscope 1996; 106: 1018-1020 [Medline].

6. Zakkar M, Sekosan M, Wenig B, Olopade CO, Rubinstein I. Immunoreactive neutral endopeptidase is decreased in uvula epithelium of patients with obstructive sleep apnea. Ann Otol Rhinol Laryngol 1997; 106: 474-477 [Medline].

7. Olopade CO, Christon JA, Zakkar M, Hua C, Swedler WI, Scheff PA, Rubinstein I. Exhaled pentane and nitric oxide levels in patients with obstructive sleep apnea. Chest 1997; 111: 1500-1504 [Abstract/Free Full Text].

From the Authors:

We greatly appreciate Dr. Rubinstein's comments on our paper (1), drawing attention to the possible role of inflammatory mechanisms in the pathophysiology of upper airway dysfunction in snoring and obstructive sleep apnea (OSA). We are well aware of the work of Dr. Rubinstein and his colleagues on mucosal inflammation in the upper airway of patients with OSA. We agree that their findings provide a rationale to evaluate sensory function at upper airway sites other than the oropharynx in these patients, and we are currently developing techniques to do this. We believe that inflammatory mediators play an important role in leading to injury of sensory, and as argued by Dr. Svanborg (2), motor nerves in the upper airway. Inflammatory mediators are also known to impair muscle contractility (3), and this could also be a factor contributing to upper airway muscle dysfunction in OSA. Interestingly, it has recently been reported that topical nasal steroids produce a modest therapeutic effect in children with OSA, without any significant change in the size of the adenoid or tonsillar tissues (4). This suggests that the benefit of topical steroids may have been due to more generalized antiinflammatory effects in the upper airway, although this hypothesis needs to be specifically tested. Clearly, much work needs to be done to more fully characterize the extent of upper airway inflammation in snoring and OSA, identify the inciting mechanisms, and determine the specific contributions of inflammatory processes to upper airway dysfunction. Only once such studies have been done would there be a sound basis for attempting antiinflammatory therapy for OSA.

McGill University Health Centre, Montreal, Quebec, Canada

1. Kimoff RJ, Sforza E, Champagne V, Ofiara L, Gendron D. Upper airway sensation in snoring and obstructive sleep apnea. Am J Respir Crit Care Med 2001; 164: 250-255 .

2. Svanborg E. Upper airway nerve lesions in obstructive sleep apnea. Am J Respir Crit Care Med 2001; 164: 187-189 .

3. Wilcox PG, Wakai Y, Walley KR, Cooper DJ, Road J. Tumor necrosis factor a decreases in vivo diaphragm contractility in dogs. Am J Respir Crit Care Med 1994; 150: 1368-1373 [Abstract].

4. Brouillette RT, Manoukian JJ, Ducharme FM, Oudjhane K, Earle LG, Ladan S, Morielli A. Efficacy of fluticasone nasal spray for pediatric obstructive sleep apnea. J Pediatr 2001; 138: 838-844 [Medline].

From the Author :

Dr. Rubinstein, in his letter concerning the recent article by Dr. Kimoff and colleagues (1) and my editorial (2), draws attention to one contributing factor of upper airway obstruction, namely mucosal swelling. For this he should have credit, although it is a rather well-known phenomenon. Mucosal inflammation in the oropharynx is apparent to anyone who is in the habit of inspecting the mouths of patients with obstructive sleep apnea (OSA) in the morning; you frequently find swollen, red tonsillar pillars and a uvula that looks like a cherry, with normalization during the afternoon. In some elegant studies utilizing sophisticated techniques, Dr. Rubinstein and his group have proven that such an inflammation is indeed a typical finding in OSA, and that it is enhanced at night. It would be interesting if a comparison was also made with patients with habitual snoring without significant apnea.

Dr. Rubinstein argues that snoring cannot be the only factor causing upper airway inflammation in OSA, since his group has shown that there are signs of inflammation in the nasal mucosa, and he states, the nose is not subjected to repeated snoring-induced injury. I do not agree with the latter statement. I believe that Dr. Rubinstein may, to some extent, have confused snoring with vibration. The vibrating structures in the upper airway (soft palate, uvula) are the ones that produce the sound and the nose is not involved in this process. The snoring phenomenon does, however, also involve heavy, forced inspiration through the nose (obvious in the typically sucked-in nostrils), which is likely to produce some mechanical irritation of the mucous membranes. That the nose is involved in snoring has been shown insofar as snoring cannot be abolished in some cases unless nasal surgery is performed (3). Also, the nasal airway resistance is reduced after uvulopalatalpharyngeal surgery with subsequent relief from snoring, probably as a consequence of disappearing edema (4). However, snoring per se is certainly not the only factor that could cause mucosal swelling due to nasal inflammation. Dr. Young and colleagues (5), among others, have pointed out that allergic rhinitis is clearly a risk factor for snoring and obstructive apnea, and anyone who has slept beside a person with a common cold knows what that might mean in terms of snoring.

University of Linköping, University Hospital, Linköping, Sweden

1. Kimoff RJ, Sforza E, Champagne V, Ofara L, Gendron D. Upper airway sensation in snoring and obstructive sleep apnea. Am J Respir Crit Care Med 2001; 164: 250-255 .

2. Svanborg E. Upper airway nerve lesions in obstructive sleep apnea. Am J Respir Crit Care Med 2001; 164: 187-189 .

3. Fairbanks DN. Snoring: surgical vs. nonsurgical management. Laryngoscope 1984; 94: 1188-1192 [Medline].

4. Welinder R, Cardell LO, Uddman R, Malm L. Reduced nasal airway resistance following uvulopalatoplasty. Rhinology 1997; 35: 16-18 [Medline].

5. Young T, Finn L, Kim H. Nasal obstruction as a risk factor for sleep-disordered breathing. J Allergy Clin Immunol 1997; 99: 757-762 [Medline].