Autonomic dysfunction, vasomotor rhinitis, and extraesophageal manifestations of gastroesophageal reflux

Autonomic dysfunction, vasomotor rhinitis, and extraesophageal manifestations of gastroesophageal reflux TODD A. LOEHRL, MD, TIMOTHY L. SMITH, MD, MPH, RONALD J. DARLING, MD, LAURA TORRICO, MD, THOMAS E. PRIETO, PHD, REZA SHAKER, MD, ROBERT J. TOOHILL, MD, and SAFWAN S. JARADEH, MD, Milwaukee, Wisconsin

OBJECTIVE: Several recent reports suggest there may be a relationship between chronic rhinitis and extraesophageal manifestations of gastroesophageal reflux (EER). It is hypothesized that this relationship is a result of autonomic nervous system (ANS) dysfunction. STUDY DESIGN: Patients with isolated vasomotor rhinitis (VR), both VR and EER, and a control group were studied by a battery of tests designed to objectively evaluate ANS function. In addition all 3 groups underwent barium esophagogram and 4site (proximal pharynx, distal pharynx, proximal esophagus, and distal esophagus) ambulatory pH monitoring. Adult patients fulfilling diagnostic criteria for VR, and with both VR and EER underwent objective ANS testing in a recently developed ANS testing laboratory. The control group consisted of age- and sex-matched adults without diagnostic criteria for VR or EER.

From the Departments of Otolaryngology and Communication Sciences (Drs Loehrl, Smith, Darling, Torrico, and Toohill), Neurology (Drs Prieto and Jaradeh), and Gastroenterology and Hepatology (Dr Shaker), The Medical College of Wisconsin. Presented at the Annual Meeting of the American Academy of Otolaryngology–Head and Neck Surgery, Denver, CO, September 9-12, 2001. This study was supported by intramural funds from the Department of Otolaryngology and Communication Sciences (Medical College of Wisconsin), an educational grant from Taps Pharmaceuticals, and the 2001 Percy Memorial Research Award from the American Academy of Otolaryngology–Head and Neck Surgery. Reprint requests: Todd A. Loehrl, MD, Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, 9200 W. Wisconsin Ave, Milwaukee, WI 53226; e-mail, [email protected]. Copyright © 2002 by the American Academy of Otolaryngology–Head and Neck Surgery Foundation, Inc. 0194-5998/2002/$35.00 + 0 23/1/123857 doi:10.1067/mhn.2002.123857

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RESULTS: In patients with VR only (n = 9), 2 patients had a positive esophagogram, whereas a positive pharyngeal reflux probe was found in 1 and an abnormal composite autonomic scoring scale (CASS) was found in 8 (mean VR CASS = 1.750 vs control CASS 0.556, P = .02). The group with VR and EER (n = 12) had a positive esophagogram in 10 patients, positive pharyngeal reflux by probe in 9, and all 12 had an abnormal CASS (mean CASS VR/EER = 2.909 vs CASS control = 0.556, P = .001 and vs VR CASS = 1.750, P = .05). The control patients (n = 9) had normal transesopohageal gastroduodenoscopy in 8, 1 had a positive pharyngeal probe study, and all 9 had a normal CASS. In addition ANS testing in patients with diagnostic criteria for both VR/EER revealed statistically significant evidence of an adrenergic deficit as compared with control patients on the basis of mean phase II blood pressure response to Valsalva maneuver (mean phase II VR/EER = -16.730 vs control = -7.780, P = .05). In the VR only group, the phase II blood pressure decrease was greater than in control patients, but did not reach statistical significance (mean phase II VR = -9.370 vs control = – 7.780, P = 0.672). CONCLUSION: Patients with VR and VR/EER have objective evidence of ANS dysfunction when compared with a group of age- and sex-matched control patients. Patients with both VR/EER demonstrate a significantly greater degree of ANS dysfunction than patients with isolated VR. The mechanism by which VR and EER interact is not entirely clear, but ANS dysfunction is objectively associated with both disorders. In addition, patients with VR/EER seem to demonstrate hypofunction of the adrenergic component of the ANS, in contrast to the generally held hypothesis that VR results from increased cholinergic activity. Further characterization of the type of ANS abnormality may allow the development of novel pharmacologic therapies for these disorders. (Otolaryngol Head Neck Surg 2002; 126:382-7.)

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Autonomic nervous system (ANS) dysfunction was proposed as a possible cause of vasomotor rhinitis (VR) approximately 50 years ago.1,2 These authors discuss the role of the ANS in maintaining sinonasal health through regulation of the vascularity and mucosal gland function of the sinonasal cavity. Electrical stimulation of the sympathetic nervous system (SNS) supply to the nose results in a large reduction in resistance to airflow whereas parasympathetic nervous system (PNS) stimulation results in a small increase in nasal resistance to airflow and profuse rhinorrhea.3 An imbalance between the 2 autonomic influences on the sinonasal cavity, with the PNS being hyperactive relative to the SNS, would therefore be expected to result in the principal symptoms of VR. This hypothesis has been the generally accepted explanation for VR for 50 years. The relationship between chronic rhinitis and the gastrointestinal tract was discussed by Holmes et al4 50 years ago when he proposed a connection between sinonasal disease and gastric hypersecretion. More recent reports have supported the relationship of reflux to chronic sinonasal disease. In 1997 Chambers et al5 reported that the presence of gastroesophageal reflux (EER) disease significantly reduced the likelihood of a good outcome after functional endoscopic sinus operation. Ulualp et al6 reported that when compared with control patients, patients with chronic rhinosinusitis refractory to conventional medical and surgical therapy were significantly more likely to have objective evidence of EER. In addition, Bothwell et al7 reported that in 30 children who were candidates for functional endoscopic sinus operation, reflux therapy resulted in 89% of the children avoiding sinus operation. Silvers et al8 reported a very positive pH probe study in patients with chronic sinusitis. Despite these reports relating chronic sinonasal disease to reflux disease, a scientifically valid relationship is yet to be established. Recently, Jaradeh et al9 performed a study on a group of patients with VR objectively validating the relationship of VR to ANS dysfunction. In that study, it was suggested that a majority of patients had symptoms or findings suggestive of EER. The

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purpose of this study is to further investigate the possible relationship of chronic sinonasal disease and EER. In addition, we hypothesize this relationship is related to ANS dysfunction. MATERIALS AND METHODS This study was approved by the Institution Research Committee of the Medical College of Wisconsin. Patients fulfilling diagnostic criteria for VR and VR/EER were recruited from the Medical College of Wisconsin affiliated hospitals’ otolaryngology clinics. A group of patients without a history of VR, EER, or symptoms of ANS abnormalities were recruited by advertisement. Diagnostic criteria for VR include characteristic symptoms of nasal congestion and secretion for at least 3 months, nasal endoscopic findings of mucous membrane swelling and thickening, absence of recent or current infection, gross nasal polyposis, pregnancy, and allergy. Patients with evidence of allergy on the basis of history or skin end point titration testing were excluded from the study. The diagnosis of EER is made on the basis of characteristic symptoms, physical findings, and objective findings on 4-site pH probe testing and esophagogram. Symptoms of EER include 1 or more of the following: globus pharyngeus, intermittent hoarseness, recurrent throat irritation, frequent throat clearing, phlegm in the throat, postnasal drainage, dysphagia, chronic cough, and asthma. One or more of the following physical findings must be present for inclusion: edema of the arytenoid mucosa, edema of the posterior third of the vocal cords, edema of the lower one-third of the pharynx, or pachyderma laryngis. Patients fulfilling the historical and physical findings above then underwent 4-site pH probe and esophagogram to confirm the diagnosis. A positive result is defined as a pH less than 4.0 at the pharyngeal probe(s) with a simultaneous drop in the esophageal probes(s).10 Findings on esophagogram considered to be positive for EER include gross reflux, hiatal hernia, esophageal dysmotility, or esophageal complications of reflux including esophageal stricture, esophagitis, or both.11 Consecutive patients with diagnoses of VR were offered enrollment in the study after a thorough

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discussion. Institutional review board approval was obtained and informed consent received in all patients volunteering for the study. In preparation for ANS testing, anticholinergics were discontinued for 48 hours, vasodilative drugs for 24 hours, and caffeine and tobacco for at least 8 hours before testing. ANS testing consists of the following: 1. The quantitative sudomotor axon reflex test is performed at the foot, distal leg, proximal leg, and forearm to measure postganglionic sudomotor function. The patient rests supine in a comfortably warm room. A small multicompartmental sweat capsule is placed on the extremity. A very small electrical current stimulus is used to iontophorese acetylcholine and to trigger sweating. The patient feels a transient local stinging sensation for 1 to 2 minutes. Nitrogen gas flows through high-pressure and low-pressure regulators, through the sweat cell, and back through the sudorometer. Sweat output (uL/cm2) is then recorded. The results are compared with a group of age- and sexmatched control patients. 2. Heart rate response to deep breathing is quantified. The patient is instructed in and allowed to practice breathing deeply and smoothly with inspiratory and expiratory cycles of 5 seconds each. The heart rate is recorded using an electrocardiogram monitor with electrodes placed at standard sites. Eight cycles of deep breathing, 10 seconds each, are accomplished in the manner practiced. The computer measures heart rate and the mean of the 5 largest consecutive responses to get the heart rate range to deep breathing. 3. The heart rate and blood pressure responses to the Valsalva maneuver are recorded using the electrocardiogram monitor and a noninvasive continuous blood pressure monitor (Colin Pilot, Colin Medical Instruments, San Antonio, TX). The patient blows into a tube connected to a manometer and maintains a pressure of 40 mm Hg for 15 seconds. The patient feels as if he or she is lifting some weight. Heart rate and blood pressure responses are recorded and analyzed. The Valsalva ratio is calculated and compared with known age-adjusted normal subjects.

4. Blood pressure and heart rate responses to upright tilt are determined. The patient rests quietly in the supine position on the tilt table for at least 5 minutes with the electrocardiogram monitor and noninvasive continuous blood pressure monitor cuff in place. Heart rate and blood pressure are recorded at baseline and continuously while the patient is tilted upright and maintained in this position for 5 minutes. The patient is then tilted back and the response is monitored for 3 additional minutes. Three straps are used to keep the patient secured to the table and keep the limb with the attached cuff at heart level, avoiding movement artifacts. 5. For a thermoregulatory sweat test the patient is placed in a sauna-like room with a temperature of 45°F to 50° C and a humidity of 28% to 35%. Wearing a disposable swimming suit (1 piece for men and 2 pieces for women) the forehead, trunk, and limbs are dusted with a mixture of red alizarin powder, sodium carbonate, and starch. The patient remains in the sauna until body temperature rises by at least 10C, or until the test can no longer be tolerated. After the patient sweats, the powder changes from orange to purple. A sweating map is configured and stored on Polaroid (Polaroid Corp, Cambridge MA) films and on shaded diagrams. The patient then showers in the study center bathroom.12-14 On the basis of the above data, sudomotor, adrenergic, and cardiovagal subscores are generated. The sudomotor and adrenergic subscores indicate primarily a disorder of the SNS. The cardiovagal subscore is an indicator of PNS function. The composite autonomic scoring scale (CASS) is a measure of overall ANS function and is a composite of the above 3 subscores. The data are analyzed and statistically compared with normal age- and sex-matched control patients using the Student t test when the difference between 2 variables are tested. The analysis of variance is used when 3 or more variables are tested. RESULTS Nine age- and sex-matched control patients were recruited through advertisement and evaluated. None of the control patients had symptoms or phys-

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ical signs of VR or EER. They ranged in age from 29 to 62 years old and there were 5 males and 4 females. Transesopohageal gastroduodenoscopy was normal in 7 of 9 patients. Two of the 9 control participants refused transesopohageal gastroduodenoscopy. Two of 9 patients refused to undergo the 24-hour pH probe study. One of the 7 control participants was found to have a positive 24-hour pH probe test. All 9 of the control patients had normal ANS testing with a mean CASS = 0.556 (Table 1). Nine patients fulfilling diagnostic criteria for VR, 5 female and 4 male, age range 23 to 57 years old, underwent the same testing battery. None of the patients in this group had symptoms of EER. Two of 9 patients had a positive esophagogram and 1 patient had findings of pharyngeal reflux on 24hour pH probe study. Eight of 9 patients had positive ANS testing, whereas 1 was normal. The mean CASS was 1.75 (vs control CASS = 0.556, P = .02). The adrenergic subscore was increased (consistent with adrenergic hypofunction) compared with control patients but not to a statistically significant degree (VR = 0.500 vs control = 0.111, P = .177). The sudomotor subscore was not significantly different from the control group. The mean phase II blood pressure change, which is another measure of adrenergic function, decreased but not to a statistically significant degree (VR = -9.370 mm Hg vs control = -7.780, P = .672). Twelve patients had diagnostic criteria consistent with both VR and EER. A positive esophagogram was found in 10 of 12 patients, whereas 24-hour pH probe study was positive in 9 patients. All 12 had abnormal CASS scores with a mean CASS = 2.909 (vs control = 0.556, P = .001; vs VR = 1.75, P =.05). The mean adrenergic subscore indicated statistically significantly adrenergic hypofunction as compared with control participants (VR/EER = 0.818 vs control = 0.111, P = .018). Similarly, the phase II blood pressure mean responses are significantly less than the control group (VR/EER = -16.73 mm Hg vs control = 7.78 mm Hg, P = .05). The sudomotor subscore was significantly different from the control group, indicating an adrenergic deficit (VR/EER =1.455 vs control = 0.333, P = .001). In summary, these results indicate that patients with VR have ANS dysfunction, and that patients

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with both VR/EER have dsyfunction of the ANS to a significantly greater degree. Furthermore, the ANS dysfunction is characterized by an imbalance between the adrenergic and cholinergic portions of the ANS. This imbalance is defined by a hypoadrenergic response as opposed to an increase in cholinergic input. DISCUSSION Rhinitis has a substantial impact on patients, healthcare systems, and resources. It is estimated to affect 33 million US residents and result in 22 to 25 million physician outpatient visits annually, resulting in total indirect and direct costs of $6 billion annually.15 Approximately one half of these patients have nonallergic rhinitis, including VR. Despite the prevalence of VR, very little is known about the pathophysiology of the disorder. Symptoms include intermittent nasal obstruction, rhinorrhea, and headaches that often occur in response to physical stimuli such as cold air, tobacco smoke, sudden temperature change, wet extremities, and emotional stimuli. Speculation regarding the pathophysiology of VR has revolved around dysfunction of the ANS, which is known to be involved with many human disease processes.12-14 Optimal function of the ANS depends on a delicate balance of the PNS and SNS, which are primarily comprised of cholinergic and adrenergic fibers, respectively. An imbalance in the levels of input from the PNS and SNS to the nasal cavity is thought to result in VR.1,3 EER denotes gastroesophageal refluxate that reaches structures above the upper esophageal sphincter. EER has been implicated in the pathogenesis of several otolaryngologic disorders such as chronic posterior laryngitis, laryngeal contact ulcer or granuloma, paroxysmal laryngospasm, vocal cord nodule, Reinke’s edema, subglottic stenosis, laryngotracheal stenosis, globus pharyngeus, laryngeal and hypopharyngeal carcinoma, sudden infant death syndrome, and chronic lung disease.16,17 The mechanism by which EER affects the lower respiratory tract may be a result of a neurogenic inflammatory process mediated (via the ANS, the vagus nerve, or both), direct contact of gastric contents with the respiratory epithelium, or both. It has been demonstrated in an animal model

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Table 1. ANS testing results Control (a) (n = 9)

VR (b) (n = 8)

Age (y) QSART foot (uL/cm2) QSART leg (uL/cm2) Valsalva ratio Phase II MBP change (mm Hg)

41.33 1.107 1.601 1.6267 -7.78

33.12 0.785 1.184 1.879 -9.37

46.00 0.598 1.352 1.5409 -16.73

Phase IV MBP change (mm Hg) HRDB (bpm) Tilt SBP change Tilt HR change Sudomotor subscore Cardiovagal subscore Adrenergic subscore CASS

17.11 19.36 21.67 22.22 0.333 0.111 0.111 0.556

16.25 18.56 9.37 16.37 1.000 0.250 0.500 1.750

13.09 14.15 12.73 19.36 1.455 0.545 0.818 2.909

Parameter

VR/EER(c) (n = 11)

P-value

bc P = .007 ns ns ns ab = ns ac P = .05 ns ns ns ns ab = ns ac P = < .001 ns ab = ns ac P = .018 ab P = .021 ac P = < .001

bc, Columns b and c; QSART, quantitative sudomotor axon reflex test; ns, not significant; MBP, mean blood pressure; ab, columns a and b; ac, columns a and c; HRDB, heart rate range to deep breathing; HR, heart rate; SBP, systolic blood pressure.

that esophageal stimulation by hydrochloric acid causes neurogenic inflammation of the airways.18 This finding suggests that there are neural pathways communicating between the esophagus and the respiratory tract. Clinically, treatment of EER results in improved pulmonary status in greater than 60% of asthmatics.19 EER has been associated with chronic nasal inflammation.5-9 Furthermore, patients with VR and EER have been found to have objective ANS abnormalities in separate studies.9 In addition, Lodi et al20 found that asthmatics with EER disease have evidence of autonomic dysfunction. Recently, ANS testing laboratories have been developed. These methods have been standardized to identify, characterize, and quantify ANS dysfunction. This allows the type of ANS abnormality to be determined (ie, increased/decreased PNS vs increased/decreased SNS). This study attempts to further delineate the degree and type of ANS abnormality in patients with VR and VR/EER. Our results indicate that patients with VR alone or VR/EER have objective evidence of decreased SNS input, resulting in a relative hyperactive PNS. It is believed that this leads to the signs and symptoms associated with VR. The dysfunction of the ANS in patients with VR, which is characterized by a hypoactivity of

the adrenergic portion of the ANS, appears to have an influence also on gastric and lower esophageal sphincter function. The results in the patients studied indicate more than a casual relationship between VR and EER. The abnormalities noted in ANS testing studies suggest that the association is on the basis of ANS dysfunction. It is well known that ANS regulation is very important in the nasal region and gastrointestinal tract. The control patients exhibited normal ANS function testing. The VR group had increased level of dysfunction whereas the VR/EER group had significantly higher levels of ANS dysfunction as compared with control participants. It is possible that as ANS dysfunction increased, patients are likely to have a more severe VR and associated EER. The patients with VR tended to be at a younger age than those with VR and EER (33 vs 46 years old, respectively, P = .007) (Table 1). This would suggest a progressive abnormality in the ANS and gives some credence to the thought that the dysfunctional ANS may eventually lead to problems with EER in many patients. Thus ANS dysfunction may account for the recent reports of EER in patients who have had chronic rhinitis develop.5-8 This relationship should be considered in patients who are failing conventional medical and surgical therapy. The possibility of using investigational drugs

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that influence the ANS may lead to greater success in treating both EER and VR and reduce the morbidity of the associated chronic rhinitis. REFERENCES

1. Williams HL. A concept of allergy as autonomic dysfunction suggested as an improved working hypothesis. Trans Am Acad Ophthalmol Otolaryngol 1950;52:123-46. 2. Goldman JL. Vasomotor rhinitis and sinusitis. In: Goldman JL, ed. Principles and Practice of Rhinology. New York, NY: Churchill Livingstone; 1987:235-47. 3. Wilde AD, Cook JA, Jones AS. The nasal response to isometric exercise in noneosinophilic intrinsic rhinitis. Clin Otolaryngol 1996;21:84-6. 4. Holmes TH, Goodell H, Wolf S, et al. The Nose: An Experimental Study of Reactions Within the Nose in Human Subjects During Various Life Experiences. Springfield, Ill: Charles C. Thomas; 1950:1-154. 5. Chambers DW, Davis WE, Cook PR, et al. Long-term outcome analysis of functional endoscopic sinus surgery: correlation of symptoms with endoscopic examination findings and potential prognositc variables. Laryngoscope 1997;107:504-10. 6. Ulualp SO, Toohill RJ, Hoffman R, et al. Possible relationship of gastroesophagopharyngeal acid reflux with pathogenesis of chronic sinusitis. Am J Rhinol 1999;13:197-202. 7. Bothwell MR, Parsons DS, Talbot A, et al. Outcome of reflux therapy on pediatric chronic sinusitis. Otolaryngol Head Neck Surg 1999;121:255-62. 8. Silvers S, Kim H, Gold S, et al. Reflux and chronic sinusitis: are they related? Paper presented at the annual meeting of the American Rhinologic Society, 2000; Orlando, FL. 9. Jaradeh SS, Smith TL, Torrico L, et al. Autonomic nervous system evaluation of patients with vasomotor rhinitis. Laryngoscope 2000;110:1828-31. 10. Postma GN. Ambulatory pH monitoring methodology. Ann Otol Rhinol Laryngol 2000;109:10-4.

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11. Sellar RJ, DeCaestecker JS, Heading RC. Barium radiology: a sensitive test for gastro-oeseophageal reflux. Clin Rad 1987;38:303-7. 12. Fealey RD. The thermoregulatory sweat test. In: Low PA, ed. Clinical Autonomic Disorders: Evaluation and Management. Boston, Mass: Little, Brown; 1993: 217-29. 13. Low PA. Laboratory evaluation of autonomic function. In: Low PA, ed. Clinical Autonomic Disorders: Evaluation and Management. 2nd ed. Philadelphia, Pa: LippincottRaven; 1997:179-208. 14. Low PA. Pitfalls in autonomic testing. In: Low PA, ed. Clinical Autonomic Disorders: Evaluation and Management. 2nd ed. Philadelphia, Pa: Lippincott-Raven; 1997:391-401. 15. Ray NF, Baraniuk JN, Thamer M, et al. Healthcare expenditures for sinusitis in 1996: contributions to asthma, rhinitis, and other airway disorders. J Allergy Clin Immunol 1999;103:408-14. 16. Koufman JA. The otolaryngologic manifestations of gastroesophageal reflux disease (GERD): a clinical investigation of 225 patients using ambulatory 24-hour pH monitoring and an experimental investigation of the role of acid and pepsin in the development of laryngeal injury. Laryngoscope 1991;101:(suppl 53). 17. Koufman JA, Amin MR, Panetti M. Prevalence of reflux in 113 consecutive patients with laryngeal and voice disorders. Otolaryngology Head and Neck Surg 2000;123:385-8. 18. Hamamoto J, Kohrogi H, Kawano O, et al. Esophageal stimulation by hydrochloric acid causes neurogenic inflammation in the airways in guinea pigs. J Appl Physiol 1997;82:738-45. 19. Harding SM, Richter JE. The role of gastroesphageal reflux in chronic cough and asthma. Chest 1997; 111:1389-1402. 20. Lodi U, Haring SM, Coghan HC, et al. Autonomic regulation in asthmatics with gastroesphageal reflux. Chest 1997;111:65-70.