Eustachian tube obstruction and allergy: A role in otitis media with effusion?

Editorials Eustachian tube obstruction and allergy: role in otitis media with effusion?

OME is an extremely common pediatric disease, characterized by an inflammation of the middle ear mucosa with subsequent development of an effusion within the middle ear. It can be manifested as an acute or chronic condition and is now considered to be a multifactorial disease process with several potential etiologies.’ Bacterial infection of the middle ear and eustachian tube obstruction are the two best documented pathogenic mechanisms responsible for the development of OME.’ An allergic etiology has also been suggested and supported by studies reporting higher prevalences of OME in allergic patients or the presence of humoral and cellular immune response components in the effusion.3msHowever, as outlined by the critics of this hypothesis, most supportive studies were retrospective, lacked adequate control of confounding variables, and failed to delineate pathophysiologic mechanisms by which an allergic condition could be translated into a middle ear pathology.’ The role of allergy in the pathogenesis of OME may involve one or more of several mechanisms: (1) the middle ear mucosa responding functionally as a sensitized tissue, (2) inflammatory swelling within the eustachian tube, and (3) inflammation and edema of the nose and nasopharynx. The first mechanism has been questioned by Bernstein et al.’ who reported that less than 15% of children with OME and proved respiratory allergy had detectable IgE antibodies in middle ear fluids. Even though this study did not document the onset or duration of the OME at the time of tympanocentesis, it appears unlikely that the middle ear functions as a primary “shock” organ for many patients, but this hypothesis deserves additional study. The latter two mechanisms would implicate abnormal eustachian tube function, and until recently, these proposed relationships had not been evaluated in controlled clinical experimental settings. In this issue of THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Walker et ah8 report their Supported by National Institutes of Health Grants ROl AI19262, PO1NS 16337, and MOl-RROO084. Reprint requests: Philip Fireman, M.D., Children’s Hospital of Pittsburgh, 125 DeSoto St., Pittsburgh, PA 15213.

A

140*.11..1.-. OME:

Otitts media with effuston

studies of the effects of aerosolized intranasal histamine on eustachian tube function as well as on nasal airway resistance and nasal airway power. It is unfortunate that these studies did not include histamine dose-response relationships in the atopic and nonatopic subjects in order to define better the observed changes in eustachian tube and nasal function. This single histamine intranasal provocative challenge resulted in eustachian tube obstruction as measured by the nine-step inflation/deflation tympanometric test in nine of 12 atopic subjects as well as increased nasal resistance and nasal airway power. In contrast, none of the 10 nonatopic subjects studied demonstrated the eustachian tube changes, even though nasal airway resistance and nasal airway power increased after intranasal histamine. Although the mean change in nasal power was significantly greater in the atopic than in the nonatopic subjects (p < 0.05), the changes in mean airway resistance were not significantly different in these two study groups. The considerable intersubject variability in baseline nasal airway resistance as well as nasal power, indicated in Table I and discussed, raises the issue of reproducibility of the observations and intrasubject variability. This was not addressed and should be examined in future studies. Nevertheless, these observations by Walker et al.” provide additional information to support the contention that upper respiratory inflammation including allergy can obstruct the eustachian tube and might thereby contribute to the development of OME. The eustachian tube provides an anatomic communication between the nasopharynx and the middle ear. Consequently, it is in an unique position to affect changes in the middle ear secondary to reactions in the nose. The eustachian tube and its relationship to the middle ear and nasopharynx may be considered to be analogous in part to the bronchial tree in its relationship to the lung and nasopharynx. Thus, abnormal eustachian tube function may predispose the 137

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middle ear !(‘I infection. atelectasis, and effusion. In this regard the eustachian tube like the bronchial airway serves several functions that include protection, ventilation. and drainage. The eustachian tube protects the middle ear from nasopharyngeal organisms, antigens, secretions, sounds. and pressures. Ventilation of the middle ear via the eustachian tube provides for equilibration of middle ear pressures with atmospheric pressure. Drainage via the eustachian tube will ctear fluids. detritus and noxious substances that may have accumulated in the middle ear cavity. Like the mucosa elsewhere in the respiratory tract, the mucosal lining of the eustachian tube and the middle ear contams mucus-producing cells. ciliated cells, plasma cells, and mast cells.” Unlike the bronchial system. the eustachian tube is usually collapsed (nonpatent) and has no submucosal muscle, and yet, the eustachian tube does open transiently during swallowing, yawning, and sneezing, and this permits the air pressure in the middle ear to equilibrate with atmospheric conditions. During swallowing. the eustachian tube opens secondary to the contraction of the tensor veli palatini muscle. and this is defined as active tubal function. There is no constrictor muscle of the eustachian tube, and closure of the tube is due to relaxation of the tensor veii palatini and elastic recoil of tissue. a passive function. The eustachian tube will also open and close passively as a result of pressure differentials between the two ends of the tube such as would take place at the proximal orifice during a Valsalva’s maneuver or at the distal orifice with externally applied pressure *b,irc;I tympanostomy tube. As reviewed by Cantekin,“’ investigations during the previous 20 years have made considerable progress m developing means to quantify eustachian tube ventilatory function by use of direct pressure and flow measurements in patients with nonintact tympanic membranes. Assessment of eustachian tube function in patients with intact tympanic membranes is more difficult but can also be quantified by use of special manometric techniques. These studies require a pressure chamber to induce different middle ear pressure conditions As an alternative. a qualitative tympanometric assessment of eustachian tube function, called the nine-step pressure swallow or inflation-defation procedure has been adapted by Bluestone” and appiied to our studies of antigen-induced eustachian tube obstruction.” This step-wise tympanometric sequence tests active tubal function. After an initial tympanogram. equilibration by swallowing of an externally applied positive pressure to the intact tympanic membrane is measured. After return to baseline tympanogram. equilibration by swallowing of negative pressure apphed to the intact tympanic membrane is assessed. This test requires patient cooperation to swal-

CLIN. IMMUNOL. AUGUST 1985

low on command and is difficult to perform in children less than 4 years of age. Approximately 10% of normal adult subjects fail the test even in the absence of ear disease and are not suitable test subjects. Walker et al.’ used this procedure in their study of the effects of intranasal histamine on eustachian tube function. When the tympanic membrane is not intact, eustachian tube ventilatory function can be assessed quantitatively by manometry. With the use of externally applied pressure via a typanostomy or perforation tube, air flow and passive tubal function can be measured as well as the active tubal resistance during swallowing. These techniques referred to as the forced response test and inflation-deflation procedure will discriminate both active and passive eustachian tube function and have been used in our experimental studies with the use of a rhesus monkey model as reported by Doyle et al.‘-‘, I4 When obstruction of the eustachian tube occurs, it can be categorized as functional or mechanical. Functional obstruction results from persistent collapse of the eustachian tube caused by increased tubal compliance or an abnormal active muscular opening mechanism. Functional eustachian tube obstruction is common in infants and young children as compared to adult subjects, perhaps the result of less cartilage and stiffness of the eustachian tube as well as less efficient tensor palatini muscle contraction in younger children than in postpubescence subjects. Mechanical obstruction of the eustachian tube can be extrinsic, intrinsic, or both. Extrinsic obstruction may be peritubular such as secondary to adenoidal enlargement or posterior nasophatyngeal, whereby edema of inflammation obstructs the eustachian tube orifice. Intrinsic obstruction results from blockage of the lumen of the tube by edema and secretions of inflammation caused by infection or possibly allergy. A number of clinical and laboratory studies by our group have contributed to establishing a causal relationship between an allergic reaction in the nasopharynx and the expression of eustachian tube obstruction. For these studies a clinical investigative model with the use of human volunteers with documented allergy and a comparable experimental passively sensitized monkey model was developed. By use of a double-blind protocol in subjects with allergic rhinitis. a provocative intranasal pollen challenge to the allergic individuals induced eustachian tube obstruction that was preceded by allergic rhinitis, but a placebo pollen challenge did not obstruct. ” A preliminary report by Cook et al. Is suggested similar findings by use of intranasal allergen solutions in an uncontrolled study. These studies have been confirmed with the perennial inhalant allergen, house dust mite, as well as the seasonal pollens, ragweed and grass.l’

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Subsequent studies have demonstrated that the eustachian tube obstruction was antigen dose-dependent and negatively correlated with the patient’s serum IgE antibody titer.17 The dose of antigen that provoked the allergic rhinitis was less than that which induced the eustachian tube obstruction. Pretreatment with antihistamines, topical intranasal aerosolized corticosteroids. and cromolyn sodium were effective in alleviating or attenuating the response.‘X Since the doses of intranasal allergen needed to provoke eustachian tube obstruction were more than inhaled naturally, the clinical relevance of these studies needs to be established. Preliminary observations of a small group of children with allergic rhinitis and a past history of OME who had weekly monitoring of eustachian tube function suggest an increased frequency of eustachian tube obstruction during the well-defined 1984 ragweed pollen season. I’) The anatomic site of the inflammation associated with the development of eustachian tube obstruction in these human intranasal challenge studies as well as their active and passive eustachian tube ventilatory function has not been established. A preliminary communication by Gold et al.“’ indicated that histamine and antigen discs applied to the anterior nasal mucosa did not consistently provoke eustachian tube obstruction. It has been postulated that posterior nasopharyngeal mucosal edema results from the antigen or histamine challenge that subsequently occludes the proximal portion of the eustachian tube. A similar extraluminal tubal obstruction has been suggested in patients with an infectious rhinitis and pharyngitis.” To define the passive and active properties of the eustachian tube, an animal model was developed. For this purpose rhesus monkeys were passively sensitized to ragweed. ” After intranasal pollen challenge the sensitized monkeys developed allergic rhinitis and eustachian tube obstruction. By use of the inflation-deflation and forced response tests via inserted tympanostomy tubes, active tubal function was markedly impaired, but passive resistance increased only slightly. These results indicated that an IgE-mediated response at the site of the nasopharynx debilitates the active muscle-assisted opening of the eustachian tube and confirmed and extended our human studies. To characterize further the relationship between allergic rhinitis and eustachian tube obstruction, nonsensitized rhesus monkeys were intranasally challenged with various doses of histamine. It was hypothesized that intranasal histamine challenge would result in eustachian tube obstruction similar to that observed in the prior intranasal antigen challenge studies. Not only did rhinitis and increased active resistance within the eustachian tube develop, but passive resistance also increased. I4 These data indicate that the intranasal his-

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tamine not only induced extraluminal obstruction but also intraluminal obstruction. Therefore, these studies document that any mechanism, allergic or infectious. that releases histamine in the nasopharynx may obstruct the eustachian tube. In addition, these studies documented age-related differences to histamine doseresponse challenges because the juvenile monkeys were more responsive to histamine than the adult monkeys. ” Although these studies have provided evidence to support the contention that nasal allergy contributes to OME, they have not confirmed the hypothesis in its entirety. The provocative intranasal antigen or histamine challenges have induced eustachian tube obstruction but have not resulted in OME. Because we wanted to minimize the possible risk of creating middle ear pathology after a provocative intranasal challenge, the absence of a resultant OME was anticipated for two reasons: (1) the relatively brief duration of eustachian tube obstruction after challenge, and (2) the use of adult study subjects. After intranasal provocative challenge, the developed tubal obstruction persisted only for several hours to a few days. In monkeys OME does not develop until 1 to 4 weeks after creating a surgical functional eustachian tube obstruction.” Thus, eustachian tube obstruction must be sustained for a week or more for OME to develop. Furthermore, a number of studies have suggested that eustachian tube function improves with age and has been related to the fact that OME is more prevalent in younger children.’ If the younger child has some degree of functional eustachian tube obstruction, then the development of an antigen-provoked, histaminemediated eustachian tube obstruction might be expected to have more severe and prolonged effects at a lesser antigen dosage. It is anticipated that in the not too distant future, further definition of these pathophysiologic events will lead to a better understanding of the role of allergy and eustachian tube obstruction in the pathogenesis of ear diseases. I acknowledgethe collaboration of coworkersDr\. Bluestone, Cantekin, Doyle, and Skoner and thank them for reviewing this manuscript. Philip Fireman. M.D. Professor of Pediatrics University of Pittsburgh School of Medicine Children’s Hospital Pittsburgh, PA 15213

REFERENCES I. Bluestone CD, Klein JO: Otitis media with effusion. atelectasis, and eustachian tube dysfunction. In Bluestone CD, Stool SE, editors: Pediatric otolaryngology. Philadelphia, 1983, WB Saunders Co, vol 1, pp 356-512 2. Bluestone CD, Douglass GS, Bernstein JM: Otitis media. In

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Middleton I(, Reed C, Ellis E, editors: Allergy, principles and practice. St. Louis, 1983, The CV Mosby Co. vol 2, pp 102338 _i. Draper WL: Secretory otitis media in children: a study of 540 children. Laryngoscope 77:636, 1967 4. Phillips MJ. Knight NJ, Manning H, et al: IgE and secretory otitis media. Lancet 2: I 176. 1974 i; Slayer JL, Plussard JH, Karr BS: Otitis media in the young infant: an IgE-mediated disease. Ann Otol Rhino1 Laryngol 89&1ppl 68): 133. 1980 6. R&man ER, Bernstein J: Allergy and secretor); otitis media. Pediatr C’hn North Am 22:2.51. 1975 -! Bernstein JIM, Lee J, Conboy K, et al: The role of IgE-mediated hypersenaitibity in recurrent otitis media with effusion. Am .l Otol 5.66. 1983 t;. Walker SB. Shapiro GG, Bierman CW. et al: Induction 01 eustachian tube dysfunction with histamine nasal provocation. J ~I.L.EK(~YCLIN IMMLINOL.76: 158, 1985 9. Sade J: Middle ear mucosa. Arch Otolaryngof 83:137, 1966 IO Cantekin EI: State of the Art: Physiology and pathophysiology of the eustachian tube. Recent advances in otitis media with effusion. 1984, BC Decker. pp 45-9 i I Bluestone CD: Assessment of eustachian tube function. In Jerger J. Northern JL, editors: Clinical impedance audiometry. New York. 1980. American Efectro-Medis Corp, pp 83-108 i2. Friedman RA, Doyle WJ, Casselbrant ML. Bluestone CD. Fireman P: Immunologic-mediated eustachian tube obstruction: d double-blmd crossover ctudy. J AL~.F.RGYCLIN IMMUNOL 71:442. 1983 I.5 Doyle WJ. f:riedman R, Fireman P, Bluestone CD: Eustachian tube obstruction after provocative antigen challenge. Arch Otolaryngol I 11X508. 1984

14. Doyle WJ, Ingraham A, Fireman P: Histamine-induced eustachian tube obstruction in monkeys. J ALLERGYCLIN IMMUNOL (in press) 15. Cook DA, Ort H, Jalowayski A, et al: Otologic response to intranasal antigen challenge. J ALLERGYCLIN IMMUNOL65:215, 1980 (abst) 16. Skoner D, Chamovitz A, Doyle WJ, Bluestone C, Fireman P: Eustachian tube obstruction (ETO) after provocative intranasal challenge with house dust mite. J ALLERGY CLIN IMhwNoL 75: 111, 1985 (abst) 17. Ackerman M, Friedman R, Doyle WJ, Bluestone C, Fireman P: Antigen-induced ETO: an intranasal provocative challenge test. J ALLERGY CLIN IMMUNOL 73:604, 1984 IX. Fireman P, Ackerman M, Friedman R. Doyle WJ, Bluestone C: Effect of drugs on provocative antigen-induced eustachian tube obstruction (ETO). J ALLERGY CLIN IMMUNOL.71:155. 1983 (abst) 19. Stillwagon P, Skoner D, Doyle WJ, Fireman P: Effect of natural pollen exposure on eustachian tube function. J ALLERGY CLIN IMMUNOL 75:154, 1985 (abst) 20. Gold S, Bernstein J, Georgitis JW: Effect of histamine and ragweed nasal provocation on eustachian tube function. J AI.LERGYCLIN IMMUNOL 75: I I 1, 1985 (abst) 21. Bluestone CD, Cantekin EI, Berry QC: Effect of inflammation in the ventilatory function of the eustachian tube. Larynposcope 871493, 1971 22. Doyle WJ, Cantekin El. Bluestone CD. Phillips CD, Kimes KK, Siegel MI: A nonhuman primate model of cleft palate and its implications for middle ear pathology. Ann Otol Rhino1 Laryngol 89(68):41. I980

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ives on the putative role of ~4~1~~~noids in airway hyperreapunsirenss At one time bronchial asthma was considered to be a disease largely restricted to airway smooth muscle resulting in reversible airflow obstruction. Although these physiologic and clinical features are undoubtedly important components of the disease, it has become increasingly apparent that an enhanced responsiveness of the airways to a wide variety of stimuli such as chemical agents, cold air. hyperventilation. or exercise is of key importance to understanding the pathogenesis of rhe disease, irrespective of the triggering rtiobgic factors. Although a small proportion of the populatic?n may exhibit enhanced airway responsiveness as defined by histamine or methacholine provocation testing, it is almost universal in clinically accive asthma in which the degree of nonspecific reactivity correlates with the severity of the symptoms and disease activity. From a clinical historical aspect,

Abbreviatims

used

HPETE: Hydroperoxyeicosatetraenoic LT: HETE:

Leukotriene Hydroxyeicosatetrdenoic

acid acid

IC,,: Concentration of a drug required to produce 50% inhibition

bronchial hyperreactivity is manifested as symptoms of chest tightness, cough, and wheezing evoked by exposure to cold air, exercise, smoke, fumes, and sprays. It is also revealed by an exaggerated diurnal rhythm of changes in airway caliber, giving rise to both nocturnal and early morning symptoms. Unfortunately, the complexity of asthma in its various forms means that there is unlikely to be a single initiating