Small airway obstruction in allergic rhinitis*

Small airway obstruction in allergic rhinitis* Jay Grossman, M.D.,** and Jerome S. Putnam, M.D. E1 Paso, Texas Applying newer techniques to assess the reactivity of small peripheral airways, we studied the effects of saline amd methavholine inhalation in patients with allergic rhiniti~. The maximum midexpiratory flow rate (MMF) and the maximum terminal flow (MTF) were used to assess the degree of small airway obstruction. Four rhinitis patients (13 per cent) had abnormal baseline MMF and/or MTF and i~ patients (38 per cent) developed a decrease in MMF and~or MTF after saline inhalation. Twenty-one patients (66 per vent) responded to methacholine ~nhalation with a greater than ~0 per cent fall in the MMF and/ormtf. This response was significantly different from that of the control ~ubjeets (p ~ 0.01). The patients' hyperresponsiveness appears to be similar to that of asthmatic patients except that the obstructivq~ is primarily limited to the small airways. Increased bronchial reactivity to methaeholine as measured by a decrease in the forced expiratory volume in one second (FEV1) can be demonstrated in most asthmatic patients. A similar response has been shown to occur much less frequently in patients with allergic rhinitis. 1-4 The FEV1 primarily reflects obstruction in the large airways, the major site of resistance in the human lung. Normally the peripheral airways, those less than 2 mm. in diameter, account for only about 10 to 20 per cent of resistance; therefore, measurement of total airways resistance, by any method used, is unlikely to detect small airways obstruction. 5 Recently, however, it has been emphasized that the early changes in chronic obstructive lung disease are reflected as obstruction of these small or peripheral airways2 Similar changes have been reported in asthmatic subjects/ but there is no information available concerning small airway function in patients with allergic rhinitis. Tests that measure flow rates at low lung volumes (less than 50 per cent of vital capacity), such as the maximum midexpiratory flow rate and maximum terminal flow, are better able to detect obstruction in these peripheral airways. 8-11 The purpose of this study is to evaluate small airway activity in patients with allergic rhinitis and to assess the effect of inhalation of saline and methacholine on the reactivity of these small airways. From the Allergy and Pulmonary Divisions, Department of Medicine, William Beaumont Army Medical Center. Presented in part at the Thirtieth Annual Meeting of the American Academy of Allergy, Miami, Fla., Jan. 22, 1974. Received for publication Feb. 15, 1974. Reprint requests to: Major J. S. Putnam, M.D., P.O. Box 70465, William Beaumont Army Medical Center, E1 Paso, Texas 79920. *The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense. **Present address: 240 New Scotland Ave., Albany, N. Y. 12208. VoL 55, -No. 1, pp. 49-55

50 Grossman and Putnam J. ALLERGY CLtN. IMMUNOL. JANUARY i975 L / f ~ ku~ J /] L-- BEFORE METHACHOLINE I I i FIG. 1. Maxium midexpiratory flow rate (MMF) depicted on an expiratory spirogram before and after methacholine challenge. FLOW LITERS 'SEC ~~.~~ oz 6-!4- m 8- BEFORE METHACHOLINE AFTER METHACHOLINE 2- O U E,- VITAL CAPACITY FIG. 2. Flow volume loops demonstrating change in maximum terminal flow (MTF)before and after methacholine challenge. Data were obtained from 32 patients with allergic rhinitis and 10 normal control subjects. The 32 patients included 23 women and nine men whose ages ranged from 17 to 56 years (mean, 33 years). Control subjects included four women and six men whose ages ranged from 20 to 49 years (mean, 29 years). Patients and control subjects were carefully screened to exclude those with prior history of any pulmonary disease, especially asthma, or history of smoking. All had normal routine pulmonary function tests (volumes and flow rates). Patients on antihistamines were asked to refrain from using them for 24 hours prior to testing. All portions of the studies were performed sequentially on the same day. We measured the total lung capacity and residual volume by the helium dilution technique. The FEV1 and MMF were recorded on a 13.5 L. Collins spirometer* with standard teelmique. The resulting data were recorded in absolute terms and expressed as a percentage of predicted normal volumes based on age, sex, and height.12 MET~ AND MATERIALS TER ~Warren Collins, Inc., Braintree, Mass.

VOLUME 55 NUMBER I Airway obstruction in allergic rhinitis 51 TABLE I. Per cent decrease in FEV~, MMF, and MTF after saline and methacholine inhalation in rhinitis patients and control subjects Patient Saline. Methacholine No. FEVI MMF I MTF FEVI I MMF I MTF Allergic rhin~tis patients 1 12 17 0 3 6 0 2 0 0 7 4 0 17 3 10 0 0 17 7 0 4 3 0 10 6 3 17 5 0 0 7 2 6 5 6 10 0 7 5 6 0 7 0 3 11 0 15 11 8 0 7 0 2 17 14 9 3 0 0 4 2 5 10 10 3 12 9 0 0 11 2 10 0 6 15 0 12 0 9 0 18 37 52 13 15 27 37 5 30 0 14 0 23 6 3 23 21 15 8 0 20 46 54 69 16 2 10 14 10 14 45 17 8 10 25 7 21 26 18 10 0 0 5 25 5 19 0 33 13 0 30 11 20 6 15 27 50 62 75 21 0 0 27 0 0 35 22 1 3 18 8 22 25 23 8 1 18 19 15 75 24 0 5 25 0 5 37 25 7 24 0 8 27 4 26 9 15 0 11 33 2 27 0 9 53 5 33 66 28 0 13 0 16 13 20 29 0 0 0 57 16 72 30 0 12 28 28 52 72 31 5 2 0 12 26 25 32 14 0 37 40 66 61 Controls 1 0 8 0 2 8 0 2 0 0 12 2 34 14 3 3 3 0 2 14 16 4 5 8 0 0 8 0 5 2 13 0 5 6 0 6 6 0 7 1 3 5 7 0 0 9 0 13 3 8 0 0 0 0 3 0 9 7 6 13 8 8 16 10 0 0 8 7 4 16 A Med Science wedge spirometer ~ was used to perform the flow-volume loop maneuver. At least two maneuvers of maximal complete inspiration followed by complete forced expiration were recorded. Instantaneous figures of flow rate and volume were taken from the spirometer and depicted on the y and x axis of a Honeywell x-y recorder.f The MTF is the instantaneous flow rate when 75 per cent of the vital capacity has been expired. The regression equation of Canter and Luehsingers was used to predict normal values for the MTF. All tests were performed in the seated position. These studies were repeated 3 minutes after five inhalations each of first normal saline and ~ed Science Electronics, St. Louis, Mo. thoneywell, Inc., Denver, Colo.

52 Grossman and Putnam TABLE Ih Comparison between methacholine inhalation J. ALLERGY CLIN, IMMUNOL. JANUARY 1975 control subjects and allergic rhinitis patients after Decrease in Decrease in i Decrease in MTF Decrease in M.MF PEV, > 20% MMF > 20% I > 10~ la~!armtf>lo~ Control subjects 0/10 (0) 1)10 (10%5 0/10 (0) 1/10 (10%) N.S. ~ p<0.1>0.05 p < 0.05 p < 0.01 Patients 5/32 (]6%) 15/32 (47%) 16/32 (50%) 21/32 (66%) ~N.S.: not significant. TABLE IIh Mean per cent decrease in pulmonary functions in the three allergic rhinitis groups and control patients after saline and methacholine inhalations FEV~ Saline I Methach01ine Saline I%l I (%) I%) Group 1 ~ (11 patients) 5 5 Group 2* (17 patients) 4 12 Group 3 ~ (4 patients) 5 34 Controls (10 patients) 2 3 M_MF i. MTF Meihacholine Saline M~cha ine ( ~ I, (%1 I l%1, 4 7 5 7 ]2 26 17 29 4 40 16 58 4 ]0 4 7 *Group 1 represents Patients 1 to ll in Table I; Group 2 represents Patients 12 to 28; Group 3 represents Patients 29 to 32. then methacholinc, 10 mg. per milliliter. The saline and methacholine were administered ~4tb a DeVilbiss nebulizer ~ using compressed air at u flow rate of 6 L. per minute. Onty a 20 per cent or greater change in any of the parameters studied was considered a significant response.18 RESULTS Fig. I shows the expiratory spirogram of an asymptomatic hay fever patient before and after methacholine inhalation. On the right is his nmvaal spirogram and on the left is the spirogram after methacholine. There is a decrease of only 11 per cent seen in the FEV1 but 44 per cent in the MMF. Fig. 2 pictures his flow volume loop before and after methacholine. The loop on the left shows a 37 per cent decrease in MTF after methacholine. Four study patients had a decrease in the MMF and 9 had a change in the MTF after saline inhalation. None of the control subjects demonstrated any reactivity to saline. Five rhinitis patients (16 per cent) demonstrated a 20 per cent decrease in FEV1 after methacholine. More significantly, however, 47 per cent had a decrease in MMF and 50 per cent a change in the MTF. On]y one control subject demonstrated a response to methaeholine, and she had a 34 per cent decrease in her MMF. She had a strong family history of allergic rhinitis but was asymptomatic herself. Sixty-six per cent of the rhinitis patients responded with a decrease in the MMF and/or MTF, and this is significantly different from the response of the controls (p ~ 0.01) (Tables I and II). To avoid the possible effect of changes in residual volume on the MTF. flows were ~The DeVilbiss Co., Somerset, Pa.

VOLUME 55 NUMBER 1 Airway obstruction in allergic rhinitis 53 30" FEV~ MMF MTF 27~ 25- u.i 2O. 21% I,LI ILl a 13~ lo. st. [7 4% AFTER AFTER AFTER AFTER AFTER AFTER SALINE METHA- SALINE METHA- SALINE METHA- CHOLINE CHOLINE CHOLINE I ~ALLERGIC I CONTROLS RHINITIS PATIENTS FIG. 3. Mean per cent decrease in pulmonary functions after saline and methacholine inhalation in control subjects and allergic rhinitis patients. also calculated as a function of the vital capacity (V2~%vc/VC) and comparable data were obtained. Fig. 3 compares mean per cent decrease in pulmonary functions between control subjects and patients after saline and methacholine challenge. The controls demonstrated a 3 per cent decrease in FEV1 after methacholine whereas the patients had a 13 per cent change. Greater differences were noted in the MMF and MTF after methacholine inhalation. A 21 per cent decrease in MM_F and 27 per cent decrease in MTF was seen in the patients whereas control subjects had only 10 per cent and 7 per cent decreases, respectively. As seen in Table III, the rhinitis patients can be divided into three groups. Group 1 (11 patients) had completely normal studies throughout. Group 2 (17 patients) had normal baseline studies but developed greater than a 20 per cent decrease in MMF and/or MTF with mcthacholine. Group 3 (four patients) had baseline abnormalities in MMF and/or MTF that markedly worsened with methacholine. Inhalation of normal saline did not induce nasal or chest symptoms in any subject, although several recorded nonspecific complaints. Following inhalation of methacholine one control subject and 13 rhinitis patients developed nasal symptoms. Nine patients experienced tightness in the chest and shortness of breath. Two patients noted wheezing but this was not confirmed on physical examination. All of the Group 3 subjects developed nasal and/or chest symptoms after methacholine whereas similar symptoms were noted in only 36 per cent of the remaining patients. None of the control subjects complained of any chest symptoms. Most patients (28/32) were having some hay fever symptoms at the time of testing. The 4 asymptomatic patients all responded with greater than a 20 per cent decrease in MMF and/or MTF after methacholine inhalation. In a preliminary study we retested four patients with seasonal hay fever

.54 Grossman and Putnam J. ALLERGY CLIN. IMMUNOL JANUARY 197~ when not in season. Three patients demonstrated a similar response to theb earlier testing (greater than a 20 per cent decrease in MMF and/or MTF). Th~ fourth patient initially had a 30 per cent decrease in MMF but had noi~la studies when asymptomatie. DISCUSSION Several techniques have been suggested to measure the resistance to airflo~ contributed by the small airways. Frequency dependency of dynamic complianc~ is probably a sensitive test of small airway function, 14 but is difficult to perform is time-consuming, and requires considerable patient cooperation and discomfort The closing volume is that lung volume at which airways begin to close in de pendent lung zones. 1~ Premature airway closure may be caused by a numbel of factors, including loss in lung elastic recoil and intrinsic disease of the airways This test is rather easy to perform but debate still exists as to what the closin~ volume actually measures. Since flow indices measured at large lung volume~, may be normal in spite of pathology of the small airways, the MMF 9 and maximum expiratory flow volume curve analyzed at low lung volumes (MTF) hav~ been suggested as more sensitive guides to the physical properties of the towei airways. 8-1~ The maximum expiratory flow volume curve is easily obtained, i~ reproducible, and has the advantage of displaying flow rates at different lun~ volumes over the course of an exhaled vital capacity. Any study evaluating small airway function must necessarily exclude smokers because asymptomatic smoker~ may demonstrate abnormalities of their peripheral airways. ~ By using methods capable of detecting obstruction at low lung volumes we were able to show that 13 per cent of patients with allergic rhinitis have baseline abnormalities that worsen by approximately 50 per cent after methachotine inhalation. In addition, 38 per cent of the patients developed obstruction with saline and 66 per cent with methacholine. In only five patients (16 per cent) could any obstruction be detected in their routine pulmonary functions (FEV~). The hyperresponsiveness to saline and methacholine is similar to that found in asthmatic patients except that the abnormalities are primarily found after 50 per cent of the vital capacity has been expired. If we assume that elastic recoil, although not measured, was normal in these relatively young healthy nonsmokers~ it seems reasonable to conclude that the changes found reflect obstruction of small airways. Several of our patients demonstrated a change in the MMF or MTF but not necessarily in both. The reason for this apparent discrepancy may be that the MMF is influenced by effort while the MTF is not. Also, the MTF is virtually unaffected by upper airway resistance and probably measures airways of smaller caliber, s-~o McFadden and Linden 9 have shown that early detection of small airways disease in smokers with abnormal MMF's but normal routine pulmonary function studies may reveal physiologic abnormalities that are reversible. Since a significant number of patients with allergic rhinitis will go on to develop asthma, it is possible that we are measuring abnormalities in the small airways that are subclinical but that may become more prominent over the years. Also, patients

VOLUME 5S Airway obstruction in allergic rhinitis 55 NUMBER 1 with more severe obstruction of the small airways may have a greater risk of developing significant pulmonary disease and should be followed more carefully. Further work is in progress to see if the patient's small airway obstruction and increased reactivity fluctuate with nasal symptoms and whether the abnormalities progress or are reversible with an adequate antiallergic regimen. We wish to thank Mrs. Marilyn Bownds and Mr. Guy Smith for their technical assistance, Captain Robert Pick for statistical analysis, and personnel of the Medical Research and Development Service for support of this project. REFERENCES 1 Townley, R. G., Dennis, M., and Itkin, I. H.: Comparative action of acetyl-beta-methylcholine, histamine, and pollen antigens in subjects with hay fever and patients with bronchial asthma, J. ALLERGY 36: 121, 1965. 2 Parker, C. D., Bilbo~ R. E., and Reed, C. E. : Methacholine aerosol as test for bronchial asthma, Arch. Intern. Med. 115: 452, 1965. 3 Townley, R. G., Rye, U. u and Kang, B. : Bronchial sensitivity to methacholine in asthmatic subjects free of symptoms for one to twenty-one years, J. ALLERGY CLIN. IMMUNOL. 47: 91, 1971. (Abst.) 4 Mathison, D. A., Stevensen, D. D., Tan, E. M., and Vaughan, 3-. H.: Meth.aeholine challenge and the diagnosis of bronchial asthma, J. ALLF~GY CLIN. IMMUNOL. 51: 94, 1973. (Abst.) 5 Macklem, P. T., and Mead, J.: Resistance of central and peripheral airways measured by a retrograde catheter, J. Appl. Physiol. 22: 167, 1971. 6 Hogg, :r. C., Macklem, P. T., and Thurlbeck, W. M. : Site and nature of airway obstruction in chronic obstructive lung disease, N. Engl. J. Med. 278: 1355, 1968. 7 Olive, 5. T., and Hyatt, R. E.: Maximal expiratory flow and total respiratory resistance during induced bronchospasm in asthmatic subjects, Am. Rev. Respir. Dis. 106: 366, 1972. 8 Canter, H. G., and Luchsinger, P. C.: Maximal terminal air flow, Med. Ann. Dist. Columbia 36: 584, 1967. 9 McFadden, E. R., Jr., and Linden, D. A.: A reduction in maximum midexpiratory flow rate. A spirographic manifestation of small airways disease, Am. J. Med. 52: 725, 1972. 10 Bass, H.: The flow volume loop: Normal standards and abnormalities in chronic obstructive pulmonary disease, Chest 63: 171, 1973. 11 Hyatt,.R.E., Schilder, D. P., and Fry, D. C. : Relationship between maximum expiratory flow and degree of lung inflation, J. Appl. Physiol. 13: 331, 1958. 12 Kory, R. C., Callahan, R., Boren, H. G., and Syner, J. C. : The Veterans Administration- Army cooperative study of pulmonary function. I. Clinical spirometry in normal men, Am. J. Med. 30: 243, 1961. 13 Spector, S. L., and Farr, R. S.: Bronchial inhalation procedures in asthmatics, Med. Clin. North Am. 58: 71, 1974. 14 Woolcock, A. J., Vincent, N. J., and Macklem~ P. T. : Frequency dependence of compliance as a test for obstruction in the small airways, J. Clin. Invest. 48: 1097, 1969. 15 Leblanc, P., Ruff, F., and Milic-Emili, J. : Effects of age and body position on "airway closure" in man, J. Appl. Physiol. 28: 448, 1970. 16 Lira, T. P. K.: Airway obstruction among high school students, Am. Rev. Respir. Dis. 108: 985, 1973.