Nonspecific Airway Hyperresponsiveness in HIV Disease

Nonspecific Airway Hyperresponsiveness in HIV Disease* Jeanne Marie Wallace, MD, FCCP; Gregory S. Stone, MD; Ben L. Browdy, Ph.D; Donald P. Tashkin, MD, FCCP; Philip C. Hopewell, MD; Jeffrey Glassroth, MD, FCCP/ Mark]. Rosen, MD, FCCP; Lee B. Reichman, MD, FCCP; Paul A Kvale, MD, FCCP; and the Pulmonary Complications of HIV Infection Study Group 1

Objectives: ON disease is frequently complicated by episodic acute bronchitis, suggesting the presence of chronic bronchial inflammation. To further examine this concept, we investigated the possible association of nonspecific airway hyperresponsiveness (AHR) and ON disease. Design: Methacholine inhalation challenge studies were performed on 66 ON-seropositive and 8 ON-seronegative members of the Pulmonary Complications of ON Infection Study Cohort. AHR was defined as 20% or more decline in FEV1 from the postdiluent value after inhalation of 125 or less cumulative breath units. The prevalence of AHR in ON-seropositive cohort members was compared with that in matched control subjects who had undergone methacholine challenge testing for two unrelated studies. Demographic, behavioral, and clinical features in ON cohort members with and without AHR were contrasted. The relationship between AHR and the occurrence of episodic airway disease or symptoms suggestive of airway disease was examined. Results: AHR was not more prevalent in ON-seropositive cohort members than control subjects (19.3% vs 12.9%; p>0.1). Within the cohort, AHR was detected more frequently in members with than without a history of asthma (60% vs 16%; p<0.05). A greater proportion with than without AHR had 1 or more episode of pneumonia within 2 years (46% vs 9%; p<0.01), 1 or more asthma episode during the study period (39% vs 1.9%; p<0.001), or wheeze noted during clinic visits (62% vs 17%; p<0.01). The proportion that experienced acute bronchitis did not differ in the two groups. Conclusions: This study suggests that ON-infected persons do not have increased prevalence of nonspecific AHR. In ON disease, AHR is associated asthma, but not episodic acute bronchitis. Thus, the possibility that airway injury without demonstrable AHR Inight complicate ON disease remains. (CHEST 1997; 111:121-27) Key words: AIDS; ai1ways hyperresponsiveness; HIV disease Abbreviations: AHR =airway hyperresponsiveness; CBU =cumulative breath unit; H/B= homosexual or bisexual men; IDU=injecting drug user; PCHIS=Pulmonmy Complications of HIV Infection Study; PD 20 FEV 1 =provocative dose of methacholine associated with decline in FEV 1 by 20% or more of the postdiluent value

*From th e Department of Medicine, Olive View-UCLA Medical Cente r, Sylmar, Calif (Dr. Wallace), and Henry Ford Hospital, Detroit (Drs. Stone and Kvale); the University of California, Los Angeles (Drs. Wallace, Browdy, and Tashkin ); the University of Caflfornia, San Francisco (Dr. Hopewell ); Northwestern University, Chicago (Dr. Glassroth); Beth Israel Medical Center, New York (Dr. Rosen ); and the Unive rsity of Medicine and Dentistry, Newark, NJ (Dr. Reichman). 1 Currently at th e Medical Colllege of Pennsylvania and Hahnemann University, Philadelphia. 1A list of participants and institutions is listed in the Appendix. This research was pursuant to contracts N01-HR7-6029, 6030, 6031 , 6032, 6033, 6034, and 6035 with the National Heart, Lung and Blood Institute and was jointly sponsored by the Nationa1 Institute of Allergy and Infectious Disease, National Institutes of Health. Manusc1ipt received May 6, 1996; revision accepted July 25. Reprint requests: Dr. Wallace, Department of Medicine, Room 2B-182, Olive View-UCLA Medical Center, 1444.5 Olive Vi ew Drive, Sylmar, CA 91342

bronchitis is a common HIV-associated respiAcute ratory illness that occurs at all stages of HIV infection_! The pathogenic mechanism responsible is unlawwn, but the high incidence has raised the question of whether chronic bronchial inflammation might be more commonly associated with HIV infection than has been recognized. Injury to the tracheobronchial tree could result from primary HIV infection of the airway mucosa, from immunologically mediated inflammation associated with HIV infection, or from secondary infection of the tracheobronchial tree in the setting of HIV-related immunocompromise. Current literature addressing the possible association of HIV infection and airway disease has been sparse. Pulmonary function tests performed on HIVCHEST /111 / 1 I JANUARY, 1997

121

infected persons have shown little abnormality except various degrees of diffusion of carbon monoxide impairment in individuals with advanced disease.2 -4 In a study published relatively early in the AIDS epidemic, airway hyperreactivity was reported in 3% of 130 patients with AIDS. 5 Subsequently, the association of advanced HIV disease and reactive airway disease was suggested by studies in which a high proportion of patients with AIDS had low forced expiratory flow rates or significant improvement in response to bronchodilators6 or airway hyperresponsiveness (AHR) to inhaled methacholine.7 This association has been disputed by a study by Moscato et al 8 which demonstrated no significant difference in AHR as assessed by methacholine challenge in a group of 25 HIV-seropositive injecting drug users (IDUs) compared with HIV-seronegative control subjects. To estimate the frequency of nonspecific AHR in HIV-infected individuals, we performed methacholine inhalation challenge testing on a group of HIVinfected subjects with varying degrees of immunocompromise. The prevalence of AHR in the HIVseropositive subjects was compared with that in a group of previously tested matched control subjects from two unrelated studies, as well as with a small group of HIV-seronegative subjects having similar HIV risk factors. In the HIV-seropositive cohort members, the relationship between AHR and the occurrence of episodic airway disease or symptoms suggestive of airway disease was examined. MATERIALS AND METHODS Participants for this study were enrolled in th e multicenter Pulmonaq Complications of HIV Infection Study (PCHIS), the design, protocol, and quality control methods of which have been desctibed in a previous publication H The study cohort ;vas composed of 1,353 homosexual or bisexual men (H/B), IDUs, and female partners of HIV-infected m en,of whom 1,171 (87%) were HIV seropositive and 182 (13%) were HIV seronegative. The enrollmen t p eriod extended from Nove mber 1988 through Februaty 1990, and cohort members were foll owed up through March 31, 1994. During the study, cohort me mbers were evaluated routinely eveq 3 or 6 months with a questionnaire, physical examination, and blood tests, including a CD4 count. Routine pulmonaq function tests were done eveq 3 to 12 months. Cohort members from the study centers located at Olive View-UCLA Medical Center, Los Angeles, and Henq Ford Hospital, Detroit, were rec111ited to undergo methacholine inhalation challenge testing during routine study clinic visits. Testing was postponed if th e following occurred in the preceding 3 weeks: (l ) a histoq of acute respiratoq infection; (2) worsening symptoms of shortness of breath , cough, or dyspn ea; or (3) influenza vaccination. Methacholine c hallenge testing was performed on 10 subjects from the UCLA Center and 64 from the Henq Ford Center. Of th ese 74 subjects, 66 were HIV seropositive and 8 were seronegative. Prior to testing, participants were asked to refrain from 122

using antihistamines for 24 h, bronchodilators for 12 h, caffeine containing beverages for 6 h , and tobacco for 2 h. Each participant provided written informed consent. Immediately prior to aerosol inhalation, baseline forced expiratory spirometry was performed with the subject seated using equipment that met all performance requirements for spirometq recom me nded by the American Thoracic Society. 10 At least three. satisfact01y and two reproducible spirometric maneuvers were perform ed according to American Thoracic Society recommendations. The largest FEV 1 from an acceptable maneuver was used as the baseline value. After acceptable baseline spirometq, as many as Hve forced expirat01y maneuvers were performed after each aerosol administration in order to obtain at least two acceptable and reproducible FEV 1 values. If decline in FEV 1 required termination of th e test, participants were treated with albuterol by metered-dose inhaler and monitored in the laboratoq until repeated spirometry return ed to baseline values. At the UCLA Center, inhalation challenge testing was perform ed according to a modiflcation of the protocol of Chai and bucoworkersn Aerosolized solution was administe red b y a ne lizer (Asthmakit; DHD Medical Products; Canastota, NY) powered b ycompressed air at 50 psi, with a flow rate of 8 Umin and a deliveq time of 1.5 s during a slow inhalation from functional residual capacity to total lung capacity, followed by a5-s breathhold. Under these conditions, the nebulizer delivered 9.6 (mean) :±: 1.15 (S D) f.I.L pe r actuation. After baseline spirometry testing, five s low, deep inhalations of saline solution were given, followed by spirometq. If FEV1 did not drop 10% or more, 5 inhalations of serially incremented doses of methacholine (0.025, 0.25, 2.5, 10.0, and 25 mglmL) were given . For each dose, if there was not a decline of 20% or more from th e postdiluent FEV1 value, 5 breaths of the next dilution we re given. At the Henq Ford Cente r, inhalation challenge testing was pe rformed acco rding to the protocol of Chatham and coworkers.12 Test res ults from this abbreviated technique have correlated closely with those obtained from th e Chai et al 11 protocol and have correctly identified el vels of airways reactivity in asthmatic patients and normal subjects. After baseline spirometq , the saline solution diluent was admin istered u sing a nebulizer (Hudson T-Updraft li; ebu-Mist; Temecula, Calif) using compressed air at 50 psi and a fl ow rate of 6 Umin during slow inhalation followed by a 5-s breath-hold. If the FEV 1 did not drop 10% or more, the subject was challenged with 1 breath of aerosolized 25-mglmL methacholine solution in the same manner and spirometq was repeated. If the FEV 1 did not decline 20% or more from the postdiluent value, the patient was challenged with 4 additional breaths of aerosolized methacholine. To standardize responsiveness to meth acholine measured by th e two protocols, cumulative breath unit (CBU) doses were calculated for each patient. These were defined as th e number of inhalations of methacholine administered multiplied b y the concentration of methacholine in milligrams pe r milliliter plus the CBU administered previously. This calculation yielded values of 0, 0.125, 1.375, 13.875, and 188.875 CBU doses in the protocol used at the UCLA Center, and 0, 25, and 125 CBU doses in the protocol used at Henq Ford Center. The methacholine-FEY 1 dose-response curves were plotted on log-linear coordinates and, for each participant, the provocative dose of methacholine associated with decline in FEV1 by 20% or more of the postdiluent value (PD 20FEV 1 ) was determined by linear inte11)olation. Participants were considered to have AHR if the FEV 1 declined 20% or more after exposure to 125 CBU or less. HIV-seropositive cohort members with AHR were compared to those without AHR in regard to age, gender, race, transmission categoq, CD4 count at the time of the methacholine challenge, smoking status, aerosolized pentamidine use, and atopic histoq. Smoking status was categmized as follows : ( 1)c.·urrent smoker, if Clinical Investigations

the subject was currently smoking or quit 1 year or less before testing; (2) fanner smoker, if the subject quit smoking 1 year or more before testing; and (3) nonsmoker, if the subject never smoked. The proportion with AHR among the 66 HIV-seropositive and 8 HIV-seronegative cohort members tested was also compared. The 66 HIV-seropositive cohort members were individually matched with control subjects who underwent methacholine testing as part of their participation in two unrelated cohort studies of the pulmonary effects of marijuana and/or cocaine with or without concomitant tobacco use. 13-15 These nonmarijuana-, noncocaine-using control subjects were recruited from the Los Angeles metropolitan area using newspaper and radio advertisements, and from UCLA Medical Center employees. They were not tested for the presence of H IV antibodies or questioned specifically about HIV risk factors other than illicit drug use. A pool of 153 control subjects was available for matching. Matching was based on age, gender, race, smoking status, history of prior asthma, and baseline FEV1 . Acceptable matching by all six factors was achieved for 62 HIV-seropositive subject/control subject pairs. Four pairs were excluded because matching according to gender and smoking status was not considered adequate. Methacholine challenge testing in the control group had been performed at some time in the preceding 3 years by the modified Chai procedure. 13 Aerosolized methacholine was administered by a breath-activated dosimeter connected to a nebulizer (DeVilbiss No. 646 Nebulizer; DeVilbiss Corp; Somerset, Pa) powered by compressed air at 20 psi and timed to deliver the aerosol over 0.6 s during a slow inhalation from functional residual capacity to total lung capacity followed by a 5-s breath-hold. Under these conditions, the nebulizer delivered 9.4 (mean) ::'::0.57 (S D ) J.LL per actuation. The inhalation challenge schedule was the same as that used in the UCLA Center described above. The proportion of the 62 matched HIV-seropositive cohort members vs matched control subjects found to have AHR was compared. To quantitate the degree of methacholine responsiveness among HIV-seropositive and control subjects with AHR, the mean PD 20 FEV 1 for both groups was calculated. To relate AHR with symptomatic and functional characteristics of airway disease noted during PCHIS participation, the following comparisons were made between HIV seropositive cohort members with and without AHR: (1) the proportion having 1 or more episode of asthma or acute bronchitis defined as a lower respirat01y tract illness with productive cough and no radiographic evidence of pneumonia; 1 (2) the proportion reporting dyspnea, cough, or wheeze during any visit; and (3) the rate of decline in FEV1 between the first and last spirometric testing. The data were also reviewed to determine if pulmonary opportunistic infection had occurred in any of the HIV-seropositive cohort members prior to or after methacholine testing. Comparisons of demographic features, HIV risk or disease stage factors, and clinical or functional characteristics of airways disease within the PCHIS cohort were made using x2 tests. Fisher's Exact Test was used preferentially for small expected cell values. Comparisons between HIV-seropositive PCHIS cohort members and matched control subjects were made using McNemar's test. 16

RESULTS

Table 1 shows the prevalence of AHR when the 66 HIV-seropositive cohort members tested were grouped according to demographic, behavioral, and clinical characteristics. Thirteen (19. 7%) of the HIVseropositive and 1 (12.5%) of the HIV-seronegative

Table !-Behavioral, Clinical, and Demographic Characteristics of HIV-Seropositive Cohort Members and Prevalence of AHR*

Total Transmission category Homosexual men IDUs Female sexual partners Race White Nonwhite Gender Male Female Age, yr 23-39 40-67 Smoking status Current Former Non Plior asthma Yes No CD4 count, mm 3 :S200 >200 Aerosol Pentamidine' Yes No

No.

No. (%)With AHR*

66

13 (19 7)

55 9 2

8 (15) 4 (44) 1 1 (50)

44 22

6 (14) 7 (32)

62 4

12 (19) 1 (25)

34 32

7 (21) 6 (19)

34 10 22

7 (21) 4 (40) 2 (9)

5 61

3(6W 10 (16)

18 48

4 (22) 9 (19)

12 54

4 (33) 9 (17)

*Defined as 20% decline in FEV1 in response to :S125 CBU of inhaled methacholine. 1 Within 1 yr prior to methacholine inhalation challenge testing. 1 p=0.0.55 compared to homosexual men. lp= 0.048 compared to cohort members without a history of prior asthma.

group had a decline of FEV 1 of 20% or more in response to 125 CBU or less of methacholine (p>0.5). Within the HIV-seropositive group, a greater proportion of cohort members with than without prior asthma had AHR (60% vs 16%; p<0.05) . There was a tendency for higher preva-

Table 2-Matching Characteristics of HIV-Seropositive Cohort Members vs Control Subjects HIV-Positive Cohort Members (n=62) Mean age, yr (range) Gender, M/F Race, white/nonwhite Smoking status, current/fanner or nonsmoker P1ior asthma Pretest FEV 1 , mean % of predicted

39.9 (23-67) 59/3 42/20 32/30 3 102

Control Subjects (n=62) 37.7 (24-55) 59/3 41/21 32/30 3 104

CHEST I 111 I 1 I JANUARY, 1997

123

lence of AHR among IDUs compared with H/B (p=0.055). Prior asthma was noted in 4 (7%) of the H/B and 1 (11 %) of the IDU participants. Table 2 shows the profile of the HIV-seropositive cohort members and control subjects with regard to the 6 hcaracteristics by which they w ere paired. Among the 62 pairs, the proportion of HIV-seropositive cohort members with AHR was 12 of 62 (19.3%) compared with 8 of 62 (12.9%) of the control subjects (p > 0.10). As seen in Table 3, there was no significant difference in the proportion responding to methacholine doses of either 25 CBU or less or 125 CBU or less between the 2 groups (p > 0.1 for both ). The mean calculated PD 20 FEV 1 value for the HIV-seropositive cohort members was 69.1 CBU compared with 60.0 CBU for the control subjects (p > 0.50). Table 4 shows the proportion of HIV-seropositive cohort members with or without AHR who had diagnoses or symptoms of airway disease during the study period. Each individual was seen at least every 6 months for a median of 54 months (range, 30 to 63 months ). A significantly g re ater proportion of those with AHR had at least 1 asthma episode compared to those without AHR (39% vs 1.9%; p < 0.001 ). The proportion having at least one episode of acute bronchitis did not differ between the two groups. The frequency of wheeze was greater in HIV-seropositive cohort members with than without AHR (62% vs 17% of visits; p < 0.01 ). Those with AHR also reported d yspnea more frequently (85% vs 59% of visits; p=0.048). The mean rate of decline in FEV 1 during the period between study entry and last pulmonary function testing was 6. 7 mL per month for those with AHR and 6.1 mL per month for those without AHR (p=0.8). Within 2 years of methachoHIV-seropositive ( line challenge testing, 6 46%) cohort members with AHR had at l aest 1 episode of pneumonia (2 bacterial pneumonia, 3 Pneumocystis carinii pneumonia, 1 bacterial and P carinii pneumonia) compared to 5 (9%) of those without AHR (3 bacterial pneumonia, 2 P carinii pneumonia) (p < 0.01). In only 1 p taient, who did not exhibit

Table 3-Cumulative Percentage of Matched HIVSeropositive Cohort Members and Nonmarijuana-, Noncocaine-Using Control Subjects with a ~20% Decline in FEV1 in Response to :S25 CBU and S125 CBU of Methacholine Methacholine Dose (CBU) Individuals Compared (n = 62)

:s25

:S 125

HIV-seropositive cohort members, No. (%) Control subjects, No. (%)

2(3.2)

12 (1 9.3)

1 (1.6)

8 (12.9)

124

Table 4 - Proportion of HIV-Seropositive Cohort Members With or Without AHR* Having Diagnoses or Symptoms of Airways Disease With AHR,* No . (%) (n= l 3) Episode of airways disease Asthma Acute bronchiti s Symptoms of aitways d isease Dyspneaf Coughf Wheezef

Without AHR,* No. (%) (n =53)

p Value

~1

5113 (39) 4/13 (31)

l/53 (1.9) 17/53 (32)

< 0.01 NS

ll/13 (85) ll/13 (85) 8/13 (62)

29/53 (59) 42153 (80) 9/53 (17)

0.048 NS < 0.05

*Defin ed as 20% decline in F EV1 in response to 125 CBU of inhaled methacholine. 1 Reported duri ng any visit.

AHR, did the episode (P carinii pneumonia) occur prior to testing ( 4 months previously) .

DISCU SSION

Several observations have suggested that the tracheobronchial tree may be affected either directly or indirectly by HIV infection, including a high frequency of symptoms associated with airway disease 17 and a high incidence of acute bronchitis noted in persons with all stages of HIV disease.1 Although serial pulmonary function testing has provided no indication that airflow obstruction is associated with progressive HIV disease, 2 -4 these studies have not addressed the possibility of airway injury associated with only minimal or intermittent airflow obstruction. Nonspecific AHR as assessed b y methacholine inhalation challenge testing has been used as a more sensitive marker of airway injury that may indicate susceptibility to the development of chronic airflow obstruction. 18-20 When considering the potential relationship of AHR to HIV disease, several questions are raised: ( 1) is nonspecific AHR associated vvith HIV disease; (2) is early airway injury manifested b y AHR in HIV disease; and (3) what is the clinical significance of AHR in persons with HIV disease? This study was designed to explore the possibility that nonspecific AHR is more prevalent in individuals with HIV disease compared to members of the general population. In our convenience sample of 66 persons with HIV disease of varying s everity, 19.7% met the study criteria for AHR. Our HIV-seropositive cohort members did not exhibit greater prevalence of AHR compared to individually matched control subjects from the general population. Furthermore, the mean PD 20 FEV 1 of those with AHR Clinical Investigations

did not differ between the two groups. The prevalence of AHR in a small number of HIV-seronegative members of our cohort who agreed to undergo methacholine challenge testing (12.5%) did not differ significantly from that in HIV-seropositive members , supporting the concept that AHR is not associated with HIV disease. The goal of this study was to obtain preliminary data to compare the prevalence of AHR in HIVinfected p ersons with that of the general population, and as such, the results are suggestive, but not definitive. Because the methacholine challenge testing was perform ed at three sites, one of which employed a modified protocol, close attention was given to the potential for bias due to lack of uniformity in th e testing procedure. At two of the sites, UCLA and Olive View-UCLA, the Chai et al protocol was followed, u and despite minor differences in the equipment used, the methacholine doses administered were nearly identical. An abbreviated version of the Chai et al protocol was used at the Henry Ford site. A previous study which has compared this procedure to the standard Chai et al protocol found that the results correlated (r =0.94 by rank order analysis ) and accurately characterized airways hyperreactivity without overlap between asthmatic patients and control subjects. 12 We standardized methacholine responsiveness measured b y the two protocols by converting the methacholine doses to CBU. Although we believe that actual methacholine dose delivered b y the two protocols was similar, a slightly higher actual dose of methacholine might have been d elivered b y the abbreviated procedure because inhalation time was not limited. Since the abbreviated m ethod was used only for testing members of the PCHIS cohort, bias due to this phenomenon could have augmented airway responsiveness in the HIV-seropositive group . Our results are not consistent with bias in this direction. Because of the small difference in AHR prevalence between our HIV-seropositive and control subjects, a substantially larger sample than ours would be required to provide sufficient power for a definitive conclusion that AHR is not associated with HIV disease. Although fmther studies comparing larger numbers of HIV-seropositive and seronegative individuals may be desirable to confirm our results, the clinical r elevance of distinguishing a evry small effect from no effect should be considered b efore testing the large number of subjects required to achieve a high level of certainty. Comparison of our data with other studies is complicated b y different techniques for assessing and defining AHR, as well as by differences in HIV disease stage among members of other subject groups. Our results would support a previously re-

ported study in which AHR, assessed b y methacholine responsiveness, was not exhibited more frequently in 25 institutionalized HIV-seropositive IDUs compared with seronegative control subjects. 8 Other studies suggesting that AHR is common among persons with AIDS used expiratory flow rates or bronchodilator responsiveness 6 or methacholine responsiveness7 to define AHR. Each of these series included a large proportion of patients with advanced HIV disease, many of whom had a history of previous pulmonary opportunistic infection, primarily due to P carinii. One group of investigators concluded that AHR in their patients with AIDS might be related to pulmonary opportunistic infection. 7 Another study has suggested that small airways dysfunction is prevalent in persons with AIDS and P carinii and does resolve after treatment. 21 Further work by th e same investigators has suggested that treatment with inhaled budesonide is effective in reversing symptoms and laboratory evidence of AHR in individuals with previous opportunistic infection complicating AIDS. 22 Our group of HIV-seropositive subjects, although varying widely in HIV stage, included only 18 (27%) individuals with CD4 counts less than 200 cells per cubic millimeter, and only 1 had P carinii pneumonia prior to methacholine inhalation challenge testing. It is possible that AHR might have been exhibited in a greater proportion of our HIV-seropositive cohort members if we had included alarger number with advanced HIV disease or with prior opportunistic infection. Lack of greater prevalence of AHR in our HIVseropositive cohort members may not exclude the possibility of ongoing ai1way injury. Many of the cells residing in the lower respiratory tract are susceptible to infection by HIV, including pulmonary lymphocytes, alveolar macrophages, and pulmonary fibroblasts.23-26 Although infection of bronchial mucosal cells has not been d emonstrated, colonic mucosal cells, which share some common characteristics, have been infected by HIV in vitro. 27 Inflammation of the lower respiratory tract could result from HIV infection 28 or from secondary infections such as bacterial or P carinii pneumonia. AHR has been a marker of airway inflammation in some animal models29·30 and according to data obtained from a human physiology-pathology correlation study. 31 However, early airway injury may be present in the absence of AHR. Individuals with well-documented occupational asthma without AHR have been described.3 2 ,33 Histopathologic evidence of tracheobronchial injury has been noted in heavy marijuana or cocaine smokers despite the lack of significant association of AHR with habitual smoking of either substance .l 3,3 4 The results of this study do suggest that, as in the general population, identification of AHR by methaCHEST I 111 I 1 I JANUARY, 1997

125

choline challenge testing is a potentially useful marker for asthma in persons with HIV disease. Of the five HIV-seropositive cohort members having a diagnosis of prior asthma, three exhibited AHR. During the period of study follow-up , a significantly greater proportion with AHR compared to those without AHR experienced at least 1 episode of asthma (39% vs 1.9%), had wheeze (62% vs 17%), or reported dyspnea (85% vs 59%). In addition, since a significantly greater proportion of our HIV -seropositive cohort members with than those vvithout AHR had at least 1 episode of pneumonia within 2 years of methacholine challenge testing (46% vs 9%), our data raise the possibility that AHR may indicate a higher risk for pulmonary infection. Our findings also suggest that AHR is not a risk factor for HIV-related episodic acute bronchitis. Finally, although administration of aerosolized pentamidine may be complicated by acute bronchospasm, use of this form of P carinii pneumonia prophylaxis within 1 year was not associated with AHR. In conclusion, this study did not indicate a higher prevalence of nonspecific AHR in our HIV-seropositive cohort members compared to control subjects selected from the general population by convenience and a small group of HIV-seronegative cohort members. It is possible that AHR is more common among persons with more advanced HIV disease and prior pulmonary infection, so that further studies ·v-rith larger samples of HIV-infected individuals belonging to that subgroup would be warranted. Our findings do suggest that nonspecific AHR is associated vvith wheeze and dyspnea in persons with HIV disease, and is predictive of asthma. Yet, although our cohort members frequently experienced acute bronchitis, that diagnosis was not associated with AHR. Thus, the question remains whether airway injury without demonstrable AHR might be a clinically significant entity in individuals vvith HIV disease. ACKNOWLEDGMENT: The authors wish to acknowledge Dr. Kenneth Poole, PhD, and associates at Research Triangle Institute, Research Triangle Park, NC, for their contribution in the PCHIS cohort database management.

APPENDIX Clinical Centers University of California, San Francisco: Philip C. Hopewell, John Stansell, Joan Turner, Cynthia Merrifield, Dennis Osmond. Northwestern University: Jeffrey Glassroth, Melinda Mossar, Robert Hirschtick. Beth Israe l Medical Center: Mark J. Rosen, Kim K. Manghisi, Lori Meiselman, Roslyn F. Schneider. University of Medicine and D entistry of New Jersey, New Jersey Medical School , University Hospital: Lee B. Reichman, Bonita T. Mangura, Sandra Barnes. University of California, Los Angeles: Jeanne lvl . Wallace, Barbara Le Maire, Barbara Richer, Virgilio 126

Clemente, Janet Au, Anne Coulson, Ben Browdy, James Sayre. H enry Ford Hospital: Paul A. Kvale, Norman Markowitz, Louis D. Saravolatz, Christine Johnson, Joanne Huitsing, Annmarie Krystoforski. Data Coordinating Center Research Triangle Institute: W. Kenneth Poole, A. Vijaya Rao, Kim Clayton, Nellie Hansen, Matt Jordan, Jim Thompson, David Myers, Lisa LaVange, Judith Katzin, William Fulkerson, Yu Lou , Tim Wilcosky. Division of Lung Disease of the National Heart, Lung and Blood Institute, and National Institute of Allergy and Infectious Disease Anthony R. Kalica, Janet Wittes, Dean Follman, (Robert vVise, consultant to NHLBI from Johns Hopkins University).

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