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* From the Joint Division of Respirology, University Health Network & Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
Correspondence to: Charles Chan, MD, FCCP, 10EN220, 200 Elizabeth St, Toronto, ON, Canada M5G 2C4; e-mail: charles.chan{at}uhn.on.ca
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Abstract |
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Design: The results of pulmonary function tests (PFTs) over a period of 5 years were retrospectively analyzed in a cohort of HIV-infected individuals.
Setting: A government-funded AP clinic in a large metropolitan center in Canada.
Patients: Among the cohort of 1,850 HIV-positive patients who received regular AP prophylaxis between 1989 and 2001 at the AP clinic, 83 received AP for ≥ 5 years. Of these 83 patients, baseline and long-term follow-up PFT data were available for 79. These subjects formed the study population for this analysis.
Results: The cohort was divided according to smoking status (smokers, 48%). The rate of decline of FEV1 in the smokers over the 5-year period was statistically significant but was comparable to that expected of healthy smokers. As for the nonsmokers, there was no significant reduction in FEV1. Flow rates at low lung volumes (ie, forced expiratory flow at 50% and 75% of FEV1) and low FEV1/FVC ratios showed significant declines in both smokers and nonsmokers. On the other hand, no significant changes in FVC, total lung capacity, residual volume, or diffusing capacity of the lung for carbon monoxide were observed. The apparent slight reduction in flow rates seems to be at the level of the small airways.
Conclusions: The PFT data suggest that AP can be well-tolerated over a 5-year period in HIV-infected patients with only modest reduction in flow rates at the level of the small airways, especially in smokers.
Key Words: HIV • inhalation • pentamidine • prophylaxis • pulmonary function tests
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Introduction |
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In the 1990s, the recommended first-line prophylaxis against PCP was trimethoprim-sulfamethoxazole. However, up to 30% of HIV-infected individuals are intolerant to long-term trimethoprim-sulfamethoxazole therapy.4 In such cases, dapsone or aerosolized pentamidine (AP) is recommended as a second-line alternative. Despite the inconvenience of AP administration and its higher costs, it remains to date an effective PCP prophylaxis regimen due to its tolerability, demonstrated effectiveness, and compatibility with most other concurrent therapy that HIV patients tend to receive. Rarely are patients prescribed other third-line PCP prophylaxis agents such as atovaquone.5
Despite being well-tolerated by most patients, it has been suggested that AP may pose some detrimental short-term effects on pulmonary function. Such effects include cough and reversible bronchospasm.6 7 These short-term exposure-related side effects usually are relieved with bronchodilator administration after therapy or are controlled by the administration of a bronchodilator before receiving the AP.7 8 The long-term pulmonary effects of AP are still controversial, but most patients with normal pulmonary function at baseline are reported to maintain relatively normal results after 1 to 2 years of AP usage.9 10 The issue of the long-term effects of AP on lung function becomes increasingly important as HIV-infected individuals can expect to live much longer than similarly infected patients from a decade ago. The definition of long-term prophylaxis for HIV patients has shifted from 6 to 12 months from a decade ago to 5 years and beyond, due primarily to the widespread utilization of the new and improved antiretroviral agents for therapy in the last few years.3 11
The objective of our study was to evaluate the long-term effects of AP therapy on the pulmonary function of HIV-positive individuals. In so doing, the pulmonary function test (PFT) data of patients from our longitudinal observational cohort followed for at least 5 years at a government-funded AP clinic were analyzed.
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Materials and Methods |
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HIV-positive patients were enrolled for primary and secondary prophylaxis if they met the criteria, as previously described.4 In short, patients were enrolled for primary prophylaxis if (1) they had experienced no prior episodes of PCP, and (2) had a CD4 count of < 300 cells/µL, had an unexplained persistent fever (ie, temperature, > 37.8°C), or had oropharyngeal candidiasis regardless of CD4 count. Secondary prophylaxis was defined as a previously suspected or proven episode of PCP. Patients should have had no evidence of active PCP at the time of enrollment, as determined by history, physical examination, chest radiograph, blood work, or PFT results. As part of the longitudinal surveillance protocol, all patients were asked to participate in pulmonary function surveillance at baseline, at 6 and 12 months, and on an annual basis thereafter.
Patient Selection
From the total patient population in the database, 83 individuals met the criteria for active patients at the central AP clinic for ≥ 5 consecutive years. Complete PFT results and some baseline data were not available for all patients in the database because testing and the release of information were voluntary and were not a requirement for AP prophylaxis at the clinic. Of those long-term patients receiving AP, 79 had complete PFT data at baseline and one or more follow-up PFT results to allow for the calculation of the changes over ≥ 5 years. These 79 patients formed the study population for this analysis. The PFT data were assembled prospectively as part of the AP clinic safety surveillance protocol rather than for the workup of respiratory symptoms.8
AP Protocol
All AP prophylaxis treatments were administered at the central AP clinic in Toronto. The clinic is government-funded, and all treatments are rendered free of charge to patients. Between 1989 and 1991, AP treatments were administered by an ultrasonic nebulizer (Fisoneb, Fisons Corp, Inglewood, CA; or Portasonic, DeVilbiss, Somerset, PA). The patients went through an initial loading phase, consisting of five 60-mg doses of pentamidine isethionate given over a 2-week period. Thereafter, 60 mg pentamidine isethionate was administered every 2 weeks. From 1992 onward for the last decade, AP was administered as 300 mg pentamidine isethionate every 4 weeks by a jet nebulizer (Respirgard II; Marquest Medical Products Inc; Englewood, CO) without a loading phase.10
PFTs
Complete PFT results were measured using computerized PFT systems (1989 to 1995: MMC Horizon 4400 system, SensorMedic Inc, Laguna, CA; 1995 to 2001: MedGraphics PF/Dx 1085D series BREEZE, Medical Graphics Corporation, St. Paul, MN). The Knudson prediction formula was used throughout both periods.10
Complete PFTs were performed at baseline, and attempts were made to repeat PFTs at 6 and 12 months. PFT results are, of course, dependent on patient compliance and scheduling. Baseline PFTs were all completed within 2 weeks of starting AP therapy, with the majority of baseline PFTs performed prior to AP prophylaxis commencement.
Data Analysis
Not all patients who were identified as having been treated at the central AP clinic for ≥ 5 years necessarily had PFT data that spanned the 5-year time frame. Some patients had a time difference between their baseline and their most recent PFTs that was < 5 years, while others had time differences that were > 5 years. In order to have a standardized means of assessing for the change in PFT results over time, we obtained rates of change by taking the difference between the baseline PFT measurement and the last PFT measurement, and dividing it by the time period (in years) for each of the PFT variables. The data distributions of those rates were tested for "normality" using the Kolmogorov-Smirnov test. We further assessed whether the mean or median values of those distributions equaled zero using t tests or sign tests, as appropriate. Comparisons between cohorts of smokers and nonsmokers were performed using Wilcoxon two-sample tests. The Bonferroni correction method for multiple comparisons was applied to maintain an 
level of 0.05, which was chosen to define statistical significance. Tests were two-tailed, where applicable. Data were analyzed using statistical software (SAS, version 8.2 for Windows; SAS Institute; Cary, NC).
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Results |
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Seventy-five patients from the cohort of 79 (95%) were men. The mean age was 37 years (age range, 21 to 59 years). Thirty-eight patients (48%) were identified as being current smokers at the start of their AP treatment. Since only patients who had been receiving AP therapy for > 5 years were included in this study, the majority of the cohort (80%) was from the era (ie, pre-1996) prior to the availability of highly active antiretroviral therapy (HAART). Two-thirds of the patients were receiving some form of antiretroviral agent at the start of AP therapy. The average CD4 count at baseline was 178 cells/µL, about one third had CD4 counts of > 200 cells/µL. Seventy patients (89%) received AP for primary prophylaxis. Sexual contact accounts for 75% of the identified risk behavior, blood product exposure for 5%, IV drug use for 1%, and unspecified for the rest.
Pulmonary Function Parameters After 5 Years of AP Prophylaxis
The PFT results of the study group (n = 79) at baseline are shown in Table 1
. As not all data followed the normal distribution, the median, first, and third interquartile values are given (Table 1)
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Of the 79 patients, 38 were classified as smokers. Analysis of annual rate of change was done separately for smokers and nonsmokers. Comparison of the annual rate of change between smokers and nonsmokers is shown on Table 2 . The rate of decline of FEV1 was significant among smokers but not among nonsmokers. The rate of decline of FEV1 in smokers over the 5 years was statistically significant but was comparable to that expected of healthy smokers.12 13 The observed median yearly rates of decline in FEV1 in nonsmokers are comparable to those expected for healthy nonsmoker adults.12 14 Forced expiratory flow at 50% of FEV1 (FEF50), forced expiratory flow at 75% of FEV1 (FEF75), and FEV1/FVC ratio showed significant yearly rates of decline both in smokers and nonsmokers, whereas total lung capacity (TLC), residual volume (RV), FVC, and diffusing capacity of the lung for carbon monoxide (DLCO) showed nonsignificant changes.
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The apparent slight reduction in flow rates seems to be at the level of small airways as the flow rates at mid-to-low lung volumes (ie, FEF50 and FEF75) also showed significant median drops.
The reported incidence of breakthrough PCP was very low in this cohort, with five episodes in a cohort of 78 patients who received AP for ≥ 5 years. Interestingly, all five patients with cases of breakthrough PCP were from the primary prophylaxis cohort.
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Discussion |
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Possible hypotheses to explain the modest decline in flow rates at the level of the small airways include the following: long-term, repeated exposure to AP, which may result in more than just acute bronchospasm, possibly leading to small airways changes5 ; changes in the immunologic status of HIV-infected patients who have been treated with HAART may lead to the development of asthma, which can be captured as airflow obstruction at mid-to-low lung volumes; and since a significant number of these patients had a substantial smoking history and continued to smoke while receiving AP, the observed changes may in part be a reflection of smoking effects on the small airways.
The lack of difference between the rates of decline in flow rates between smokers and nonsmokers in this study may well be due to a type-II error with our relatively small sample size. It has been suggested that HIV-infected men who smoke are especially susceptible to bronchial hyperresponsiveness, as defined by significant drops in FEV1/FVC and FEV1.15 HIV-infected patients may therefore be more likely to demonstrate a particular susceptibility to the adverse effects of cigarette smoking. The results of our study cannot help in delineating any interactions among smoking, AP, and HIV infection. Also, the reported incidence of breakthrough PCP was very low in this cohort, plus our database did not capture intercurrent lower respiratory tract infections in a reliable fashion to allow for the exploration of PCP or non-PCP chest infections as a possible confounder.
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Footnotes |
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This research was supported in part by program funding from the Ministry of Health of Ontario, Canada.
Received for publication August 20, 2002. Accepted for publication December 27, 2002.
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