Jeanne Marie Wallace

Bacterial Pneumonia in Persons Infected with the Human Immunodeficiency Virus

BACKGROUND Patients with human immunodeficiency virus (HIV) infection are at increased risk for bacterial pneumonia in addition to opportunistic infection. However, the risk factors for bacterial pneumonia and its incidence in this population are not well defined. METHODS In a multicenter, prospective, observational study, we monitored 1130 HIV-positive and 167 HIV-negative participating adults for up to 64 months for pulmonary disease. The HIV-positive group comprised 814 homosexual or bisexual men, 261 injection-drug users, and 55 female partners of HIV-infected men. RESULTS There were 237 episodes of bacterial pneumonia among the HIV-positive participants (rate, 5.5 per 100 person-years), as compared with 6 episodes among the HIV-negative participants (rate, 0.9 per 100 person-years; P < 0.001). The rate of bacterial pneumonia increased with decreasing CD4 lymphocyte counts (2.3, 6.8, and 10.8 episodes per 100 person-years in the strata with more than 500, 200 to 500, and fewer than 200 cells per cubic millimeter, respectively; P < or = 0.022 for each comparison). Injection-drug users had a higher rate of bacterial pneumonia than did homosexual or bisexual men or female partners. In the stratum with the fewest CD4 lymphocytes, cigarette smoking was associated with an increased rate of pneumonia. Mortality was almost four times higher among participants with an episode of pneumonia than among the others. Prophylaxis with trimethoprim-sulfamethoxazole was associated with a 67 percent reduction in confirmed episodes of bacterial pneumonia (P = 0.007). CONCLUSIONS Bacterial pneumonia is more frequent in HIV-positive persons than in seronegative controls, and the risk is highest among those with CD4 lymphocyte counts below 200 per cubic millimeter and among injection-drug users.

INCIDENCE OF TUBERCULOSIS IN THE UNITED STATES AMONG HIV-INFECTED PERSONS. THE PULMONARY COMPLICATIONS OF HIV INFECTION STUDY GROUP

Among opportunistic pathogens associated with the acquired immunodeficiency syndrome (AIDS), Mycobacterium tuberculosis is distinguished by its relative virulence and potential for person-to-person transmission. Persons infected with human immunodeficiency virus (HIV) are particularly susceptible to tuberculosis, both from the reactivation of latent infection and from new infection with rapid progression to active disease [1-4]. The annual incidence of tuberculosis in the United States was 8.7 per 100 000 persons in 1995 [5], but rates 1000-fold higher have been reported in some HIV-seropositive populations [6-14]. Most studies have been restricted by geography, HIV-risk group, or specific high-prevalence settings; such restrictions have resulted in an inaccurate assessment of the overall effect of the HIV epidemic on the incidence of tuberculosis in the United States [15, 16]. The Pulmonary Complications of HIV Infection Study (PCHIS) [17] prospectively followed HIV-seropositive patients who had demographic variables similar to those of patients with AIDS in the United States. Participants with asymptomatic or symptomatic HIV infection were recruited from sites in the eastern, midwestern, and western United States. A previous report on this cohort [18] identified determinants of delayed-type hypersensitivity response and risk factors for tuberculin reactivity. We examined the incidence of tuberculosis among patients enrolled in the PCHIS for a median observation period of approximately 4.5 years. Methods Patients and Study Design The PCHIS was a multicenter, prospective study of the frequency and spectrum of pulmonary disorders in persons infected with HIV. From November 1988 through February 1990, 1171 HIV-seropositive persons and 182 HIV-seronegative persons were enrolled at centers in six U.S. cities: New York; Newark, New Jersey; Detroit; Chicago; San Francisco; and Los Angeles. Participants were followed through 31 March 1994. We report on 1130 HIV-infected persons from the PCHIS who were followed past baseline. Participants were recruited to represent a range of severity of HIV disease. Approximately half of the participants at each center had CD4 lymphocyte counts of 400 cells/mm3 or more and no HIV-related symptoms, and half had CD4 lymphocyte counts of less than 400 cells/mm3 or symptomatic HIV infection. Both groups included persons from one of three HIV-transmission categories: homosexual men, male and female injection drug users, and women who had acquired HIV through heterosexual contact. Exclusion criteria were AIDS, as defined by the Centers for Disease Control and Prevention (CDC) [19]; acute pulmonary processes; use of immunosuppressive therapy in the past 6 months; and treatment of tuberculosis in the past 12 months. The study was approved by the institutional review board at each site, and participants gave informed consent. At baseline and at regular intervals, clinical monitoring (including T-lymphocyte subset analysis and chest roentgenography) was done, and participants were acutely evaluated if new pulmonary symptoms occurred. Centers used the same predetermined diagnostic algorithms that were initiated if specified criteria were met. Complete details of the study design have been described elsewhere [17]. Delayed hypersensitivity was tested at baseline and then annually using purified protein derivative (PPD) tuberculin at a strength of 5 TU per 0.1-mL dose and mumps antigen (Connaught Laboratories, Inc., Swiftwater, Pennsylvania). Tests were administered by intradermal injection of 0.1 mL of antigen by the Mantoux method and read by experienced nurses 48 to 72 hours later in most cases (the interval exceeded 4 days in 18 persons). A positive response to PPD was defined as an induration at least 5 mm in diameter. Any person who was not positive when first tested but who became positive on any subsequent test was considered to be a tuberculin converter. A positive response to mumps was defined as any degree of induration (>0 mm). The criteria for anergy was nonreactivity (0 mm) to both PPD and mumps antigen. Pulmonary tuberculosis was defined by the isolation of M. tuberculosis from a respiratory tract specimen or by improvement on chest radiography in response to specific multidrug antituberculous therapy. Patients who were diagnosed with extrapulmonary tuberculosis had clinically compatible disease and response to specific therapy, with or without the isolation of the organism from a site outside the lung. Patients who were considered to have both pulmonary and extrapulmonary tuberculosis met each set of criteria. These requirements are consistent with those of the CDC for reporting cases of tuberculosis [20], except that we did not require patients to be PPD positive if they had disease that was not mycobacteriologically confirmed. Statistical Analysis Tuberculosis rates were calculated as the number of cases divided by the number of years that patients were followed multiplied by 100. Except as noted below, the length of time that patients were followed was calculated for each person starting from enrollment and continuing until one of the following occurred: diagnosis of tuberculosis, death from any cause, the last study visit, or 31 March 1994. Statistical significance for comparison of rates was determined by tests for person-time data done on the basis of binomial distribution [21]. P values were determined by an exact test when sample sizes were insufficient and by an asymptotic test when sizes were sufficient. All tests were two-sided, and a P value of 0.05 was considered significant. Exact 95% CIs were calculated for rates by assuming the numerator to be a Poisson variable [22] and for rate ratios using a modified binomial model [21]. Adjusted rate ratios for comparisons among groups defined by demographic variables were calculated by using a Mantel-Haenszel type estimator for incidence-rate data with approximate 95% confidence limits based on the tests [21]. Seventy-three participants, including women who had acquired HIV through heterosexual contact and persons were not black, white, or Hispanic, were excluded from some calculations of adjusted rates because of small sample sizes. Distributions of time to death among patients with tuberculosis were estimated using the Kaplan-Meier method, and comparisons were made using the log-rank test. To calculate tuberculosis rates by immunologic status, we divided the time each participant was followed into the number of years during which CD4 lymphocyte counts were 200 cells/mm3 or greater and the number of years after CD4 lymphocyte counts were less than 200 cells/mm3. Time for these CD4 groups was then summed for all participants. Rates were calculated as the number of tuberculosis cases in each group divided by the number of years followed. One participant who did not have CD4 measurements was omitted from these calculations. Twenty-three participants who were never tested for PPD response were excluded from PPD conversion rates and calculations of tuberculosis rates by PPD status. Participants who were tested for PPD response at least once were classified into one of three groups: positive at entry, newly positive (converted), or negative. One hundred seventy-two of 1107 participants were assigned to groups on the basis of only one test. Baseline PPD status was assigned for 66 participants who were not tested at study entry by using the first reported test and time followed calculated from the date of that test. For participants who developed tuberculosis, only the results of PPD tests done before diagnosis were considered. Tuberculin converters were considered to be part of the negative group before becoming PPD positive and to be part of the newly positive group after converting. Persons who reported a history of isoniazid use or tuberculosis before the study or who received isoniazid for at least 6 months during follow-up were considered to have completed prophylactic therapy. All others were considered to have not been given prophylaxis. Time before completion of isoniazid therapy was included with time followed in the untreated group. Restricted tuberculosis rates were calculated by PPD status for those considered to have not received prophylaxis. Results Patient Characteristics at Baseline Overall, 1171 HIV-seropositive persons entered the study. Follow-up was completed for 1130 persons (96%), whose baseline characteristics are shown in Table 1. Approximately 1% of patients reported a history of tuberculosis, 8% reported a previous positive result on a PPD test, and 4% reported previous use of isoniazid. The median CD4 T-lymphocyte count among HIV-seropositive patients was 410 cells/mm3: Thirty-six percent of patients had counts of at least 500 cells/mm3, 44% had counts between 200 and 499 cells/mm3, and 19% had counts of less than 200 cells/mm3. At study entry, 6% of patients were PPD positive, 42% were reactive to mumps antigen, and 54% were anergic. A cross-sectional analysis of skin-test results at baseline in this cohort has been described in detail elsewhere [18]. Table 1. Baseline Characteristics of the Study Chart* Patient Follow-up The median duration of follow-up was 53 months. By the end of the study, 655 persons had survived after a median follow-up of 57 months (range, 31 to 64 months), 354 had died after a median follow-up of 31 months (range, 1 to 63 months), and 121 withdrew or were lost to follow-up after a median of 25 months (range, 1 to 61 months). Participants received PPD skin tests a median of three times, and 1107 (98%) participants were evaluated at least once. Sixty-six (6%) participants were PPD positive when first tested. Among the 1041 patients who were PPD negative at first testing, 29 subsequently became PPD positive (0.8 conversions per 100 person-years). During follow-up, isoniazid prophylaxis was prescribed for 110 persons (10%), but only 53 (5%) received therapy for 6 months or more. Inc

Tuberculin and Anergy Testing in HIV-Seropositive and HIV-Seronegative Persons

Human immunodeficiency virus (HIV) is playing a substantial role in the resurgence of tuberculosis in the United States. Particularly affected are people in urban areas, where there are large populations of HIV-infected persons [1-8]. Urban subpopulations with a high prevalence of HIV infection, such as intravenous drug users (a group already at increased risk for tuberculosis before the appearance of the acquired immunodeficiency syndrome [AIDS]), have the highest tuberculosis attack rates [3]. Unlike other AIDS-associated opportunistic pathogens, Mycobacterium tuberculosis is readily communicable among persons with all levels of immunity. Recently, tuberculosis outbreaks, some with multidrug-resistant strains, have occurred among HIV-positive patients with transmission to HIV-negative patients and health care workers [9-13]. Prevention strategies rely heavily on the use of tuberculin purified protein derivative (PPD) to identify persons harboring M. tuberculosis [14]. Anergy, a consequence of HIV infection, undermines these strategies in persons at the highest risk for tuberculosis infection and subsequent active disease [15-18]. A negative PPD test result in this setting could be attributable to a true lack of exposure to tuberculosis or simply to the incapacity of the patient to manifest an appropriate cell-mediated immune response. To reduce the measured prevalence of anergy and thereby increase the proportion of tuberculin nonreactors who can be considered truly PPD negative, the Centers for Disease Control and Prevention (CDC) has recommended the additional use of at least two delayed-type hypersensitivity control antigens (mumps antigen plus Candida antigen or tetanus toxoid) when screening HIV-infected patients. Thus, persons from populations with a prevalence of tuberculous infection of 10% or more and who are tuberculin negative but not anergic may be spared preventive therapy with isoniazid [19]. However, the ability of control antigens to predict the likelihood that a negative PPD test result is truly negative in this highly anergic population is unknown. To improve approaches to tuberculosis prophylaxis, more data are needed about the relations among delayed-type hypersensitivity responsiveness, the prevalence of tuberculosis, and the waning immunity associated with progressive HIV infection. In an ongoing multicenter study of the natural history of the pulmonary complications associated with HIV infection, we have been examining these factors prospectively in a cohort of 1353 persons in 6 U.S. geographic areas. Recently, we evaluated baseline delayed-type hypersensitivity responses in this cohort of HIV-seropositive and HIV-seronegative persons and identified variables associated with tuberculin reactivity and anergy. Methods Patients and Study Design The Pulmonary Complications of HIV Infection Study is a multicenter study designed to prospectively describe the frequency, types, and effect of pulmonary complications in HIV-infected persons, both before and after the development of AIDS. All diagnoses, treatments, and outcomes are recorded and monitored in a common database. Because our purpose was to evaluate longitudinally both the early and late pulmonary manifestations of HIV infection, each center attempted to recruit about 170 HIV-seropositive participants, half with CD4 lymphocyte counts of 400 cells/mm3 or more and no HIV-related symptoms and half with fewer than 400 CD4 cells/mm3 or symptomatic HIV-infection (defined by a temperature of 38 C or more for at least 2 weeks, involuntary weight loss of 10% or more from baseline, diarrhea of at least a 1-month duration, oral candidiasis, or oral hairy leukoplakia). Within each group, participants were drawn from one of three HIV transmission categories (homosexual men, male and female intravenous drug users, and women with heterosexually acquired HIV infection) to reflect their approximate distribution at each clinical site. About 30 HIV-seronegative homosexual men and intravenous drug users were also recruited at each site to serve as controls. Participants had to be willing and able to comply with the protocol and were required to give informed consent. The study was reviewed and approved by the institutional review board at each site. Exclusion criteria included Centers for Disease Control and Prevention (CDC)-defined AIDS [20], severe non-HIV-related disease likely to affect survival, lung disorders likely to interfere with the required evaluations, acute pulmonary processes, immunosuppressive therapies within the previous 6 months, and treatment for active tuberculosis within the past 12 months. From November 1988 through February 1990, we enrolled 1353 persons in the study, of whom 1171 were HIV seropositive and 182 were HIV seronegative. Human immunodeficiency virus serologic status was confirmed at study entry using a licensed enzyme-linked immunosorbent assay and a Western blot assay. Further baseline evaluation included a complete medical history, a physical examination, hematologic and biochemical studies, T-lymphocyte subset analysis, delayed-type hypersensitivity testing, a chest roentgenogram, and pulmonary function measurements. Measurement of Delayed-Type Hypersensitivity Response We tested delayed-type hypersensitivity with the following antigens: mumps antigen (Connaught Laboratories, Inc., Swiftwater, Pennsylvania); Dermatophytin 0 (Candida) at 1:100 dilution (Hollister-Stier, Spokane, Washington); Dermatophytin (trichophytin) at 1:100 dilution (Hollister-Stier); and tuberculin PPD at a strength of 5 tuberculin units per 0.1-mL dose (Connaught Laboratories, Ltd., Willowdale, Ontario, Canada). Tests were administered by intradermal injection of 0.1 mL of antigen (Mantoux method) and read by a trained observer 48 to 72 hours after application in most participants (the interval exceeded 4 days in 18 persons). Response was recorded as the greatest diameter of induration. We used the current standard operational criteria for a positive response: induration of at least 5 mm for all antigens except PPD, for which an induration of 10 mm was required among HIV-uninfected persons [19]. Anergy was defined as 0 mm of induration for all delayed-type hypersensitivity antigens administered in a given panel. Unless otherwise specified, a test battery of tuberculin PPD, mumps antigen, and Candida antigen was used to define anergy. At one site, however, the investigators did not distinguish between induration and erythema for the mumps, Candida, and trichophytin tests, documenting reactions to these antigens in terms of millimeters of erythema. When examined by zone diameter, their measurements were generally consistent with those from the other centers. Furthermore, the results of multivariate analyses with and without the data from this site were similar. Other investigators have shown a high degree of correlation between induration and erythema with these antigens [21]. Thus, for the purposes of our analysis, responses were recorded in millimeters of induration. Because trichophytin elicited a positive reaction in only 14.0% of those tested, it was dropped from the delayed-type hypersensitivity battery midway through the enrollment period. Although lot numbers varied, the skin tests used at the centers were supplied by the same manufacturers, with a single exception: At one site, investigators used a different Candida preparation. The Candida test results for this center (247 participants) were excluded from all analyses involving this antigen. Determination of Lymphocyte Subsets Lymphocyte subsets were determined for CD3, CD4, and CD8 receptor-bearing cells by the same laboratory at each site. All laboratories participated in the flow cytometry quality control program sponsored by the National Institute of Allergy and Infectious Diseases [22]. Statistical Analysis All analyses are based on data collected during the baseline evaluation. Statistical significance for comparisons of proportions was determined by chi-square or Fisher exact test [23]. For comparisons among nonindependent groups, repeated-measures analysis for categorical outcomes was used to determine statistical significance [24, 25]. Logistic regression models were used to study the relation between PPD positivity or anergy and potential risk factors [26]. Risk factors considered were HIV status; CD4 count among HIV-seropositive persons; intravenous drug use; race or ethnicity; a history of a positive PPD test result, tuberculosis, or BCG vaccination; age; gender; and socioeconomic status. Seventy-seven participants, including women with heterosexually acquired infection and persons who were not white, black, or Hispanic, were excluded from all multivariate analyses because of small sample sizes. Initial models included HIV status (positive or negative), intravenous drug use (presence or absence), race or ethnicity (white, black, or Hispanic), a history of a positive PPD test result, and age, as well as interaction terms, to determine whether the effect of HIV positivity varied among these groups or whether the effect of drug use varied by race. No statistically significant interactions were observed. All odds ratios presented were derived from subsequent models containing main effects only. A dichotomous variable indicating the 12% of the cohort who did not have a high school diploma was used as an index of socioeconomic status and was included in all final models. All tests were two sided. A P value of 0.05 was considered statistically significant. Ninety-five percent CIs are given when appropriate. Results Patient Characteristics During the 16-month enrollment period, 1171 HIV-seropositive and 182 HIV-seronegative persons entered the study. The two groups were similar with regard to age, sex, race, transmission category, and tuberculosis-associated history (Table 1). Of the 1165 men, 966 (82.9%) were homosexual; of the 188 women, 132 (70.2%) were intravenous drug users.

Impact of Bacterial Pneumonia and Pneumocystis carinii Pneumonia on Human Immunodeficiency Virus Disease Progression

The course of pneumonia caused by pyogenic bacteria and Pneumocystis carinii was examined in a multicity cohort study of HIV infection. The median duration of survival among 150 individuals following initial bacterial pneumonia was 24 months, compared with 37 months among 299 human immunodeficiency virus (HIV)-infected control subjects matched by study site and CD4 lymphocyte count (P<.001). For 152 subjects with P. carinii pneumonia, median survival was 23 months, compared with 30 months for 280 matched control subjects (P = .002). Median durations of survival associated with the two types of pneumonia differed by only 47 days, despite a higher median CD4 lymphocyte count associated with bacterial pneumonia. These results suggest that both P. carinii pneumonia and bacterial pneumonia are associated with a significantly worse subsequent HIV disease course. The similarity of prognosis after one episode of bacterial pneumonia vs. an AIDS-defining opportunistic infection and the proportion of cases occurring in association with a CD4 lymphocyte count of >200 suggest that measures to prevent bacterial pneumonia should be emphasized.

Overall and cause-specific mortality in a cohort of home-/bisexual men, injecting drug users, and female partners of HIV-infected men

OBJECTIVE To study the overall and cause-specific HIV-related mortality in a cohort of HIV-seropositive subjects according to transmission category, race/ethnicity, sex and severity of immunosuppression. DESIGN A cohort of 1129 HIV-seropositive homo-/bisexual men, injecting drug users, and female partners of HIV-infected men were enrolled at six centers in San Francisco, Los Angeles, Chicago, Newark, Detroit and New York between 1 November 1988 and 1 November 1989. Subjects were evaluated every 6 months at least until 31 March 1994. METHODS The analyses of overall mortality for the subgroups of interest were performed with Kaplan-Meier plots and Cox proportional hazards models. Cause-specific analyses were performed on the primary cause of death using rates per 100 person-years of exposure. RESULTS AND CONCLUSIONS Baseline severity of immunosuppression is the strongest predictor of mortality. There were no statistically significant differences in overall HIV-related mortality among transmission categories, race/ethnicity groups or sexes. There were differences, however, in cause-specific mortality among the different risk groups.

Efficacy and complications of transthoracic needle biopsy of lung in patients with Pneumocystis carinii pneumonia and AIDS.

Transthoracic needle biopsy of lung was performed under fluoroscopic guidance in 16 patients with AIDS or suspected AIDS for diagnosing 18 episodes of possible P carinii infection. Diagnostic information was obtained in 15 of 18 cases. P carinii (10) and other infections agents (5) were diagnosed by TNB. The complications were pneumothorax in 44% (17% requiring chest tube drainage) and minor hemoptysis in 11%. Our incidence of pneumothorax following TNB in patients with diseases other than AIDS is 17% with 4.8% requiring chest tube drainage. Although TNB under fluoroscopic guidance is a cost-effective, rapid procedure with a high diagnostic yield, it is frequently complicated by pneumothorax in AIDS patients with diffuse pulmonary disease. This procedure should therefore only be performed in AIDS patients when transbronchial biopsy has failed to provide the diagnosis and prior to considering such patients for open lung biopsy.

Chemotaxis of Peripheral Blood and Lung Leukocytes Obtained from Tobacco and Marijuana Smokers

†Supported by U.S. Public Health Service CRC Grant RR-00865 and National Institutes of Health Grant 2R01-DA-03018.

Update in Pulmonary Diseases

Pulmonary Hypertension: New Treatments and Outcomes The hallmark of pulmonary arterial hypertension is an increase in pulmonary vascular resistance, which may be 20 times normal, leading to mean pulmonary artery pressures exceeding 25 mm Hg at rest and 30 mm Hg during exercise. If untreated, the condition leads to right ventricular failure and ultimately death. All layers of the pulmonary vessel walls are affected. Proliferation of the adventitia limits vascular elasticity, while hypertrophy of the medial smooth muscle promotes vasoconstriction in what is normally a high-flow, low-pressure system. Intimal proliferation and in situ thrombosis may eventually occlude the vascular lumen. Endothelial cell dysfunction is part of the disease process, and mounting evidence shows that endothelin-1, a strong endogenous vasoconstrictor, has a key pathogenic role. According to the 1998 World Health Organization (WHO) classification, subtypes of pulmonary arterial hypertension include primary pulmonary hypertension and pulmonary arterial hypertension associated with collagen vascular diseases (especially scleroderma), congenital heart disease with a left-to-right shunt, portal hypertension, HIV infection, and assorted drugs and toxins. In the first, preclinical stage of pulmonary arterial hypertension, pulmonary vascular resistance and pulmonary arterial pressure increase but there are no symptoms. The disorder is seldom diagnosed at this stage, which corresponds to functional class I in the New York Heart Association (NYHA)/WHO classification system. In stage 2 (NYHA/WHO functional classes II and III), the pulmonary vascular bed can no longer accommodate increased blood flow during exercise, and the patient experiences progressive dyspnea on exertion. In patients with stage 3 pulmonary arterial hypertension (NYHA/WHO functional class IV), the right ventricle begins to fail, cardiac output decreases, and the patient becomes symptomatic at rest. Patients with primary pulmonary hypertension live an average of less than 3 years after diagnosis. Treatment is based in part on disease severity, which may be gauged by echocardiography or right-heart catheterization or more simply and quite accurately by the distance covered in a 6-minute walk. Ideally, treatment begins at stage 2 or earlier, because in stage 3 the outlook is very poor. Until recently, the accepted treatment of pulmonary arterial hypertension has been long-term anticoagulation to prevent intravascular thrombosis, as well as deep venous thrombosis and pulmonary embolism that may be complications of right-heart failure. Diuretics and oxygen have been used to relieve symptoms, and calcium-channel blockers have been used to combat abnormal intracellular calcium kinetics in smooth muscle. Only a minority of patients, perhaps 10% to 20% (identified by testing for acute vasoreactivity during right-heart catheterization), respond to treatment with calcium-channel blockers. It is the majority of patients, who do not vasodilate in response to nitric oxide or prostacyclin, who are candidates for the newer treatments. These treatments are directed at excessive production of endothelium-derived vasoconstrictors and insufficient production of beneficial vasoactive factors, such as prostacyclin and nitric oxide. These agents, in addition to stimulating vasodilation, inhibit platelet aggregation and counter endothelial proliferation. Ongoing Treatment with Epoprostenol Improved Survival of Patients with Pulmonary Hypertension Kuhn KP, Byrne DW, Arbogast PG, et al. Outcome in 91 consecutive patients with pulmonary arterial hypertension receiving epoprostenol. Am J Respir Crit Care Med. 2003; 167:580-6. [PMID: 12446266] If left untreated, patients with pulmonary arterial hypertension will develop a sustained increase in pulmonary vascular resistance, which eventually leads to right-heart failure and death. Epoprostenol is the synthetic salt of prostacyclin and shares its vasodilating action, in addition to inhibiting platelet aggregation and smooth-muscle growth. The purpose of this retrospective cohort study, which involved 91 patients with pulmonary arterial hypertension, was to determine the effect, if any, of long-term epoprostenol infusion on long-term survival and to identify predictors of survival. Patients in this study had not responded to calcium-channel blockers or had a less than 20% decrease in mean pulmonary artery pressure on acute vasodilator testing. Epoprostenol was infused into a permanent venous catheter in an average dosage (at hospital discharge) of 4 to 6 ng/kg of body weight per minute. The goal was to deliver 20 ng/kg per minute after 4 to 6 months. The mean dose of epoprostenol at 12 months was 23 ng/kg per minute. Average follow-up was 2.4 years. Catheter-related complications included sepsis in 2 patients and septic embolism in a third; these infections resolved. The 6-minute walk distance had increased significantly after 12 months of treatment. Pulmonary artery pressure decreased by 15%, pulmonary vascular resistance decreased by 38%, and cardiac output increased by 29% in the 62 patients available for repeated hemodynamic assessment. Overall survival rates after 1, 2, and 3 years of follow-up were 79%, 70%, and 59%, respectively. The subgroup with primary pulmonary hypertension did somewhat better than the overall group, whereas those with associated connective tissue disease did worse (3-year survival rate, 65% vs. 34%). Predictors of a worse outcome included older age at disease onset, NYHA/WHO functional class IV, and the scleroderma spectrum of disease. No hemodynamic factors at baseline or follow-up predicted the outcome. The investigators believe that these results justify referring patients with pulmonary hypertension for long-term intravenous epoprostenol treatment, despite its high cost and the need for continuous infusion. One recently published study also documented increased long-term survival in patients given infused epoprostenol (1), and another identified the same prognostic factors of long-term survival (2). In 1996, the U.S. Food and Drug Administration (FDA) approved this treatment for patients with NYHA/WHO functional class III and class IV disease. Long-term epoprostenol therapy is complicated and costly. The very short half-life of this drug mandates continuous infusion, which may lead to rebound symptoms or sudden death if abruptly discontinued. In addition, the patient must mix the drug and inject the solution into a reservoir. Despite these drawbacks, however, this treatment does provide immediate, sustained functional and hemodynamic improvement and lengthens survival. Like all prostacyclin analogues, epoprostenol may cause gastrointestinal side effects, headache, hypotension, pain in the jaw, and flushing, all of which usually subside during ongoing treatment. High-output heart failure can occur at high infusion rates, and catheter-related complications occur. U.S. and European Trials Demonstrated the Clinical Value of Prostacyclin Analogues in Patients with Pulmonary Arterial Hypertension Galie N, Manes A, Branzi A. The new clinical trials on pharmacological treatment in pulmonary arterial hypertension. Eur Respir J. 2002; 20:1037-49. [PMID: 12412701] Recent controlled clinical trials in the United States and Europe, with a combined study sample exceeding 1100 patients, evaluated 5 drugs for the treatment of pulmonary arterial hypertension. One was terbogrel, an orally active and potent thromboxane-receptor antagonist that also inhibits thromboxane synthetase. Three trials evaluated different prostacyclin analogues: treprostinil, a subcutaneously administered epoprostenol analogue; aerosolized iloprost, which is given by inhalation; and beraprost, an orally active agent. A fifth trial evaluated an endothelin-1-receptor antagonist, bosentan. Patients with primary pulmonary hypertension and others with associated conditions, including connective tissue disorders, were enrolled in these studies. At the outset, participants were classified as having NYHA/WHO functional class II to IV disease. Most of the trials lasted 12 to 16 weeks. The terbogrel study was halted when patients developed leg pain, which resolved on cessation of treatment. Treprostinil, like the other prostacyclin analogues, was associated with improvement in the 6-minute walk test; sicker patients benefited the most. The dyspnea index also improved, as did hemodynamic variables such as mean pulmonary artery pressure and cardiac index. Pain at the infusion site was the most common side effect. Patients who were given aerosolized iloprost improved their 6-minute walk time by more than 10% after 12 weeks, improved their NYHA functional class, and had lower pulmonary vascular resistance. Adverse effects included flushing, pain in the jaw, and syncope. Beraprost increased walking distance in patients with primary pulmonary hypertension but not in those with pulmonary arterial hypertension associated with other disorders. Hemodynamic variables improved, but only modestly. Exercise capacity, hemodynamic function, and clinical status all improved in 2 double-blind trials of bosentan. In some patients, liver aminotransferase levels increased in a dose-related manner. Documenting the effect of these agents on mortality will require longer-term studies. At present, only treprostinil and bosentan are available in the United States. The prostacyclin analogues have vasodilating properties, inhibit platelets, and control cellular proliferation. Endothelin-1-receptor antagonists, such as bosentan, inhibit vasoconstriction as well as cellular proliferation and fibrosis. Side effects of these drugs are unpredictable in individual patients. Infusion-site pain from treprostinil may require substantial analgesia or even withdrawal of treatment. Iloprost must be inhaled every 2 to 3 hours, which is impractical for most patients. Although these agents are clinically effective, none