Pulmonary Hypertension Associated With HIV Infection.

ABSTRACT: Pulmonary hypertension occurs with increased frequency among patients with human immunodeficiency virus (HIV) infection. Although the pathogenesis of HIV-associated pulmonary hypertension remains unknown, it appears to occur independently of other risk factors associated with pulmonary vasculopathy, such as chronic hepatitis C infection and intravenous drug use. Signs and symptoms are typical of those immunocompetent patients with primary pulmonary hypertension, but because many HIV-infected patients are receiving intensive medical supervision, the diagnosis of pulmonary hypertension is often made at an earlier stage. Acute responses to epoprostenol are similar to those among non-HIV-infected individuals, but the benefits of long-term, intravenous treatment with epoprostenol in HIV-infected patients is unknown. Future investigations should define the true incidence of pulmonary hypertension and the long-term effects of epoprostenol on survival among HIV-infected individuals. Physicians should be ale rt to possible pulmonary hypertension in persons infected with HIV.

HUMAN IMMUNODEFICIENCY virus has been associated with multiple infectious and noninfectious pulmonary diseases. As a result of better prophylaxis against opportunistic infections and longer survival, noninfectious complications, such as lymphocytic interstitial pneumonia, non-Hodgkin's lymphoma, and pulmonary hypertension, are becoming more prominent. [1,2] We review the literature concerning HIV-associated pulmonary hypertension, and we suggest therapeutic options and future areas of study.

Kim and Factor [3] first reported pulmonary hypertension associated with HIV infection in a hemophiliac with membranoproliferative glomerulonephritis. Other cases of pulmonary hypertension were described among HIV-infected hemophiliacs, suggesting a causative role of treatment with low-purity factor VIII. [4] However, as subsequent nonhemophilia cases were described, suspicion rose that the pulmonary hypertension might be directly related to HIV infection. [5-7]

Many patients with HIV-associated pulmonary hypertension have other known risk factors for pulmonary hypertension, such as intravenous drug abuse or chronic liver disease. This initially cast doubt on an HIV-mediated pathogenesis. Illicit intravenous drugs derived from tablets or pills contain insoluble microcrystals that can cause angiocentric foreign body granulomatous inflammation, thrombosis, and pulmonary hypertension when injected long-term. [8] However, fewer than 5% of intravenous drug abusers inject tablet derivatives, making this explanation for most cases of HIV-associated pulmonary hypertension unlikely. [9] Furthermore, in a recent review of HIV-associated pulmonary hypertension by Mesa et al, [10] none of the 33 reported cases with known histology had pathologic evidence of foreign body granulomatosis.

Portal hypertension and cirrhosis have also been associated with pulmonary hypertension. [11] In a prospective study [12] of 507 patients with portal hypertension, prevalence of pulmonary hypertension was 2%, with the majority of patients having plexogenic pulmonary arteriopathy on biopsy or autopsy. Liver disease could account for only a minority of cases of HIV-associated pulmonary hypertension, since only 15% of patients in whom HIV-associated pulmonary hypertension has been reported have a history of hepatitis, evidence of cirrhosis, or portal hypertension. [10]

EPIDEMIOLOGY

It has been estimated that the incidence of pulmonary hypertension among HIV-positive persons is several thousand times greater than among the general population. The incidence of primary pulmonary hypertension (PPH) in the general population has been reported to be one to two cases per million yearly. [13] Two studies, evaluating more than 1,200 patients each, have estimated the incidence of symptomatic pulmonary hypertension to be approximately 1 in 200 HIV-infected patients or 0.5%. [14,15] The true incidence may be underestimated, since it was determined from symptomatic cases. The observed male-to-female ratio among the H1V cases has been 1.6:1, in contrast to the female predominance of PPH. Associated HIV risk factors have included intravenous drug use in 42%, homosexual transmission in 25%, hemophilia in 13%, heterosexual transmission in 10%, non-hemophiliac blood transfusion in 4%, multiple risk factors in 3%, and vertical transmission by maternally acquired infection in 4%. [10]

CLINICAL FINDINGS AND NATURAL HISTORY

There appears to be no correlation between either CD4 count or the stage of HIV infection and the prevalence or severity of pulmonary hypertension. Among reported cases, CD4 cell counts have ranged from 0 to 937/[mm.sup.3] (mean, 269/[mm.sup.3]). [16] The most common symptoms among patients with HIV-associated pulmonary hypertension have been dyspnea, syncope, fatigue, chest pain, and nonproductive cough. Physical signs have usually included an increased pulmonic component of the second heart sound and a murmur of tricuspid regurgitation. In advanced cases, peripheral edema, ascites, and hepatomegaly have been present. [10,16,17]

Petitpretz et al [18] compared 20 patients with HIV-associated pulmonary hypertension with 93 control patients who had PPH. The HIV group was younger (32 [+ or-] 5 vs 42 [+ or -] 13 years), less severely impaired (New York Heart Association [NYHA] class I or II, 50% vs 25%), and had lower peak pulmonary artery pressures at initial diagnosis (50 [+ or-] 11 vs 62 [+ or-] 15 mm Hg). The lower pulmonary artery pressures and better initial NYHA class may relate to earlier diagnosis in the group under close surveillance for HIV-associated complications. The reported interval between onset of symptoms and diagnosis was only 6 months for the HIV group and was 30 months for the PPH group. No significant difference in survival from the time of diagnosis between the two groups was observed.

Opravil et al [19] compared 19 HIV-infected persons with a pulmonary hypertension diagnosis to 19 HIV-infected persons without pulmonary hypertension. Cases and controls were matched for CD4 counts (range, 1 to 740/[mm.sup.3]), age, sex, risk factors, hospital center, and stage of HIV infection. Pulmonary hypertension was the cause of death in 8 of the 17 patients who died during the study. The researchers determined pulmonary hypertension to be an independent predictor of mortality (relative risk, 2.14; 95% confidence interval, 1.0 to 4.5; P [greater than] .05) among HIV patients. The median survival from the time of diagnosis was 1.3 years for the pulmonary hypertension group vs 2.6 years for the group without pulmonary hypertension. Although autoimmune diseases have been associated with pulmonary hypertension, there was no difference in autoimmune serologies between the two groups. Therefore, an autoimmune phenomenon in the pathogenesis of HIV-associated pulmonary hypertension would be unlikely. [19]

In contrast to the observations of Petitpretz et al, [18] survival in other reported cases of HIV-associated pulmonary hypertension has been worse than reported survival for patients with PPH. In the review by Mesa et al, [10] the 1-year survival rate among patients with HIV-associated pulmonary hypertension was 51%, while the 1-year survival rate reported by the National Institutes of Health registry for PPH was 68%. [20,21]

PATHOPHYSIOLOGY

Histopathologic changes in the pulmonary blood vessels of patients with clinically diagnosed PPH may consist of arterial, capillary, or venular lesions. [22] Hypertensive pulmonary arteriopathy occurs most commonly and includes medial hypertrophy, intimal fibrosis, plexogenic arteriopathy, and in situ thrombosis. Only hypertensive arteriopathy and veno-occlusive disease have been described in HIV-associated pulmonary hypertension. Of the reported cases of HIV-associated pulmonary hypertension with available pathology 78% (36 of 46) had plexogenic pulmonary arteriopathy. Eleven percent had medial hypertrophy and intimal fibrosis without plexiform lesions, 7% had pulmonary veno-occlusive disease, and 4% had in situ thrombosis as the prominent histologic finding. [16]

The etiology of PPH remains unknown, but its development is thought to require both a genetic predisposition and a precipitating event. At the core of the pathogenesis is evidence of endothelial cell dysfunction manifested by enhanced vasoconstrictor synthesis, diminished vasodilator production, and enhanced thrombogenesis. [23-28] Cool et al [27,28] identified endothelial cells as the predominant component of plexiform lesions and concentric obliterative vascular lesions. Furthermore, plexiform lesions with proliferating endothelial cells and perivascular inflammatory cells, made up of T lymphocytes and macrophages, have been shown to predominate in PPH and HIV-associated pulmonary hypertension lesions. [27] Initially, it was thought that HIV might play a direct role by infecting and injuring endothelial cells. However, evidence for direct involvement by the virus has been lacking. Mette et a1 [29] were not able to identify either HIV-1 p24 antigen or the HIV gag RNA in pulmonary arteries of patients with H IV-associated pulmonary hypertension.

It has been suggested that the increased incidence of pulmonary hypertension in patients with HIV might be due to an indirect role of the virus, stimulating the host to release proinflammatory cytokines or growth factors, which would result in pulmonary hypertension in genetically predisposed individuals. [26,30] Ehrenreich et al [31] have shown increased production of endothelin 1, a potent pulmonary vasoconstrictor, by cells stimulated by glycoprotein 120. These investigators have also demonstrated an elevation of endothelin-1 in HIV patients. Exogenous tat-protein, an HIV gene product, has been shown to activate endothelial cells. [32] Humbert et al [33] have shown increased expression of platelet-derived growth factor-[alpha] (PDGF-[alpha]), in persons with HIV infection and pulmonary hypertension but not in HIV-infected persons without pulmonary hypertension. They have suggested a role for PDGF-[alpha], which induces smooth muscle and fibroblast proliferation, in the pathophysiology of pulmonary hyperte nsion. [33] Chalifoux et al [34] studied macaque monkeys infected with the simian immunodeficiency virus, an animal model of HIV infection. They observed perivascular inflammatory cells and pulmonary artery inflammation in the absence of evidence of direct pulmonary artery retroviral infection. Gillespie et al [35] described a murine model of HIV-induced pulmonary hypertension. The mice had endothelial proliferation similar to that described in the macaque monkeys.

Genetic risk factors are poorly understood. Morse et al [36] described an increased incidence of HLA-DR6 and HLA-DR52 genes in patients with HIV-associated pulmonary hypertension. The HLA-DR6 subtype has also been associated with diffuse infiltrative lymphocytosis syndrome. This syndrome, which has been characterized by an exaggerated CD8 lymphocytic response to HIV-1 infection, resembles Sjogren's disease and has been associated with a prolonged survival in HIV-infected individuals. [36]

The gene responsible for familial PPH has been mapped to the 2q33 chromosome. [37-39] Recent studies by Deng et al [40] have shown that mutations in the bone morphogenetic protein type II receptor (BMPR2) gene cause familial PPH. Mutations in the BMPR2 gene have also been found in 26% of sporadic cases of PPH. [40] However, the age of disease onset is variable within families and between subjects carrying identical mutations. These findings suggest that additional factors, either environmental or genetic, are required for the pathogenesis of the disease. [41] Further studies evaluating BMPR2 gene mutations among patients with HIV-associated pulmonary hypertension may help elucidate the molecular pathology and the relationship between genetic and environmental factors in the development of pulmonary hypertension. This may allow for future genetic screening of HIV-infected individuals.

TREATMENT AND FUTURE OBJECTIVES

Few reports describe the efficacy of treatment for pulmonary hypertension in HIV. In the study by Opravil et al, [19] 7 of the 19 patients studied received symptomatic treatment with diuretics, 3 with calcium channel blockers, and 1 with anticoagulation. Eight patients were treated with zidovudine or didanosine after the diagnosis of pulmonary hypertension was established. Baseline and posttreatment pulmonary artery pressures were obtained in 13 patients, 7 of whom were treated with antiretroviral agents. Among patients who received antiretroviral therapy, mean pulmonary artery pressure dropped 3.2 mm Hg, while it rose an average of 19 mm Hg among those not receiving antiretroviral therapy. However, the median survival was 2 years for both groups. These investigators did not report if any of the patients receiving antiretroviral therapy also received adjunctive therapy with calcium channel blockers or anticoagulants. However, there have been case reports of progression of pulmonary hypertension despite effec tive antiretroviral therapy and a low viral load [42]

Rich et al [43] estimated that approximately 25% of patients with PPH may respond favorably to calcium channel blockers with both a reduction in pulmonary vascular resistance and a drop in pulmonary artery pressure. Few data are available on the prevalence of vasodilator responsiveness among patients with HIV-associated pulmonary hypertension. In one series, none of the five cases of HIV-associated pulmonary hypertension responded to calcium channel blockers, and intolerable side-effects occurred in four of the cases [44]

Domiciliary, continuous intravenous epoprostenol improves hemodynamics, symptoms, and survival in PPH patients with NYHA class III or IV symptoms. [45,46] Petitpretz et al [18] showed that acute hemodynamic responses during a short-term vasodilator trial with epoprostenol were similar in both HIV-associated pulmonary hypertension and PPH. However, no long-term follow-up was reported. Stricker et al [47] reported two cases of HIV-associated pulmonary hypertension treated with inhaled epoprostenol. Both patients had a pulmonary artery catheterization to confirm response to inhaled epoprostenol. The authors reported a reduction in NYHA class and reduction in pulmonary artery pressures at 7 months of follow-up. Other less invasive treatments, such as inhaled iloprost, oral beraprost, and subcutaneous uniprost, are currently being studied in PPH patients. They may be an attractive alternative for persons with HIV because of the possible risk of infection with continuous intravenous epoprostenol in this patient gr oup. Patients with HIV-associated pulmonary hypertension are currently being enrolled in a study with uniprost, [48] and protocols are being developed to include patients with HIV-associated pulmonary hypertension in a study using endothelin-1 inhibitors. [49] Potential drug interactions between these agents and highly active antiretroviral therapy (HAART) are unknown.

Additional studies are needed to better define the effect of HAART on HIV-associated pulmonary hypertension. With the increased use of HAART for HIV it will be interesting to note whether a measurable change occurs in prevalence of HIV-associated pulmonary hypertension. Investigations of the effects of vasodilators on the natural history of HIV-associated pulmonary hypertension are also needed. Especially important is understanding the effects, if any, of therapy with prostacyclin and its analogues on HIV viral load and on HAART.

In the interim, without supporting evidence, we recommend screening with transthoracic echocardiogram for all HIV-infected persons with unexplained shortness of breath or syncope. Furthermore, we recommend the initiation of combination antiretroviral therapy in all HIV-infected patients with pulmonary hypertension irrespective of CD4 counts or viral load. Initiation of continuous intravenous epoprostenol for all patients with NYHA class III or IV symptoms who fail to respond to calcium channel blockers seems prudent.

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KEY POINTS

* Many patients with HIV-associated pulmonary hypertension have other known risk factors for the condition, such as intravenous drug abuse or chronic liver disease.

* The incidence of pulmonary hypertension in HIV-positive persons is several thousand times greater than in the general population.

* There appears to be no correlation between either CD4 count or the stage of HIV infection and the prevalence or severity of pulmonary hypertension.

* The etiology remains unknown, but its development is thought to require both a genetic predisposition and a precipitating event.

* Few reports describe the efficacy of treatment for pulmonary hypertension in HIV, and there have been reports of progression despite effective antiretroviral therapy and a low viral load.

* Screening with transthoracic echocardiogram for all HIV-infected persons with unexplained shortness of breath or syncope is recommended.