Clinical Manifestations and Diagnosis of HIV-Associated Pulmonary Hypertension

In the largest clinical series of HIV-associat­ed pulmonary hypertension, 47-54% of all

Table 1 Pathogenetic hypotheses of HIV-associated pulmonary hypertension

Pathogenetic hypothesis

Clinical evidence

Cytokines hypothesis (Fig.

αι-Adrenergic hypothesis (Fig. 3)

Toxic substances

Liver disease and HIV-associated pulmonary hypertension

Several studies have found an increased production of cytokines-e.g., endothelin-1 (ET-1), interleukin-6 (IL-6), interleukin-1-beta (IL-1b), plateletderived growth factor (PDGF), and tumor necrosis-factor-alpha (TNF-α)-in patients affected by primary pulmonary hypertension, evok­ing a potential role of these substances in the pathogenesis of the disease [6-9].

In HIV-infected patients different factors can induce a chronic stimulation of α₁-adrenoreceptors of the pulmonary vasculature, including: chronic hy­poxia, high circulating levels of norepinephrine, appetite suppressant agents, or cocaine use. The chronic stimulation of pulmonary vascular α₁-adrenore- ceptors can induce the local production of a large amount of cytokines, par­ticularly ET-1, IL-1b, IL-6, and PDGF, which in turn stimulate the growth of new pulmonary capillaries, induce vasoconstriction of resistance-sized pul­monary arteries, and have an anti-apoptosis effect [10].

Patients with a history of chronic intravenous drug use may develop pul­monary hypertension. Pulmonary artery thrombosis is the main patholog­ical finding in such conditions, and is believed to be due to foreign parti­cle pulmonary emboli, following injections of solutions derived from heroin or from crushed oral medications in which talc was a frequent component [11, 12].

The use of appetite suppressant agents and/or cocaine has been associat­ed with pulmonary hypertension, even in HIV-infected patients, possibly as a consequence of an increased α1-adrenoreceptor stimulation [12, 13].

Porto-pulmonary hypertension is now a well-described disease character­ized by a clinical and hemodynamic picture substantially identical to pri­mary pulmonary hypertension. In liver cirrhosis, an increased production and a decreased metabolism of some cytokines (e.g., ET-1) have been reported.

Kuddus et al. demonstrated that an enhanced synthesis and a reduced metabolism of ET-1 in hepatocytes can be an important mechanism of elevated endogenous and circulating ET-1 in patients affected by liver cirrhosis [14, 15].

Pellicelli et al. reported higher values of systolic pulmonary arterial pres­sure in HIV-infected patients with HCV/HBV-associated liver cirrhosis compared to other HIV-infected patients without cirrhosis [12].

Genetic factors (HLA antigens)

In a study conducted by Morse and co-workers, it was found that in ten racially mixed HIV-infected patients with HIV-associated pulmonary hypertension, there was a significant increase in the frequency of human leukocyte antigen (HLA) class II DR52 and DR6, and of the linked alle­les HLA-DRB1-1301/2, -DRB3-0301, -DQB1 0603/4, compared to the fre­quencies of the same alleles in normal Caucasian control subjects [16]. HLA-DR6 and its DRB1-1301/2 subtypes were also significantly increased in HIV-associated pulmonary hypertension patients compared to the respective frequencies of racially diverse HIV-positive control subjects. Furthermore, HLA-DR6 and the DRB1-1301 subtype have also been reported to increase in HIV-positive patients who develop diffuse infiltra­tive lymphocytosis syndrome [17, 18]. It is possible that both entities rep­resent different spectra of a common HLA-DR-determined host response to HIV-1.

Fig. 2 The possible pathogenetic mechanisms in­volved in the development of HIV-associated pul­monary hypertension. HIV-infected macrophages, platelets, and lymphocytes may release multifunc­tional cytokines-endothelin-1 (ET-1), platelet-de­rived growth factor (PDGF), interleukin-6 (IL-6), in­terleukin-1 beta (IL-1b), tumor necrosis factor al­fa (TNF-α)-which may affect the endothelial cells of the pulmonary vessels, inducing their prolifera­tion and vasoconstriction by a reduction of nitric oxide (NO) production.

Fig. 3 Chronic stimulation of α1-adrenoreceptors of the pulmonary vasculature can induce the local pro­duction of a large amount of cytokines and particularly of ET-1, IL-1b, IL-6, and PDGF, which in turn stim­ulate the growth of new pulmonary capillaries, induce vasoconstriction of resistance-sized pulmonary arteries, and have an anti-apoptosis effect. (From [21], with permission from Wiley-Blackwell)

the patients were male, and the age at the time of diagnosis ranged from 2 to 56 years (mean 33 years). Intravenous drug use was the most common risk factor and ranged from 50 to 58%, while homosexual behavior was present in 20% of the patients, hemo­philia in 9%, heterosexual contacts in 9%, and other risk factors in 6% of the patients [2, 11, 12], reflecting the epidemiology of HIV infection in the general population. The mean CD4+ count was 300 mm³ (range 0-937/mm³). Currently, no correlation has been found between the CD4+ count and the presence of opportunistic infections and the development of pulmonary hypertension.

The most common presenting symptom was dyspnea (from 49 to 85%), while pedal edema ranged from 11 to 30% of the patients, nonproductive cough from 7 to 19%, syncope from 8 to 12%, and chest pain was present in 7% of the patients. Raynaud’s syndrome, which is more frequently found in patients affected by pulmonary hypertension associated to connective tissue disease, was present in only one patient (1%) [2,12].

Signs of pulmonary hypertension on physical examination are subtle and often overlooked. An accentuated pulmonary component of the second heart sound, audi­ble at the apex, may be noted in more than 90% of patients, reflecting an increased force of pulmonary valve closure due to ele­vated pulmonary artery pressure [19]. Other signs of increased pulmonary artery pres­sure may include the following [19]:

a.

b. A midsystolic ejection murmur caused by turbulent transvalvular pulmonary flow

c. A palpable left parasternal lift produced by the impulse of the hypertrophied high-pressure right ventricle

d. A right ventricular S4 gallop

e. A prominent jugular “a” wave suggesting high right ventricular filling pressure Physical signs of more advanced disease

include the diastolic murmur of pulmonary regurgitation and the holosystolic murmur of tricuspid valve regurgitation, which is audible at the lower left sternal border and augmented with inspiration. A right ventric­ular S3 gallop, marked distension of the jugular veins, pulsatile hep atomegaly, peripheral edema, and ascites are indicative of right ventricular failure [19]. The princi­pal diagnostic tests used for diagnosis of HIV-associated pulmonary hypertension with related clinical verification are report­ed in Table 2.

Table 2 Principal diagnostic tests for diagnosis of HIV-associated pulmonary hypertension

cont. →

Table 2 cont.

Table 3 Treatment of HIV-associated pulmonary hypertension

Table 3 cont.

Fig. 4 ECG recording in a patient with HIV-associated pulmonary hypertension. A right-axis deviation (S1Q3T3 aspect or McGinn-White sign) along with tall, prominent P waves in leads II, III, aVF (secondary to right atrial enlargement) and complete right bundle branch block is evident

Fig. 5 Chest radiogram in a patient with HIV-associated pulmonary hypertension. A prominent main pulmonary artery along with enlarged hilar vessels (arrow) accompanied by a decrease in peripheral vessels and cardiomegaly is evident. (From [28], with permission from Wiley- Blackwell)