On 8 Jan 2007 04:29:39 -0800, "joyo" <kqurtyhar@gmail.com> wrote:
http://www.medscape.com/viewarticle/410809
Pulmonary Hypertension Associated With HIV Infection
Leonardo Seoane, MD, Judd Shellito, MD, David Welsh, MD, Bennet P.
Deboisblanc, MD, Section of Pulmonary/Critical Care Medicine,
Louisiana State University Health Sciences Center, New Orleans
South Med J 94(6):635-639, 2001. © 2001 Southern Medical Association
Abstract and Introduction
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 alert to
possible pulmonary hypertension in persons infected with HIV.
Introduction
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 HIV 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%, nonhemophiliac
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/mm3 (mean, 269/mm3).[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 ± 5 vs 42 ± 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 ± 11 vs
62 ± 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/mm3), 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 < .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 al[29] were not able to identify
either HIV-1 p24 antigen or the HIV gag RNA in pulmonary arteries of
patients with HIV-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-a (PDGF-), in
persons with HIV infection and pulmonary hypertension but not in
HIV-infected persons without pulmonary hypertension. They have
suggested a role for PDGF-, which induces smooth muscle and fibroblast
proliferation, in the pathophysiology of pulmonary hypertension.[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 Sjögren'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
effective 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 group. 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.
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.
References
1. Mitchell DM, Miller RF: AIDS and the lung: new developments in
pulmonary diseases affecting HIV infected individuals. Thorax 1995;
50:294-302
2. Meduri GU, Stein DS: Pulmonary manifestations of acquired
immunodeficiency syndrome. Clin Infect Dis 1992; 14:98-113
3. Kim KK, Factor SM: Membranoproliferative glomerulonephritis and
plexogenic pulmonary arteriopathy in a homosexual man with acquired
immunodeficiency syndrome. Hum Pathol 1987; 18:1293-1296
4. Goldsmith GH Jr, Baily RG, Brettler DB, et al: Primary pulmonary
hypertension in patients with classic hemophilia. Ann Intern Med 1988;
108:797-799
5. Mani A, Smith GJ: HIV and pulmonary hypertension: a review.
South Med J 1994; 87:357-362
6. Coplan NL, Shimony RY, Iochim HL, et al: Primary pulmonary
hypertension associated with human immunodeficiency viral infection.
Am J Med 1990; 89:96-99
7. Polos PG, Wolf D, Harley RA, et al: Primary pulmonary
hypertension and human immunodeficiency virus infection: two reports
and a review of the literature. Chest 1992; 101:474-478
8. Tomashefski JF Jr, Hirsch CS: The pulmonary vascular lesions of
intravenous drug abuse. Hum Pathol 1980; 11:133-145
9. Arnett EN, Battle WE, Russo JV, et al: Intravenous injection of
talc-containing drugs intended for oral use: a cause of pulmonary
granulomatosis and pulmonary hypertension. Am J Med 1976; 60:711-718
10. Mesa RA, Edell ES, Dunn WF, et al: Subspecialty clinics: human
immunodefiency virus infection and pulmonary hypertension: two new
cases and a review of 86 reported cases. Mayo Clin Proc 1998; 73:37-45
11. McDonnell PJ, Toye PA, Hutchins GM: Primary pulmonary
hypertension and cirrhosis: are they related? Am Rev Respir Dis 1983;
127:437-441
12. Hadengue A, Benhamon MK, Lebrec D, et al: Pulmonary hypertension
complicating portal hypertension: prevalence and relation to
splanchnic hemodynamics. Gastroenterology 1991; 100:520-528
13. Rubin LJ: Primary pulmonary hypertension. N Engl J Med 1997;
336:111-117
14. Himelmann RB, Dohrmann M, Goodmann P, et al: Severe pulmonary
hypertension and cor pulmonale in the acquired immunodeficiency
syndrome. Am J Cardiol 1989; 64:1396-1399
15. Speich R, Jenni R, Opravil M, et al: Primary pulmonary
hypertension in HIV infection. Chest 1991; 100:1268-1271
16. Mehta NJ, Ijaz KA, Rajal N, et al: HIV-related pulmonary
hypertension analytic review of 131 cases. Chest 2000; 118:1133-1141
17. Golpe R, Fernandez-Infante B, Fernandez-Rozas S: Primary
pulmonary hypertension associated with human immunodeficiency virus
infection. Postgrad Med J 1998; 74:400-404
18. Petitpretz P, Brenot F, Azarian R, et al: Pulmonary hypertension
in patients with human immunodeficiency virus infection: comparison
with primary pulmonary hypertension. Circulation 1994; 89:2722-2727
19. Opravil M, Pechere M, Speich R, et al: HIV-associated primary
pulmonary. a case control study. Am J Respir Crit Care Med 1997;
155:990-995
20. Rubin LJ: Primary pulmonary hypertension. Chest 1993;
104:236-250
21. D'Alonzo GE, Barst RJ, Ayres SM, et al: Survival in patients
with primary pulmonary hypertension: results from a national
prospective registry. Ann Intern Med 1991; 155:343-349
22. Pietre GG: Histopathology of primary pulmonary hypertension:
Chest 1994; 105(suppl 2):2s-6s
23. Rich S, Brundage B: Pulmonary hypertension: a cellular basis for
understanding the pathophysiology and treatment. J Am Coll Cardiol
1989; 14:545-550
24. Rubin LJ: Pathology and pathophysiology of primary pulmonary
hypertension. Am J Cardiol 1995; 75:51A-54A
25. Rich S: Clinical insights into the pathogenesis of primary
pulmonary hypertension. Chest 1998; 114:237S-241S
26. Voelker NF, Tuder RM: Cellular and molecular mechanisms in the
pathogenesis of severe pulmonary hypertension. Eur Respir J 1995;
8:2129-2138
27. Cool CD, Kennedy D, Voelkel NF, et al: Pathogenesis and
evolution of plexiform lesions in pulmonary hypertension associated
with scleroderma and human immunodeficiency virus infection. Hum
Pathol 1997; 28:434-442
28. Cool CD, Stewart JS, Werahera P, et al: Three-dimensional
reconstruction of pulmonary arteries in plexiform pulmonary
hypertension using cell-specific markers. Am J Pathol 1999;
155:411-419
29. Mette SA, Palevsky HI, Pietra GG, et al: Primary pulmonary
hypertension in association with HIV infection. a possible viral
etiology for some forms of hypertensive pulmonary arteriopathy. Am Rev
Respir Dis 1992; 145:1196-2000
30. Tuder RM, Weinberg A, Bates TO, et al: Tat-protein of HIV
enhances inflammatory cell binding and PDGF levels in CMV infected
endothelial cells (Abstract). Circulation 1994; 90:I-417
31. Ehrenreich H, Rieckmann P, Sinowatz F, et al: Potent stimulation
of monocytic endothelin-1 production by HIV-1 glycoprotein 120. J
Immunol 1993; 150:4601-4609
32. Hofmann FM, Wright AD, Dohadwala MM, et al: Exogenous tat
protein activates endothelial cells. Blood 1993; 82:2774-2780
33. Humbert M, Monti G, Fartoukh M, et al: Platelet derived growth
factor expression in primary pulmonary hypertension: comparison of HIV
seropositive and HIV seronegative patients. Eur Respir J 1998;
11:554-559
34. Chalifoux LV, Simon MA, Pauley DR, et al: Arteriopathy in
macaques infected with simian immunodeficiency virus. Lab Invest 1992;
67:338-349
35. Gillespie MN, Hartsfield CL, O'Conner WN, et al: Pulmonary
hypertension in a murine model of AIDS. Am J Respir Crit Care Med
1994; 150:194-199
36. Morse JH, Barst RJ, Itescu S, et al: Primary pulmonary
hypertension in HIV infection: an outcome determined by particular HLA
class II alleles. Am J Respir Crit Care Med 1996; 153:1299-1301
37. Morse JH, Jones AC, Barst RJ, et al: Mapping of familial primary
pulmonary hypertension locus (PPH1) to chromosome 2q31-q32.
Circulation 1997; 95:2603-2606
38. Nichols WC, Koller DL, Slovis B, et al: Localization of the gene
for familial primary pulmonary hypertension to chromosome 2q31-32. Nat
Genet 1997; 15:277-280
39. Deng Z, Haghighi F, Helleby L, et al: Fine mapping of PPH1, a
gene for familial primary pulmonary hypertension, to a 3-cM region on
chromosome 2q33. Am J Resp Crit Care Med 2000; 161:1055-1059
40. Deng Z, Morse JH, Slager SL, et al: Familial primary pulmonary
hypertension (gene PPH1) is caused by mutations in the bone
morphogenetic protein receptor-II gene. Am J Hum Genet 2000;
67:737-744
41. Machado RD, Pauciulo MW, Thompson JR, et al: BMPR2
haploinsufficiency as the inherited molecular mechanism for primary
pulmonary hypertension. Am J Hum Genet 2001; 68:92-102
42. Pellicelli AM, Palmieri F, D'Ambrosio C, et al: Role of human
immunodeficiency virus in primary pulmonary hypertension -- case
reports. Angiology 1998; 49:1005-1011
43. Rich S, Kaufmann E, Levy PS: The effect of high dose
calcium-channel blockers on survival in primary pulmonary
hypertension. N Engl J Med 1992; 327:76-81
44. Louis M, Thorens JB, Chevrolet JC: Calcium channel blockers.
testing for primary pulmonary hypertension associated with HIV
infection (Abstract). Am Rev Respir Dis 1993; 147:536A
45. Shapiro SM, Oudiz RJ, Cao T, et al: Primary pulmonary
hypertension: improved long-term effects and survival with continuous
intravenous epoprostenol infusion. J Am Coll Cardiol 1997; 30:343-349
46. Barst RJ, Rubin LJ, McGoon MD, et al: A comparison of continuous
intravenous epoprostenol (prostacyclin) with conventional therapy for
primary pulmonary hypertension. Primary Pulmonary Hypertension Study
Group. N Engl J Med 1996; 334:296-302
47. Stricker H, Domenighetti G, Mombelli G: Prostacyclin for
HIV-associated pulmonary hypertension (Letter). Ann Intern Med 1997;
127:1043
48. McAllister RG, Crow JW, Wade M, et al: International multicenter
double blind randomized parallel placebo controlled comparison of the
safety and effects of chronic subcutaneous UT-15 plus conventional
therapy to conventional therapy in patients with primary pulmonary
hypertension. Research Triangle Park, NC, United Therapeutics Corp,
1999
49. Roux S: Double blind randomized placebo controlled study to
assess the effects of Ro 47-0203 (Bosentan) on exercise capacity in
patients with pulmonary artery hypertension. Voorhees, NJ, Hesperion
USA, 2000
Reprint Address
Reprint requests to Leonardo Seoane, MD, 1901 Perdido St, Suite 3205,
New Orleans, LA 70112.
