Pulmonary Hypertension and Human Immunodeficiency Virus Infection

Pulmonary Hypertension and Human Immunodeficiency Virus Infection* Two Reports and a Review of the Literature Peter G. Polos, M .D. , Ph.D.; Douglas Wolfe, ;\ I.D.; Russell A. lIarley, M .D., FC.C .P.; Charlie Strange, M.D. , FC.C.P.; and Steven A. Sa/Ill, Jf.D ., FC.C.P. Pulmonary hypertension may be primary (idiopathic) or secondary. While the etiologies for secondar y pulmonary hypertension are diverse, infection with the human immunodeficiency virus (HIV) has not been included. To date there have been 16 reported cases of pulmonary hypertension in the HIV-infected population. Plexogenic arteriopathy was the most common pathologic finding. We report two HIV-infected patients who were concomitantly found to have pulmonary hypertension with plexogenic arteriop-

athy. One patient had lymphocytic interstitial pneumonitis, an entity not previously associated with pulmonary hypertension. We review the 16 previous cases of pulmonary hypertension and HIV infection and discuss this association. (Chest 1992; 101:474-78)

the first case of a patient with acquired Sinceimmunodeficiency syndrome (AID S) was reported

Wdl; hematocrit, 46 percent; platelet count , 69 X Hl"/cu rnm : leukocyt e count , 4.1 X }O' mm' with 52 percent segmented ce lls and 48 percent lymphocytes. Room air blood gas valu es revealed a pH of 7.46, Pco, of 24 mm Hg .and Po , of Il8 mm I1~. The elect roca rdiogram showed sinu s tachycardia , right atrial e nlarge me nt , right ventricular hypertrophy; and left posterior hernihlock. Th e hospital ad mission chest roentgenogram showed cardiomegaly and prominent pulmonary ar teries without infiltrates. A right heart catheterization demonstrated a pulmonary ar te ry pressure of 72138mm II/.((Table 1). Therapeutic tri als of}OO percent oxygen and sublingual nifedipine had no effect on pulmonary art eri al pressur e or pulmonary vascular res istance . Th e hospital course included a workup for and diagnosis of type 3 mixed crvoglohulinem ia. An open lung biopsy specimen show ed severe pulmonary vascular dis ease involving small muscular ar te ries. Intimal proliferation was noted , and plex iform lesions were found with dilat ed distal pulmonary arteries (Fig 1). Examination hy polari zed light revealed a minimal amount of bir efringent material in and about vessels, consistent with the history of intravenous drug use , ye t incongruous with the severity of th e plexogenic ar te riopathy (Fig 2). Lymphocyte predominant focal int erstitial and peribronchial inflammatory infiltrates were pr esent , hut the majority of alveolar and interstitial tissues were normal. Six months aft er biops y, the patient was readmitt ed to the hospital

in 1981, our knowledge of th e diversity of the protean manifestations of this syndrome has expanded continually. The spectrum of clinical states includes opportunistic and nonopportunistic infections, neurologic abnorm aliti es, and constitutional syndromes. The lungs , the primary site for infectious complications of AIDS, I are also involved by a variety of noninfectious cardiopulmonary manifestations, including cardiomyopathy, pericardia] and pleural effusions, pulmonary thromhoembolism, and cor pulmonale .s-' \\'e report two human immunodeficiency virus (Hl'Vl-infected patients with severe pulmonary hypertension in association with plexogenic arteriopathy. One of th ese patients had AIDS . In addition, one of the two patients was found to have lymphocytic interstitial pneumon itis (LIP) and pulmonary vasculitis. 1i1 our knowledge, the association between LIp, pulmonary hypertension , pulmonary vasculitis, and plexogenic arteriopathy has not been reported previously. Finally, we review the literature pertaining to pulmonary hypertension and HIV infection.

=

~TP i.d!opathic thro."?bocytopenic purpura; LIP interstitial pneumonitis

=lymphocytic

CASE REI'OHTS CASE

I

A :3.'5-",·a r-old white man with a historv of int ravenous drug use was 'l(Ir~illt'd for dyspnea. cough , anti Iatigue of four months' duration . Appearance and vital si/.(n s were normal. Card iac examination reveal ed a loud 1'2 and /.(rade 316 holosystolic murmur along the left sternal borde r compatible with tri cuspid ref..,'urgitation . Pertinent laboratorv fiud ings were as follows: hemoglobin. 15.3

*From th e Medical Uni versitv of South Carolina, Divis ion of Pulmonarv and Critical Care Medicine , Charleston. Manuscr ipt rec eived March 21>; revision acc epted June 2i. Reprint requests: Dr. Polus. Medi cal University of South Cllmlinll , Charleston 29-12.5

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FIt: lIRt: 1. Plexiform lesion of small muscular pulmonary artery (hematoxylin-eosin , original magn ification X 2(0). Pulmonary Hypertension and HIV Infection (Fblos elal)

Table I-Profiles of 18 HIV-Positive Patients with PulfTWnary Hypertension* Patient Age , yr

U24 2/23 3/52

4156 5/25 6148 7131 8138 9/38 10140 lU30 12135 13138 14/43 15/44 16149 17/35 18128

HlY Risk

AIDS Diagnosis

Hemophilia Hemophilia Hemophilia Hemophilia Hemophilia Homosexual Bisexual Homosexual Homosexual Homosexual Bisexual IVDA Homosexual IYDA Homosexual Homosexual IVDA IVDA Sexual contact

None None None None None KS None None None PCP Dementia PCP PCp, ITP KS PCp, CMV Dementia PCP None

Infections

PaO,

Abnormality

RAP

PAP/SO

PAP Mean

Dyspnea None Dyspnea None Dyspnea None Dyspnea None Dyspnea None None Dyspnea Dyspnea None Dyspnea None None Edema Dyspnea, edema PCP Strep, Kleb Dyspnea PCp, Strep Dyspnea Dyspnea, edema PCP Dyspnea, edema None PCp, CMV Dyspnea Dyspnea Bronchitis Dyspnea PCP Dyspnea None

NR NR NR 81 88 NR NR NR NR NR 67 51 66 73 62

Ip, PL NR IP, PL NR NR MH, PL NR NR PL PL NR Fibrosis NR NR Fibrosis NR Ip, PL LIp, PL

30 14 14 14 20 NR NR NR NR 10 30 14 16 14

106160 85/45 55/34 90/40 80/40 50/22 6U44 86140 84 70/40 67/43 68122 51/31 100150 56/38 NR 72/38 103/42

71l 60 42 57 50 NR NR NR NR NR 48 34 38 66 42 60 49 62

Symptoms

Lun~

53 87 89

Lun~

III

NR 13 17

PAWP CO 10 9 7

s

NR 6 4 6 NH 10 17 Il 12 12 12 NR 17 15

PVR

NR NR NR 1060 NR 400 NR 7114 NR NR NR NR NH NH NR NH NH NH NR NH 3.5 709 3.2 Mil 3.1l 555 3 1440 55,'} 4.5 NR NR NH IlO4 NH 779

*NR = not reported; Ip, PL= intimal proliferation, plexogenic lesions ; MH , PL = medial hypertrophy, plexogenic lesions; PL = plexogenic lesions; LIp, PL=lymphocytic pneumonitis, plexogenie lesions ; RAP=right atrial pressure, mm H~; CO=cardiac output, Umin; PAWP= pulmonary artery wedge pressure, mg H~; PAP = pulmonary artery pressure, systolic/diastolic, mm H~; PVR = peripheral vascular resistance, dynes S cm-", HIV = human immunodeficiency virus; AIDS = acquired immunodeficiency syndrome; IVDA = intravenous drug abuse; PCP = Pneumocqstis carinii pneumonia; ITP = idiopathic thrombocytopenic purpura; KS = Kaposi's sarcoma: CMV = Cytomegalovirus. patients 1-5, ref6; patients 6-9, refS; patient 10, ref 4; patients 11-16, ref3; and patients 17 and Ill, see text. for dyspnea and fever. The HIV serologic tests were positive. Bronchoscopy was diagnostic for Pneumocqstis carinii . The patient responded to intravenous sulfamethox3Zole-trimethoprim, with resolution of fever and dyspnea. He died six months after hospital discharge from progressive pulmonary hypertension.

A 28-year-old black woman presented in November 1989 with dyspnea on exertion, hemoptysis, menorrhaghia, and severe thrombocytopenia. The chest roentgenogram and computed tomographic (Cf) scan revealed hilar adenopathy and bilateral interstitial infiltrates. She was diagnosed as having immune thrombocytopenia, given a ten-day course of corticosteroid therapy, and placed on a regimen of oral contraceptives with resolution of the thrombocytopenia and menorrhaghia. Bronchoscopy and results of transbronchial biopsies were normal. Three months later, she was referred to our institution with complaints of increasing dyspnea on exertion. The HIV serologic tests were positive. She admitted sexual contact with a known intravenous drug abuser, but denied self use . Physical examination revealed an obese woman with a pulse of

loo/min, and temperature of 36.9°C. The hospital admission chest roentgenogram remained unchanged from her previous roentgenogram . Repeated bronchoseopic examination with transbronchial biopsy showed diffuse interstitial inflammation. Bronchoalveolar lavage revealed 62 percent lymphocytes, 30 percent neutrophils, and 8 percent macrophages, Open lung biopsy specimens showed scattered telangiectasis on the lung surface without si~ns of fibrosis or nodularlty Three hundred milliliters of straw-colored fluid was removed from the pericardial sac and a pericardial window was done . Culture and cytologic study of the fluid were negative. Pathologic examination of the open lun~ biopsy specimen (Fi~ 3 and 4) revealed extensive lymphocytic interstitial pneumonitis, especially associated with bronchioles, but extending into alveolar walls and interstitial structures. There was extensive muscular hypertrophy and focal intimal sclerosis of the pulmonary arteries. Occasional plexiform lesions were noted (Fig 5), and foci of acute necrotizing vasculitis were seen (Fi~ 6). On the second postoperative day, she became hypotensive and tachypneic. In the intensive care unit, a pulsus paradoxus of30 mm H~ was noted and a flow-directed pulmonary artery catheter W'LS placed. Pulmonary artery pressures of 103/42 mm H~ failed to

FIGURE 2. Birefringent material in wall of small pulmonary artery (hematoxylin-eosin, original magnification x 200, partially polarized light).

FIGURE 3 . Lymphocytic interstitial pneumonia (LIP) in open biopsy specimen of human immunodeficiency virus (HIV)-positive patient (hematoxylin-eosin, original magnification x BO).

CASE

2

CHEST I 101 12 I FEBRUARY, 1992

475

FICIIIlE 4. Plexiform lesions of small muscular pulmonary artery, in association with lymphocytic interstitial pneumonia (LIP) and moderate vasculitis (hematoxylin-eosin, original magnification X 200).

decrease with !OO percent oxygen and nifedipine (Table 1). After clinical improvement, she was discharged [rom the hospital on a regimen of aerosolized pentamidine, zidovudine, prednisone, and nifedipine . lIer course has heen stahle for ten months since hospital discharge . DISCUSSION

We report two HIV-infected patients, one with AIDS, who had pathologic and hemodynamic confirmation of pulmonary hypertension. One of the two patients also had LIP. Pulmonary hypertension in the HIV-infected patient appears to be rare, with 18 cases reported since 1981. 3 -6 Table 1 summarizes the findings in these cases. The mean age of the patients was 37.5 years and they reflect all the major risk factors for HIV positivity. Dyspnea was the most common presenting symptom. The majority had no lung infection at the time of

FI(;lIIlE S. Vasculitis of small pulmonary vessel (hematoxylin-eosin, original magnification x 4(0).

476

diagnosis, a surprising finding given the incidence of pulmonary infection in these patients. Within the limits of the interpretation of a single Pa0 2, hypoxic pulmonary vasoconstriction is an unlikely mechanism for the pulmonary hypertension, as only two patients had significantly reduced oxygen tensions. Pulmonary artery systolic pressures ranged from 50 to 106 mm Hg, and only two patients had marginally elevated pulmonary capillary wedge pressures. Pathologic confirmation of pulmonary hypertension was obtained in 9 of the 18 patients; 7 were described as plexogenic pulmonary arteriopathy. Plexogenic arteriopathy has been associated with primary pulmonary hypertension and hypertension secondary to congenital cardiac shunts, portal hypertension, and aminorex fumarate ingestion. 7 In addition, conditions in which diffuse emboli may obliterate the majority of the vascular bed, such as pulmonary schistosomiasis, hydatid cysts, or talc from intravenous drug use, may produce plexogenic changes." The first patient had a history of intravenous drug use . The lung biopsy specimen showed only rare foreign body material on examination with polarized light. The amount of talc was less than is usually associated with pulmonary hypertension, with only scant crystals being seen. Furthermore, plexiform lesions were found in areas where there was no evidence of talc or foreign material. At the time of this patient's diagnosis of plexogenic arteriopathy, serologic tests for HIV were not done . On readmission to the hospital six months later, HIV serologic tests were positive . It is likely that he was seropositive at initial presentation, given the short interval between hospital admissions, and that HIV infection may have been causal in the development of his pulmonary hypertension . It is rare to observe pathologic evidence of pulmonary hypertension without concomitant evidence of the presence of substantial talc crystals; this suggests an alternative cause for this patient's hypertension. Cryoglobulinemia is an unlikely cause as it has not been associated with pulmonary hypertension.? The second patient demonstrated severe pulmonary hypertension, plexogenic arteriopathy, and LIp, in the setting of HIV-induced idiopathic thrombocytopenic purpura (ITP). LIp, first reported by Carrington and Liebow'? in 1966, is a distinct interstitial pneumonitis characterized by massive numbers of lymphocytic cells in the interstitial space, with occasional formation of noncaseating granulomas, perivascular and paraseptal amyloid deposition, and lymphoid germinal centers. ll . 12 LIP has been associated with a number of disease states, and, when present with HIV seropositivity in children younger than 13 years of age, establishes a diagnosis of AIDS .13 However, LIP with HIV infection does not meet the case definition for Pulmonary Hypertension and HIV Infection (Polos et al)

AIDS in adults. Other disease states with which UP has been associated include dysproteinemia.v-" hypogammaglobulinemia in adults's and children, 17 Sjogren's syndrome," monoclonal gammopathy 19 and systemic lupus erythematosus (SLE)20; however, pulmonary hypertension or plexogenic arteriopathy has not been demonstrated in these disease states or in those UP cases associated with pediatricll l . l!3 or adult AIDS .l!4-1I8 Whereas perivascular lymphocytic infiltration, and even penetration of vessel walls by lymphocytes has been observed in Up, a necrotizing vasculitis, as found in our case, has not been documented. It is unlikely that rare areas of platelet thrombosis seen in this patient could have accounted for the degree of hypertensive changes. Furthermore, to our knowledge, there is no association between pulmonary hypertension and ITP. Considering the unusual occurrence of UP and plexogenic arteriopathy in the same patient, it seems likely that the vasculitis may have resulted in either vasoconstriction or a sufficient degree of vascular wall damage to result in pulmonary hypertension and initiate the plexogenic process. The pathogenesis of pulmonary hypertension in HIV-infected patients has not been elucidated; however, an immunologic response to the HIV infection is a plausible explanation. Viral-induced mechanisms have been suggested by several authors. 6.l18-2lI We cannot exclude the possibility of primary pulmonary hypertension occurring in these patients. To our knowledge, the incidence in the general population has not been reported; however, the rate in patients undergoing right heart catheterization has been reported to be 1.1 percent." It is not clear how diligently pulmonary hypertension has been searched for in the HIV-infected population. Possibly, longer survival following HIV infection will lead to an increased incidence. In summary, we report plexogenic pulmonary arteriopathy in two patients with HIV infection, one of whom had UP. There have now been 18 reported cases of pulmonary hypertension in HIV-infected patients and patients with AIDS, seven with a pathologic diagnosis of plexiform arteriopathy, and now one report of UP in association with pulmonary hypertension. The cause of pulmonary hypertension in HIV infected patients is unclear. While HIV infection is the likely mechanism, it is premature to conclude that pulmonary hypertension in these patients is a distinct HIV-related phenomenon. ACKNOLWEDGMENTS: The authors wish to express their thanks to Deborah Stokes and Viclde Plunkett, R.N., for their assistance with this manuscript. REFERENCES 1 Murray JF, Mills J. Pulmonary infectious complications of human immunodeficiency virus infection. Am Rev Respir Dis 1990;

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7th World Congress for Bronchology 7th World Congress of Bronchoesophagology This world congress will be held at the Mayo Clinic and Mayo Medical Center, Rochester, Minnesota , September 28-0ctober 2, 1992. Deadline for submission of abstracts is May 15, 1992. The congress will be jointly sponsored by the ACCp, the World Association for Bronchology, the International Bronchoesophagological Society, and the American BronchoEsophagological Association. For information, contact Dr. Udaya Prakash, Secretary General and Director, East-lB , Mayo Clinic, Rochester, Minnesota 55905.

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Pulmonary Hypertension and HIV Inlection (PoIo8 et 81)