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Journal of Clinical Virology 37 (2006) 79–82

Occult lymphadenopathic Kaposi’s sarcoma associated with severepulmonary hypertension: A clinical hint about the potential role

of HHV-8 in HIV-related pulmonary hypertension?

Felix Gutierrez a,∗, Mar Masia a, Sergio Padilla a, Jose M. Ramos a, Enrique Bernal a,Pilar Morales b, Francisco Pozo c, Encarnacion Andrada d, Alberto Martin-Hidalgo a

a Infectious Diseases Unit, Internal Medicine Department, Hospital General Universitario de Elche, Alicante, Spainb Respiratory Medicine, Hospital Universitario La Fe, Valencia, Spain

c Virology Laboratory, Centro Nacional de Microbiologıa, Instituto de Salud Carlos III, Madrid, Spaind Pathology Department, Hospital General Universitario de Elche, Alicante, Spain

Received 6 December 2005; received in revised form 30 May 2006; accepted 30 May 2006

bstract

Severe pulmonary hypertension (PH) mimicking idiopathic PH is an increasingly recognized complication of human immunodeficiencyirus (HIV) infection. PH shares several histopathologic features with Kaposi’s sarcoma (KS), the most common malignancy in AIDS patients,nd molecular evidence of the vasculotropic Kaposi’s sarcoma-associated herpesvirus or human herpesvirus 8 (HHV-8) has been found in theung tissue of patients with the disease. Although the prevalence of HHV-8 infection is increased among HIV-infected patients, no clinicalssociation between KS and PH has ever been reported. Herein, we described a 30-year-old HIV-infected female co-infected with HHV-8ho developed severe PH coincident with occult KS. The clinical presentation of KS was unusual and remained masqueraded for years as

n indolent cervical lymphadenopathy, without the typical cutaneous lesions. This is the first ever-reported case of PH associated with KS.lthough the co-occurrence of both diseases in this patient could have been just a coincidence, the observation may also indicate that a

elationship between HHV-8 infection and HIV-associated PH exists. Coinfection with HHV-8 and occult lymphadenopatic KS should beonsidered in HIV-infected patients developing PH.

2006 Elsevier B.V. All rights reserved.

eywords: Kaposi’s sarcoma; Pulmonary hypertension; Human herpesvirus 8; HHV-8; HIV; AIDS

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. Introduction

The role of the vasculotropic Kaposi’s sarcoma-associatederpesvirus or human herpesvirus 8 (HHV-8) in pulmonary

ypertension (PH) remains unclear. Although molecular evi-ence of HHV-8 was found in the lung tissue of patients withdiopathic PH by Cool et al. (Cool et al., 2003), recent dataave not supported a significant role for HHV-8 infection in

∗ Correspondence to: Unidad de Enfermedades Infecciosas, Hospital Gen-ral Universitario de Elche, Camı de la Almazara S/N, 03203 ELCHE,licante, Spain. Tel.: +34 96 667 91 54; fax: +34 96 667 91 56.

E-mail address: gutierrez fel@gva.es (F. Gutierrez).

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386-6532/$ – see front matter © 2006 Elsevier B.V. All rights reserved.oi:10.1016/j.jcv.2006.05.011

his disease (Daibata et al., 2004; Henke-Gendo et al., 2005;atano et al., 2005; Laney et al., 2005).PH is an increasingly recognized complication of HIV

nfection (Himelman et al., 1989; Mehta et al., 2000; Mettet al., 1992; Opravil et al., 1997; Petitpretz et al., 1994;osenkranz et al., 2005). The mechanism for the develop-ent of PH in HIV disease is unknown. Although HIV virus

tself was postulated to play a major role, neither the viralenome nor viral antigens have been demonstrated in patho-ogic lesions (Mette et al., 1992).

The prevalence of the HHV-8 infection is increased amongIV-infected patients, and subjects who are coinfected withHV-8 and HIV are at high risk for developing Kaposi’s sar-

oma (KS) (Antman and Chang, 2000; Lennette et al., 1996).

8 f Clinical Virology 37 (2006) 79–82

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Table 1Patient’s hemodynamics parameters

CO (l/min) 3.9PAP (s/d/m) mmHg 81/36/53PWP (mmHg) 12PVR (wood units) 841SaO2 (%) 94

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n addition to causing KS, HHV-8 is thought to cause rareymphoproliferative disorders associated with HIV-infection,uch as primary effusion lymphoma and multicentric Castle-an’s disease (Hengge et al., 2002).The most dominant histopathologic finding of idiopathic

H is plexiform arteriopathy, a pathologic lesion that resem-les the endothelial abnormalities of cutaneous KS. Indeed,diopathic PH shares several histopathologic features withS, and a possible pathogenic relationship between bothiseases has been suggested (Cool et al., 2003). However,linical data confirming the association between KS and PHre lacking.

Herein, we describe an HIV-infected patient co-infectedith HHV-8 who developed severe PH coincident with occult

ymphadenopathic KS.

. Case report

A 30-year-old white woman, who was infected with HIVhrough intravenous drug use prior to 1993, was diagnosedith PH in 2002. She was co-infected with hepatitis C virus.hen she was first seen in our clinic in February 1997 she

ad multiple cervical lymph nodes ranging in size from pea-ized to 1 cm in diameter and an enlarged liver and spleen.er CD4 cell count was 744 cells/mm3 and her viral loadas 10,000 copies/mL. PPD test was negative. From Febru-

ry 1997 to October 2001 her CD4 lymphocyte count pro-ressively decreased to 321 cells/mm3, the plasma viral loadose to 200,000 copies/mL, and some of the cervical lymphodes increased slightly in size. In November 2001, a fine-eedle aspiration of a cervical node revealed a polymorphousopulation of lymphocytes, histiocytes, and acute inflamma-ory cells, without evidence of malignancy or granuloma.acterial and mycobacterial cultures of the aspirate wereegative. From January 2002 to December 2002 she wasreated with numerous antiretroviral regimens, but because of

ultiple drug side effects the overall therapeutic adherenceas poor.In July 2003, physical examination and CT of the neck and

he chest demonstrated multiple cervical, axillary and medi-stinal lymph nodes, most of them less than 1 cm in diameter.second fine-needle aspiration revealed a non-specific poly-orphous population of cells. A histopathological study was

equested but the patient refused an excisional biopsy.In December 2003, she complained of fatigue, weakness

nd shortness of breath on exertion. On physical examina-ion the arterial blood pressure was 110/60 mmHg and thereas jugular vein distension, hepatomegaly and mild periph-

ral oedema. Laboratory tests showed an arterial blood gasH of 7.47, PaO2 of 69 mmHg, PaCO2 of 24 mmHg, andrterial oxygen saturation of 98%. A chest radiograph demon-

trated cardiomegaly with hilar prominence and an ECGas consistent with right ventricular hypertrophy. Pulmonary

unction tests revealed a moderate restrictive pattern andnormal ventilation-perfusion scan. Transthoracic doppler-

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O, cardiac output; PAP, pulmonary arterial pressure (s: systolic; d: dyas-olic; m: mean); PWP, pulmonary capillary wedge pressure; PVR, pulmonaryascular resistance; SaO2, oxygen arterial saturation.

chocardiography (TTE) showed dilatation of the right hearthambers, paradoxical motion of the ventricular septum, andevere tricuspid regurgitation with an estimated systolic pul-onary artery pressure of 87 mmHg; left ventricular systolic

unction was normal, and there was no evidence of intracar-iac shunting.

The patient was prescribed furosemide and oral anticoag-lation therapy. She refused antiretroviral drugs. A new TTEerformed 3 months later showed an estimated systolic pul-onary artery pressure of 90 mmHg. Right heart catheteriza-

ion confirmed severe PH (Table 1). The acute vasoreactivityesting with a short-term intravenous infusion of epoprostenolas positive. A new CT of the neck demonstrated multiple 1-

m anterior and posterior cervical nodes that enhanced withontrast. A cervical lymph node excisional biopsy demon-trated classic features of KS (Fig. 1). Physical examinationid not reveal lesions consistent with cutaneous KS, nor wereymptoms of visceral involvement present. However, a thor-ugh examination of oral cavity disclosed a slightly raisedoorly demarcated purple plaque localized at the maxillaryingival mucosa that revealed typical findings KS on biopsy.t that time her CD4 cell count was 490 cells/mm3 and theiral load 63,000 copies/mL.

Serum IgG antibodies against HHV-8 (titer of 1/640) wereetectable by an indirect immunofluorescence assay (HHV-IgG IFA, Biotrin International, Ireland) and HHV-8 DNAas detected in two different samples of whole blood by poly-erase chain reactions using a method previously described

Pozo and Tenorio, 1999). Lung tissue for virologic studiesas not available.

. Discussion

Despite the histopathologic similarities between KS andH, no clinical association between both diseases had beeneported. The clinical presentation of KS in the patienteported herein was unusual and remained masqueraded as anndolent cervical lymphadenopathy. Cervical lymphadenopa-hy is a frequent problem in HIV-infected patients that maye related to HIV-infection itself and to many other oppor-unistic infections or tumors. Lymphadenopathic indolent KS

ithout mucocutaneous lesions is an uncommon presentationf KS in AIDS patients (Friedman-Kien and Saltzman, 1990)nd, as in our case, this diagnosis may have been missed inther HIV-infected patients with PH.

F. Gutierrez et al. / Journal of Clinical Virology 37 (2006) 79–82 81

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ig. 1. Tissue section from the patient’s lymph node demonstrating classic ff spindle cells forming splits containing red blood cells and ectatic vessels

The role of HHV-8 in the pathogenesis of PH remainsontroversial. Cool et al. in 2003 found molecular evidencef HHV-8 in lung tissue from 10 of 16 patients with idio-athic PH, including 1 of 3 patients with HIV-related PHCool et al., 2003). The same group described two patientsith PH and Castleman’s disease that were infected by HHV-; there was evidence of HHV-8 infection in the lung tis-ue from one of the patients (Bull et al., 2003). However,hese findings have not been confirmed by other investiga-ors studying idiopathic PH (Daibata et al., 2004; Galambost al., 2006; Henke-Gendo et al., 2005; Katano et al., 2005),nd no increase in the prevalence of antibodies against HHV-has been found in either lung transplantation candidatesith PH (Nicastri et al., 2005), nor in HIV-infected patientsith PH (Montani et al., 2005a). In a recent study by Henke-endo et al., infection by HHV-8 could not be confirmed

n 26 lungs explanted from patients suffering from idio-athic PH that were tested for the presence of HHV-8 anti-en and genomes by immunohistochemistry and polymerasehain reaction (Henke-Gendo et al., 2005). A case-controltudy also failed to find a higher seroprevalence of HHV-

among patients with idiopathic PH than among controlubjects (Laney et al., 2005). Of the 29 patients with sec-ndary PH studied by these investigators, three (10.3%)ere HHV-8 seropositive. Significantly, two of the three

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of Kaposi’s sarcoma: (a) Sinusoidal infiltrate characterized by proliferation× and (b) PAS-positive hyaline globules (arrow). PAS 40×.

HV-8-infected patients with secondary PH were also HIVositive, thus underscoring the possible link between HHV-infection and HIV-related PH (Laney et al., 2005). The

otential role of HHV-8 in some instances of HIV-relatedH is also suggested from a recent observation of a casef PH associated with multicentric Castleman’s disease inpatient infected with HIV and HHV-8 (Montani et al.,

005b).This is a single case that precludes any definite conclusion.

he co-occurrence of PH and KS in this patient could haveeen pure coincidence, but this clinical observation mightlso indicate that a relationship between HHV-8 infectionnd HIV-associated PH exists. Occult lymphadenopathic KSarcoma should be considered in HIV-infected patients devel-ping PH.

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