Correspondence

HHV-8 in Pulmonary Hypertension

N Engl J Med 2004; 350:194-195January 8, 2004

Article

To the Editor:

Cool et al. (Sept. 18 issue)1 suggest that human herpesvirus 8 (HHV-8) has a role in the pathogenesis of primary pulmonary hypertension. We performed tests for HHV-8 antibodies in plasma samples from 49 patients with primary pulmonary hypertension who were negative for the human immunodeficiency virus and 17 patients with other forms of pulmonary hypertension (10 with chronic thromboembolic pulmonary hypertension and 7 with pulmonary arterial hypertension that was not due to primary pulmonary hypertension). Antibodies against a structural HHV-8 glycoprotein, K8.1, were detectable in three patients (one with primary pulmonary hypertension, one with chronic thromboembolic pulmonary hypertension, and one with pulmonary arterial hypertension that was not due to primary pulmonary hypertension), all of whom had been born and raised in Germany. Two of these three patients (the patient with primary pulmonary hypertension and the patient with chronic thromboembolic pulmonary hypertension) also had antibodies against latency-associated nuclear antigen 1 (LANA-1). Two of 73 healthy blood-donor controls were positive for K8.1 antibodies but were negative for LANA-1 antibodies. The sensitivity of these serologic assays is 80 percent for the LANA-1 immunofluorescence assay and more than 90 percent for the K8.1 enzyme-linked immunosorbent assay.2,3 Since we did not find a significant difference in the prevalence of HHV-8 between patients and controls in a country where HHV-8 infection is uncommon, we conclude that in countries where HHV-8 infection is not endemic, it is rarely involved in the pathogenesis of primary pulmonary hypertension.

Cornelia Henke-Gendo, M.D.
Thomas F. Schulz, M.D.
Marius M. Hoeper, M.D.
Hannover Medical School, 30625 Hannover, Germany
hoeper.marius@mh-hannover.de

3 References

1. 1

   Cool CD, Rai PR, Yeager ME, et al. Expression of human herpesvirus 8 in primary pulmonary hypertension. N Engl J Med 2003;349:1113-1122
   Full Text | Web of Science | Medline

2. 2

   Engels EA, Sinclair MD, Biggar RJ, et al. Latent class analysis of human herpesvirus 8 assay performance and infection prevalence in sub-Saharan Africa and Malta. Int J Cancer 2000;88:1003-1008
   CrossRef | Web of Science | Medline

3. 3

   Simpson GR, Schulz TF, Whitby D, et al. Prevalence of Kaposi's sarcoma associated herpesvirus infection measured by antibodies to recombinant capsid protein and latent immunofluorescence antigen. Lancet 1996;348:1133-1138
   CrossRef | Web of Science | Medline

Author/Editor Response

We are pleased that our report is of interest in the pulmonary-hypertension community and that Henke-Gendo et al. examined plasma samples using serologic assays. Without doubt, an accurate diagnosis of HHV-8 infection is very desirable, yet the sensitivity and specificity of various plasma protein markers vary widely from study to study, and methodologic details such as repeated cycles of freezing and thawing of samples probably affect seropositivity rates.1 Even among patients with Kaposi's sarcoma, approximately one fifth of serum samples were negative when tested against HHV-8 antigens.1 On the basis of our observation of spindle-cell morphologic features in plexiform lesions from patients with primary pulmonary hypertension and the likelihood of negative serologic tests in the presence of disease, we hypothesized that direct examination of lung tissue would provide the best evidence of viral infection. Indeed, when liver, bone marrow, and lymph nodes from four patients with primary pulmonary hypertension and LANA-1–positive lung tissue (Figure 1Figure 1High-Power View of a Plexiform Lesion from a Patient with Primary Pulmonary Hypertension (×1000).) were examined, only one bone marrow sample from one of these patients was positive for LANA-1. Thus, we conclude that the results of plasma serologic tests are unlikely to reflect organ-specific HHV-8 infection.

Carlyne D. Cool, M.D.
Pradeep R. Rai, M.D.
Norbert F. Voelkel, M.D.
University of Colorado Health Sciences Center, Denver, CO 80262
norbert.voelkel@uchsc.edu

1 References

1. 1

   Gao S-J, Kingsley L, Hoover DR, et al. Seroconversion to antibodies against Kaposi's sarcoma-associated herpesvirus-related latent nuclear antigens before the development of Kaposi's sarcoma. N Engl J Med 1996;335:233-241
   Full Text | Web of Science | Medline

Citing Articles (10)

Citing Articles

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   Stefania Cicalini, Pierangelo Chinello, Nicola Petrosillo. (2011) HIV infection and pulmonary arterial hypertension. Expert Review of Respiratory Medicine 5:2, 257-266
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   D. Murphy, R. E. Girgis. (2009) HIV-associated pulmonary arterial hypertension: a clinical problem that is here to stay?. International Journal of Clinical Practice 63, 19-21
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3. 3

   Marc Humbert. (2008) Mediators involved in HIV-related pulmonary arterial hypertension. AIDS 22:Suppl 3, S41-S47
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   D. Bendayan, R. Sarid, A. Cohen, D. Shitrit, I. Shechtman, M.R. Kramer. (2008) Absence of Human Herpesvirus 8 DNA Sequences in Lung Biopsies from Israeli Patients with Pulmonary Arterial Hypertension. Respiration 75:2, 155-157
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   Naushad Hirani, Alessandra Manes, Carlo Parravicini, Chiara Scalamogna, Massimiliano Palazzini, Luca Negro, Serena Romanazzi, Erika Longhi, Giovanna Bestetti, Roberta Piolin, Giovanna Lunghi, Anna Orlandi, Angelo Branzi, Mario Corbellino, Nazzareno Galiè. (2007) Evidence for Kaposi's sarcoma-associated herpes virus infection in patients with idiopathic pulmonary arterial hypertension: a case series and review of the literature. Current Medical Research and Opinion 23:s2, S83-S87
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   Paul Bresser, Marion I. Cornelissen, Wim van der Bij, Carel J.M. van Noesel, Wim Timens. (2007) Idiopathic pulmonary arterial hypertension in Dutch Caucasian patients is not associated with human herpes virus-8 infection. Respiratory Medicine 101:4, 854-856
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7. 7

   Csaba Galambos, Jill Montgomery, Frank J. Jenkins. (2006) No Role for Kaposi Sarcoma-Associated Herpesvirus in Pediatric Idiopathic Pulmonary Hypertension. Pediatric Pulmonology 41:2, 122-125
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8. 8

   Thomas F Schulz. (2006) The pleiotropic effects of Kaposi's sarcoma herpesvirus. The Journal of Pathology 208:2, 187-198
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9. 9

   David Montani, Anne-Genevieve Marcelin, Olivier Sitbon, Vincent Calvez, Gérald Simonneau, Marc Humbert. (2005) Human herpes virus 8 in HIV and non-HIV infected patients with pulmonary arterial hypertension in France. AIDS 19:11, 1239-1240
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10. 10

    Masanori Daibata, Isao Miyoshi, Hirokuni Taguchi, Hiromi Matsubara, Hiroshi Date, Nobuyoshi Shimizu, Yuji Ohtsuki. (2004) Absence of human herpesvirus 8 in lung tissues from Japanese patients with primary pulmonary hypertension. Respiratory Medicine 98:12, 1231-1232
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