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TUMORS: A. Scott Laney, Teresa De Marco, Jonathan S. Peters, Mary Malloy, Carla Teehankee, Patrick S. Moore, and Yuan Chang Kaposi Sarcoma-Associated Herpesvirus and Primary and Secondary Pulmonary Hypertension Chest 2005; 127: 762-767 [Abstract] [Full text] [PDF]

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Kaposi sarcoma-associated herpesvirus in primary and secondary pulmonary hypertension

Norbert F. Voelkel, Pradeep R. Rai, M.D. and Carlyne D. Cool, M.D.   (7 July 2005)

Kaposi sarcoma-associated herpesvirus in primary and secondary pulmonary hypertension 7 July 2005
Norbert F. Voelkel, M.D. UCHSC, Pradeep R. Rai, M.D. and Carlyne D. Cool, M.D. Send letter to journal: Re: Kaposi sarcoma-associated herpesvirus in primary and secondary pulmonary hypertension Norbert.Voelkel{at}uchsc.edu Norbert F. Voelkel, et al.	Laney and coworkers recently published a serological study in Chest, investigating the role of human herpesvirus-8 (HHV-8) infection in patients with primary, or idiopathic, arterial pulmonary hypertension (1). Apparently, the interest in this topic had been generated by our previous publication in the New England Journal of Medicine, where we had documented the presence of HHV-8-infected lung cells, using immunohistochemistry, in particular staining for the latency-associated nuclear antigen-1(LANA-1) (2). We are very pleased that finally virologists are taking an active interest in the pathoetiology of severe pulmonary hypertension, a field that has been very ripe for investigation since the discovery of the association of HIV infection and primary pulmonary hypertension (3). Whereas, until today, neither HIV particles nor viral proteins have been identified in the complex pulmonary vascular lesions, the pulmonary hypertension community has accepted HIV infection as a trigger for severe PH. In their paper, the authors use their repertoire of serological tools to test serum specimens from patients with primary and secondary pulmonary hypertension—a difficult distinction to make in 100% of the cases, since the diagnosis is usually made as a diagnosis of exclusion, which every expert will admit can be quite difficult. It is not unusual that cases have to be reclassified at the time of autopsy, or following lung transplantation. Pulmonary hypertension in pulmonary sarcoidosis, without hilar lymph node involvement, and veno-occlusive disease are just two examples of severe pulmonary hypertension that do not neatly fit into the category of primary pulmonary hypertension, and are perhaps missed. As the authors believe in the strength of their serological data, we must maintain the validity of our findings, i.e. lung cell infection with the HHV-8 virus. Unfortunately, we cannot accept any other interpretation, specifically not the interpretation offered by the authors, i.e. an “edge effect”. “Edge artifacts” are typically found at the edge of the tissue section, not in the center of the parenchyma. Whereas the authors argue, based on their serological data, that there is no association between HHV- 8 infection and primary pulmonary hypertension, we consider that such an association is likely, based on tissue data and published reports of HHV-8 -caused diseases like Castleman’s lymphoma and the POEMS syndrome, which recently have been associated with severe pulmonary hypertension (4, 5). Laney and colleagues criticize our cohort of patients with PPH, based on the age of this group. Yet, their own cohort has a similar mean age, and four recently published studies on patients with PPH (6-9) have a comparable age distribution (Table 1). Laney and associates further argue that the lung cannot be a privileged site for HHV-8 infection without corresponding evidence of latently infected peripheral blood monocytes. Of course, investigators examining the pathophysiology of PPH have asked, for decades, why there is no organ other than the lung involved in severe pulmonary hypertension. On the other hand, every patient with asthma acknowledges the fact that the lung is indeed an immune privileged site. Hypersensitivity pneumonitis and bronchiolitis obliterans/organizing pneumonitis (cryptogenic organizing pneumonia - COP), are other highly lung specific disease manifestations. The respiratory mucosa interfaces broadly with the environment, and a vast quantity of antigens presented via the inhalational route activate the immune system. In addition, there is increasing evidence that pulmonary dendritic cells are phenotypically distinct, and, in part, responsible for organ-specific immune responses. In this context, it is of interest that three transplanted patients with primary pulmonary hypertension, in our original case series (2), with LANA -1-positive lung cells, live in the same community in Northern New Mexico. We also draw strength, paradoxically, from a recent Japanese publication (10), where the investigators examined lung tissue samples from patients with primary pulmonary hypertension, using the same methodology used by us, including the staining of the lung tissue samples with an antibody directed against LANA-1, and reporting that the tissues obtained from their patients were negative for LANA-1. We agree with the interpretation of their data, namely that their PPH patients were not infected with the KS virus—providing now an opportunity to search for other viral etiologies. The importance of tissue analysis is illustrated by another recent publication (11). In addition, we have found a recent patient to be LANA-1 positive by immunohistochemistry (data not shown). Let us now turn to the examination of the validity of serological techniques in the accurate detection of HHV-8-associated diseases. Since the paper by Laney and associates does not provide an assessment of how serology holds up in providing evidence for HHV-8 infection in patients with Kaposi’s sarcoma—which we do not doubt is being caused by infection with HHV-8—we reviewed a small number of recent publications from different parts of the world, including one publication by the first author (12). Martró et al (13) examined 13 HIV-infected HHV-8 seropositive men (9 of which had a KS history!), and found that 3/9 KS patients were negative, even when a large amount of PBMC DNA was used to detect the HHV-8 genome. Plancoulaine et al (14) conducted a large study in a village in Cameroon, Africa, where HHV-8 infection is endemic. Studying 608 individuals, they found no correlation between anti-HHV-8 antibody levels and buffy coat HHV-8 viral loads (in a subset of 95 infected subjects). In this context, it is of interest that Laney et al (12) published in “AIDS”, in 2004, their data, based on the examination of 42 men with KS, reporting that only 37.1% of these had PCR positive PBMC, that 21.8% had high antibody titers against K8.1, and that 36.5% had high titers against K8.1 and/or ORF65. In their own words, the authors state (12) “. . . we found the prevalence of HHV-8 DNA in body fluids and the geometric mean HHV-8 antibodies to be higher in the group with KS than in the group without KS.” “More men with KS than without KS had HHV-8 DNA in oral fluid, or PBMC at one or more visits (71.4% vs 55.6%)." The point is that not every KS patient has HHV-8 DNA positive PBMC, as this study shows. Lastly, in a recent study from Hungary, where the sarcoma had been originally described, Szalai et al (15) make a clear reference to a geographical distribution of different HHV-8 subtypes and, sequencing ORF26 and ORF1 fragments, come to the conclusion that there are even intraperson and intrasample genotypic differences in KS lesions and blood samples, based on sequence analysis of ORFs 26 and 73 and K1. Co- infection with EBV also appears to affect the KSHV-infected cell genotype (16). In contrast, LANA immunohistochemistry appears to be preferable to HHV-8 PCR for the evaluation of “problematic vascular proliferations”, as expression is seen in 92% of the KS lesions (11). Only one third of our LANA-1 lung lesion positive cases was LANA-1 positive when we examined the DNA of these patients’ PBMC. N. F. Voelkel, M.D; P. R. Rai, M.D; and C. D. Cool, M.D. University of Colorado at Denver and Health Sciences Center Pulmonary Hypertension Center and Dept. of Pathology Table 1 Ages of patients with primary idiopathic pulmonary arterial hypertension: Number of Patients Ages Ewert et al (6) 64 46 ± 13 years Humbert et al (7) 27 47 ± 19 years Bhatia et al (8) 11 40 to 76 years Machado et al (9) 17 51 ± 4 years Reference List 1 Laney,A.S., De,M.T., Peters,J.S., Malloy,M., Teehankee,C., Moore,P.S. and Chang,Y. Kaposi sarcoma-associated herpesvirus and primary and secondary pulmonary hypertension, Chest, 127: 762-767, 2005. 2 Cool,C.D., Rai,P.R., Yeager,M.E., Hernandez-Saavedra,D., Serls,A.E., Bull,T.M., Geraci,M.W., Brown,K.K., Routes,J.M., Tuder,R.M. and Voelkel,N.F. Expression of human herpesvirus 8 in primary pulmonary hypertension, N.Engl.J Med., 349: 1113-1122, 2003. 3 Speich,R., Jenni,R., Opravil,M., Pfab,M. and Russi,E.W. Primary pulmonary hypertension in HIV infection, Chest, 100: 1268-1271, 1991. 4 Bull,T.M., Cool,C.D., Serls,A.E., Rai,P.R., Parr,J., Neid,J.M., Geraci,M.W., Campbell,T.B., Voelkel,N.F. and Badesch,D.B. Primary pulmonary hypertension, Castleman's disease and human herpesvirus-8, Eur.Respir J, 22: 403-407, 2003. 5 Hudnall,S.D., Chen,T., Brown,K., Angel,T., Schwartz,M.R. and Tyring,S.K. Human herpesvirus-8-positive microvenular hemangioma in POEMS syndrome, Arch.Pathol.Lab Med., 127: 1034-1036, 2003. 6 Ewert,R., Opitz,C., Wensel,R., Winkler,J., Hoffken,G., Frank,W., Berger,F., Kleber,F.X. and Hetzer,R. [Iloprost as inhalational and intravenous long-term treatment of patients with primary pulmonary hypertension. Register of the Berlin Study Group for Pulmonary Hypertension]], Z.Kardiol., 89: 987-999, 2000. 7 Humbert,M., Barst,R.J., Robbins,I.M., Channick,R.N., Galie,N., Boonstra,A., Rubin,L.J., Horn,E.M., Manes,A. and Simonneau,G. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE- 2, Eur.Respir J, 24: 353-359, 2004. 8 Bhatia,S., Frantz,R.P., Severson,C.J., Durst,L.A. and McGoon,M.D. Immediate and long-term hemodynamic and clinical effects of sildenafil in patients with pulmonary arterial hypertension receiving vasodilator therapy, Mayo Clin.Proc., 78: 1207-1213, 2003. 9 Machado,R.F., Londhe Nerkar,M.V., Dweik,R.A., Hammel,J., Janocha,A., Pyle,J., Laskowski,D., Jennings,C., Arroliga,A.C. and Erzurum,S.C. Nitric oxide and pulmonary arterial pressures in pulmonary hypertension, Free Radic.Biol.Med., 37: 1010-1017, 2004. 10 Katano,H., Ito,K., Shibuya,K., Saji,T., Sato,Y. and Sata,T. Lack of human herpesvirus 8 infection in lungs of Japanese patients with primary pulmonary hypertension, J Infect.Dis., 191: 743-745, 2005. 11 Hammock,L., Reisenauer,A., Wang,W., Cohen,C., Birdsong,G. and Folpe,A.L. Latency-associated nuclear antigen expression and human herpesvirus-8 polymerase chain reaction in the evaluation of Kaposi sarcoma and other vascular tumors in HIV-positive patients, Mod.Pathol., 18: 463-468, 2005. 12 Laney,A.S., Dollard,S.C., Jaffe,H.W., Offermann,M.K., Spira,T.J., Gunthel,C.J., Pellett,P.E. and Cannon,M.J. Repeated measures study of human herpesvirus 8 (HHV-8) DNA and antibodies in men seropositive for both HHV-8 and HIV, AIDS, 18: 1819-1826, 2004. 13 Martro,E., Cannon,M.J., Dollard,S.C., Spira,T.J., Laney,A.S., Ou,C.Y. and Pellett,P.E. Evidence for both lytic replication and tightly regulated human herpesvirus 8 latency in circulating mononuclear cells, with virus loads frequently below common thresholds of detection, J Virol., 78: 11707-11714, 2004. 14 Plancoulaine,S., Abel,L., Tregouet,D., Duprez,R., van,B.M., Tortevoye,P., Froment,A. and Gessain,A. Respective roles of serological status and blood specific antihuman herpesvirus 8 antibody levels in human herpesvirus 8 intrafamilial transmission in a highly endemic area, Cancer Res, 64: 8782-8787, 2004. 15 Szalai,E., Takacs,M., Otvos,R., Szlavik,J., Juhasz,A. and Berencsi,G. Genotypic distribution of human herpesvirus-8 strains circulating in HIV-positive patients with and without Kaposi's sarcoma in Hungary, Arch.Virol., 2005. 16 Fan,W., Bubman,D., Chadburn,A., Harrington,W.J., Jr., Cesarman,E. and Knowles,D.M. Distinct subsets of primary effusion lymphoma can be identified based on their cellular gene expression profile and viral association, J Virol., 79: 1244-1251, 2005.