Is There a Viral Cause for Idiopathic Pulmonary Arterial Hypertension?

Student guest post Dayna Groskreutz

Pulmonary hypertension (PH) refers to a condition in which there is high blood pressure in the vessels carrying blood from the heart to the lungs. Pulmonary arterial hypertension (PAH) is a subset of PH referring specifically to an increase in the pressure within the pulmonary arteries (rather than the pulmonary veins or capillaries). The high blood pressure in the vessels causes thickening of these arteries, making it hard for the heart to pump blood to the lungs. Pressure builds up and backs up. Over time, stress on the heart causes it to enlarge, and it becomes more difficult for blood to get to the lungs so that it can get oxygen. Patients become tired, dizzy, and short of breath. Their quality of life is significantly reduced. Data from the National Institute of Health PAH registry in the 1980s concluded that the average survival of untreated PAH is 2.8 years from diagnosis, with 1-year, 3-year, and 5-year survival rates of 68%, 48%, and 34%, respectively. With the development of effective therapy over the last 30 years, survival has improved slightly.

In some cases, PH is caused by an underlying disease, such as sleep apnea, lung disease, or heart disease. A familial form of PH has been described and characterized. PH caused by diet medications like Fen-Phen has been widely publicized. One infectious agent, human immunodeficiency virus (HIV), has been shown to be an independent risk factor for pulmonary hypertension, but neither the virus nor its proteins have been demonstrated in the pulmonary arteries. In many cases, the cause of PH is idiopathic, meaning we do not know why the patient has pulmonary hypertension. This lack of knowledge has led researchers to search for an infectious agent as a cause for idiopathic pulmonary arterial hypertension (IPAH).

Although a causal relationship between IPAH and a viral infection has not been established, a relationship is suspected. Human herpesvirus-8 (HHV-8) is the causative agent of Kaposi's sarcoma, primary effusion lymphoma, and Castleman's disease, a rare blood disorder. In 2003, Bull and colleagues reported HHV-8 infection in the lung tissue and in the cells of the pulmonary artery of a patient with PH and Castleman's disease. They suggested that HHV-8 might be a causative agent for this patient's PH. The same year this group published a case-control study in the New England Journal of Medicine. The cases consisted of 16 patients with IPAH, and the controls consisted of 14 patients with PH caused by an underlying disease (or secondary PH). They detected HHV-8 infection using both antibody and polymerase chain reaction (PCR)-based techniques. 10 of 16 patients (62%) with IPAH had HHV-8 detected with antibody and PCR techniques, while none of the control (secondary) PH group had HHV-8 detected with antibody, and one patient had PCR evidence of virus. This study provided evidence of HHV-8 infection in the lung and pulmonary arterial cells of patients with IPAH; however, the study did not provide evidence of causation as it was not prospective in design.

A subsequent study by Laney et al compared 19 patients with IPAH, 29 patients with secondary PH, and 150 controls, and looked for evidence of HHV-8 in their blood using serologic tests. The rate of HHV-8 in the blood of IPAH was 0%, controls 0.7%, and secondary PH 10.3%. Two of the three secondary PH patients with HHV-8 in their blood had HIV-associated PH, and the association of HIV and HHV-8 is well documented. The authors concluded that HHV-8 does not have a role in IPAH or non-HIV-associated PH.

Nicastri et al next retrospectively analyzed data from 75 patients referred to their institution for lung transplant. 16 had IPAH, 17 had secondary PH, 7 had PH due to repetitive blood clots in the lung, and the remaining 10 had PH associated with miscellaneous other diseases including autoimmune disease and HIV. The 42 patients without PH consisted of patients with cystic fibrosis and other lung diseases. They performed antibody tests to detect HHV-8 in the blood. Of the patients with PH, 3% had HHV-8 detected in their blood, while 19% of patients without PH had HHV-8 detected. The authors concluded there was no direct relationship between HHV-8 infection and PH.

Finally, a German study by Henke-Gendo et al examined lung tissue from 26 patients who underwent lung transplant for IPAH from 1993-2003. Using an antibody test, they detected HHV-8 protein in the diseased lungs removed at the time of transplant in 61.5% of the cases; however, they were unable to confirm HHV-8 infection by PCR in all cases. They concluded that HHV-8 is unlikely to play a role in the pathogenesis of IPAH.

In recent years, there has been a search for a causative infectious agent for idiopathic pulmonary arterial hypertension. Two papers published by the same group at the University of Colorado provided some evidence that an association might exist, but these findings have not been confirmed in three subsequent studies by other investigators. The original authors at the University of Colorado recently published a cell-based study showing that HHV-8 can infect pulmonary endothelial cells, or the cells that make up the pulmonary arteries, lending further plausibility to the association

However, in absence of further evidence at this time, HHV-8 and PH appears to be an inconclusively proven association.


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5.Laney, A. S., De Marco, T., Peters, J. S., Malloy, M., Teehankee, C., Moore, P. S., and Chang, Y. (2005) Chest 127, 762-767

6.Nicastri, E., Vizza, C. D., Carletti, F., Cicalini, S., Badagliacca, R., Poscia, R., Ippolito, G., Fedele, F., and Petrosillo, N. (2005) Emerg Infect Dis 11, 1480-1482

7.Henke-Gendo, C., Mengel, M., Hoeper, M. M., Alkharsah, K., and Schulz, T. F. (2005) Am J Respir Crit Care Med 172, 1581-1585

8.Bull, T. M., Meadows, C. A., Coldren, C. D., Moore, M., Sotto-Santiago, S. M., Nana-Sinkam, S. P., Campbell, T. B., and Geraci, M. W. (2008) Am J Respir Cell Mol Biol 39, 706-716

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Tara, a simpler hypothesis (IMO) is that there is an autoimmune component to idiopathic pulmonary arterial hypertension.

In many diseases, people try to correlate incidence with one specific organism. But what if many organisms have similar effects, e.g., exposing epitopes that are normally concealed? Then the correct correlation is not with the pathogen but with immune status.

Technically, it's perhaps a more difficult analysis (though I suspect constructing an affinity capture column would not be all that difficult) than screening for pathogen exposure. But it forms a very general hypothesis for disease and especially the diseases of aging, one that could embrace not only biotic but environmental and genetic causation.

hypertension is caused from a diet high in junk food and low in nutrients...compounded by a lack of exercise.

I'll go with inherited immune pathology risk, but note that previous viral infection may elevate and precipitate autoimmune disease because of similarity in vascular membrane receptor and viral epitopes.

Technically, it's perhaps a more difficult analysis (though I suspect constructing an affinity capture column would not be all that difficult) than screening for pathogen exposure. But it forms a very general hypothesis for disease and especially the diseases of aging, one that could embrace not only biotic but environmental and genetic causation.