Table 54.6Assessment of the Hill criteria for the role of KSHV infection in the etiology of Kaposi’s sarcoma

Criterion Comment
Temporality Demonstrating that KSHV infection precedes KS is the sine qua non for causality. KSHV infection has been shown to precede KS in several studies (Whitby et al., 1995; Gao et al., 1996; Martin et al., 1998; Renwick et al., 1998; O’Brien et al., 1999; Moore et al., 1996; Lefrere et al., 1996) thus dispelling notions that KS tumors, by being hospitable breeding grounds, result in the subsequent presence of KSHV. Importantly, KSHV infection is temporally associated with KS independent of degree of sexual exposure (Martin et al., 1998) (excluding the possibility that KSHV is just a marker for another as-yet-undiscovered sexually transmitted pathogen) and immunocompromise (Whitby et al., 1995; Gao et al., 1996; Martin et al., 1998; Renwick et al., 1998; O’Brien et al., 1999).
Strength of Association After adjusting for all known potential confounding factors, statistical associations between a putative cause and disease that maintain a large magnitude are less likely to be explained by unaccounted for confounding factors and hence more likely to be valid associations. In longitudinal studies of KSHV and KS, the relevant association to be evaluated is KS incidence in KSHV-infected persons compared to KSHV-uninfected persons. If it is accepted that KS per se does not cause KSHV infection to be detected, associations from case-control studies are also relevant. Of studies of AIDS-related KS that measured KSHV infection by serologic means and directly controlled for number of sexual partners (Martin et al., 1998) or restricted analyses to homosexual men (Gao et al., 1996; Renwick et al., 1998; O’Brien et al., 1999; Miller et al., 1996; Kedes et al., 1996; Gao et al., 1996; Simpson et al., 1996; Lennette et al., 2002) the magnitude of association between KSHV and KS ranges from 2.5 to 5.2 (hazard ratios) in longitudinal studies and 1.8 to 18.9 (odds ratios) in case-control studies.
Consistency All published epidemiologic reports addressing a possible association between KSHV and, KS, with the exception of one have found a direct association. While it is formally possible that an unrecognized bias in either subject selection or variable measurement could account for the association between KSHV and KS seen in all studies to date, this is improbable because such a bias is unlikely to be consistently present in such a wide array of studies which vary by design, participant selection, and assay formats. Furthermore, the remarkable consistency in results makes chance a very unlikely explanation.
Biologic Plausibility There are several potential mechanisms by which KSHV may cause, KS, described in Chapter 56.
Dose-Response Relationship Among HIV and KSHV co-infected homosexual men, this criterion has been satisfied by the finding that detectable peripheral blood mononuclear cell-associated KSHV is associated with the subsequent development of KS (Engels et al., 2003).
Coherence This criterion implies that a cause-and-effect interpretation for the association in question does not conflict with what is otherwise known about either the disease or the putative causal agent. A causal role for KSHV in KS is compatible with existing knowledge in that the epidemiology of KSHV per se matches that long predicted for the agent of KS (e.g., highest prevalences in groups at greatest risk for, KS, and, in developed settings, sexually transmitted).
Analogy Although a weak criterion, there is analogous evidence for a causal role of KSHV in KS. Two herpesviruses closely related to KSHV, herpesvirus saimiri and Epstein-Barr virus (EBV), are oncogenic.
Specificity That a single cause must cause a single disease is clearly outdated (Rothman and Greenland, 1998) and likely violated by KSHV which has also at least been associated with primary effusion lymphoma (Cesarman et al., 1995) and multicentric Castleman’s disease (Soulier et al., 1995).
Experimental evidence In SCID mice, injection of KSHV into transplanted human skin results in the formation of lesions that are morphologically and phenotypically consistent with KS (Foreman et al., 2001).

From: Chapter 54, The epidemiology of KSHV and its association with malignant disease

Cover of Human Herpesviruses
Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis.
Arvin A, Campadelli-Fiume G, Mocarski E, et al., editors.
Cambridge: Cambridge University Press; 2007.
Copyright © Cambridge University Press 2007.

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