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Institute of Medicine (US) Forum on Microbial Threats; Knobler SL, O'Connor S, Lemon SM, et al., editors. The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects: Workshop Summary. Washington (DC): National Academies Press (US); 2004.

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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects: Workshop Summary.

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PATHOGENS AND DISEASE: ISSUES IN DETERMINING CAUSALITY

.

University of Pittsburgh, Pittsburgh, PA

Successful new pathogen discovery requires the talents of multiple disciplines, including epidemiology, clinical medicine, molecular biology, and pathology. In this paper, the identification of Kaposi's sarcoma-associated herpesvirus (KSHV) illustrates general issues in causality and shows the limits on our ability to determine a causality for a newly discovered agent and disease (Moore and Chang, 1998).

The mysterious outbreak of Kaposi's sarcoma among gay men was the harbinger of the AIDS epidemic. It is now clear, however, that the AIDS-associated Kaposi's sarcoma epidemic was actually due to the collision of two independent viruses in a susceptible population: HIV and a new virus, KSHV or HHV8, which was found using molecular techniques (O'Brien et al., 1999).

Over 20 different agents had been put forward as the cause of KS before 1994. To look for the “KS agent” (Beral et al., 1990), Yuan Chang used representational difference analysis (RDA) to compare DNA from a Kaposi's sarcoma lesion to uninvolved, sterile-site tissue from the same patient on the assumption that the two samples would be genetically identical except for the presence of the putative agent's genome (Chang et al., 1994).

As shown in Figure 3-1, RDA is a subtractive hybridization technique in which PCR adapters are ligated onto digested DNA from the KS tissue (tester) (Lisitsyn et al., 1993). The tester DNA was then rehybridized back to a ten-fold excess of uninvolved sample DNA (driver) that had been identically digested. For human genomic fragments present in the KS sample, 90 percent of these fragments will form pairs with the corresponding antisense strand lacking the adapter from the normal tissue DNA. PCR with a primer specific to this adapter linearly amplifies these common sequences and, of course, there was no amplification of the DNA rehybridized from the driver alone. Sequences that were unique to the KS lesion, however, reanneal to each other and have adaptors on both ends, so that amplification occurs exponentially. The initial PCR products are then rehybridized again to the adapter-less healthy tissue DNA and the process is repeated, each time selectively enriching for the unique sequences found only in the KS lesion (Gao and Moore, 1996).

FIGURE 3-1. Representational differential analysis comparing DNA from a Kaposi's sarcoma lesion to sterile-site tissue from the same patient.

FIGURE 3-1

Representational differential analysis comparing DNA from a Kaposi's sarcoma lesion to sterile-site tissue from the same patient.

Four RDA fragments were generated by this process, two of which were found to be specific for the KS agent. Although these two fragments account for less than 1 percent of the entire 145-kilobase viral genome, the few base-pairs worth of unique information they provided made it possible to develop enough tools to identify the agent.

The two fragments were used as Southern hybridization probes and tested against KS lesions, showing that about three-quarters of the KS lesions were positive for viral DNA. Using internal specific primers from the KS 330 band, a PCR assay was developed that showed 25 out of 27, or 93 percent, of the initial KS lesions tested positive. Moreover, the negative samples were equally telling: one of the two negatives had degraded DNA and was not amplifiable by using cellular primers, and the other one was mislabeled normal human kidney.

KSHV is a gamma herpesvirus belonging to the same class as Epstein-Barr virus (EBV). It is associated with three different major proliferative diseases: Kaposi's sarcoma, primary effusion lymphoma (PEL) (Cesarman et al., 1995a), a monoclonal B cell lymphoma, and multicentric Castleman's disease (Soulier et al., 1995), which is a polyclonal hyperplasia caused by a virus-encoded cytokine expressed by KSHV (Parravicini et al., 1997). Nearly all KS and PEL patients have KSHV infection, but only about half of HIV-negative, multicentric Castleman's disease patients are positive for KSHV infection indicating that this disease has a heterogeneous pathogenesis.

The two aforementioned RDA fragments of the KSHV genome facilitated the identification of infected cell lines to serve as source material for viral DNA and as a reagent for biologic studies (Cesarman et al., 1995b). Genomic library walking was performed using cosmid and lambda libraries from one of these cell lines allowing sequencing of the remainder of the genome (Russo et al., 1996). Using this information, various techniques were used to identify likely antigens and generate serologic tests (Gao et al., 1996a,b; Kedes et al., 1996; Simpson et al., 1996). While identification of high-titered infected cell lines sped up this process, isolating the agent was not essential for developing tools to detect it. Molecular biology has reached the point where it is straightforward to identify a new agent, sequence its genome and develop serologic tests for it without ever having actually purified, living sample of the agent. The virus does not have to be grown in order to apply traditional techniques for determining whether or not an agent is present.

The virus itself is a tremendously interesting scientific problem. It has a long unique coding region containing all of the viral open reading frames. Unlike most viruses, KSHV has pirated cellular genes over its evolution and the viral genes are recognizable homologues to cellular genes of known function. Many of these genes provide new insights into tumor virology through their control of the cell cycle, prevention of apoptosis, or immune evasion properties.

One might conclude that this virus is completely different from other viruses and not much can be learned from it to extend to other viruses. In fact, the opposite is true. EBV, for example, induces cellular cyclin D2 to drive the cell through the G1/S cell cycle checkpoint; KSHV encodes its own version of a cyclin D with an analogous function. Other examples of functional correspondence between the KSHV homologues and viral genes encoded by even distantly related viruses can be readily seen (Moore and Chang, 1998a, 2001). For this reason KSHV might be considered something like a molecular Rosetta stone because by using it, we can begin to interpret the language of molecular virology in terms of cell biology for many different viruses.

The importance of new pathogen discovery is illustrated by a timeline of KS research. This would be equally true also for hepatocellular carcinoma and hepatitis C or a wide range of diseases where a new pathogen has been found. The point is that things change quite rapidly once the agent is finally found. Moritz Kaposi initially described the disorder in 1873, but not until 70 years later was there a suggestion of an infectious etiology. In 1981, the onset of the AIDS epidemic brought a tremendous increase in scientific interest in this cancer. There was still, however, little known about the pathogenesis of this disorder in 1993 when there were over 200,000 cases of AIDS in the United States. At that time over 20 different agents had been proposed at one time or another as the causal agent for Kaposi's sarcoma.

The description of KSHV was first published in 1994 and within two years its viral genome was completely sequenced (Neipel et al., 1997; Russo et al., 1996). By that time it was known that the virus was found in all forms of Kaposi's sarcoma (Boshoff et al., 1995; Chang et al., 1996; Moore and Chang, 1995), serologic tests had been developed (Gao et al., 1996a,b; Kedes et al., 1996; Miller et al., 1996; Simpson et al., 1996) and studies initiated to understand the epidemiology of this virus in KS (Moore et al., 1996; Whitby et al., 1995). Shortly thereafter, studies were performed to see whether ganciclovir, a specific antiviral agent, could be used to treat KS (Martin et al., 1999). At the present, there have been over 2,000 papers published on KSHV and its role in malignancy.

Finding a new pathogen also can benefit other fields. When KSHV was first described, only two other related rhadinoviruses had been described in new world primates. Although we live in North America, humans are still considered old world apes. One was herpesvirus saimiri from squirrel monkeys and the other herpesvirus ateles from spider monkeys. Researchers at the University of Washington began to look for other primate KSHV-like viruses (Rose et al., 1997). Using consensus PCR, two were found in rhesus macaques, and subsequently in all the various branches of the primates, both lower and higher primates. This suggests that the viral ancestor of KSHV evolved with us over time. Even more interesting, another group found a closely-related but distinctly different virus in rhesus macaques (Desrosiers et al., 1997). It was named rhesus rhadinovirus (RRV) and belongs to a second lineage of rhadinoviruses. RRV was initially only found in the lower primates, but last year an RRV was found in chimps (Greensill et al., 2000; Lacoste et al., 2000; Lacoste et al., 2001). The implication is that there is an ancestral KSHV/RRV-like virus split off in the primate evolution and has followed through with the different primate lineages, probably including humans. Thus, it is almost certain that there is an undiscovered HHV 9.

An issue in new pathogen discovery is making the step from finding a new DNA sequence to determining whether or not it causes a specific disease. Applying Koch's postulates (Koch, 1942) can elucidate the process:

  • The agent occurs in every case of disease.
  • The agent never occurs as a fortuitous or non-pathogenic strain.
  • The agent can be isolated from the lesion, grown in pure culture, induce disease in a susceptible host and can be re-isolated from an infected susceptible host.

These were postulates that Koch developed for determining the cause of tuberculosis at a time when not much was known of viruses or the carrier state. This was a brilliant attempt to develop a scientific rationale for determining whether an agent is causal for disease or not.

Bradford Hill also developed epidemiologic criteria for causality which are shown here for KSHV and KS (Hill, 1965). Though developed specifically for cigarette smoking, most epidemiologists now use these criteria to determine causality:

  • Is the infection present in cases; do all types of the disease involve infection? Is it reproducible in multiple settings?
  • Does infection precede disease?
  • Is the infection specific to the disease or is it ubiquitous infection among humans?
  • Is the virus localized to the tumor (one interpretation of a biologic gradient)?
  • Do the epidemiologic studies make sense (are they coherent?)?
  • Is it biologically reasonable and do experiments confirm the relationship?

With regard to KSHV, the answers to these questions are largely true. KSHV is present in more than 95 percent of KS lesions. It can be said that the remaining negative 5 percent is probably spurious due to technical difficulties in detection or misdiagnosis, and in fact the virus is absolutely necessary for disease. Though this cannot be proven at present, it can be argued that the situation is very similar to that of papillomavirus and cervical cancer 5 years ago. Is it generalizable? Yes. All types of KS are infected as far as is known. It also appears to have the correct temporal association in that cohort studies show that patients are infected before developing disease, and not afterwards.

But specificity is an important question. KSHV is not singly associated with Kaposi's sarcoma. It is also associated with two other diseases. However, the epidemiology of these two diseases makes some sense in terms of Kaposi's sarcoma, so multiple outcomes are not too worrisome. Depending on the assay that is used, some researchers suggest that the infection rate in the general population for this virus is much higher than alluded to here, but careful studies suggest that less that 5 percent of Americans are infected with KSHV.

Is there a biologic gradient? Yes, there is. Are the epidemiologic findings coherent? Yes, a wide range of epidemiologic studies seem to come to exactly the same set of conclusions. Is it biologically plausible? Yes, there are multiple oncogenes in this virus, related viruses cause cancers, and there are blinded clinical trials which seem to suggest that treatment with ganciclovir prevents the development of Kaposi's sarcoma.

KSHV and KS was a relatively easy case even though it took two years and seven or eight different studies before these conclusions could be reached. Nonetheless, the case for causality was relatively easy.

Now let's consider issues where causality is more problematic. First, KSHV has been claimed not only to cause Kaposi's sarcoma, but also a wide variety of diseases that don't fit its epidemiologic pattern, such as multiple myeloma and sarcoidosis. Although studies supporting these associations were published in reputable journals, they were based on PCR or had other problems and remain questionable in terms of contemporary epidemiological knowledge. In the age of PCR, it is difficult for the casual observer to sort out what is true and what is not.

Assuming that the problem of poor laboratory technique can be solved, there are three more fundamental problems in determining causality. First, causality is relative and should not be thought of as being cast in stone. Causality depends on pathogenic assumptions. That is where Koch's postulates fall down and also where Hill's criteria fall down as well.

For example, if a virus is associated with autoimmune disorders, it can be assumed that one would have an immune response against that virus. In that case the individual may actually clear the virus, so a reverse association would be seen from what would normally be expected following Hill's criteria. The criteria simply do not apply in this case, even though it is a reasonable possibility.

Second, causality is normative. Researchers can get together and study the data but only a few agree to particular conclusions. When the studies describing KSHV as the cause of KS were completed, it was thought that the issue of causality would be resolved. However, it still required a great deal of interpretation. There were many contradictory studies that were ignored because they were not considered valid. But others might disagree, and this is true for just about any contentious issue. An agent is only considered causal for a disease when a majority of scientists agree and it is passed on as received wisdom to others. By then, few scientists probably know the actual studies that were actually used to determine causality.

Third, no agent causes disease alone. There are some fairly convincing examples, HIV as well as rabies virus. Simply not enough is understood about the epidemiology of rabies virus to know whether or not there are people who have been exposed to it who have not developed disease. But with the possible exception of those two viruses, virtually every other infection can have a symptomatic infection, and disease is determined by other factors than the virus alone.

There are several examples where current methods of determining causality break down. One is the role of EBV in nasopharyngeal carcinoma (NPC). There is extremely strong evidence that EBV is the cause of nasopharyngeal carcinoma, but EBV is a near ubiquitous infection. So Hill's criteria cannot be used to determine that EBV causes nasopharyngeal carcinoma since it is likely to be a composite risk factor and additional causal factors have to be used in conjunction with EBV infection. These factors are unknown for NPC, but it is easy to see that rather than using EBV infection alone as an exposure variable, it may be more valuable to measure exposure as EBV infection at a certain susceptible age or EBV infection in a cell having a specific mutation.

EBV and NPC shows another problem with Hill's criteria for causality. Raab-Traub developed an assay for EBV terminal repeat monoclonality and using this assay found that in NPC tumors, the precursor cell forming the monoclonal tumor was infected with a monoclonal form of the virus (Raab-Traub and Flynn, 1986). For molecular biologists and virologists, this is overwhelming proof that the virus causes the tumor since the odds of this happening by chance are so small. It is extremely unlikely that a healthy cell was first infected with the virus, and by chance the same cell independently became transformed into an expanding tumor cell population with EBV growing inside of it as a passenger virus. However, this does not neatly fit Hill's criteria and epidemiologists have no way of weighing the importance of this “overwhelming” piece of molecular evidence, especially in comparison to contradicting evidence such as the ubiquity of EBV infection among humans.

Multicentric Castleman's disease (MCD) illustrates additional problems related to determining causality for different diseases which look identical. About half of MCD tumors are positive for KSHV and so it seems that there are actually two diseases, not just one, under the label of MCD. KSHV is only considered necessary for the KSHV positive form. Now that it is known what to look for, there may be subtle clinical and pathologic clues that can distinguish the two forms of MCD. Analogous situations can be drawn for hepatocellular carcinoma and hepatitis virus C positive hepatocellular carcinoma, or for meningitis and any of the many causes of meningitis. While hepatitis virus C is not necessary for all liver cancers, it is obviously necessary for hepatitis virus C positive tumors. By defining a subset of diseases associated with a viral infection post-hoc, the causality argument becomes circular even though we now have good reasons for splitting up a disease manifestation into different diseases with different manifestations.

It is likely that in the future, improved knowledge of pathogenic mechanisms will reveal novel causal relationships. For example, not too long ago the idea that a bacteria could cause stomach ulcers would have been considered laughable. Helicobacter pylori and peptic ulcer disease had a pathogenic mechanism that was poorly understood and thus there was no framework to gauge whether or not a bacteria was the possible cause. In fact, pathologists had seen bacteria associated with ulcers for decades but didn't remark on them because there was no way to measure their significance.

New ways of determining causality that go beyond Hill's criteria and Koch's postulates need to be developed if new and complex mechanisms for disease are to be understood. Researchers have attempted to do this by taking into consideration new techniques of molecular biology (Fredericks and Relman, 1996). It seems clear that epidemiologists developing new criteria for causality will have to incorporate new pathogenic mechanisms that are not currently accounted for.

Unfortunately, no one can predict what new pathogenic mechanisms will be discovered and therefore there are no universal criteria for causality that will not need future revisions. In the end, it cannot be absolutely proved that an agent causes disease, only that it does not. Instead, while criteria such as Hill's or Koch's postulates are enormously helpful in guiding our thinking, we should not be constrained by them as has happened in cases like EBV and nasopharyngeal carcinoma. In this case, both science and public health have suffered from rigid adherence to abstract criteria. For cases where established criteria break down, all that can be done is to develop a detailed pathogenic model which can be tested using epidemiologic studies and further modified. In essence, to use the scientific method which is employed by scientists every day.

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Copyright © 2004, National Academy of Sciences.
Bookshelf ID: NBK83681

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