Chicago—West Nile Virus, SARS, Lyme disease, HIV—these aren’t our parents’ infectious diseases anymore. When it comes to diagnosing the often misleading manifestations and defining the puzzling pathways behind these and many other diseases, today’s physician must be part scientist, part sleuth.
“When we think in terms of traditional infections, we like to think of effects that are manifested at the site of the infection, such as polio virus where you have paralysis, or infections of the intestinal tract where you have symptoms like diarrhea,” said W. Ian Lipkin, MD. “In recent years, though, new paradigms are emerging… and there are much more complicated mechanisms to consider.”
Dr. Lipkin discussed the significance of these new paradigms as the Triological Society‘s Presidential Speaker here at the 2006 Combined Otolaryngology Spring Meetings (COSM). Dr. Lipkin is the Greene Professor of Epidemiology and Professor of Neurology and Pathology at the Mailman School of Public Health and College of Physicians and Surgeons at Columbia University in New York City. He is also the director of the Jerome L. and Dawn Greene Infectious Disease Laboratory and principal investigator of the Northeast Biodefense Center.
In the late 1800s, the German physician Robert Koch, in an effort to demonstrate that tubercle bacillus was responsible for tuberculosis, defined the set of criteria that must be present in order to determine a causal relationship between a microbial agent and an infectious disease. Koch’s Postulates held that the microbe had to be present in every case of the disease; it had to be specific; and scientists had to be able to isolate it, grow it, and introduce it into animals to cause a similar disease. And, for the past century or so, that has all pretty much held true.
“In this new era of molecular microbiology, however, Koch’s Postulates don’t work,” Dr. Lipkin said. “We’re not entirely sure yet what the new postulates will be. But we do know that there are microbes that we can’t grow in the laboratory, that not everybody infected with the same agent has the same manifestations, and that the sequelae may be long term.”
Dr. Lipkin points to instances of disease where the infection itself is not the problem, but the immune response of the infected host and the resulting damage—such as a virus or bacterium that manifests in immunosuppression, which may predispose to a variety of other disorders.
“Still more interesting are those situations where we have cryptic infection, infection not readily appreciated,” Dr. Lipkin said. “There are instances where viruses can infect cells. You see no evidence of damage whatsoever, but the cell doesn’t make a hormone that’s necessary. This is likely to be extremely important in some forms of diabetes and hypothyroidism.”
Current research is providing some very interesting information on the relationship between prenatal infection and certain behavioral disorders, and may hold the key to further understanding diseases such as cerebral palsy, epilepsy, and multiple sclerosis.
Current research, he said, is providing some very interesting information on the relationship between prenatal infection and certain behavioral disorders, and may hold the key to further understanding diseases such as cerebral palsy, epilepsy, and multiple sclerosis. Going back decades, there have been data suggesting that exposure, in utero, to a variety of infectious agents triggers stimulation of the immune response, which results in damage to the developing fetus. Now researchers are discovering that the timing of prenatal exposure may determine how the infection manifests.
“As this has been modeled using a variety of different animal’s systems, it’s become clear that pathogenesis is not specific to the agent, but rather to the host immunoresponse,” Dr. Lipkin said. “And as you begin to understand more about the genetics of immunity, you can understand how these things might funnel through a common pathway to result in various sorts of common pathways for damage.”
One way in which this can be modeled, without considering a specific virus or bacterium, is to directly stimulate the immune response, which Dr. Lipkin said has been done using a double-stranded RNA molecule as a viral mimic that looks like a replicating virus and introducing this into animal models at different stages of gestation.
“Depending on when you’re exposed during the development of the central nervous system, you may have one manifestation or another,” he said. One model, for example, may lead to the expression of withdrawal behavior that looks like autism, while another exposed to the same agent at a different stage might look like attention deficit hyperactivity disorder.
“Now I’m not saying that all individuals with these kinds of disorders, in fact, have this as a result of prenatal infection,” Dr. Lipkin noted. “But this certainly speaks to biological plausibility and, if you put it together with what is known epidemiologically, it makes sense.”
Acute Infectious Disease
A topic of great concern to physicians and the general public is the potential for widespread human infection from animal viruses. Dr. Lipkin and his colleagues are part of a worldwide network of cutting-edge researchers on the front line of medical research in this area.
“If you think in terms of emerging infectious diseases in general, 70 percent of them originate in animals. SARS is a perfect example of how viruses can move from the animal population into humans.”— – W. Ian Lipkin, MD
“If you think in terms of emerging infectious diseases in general, 70 percent of them originate in animals,” Dr. Lipkin said. “SARS is a perfect example of how viruses can move from the animal population into humans. We’re talking about one physician, who picked up the virus in China, checked into a hotel in Hong Kong and, over the course of a few days, disseminated this virus widespread.”
Dr. Lipkin said this illustrates the need for rapid diagnostic systems to be available and accessible to physicians if similar, or more serious, outbreaks are to be avoided. And the technological weapons that physicians need in the war against infectious disease may be just around the corner.
When it comes to diagnosing the often misleading manifestations and defining the puzzling pathways behind these and many other diseases, today’s physician must be part scientist, part sleuth.
Developing Tools for Detection
“One of the things that we have been trying to do in my group now, for more years than I care to think about, is to develop a variety of tools that will allow us to find footprints of infectious agents,” he said. “When thinking about acute diseases and cryptic diseases and how to approach these kinds of problems, we set up a project to develop rapid, high-throughput tools so that we can characterize and investigate outbreaks of acute disease and survey animals for diseases that might emerge into the human population.”
Among the most promising tools coming online involve advancements in polymerase chain reaction (PCR) and gene-chip technologies, which will allow physicians to look at numerous different infectious agents at one time in both a timely and cost-effective manner. Currently most of the funding for the research and development of these technologies is coming from government sources, such as the Department of Homeland Security, to be used for viral hemorrhagic fevers and for poxviruses, but Dr. Lipkin believes these tools will soon be available in clinical practice, and not a moment too soon.
“Over the past decade, all of these emerging infections have been described worldwide and they all have the capacity to spread around the world,” he said. “There are unknowns, like SARS, that are going to be cropping up all the time. Once something starts here—because of globalization, tourism, and trade—it can spread from one hotel and a single individual returning home from a trip and go every which way.”
©2006 The Triological Society