Hemolytic uremic syndrome (HUS) in history–part 4: the bigger picture

As I’ve laid out this week (part 1, part 2, part 3), the realization that a fairly simple, toxin-carrying bacterium could cause a “complex” and mysterious disease like hemolytic uremic syndrome came only with 30 years’ of scientific investigation and many false starts and misleading results. Like many of these investigations, the true cause was found due to a combination of hard work, novel ways of thinking, and simple serendipity–being able to connect the dots in a framework where the dots didn’t necessarily line up as expected, and removing extraneous dots as necessary. It’s not an easy task, particularly when we’ve had mostly culture-based methods to rely on since the dawn of microbiology.

If you read start digging around in the evolutionary medicine literature, you’ll see that one oft-repeated tenet is that many more “chronic” and “lifestyle” diseases are actually caused by microbes than we currently realize. (I’ll note that there is active disagreement here in the field–one reason noted is that many of these diseases would decrease one’s fitness and thus they are unlikely to be genetic, but many of them also have onset later in life than the prime reproductive years, so–still controversial). But whether you agree on the evolutionary reasoning or not, I think it’s safe to say that those who make this claim (like the Neese & Williams book I linked) are probably right on the overall assertion that more and more of these “lifestyle/genetics” diseases are going to be actually microbial in cause than we currently realize.

Why do I agree with this claim? History is a great indicator. Many infectious diseases were thought to be due to complex interactions of genetics (or “breeding,” “lineage,” etc.) with “lifestyle.” Think of syphilis and tuberculosis in the Victorian era. Syphilis (and many other diseases which we know now to be sexually-transmitted infections) was considered a disease which affected mainly the lower social classes (“bad breeding”), and was thought to be rooted in both family history as well as an over-indulgence in sex or masturbation. Tuberculosis, because it affected those throughout the income spectrum, was still blamed on “poor constitution” in the lower classes, but was a disease of the “sensitive” and “artistic” in the upper classes. It was also thought to be due to influences of climate in combination with genetics. Or, look to more recent examples of Helicobacter pylori and gastric ulcers, which were also ascribed to dietary habits and stress for a good 30 years before their infectious nature was eventually proven. And from that same era, HIV/AIDS–which even today, some are still all too ready to write off as merely a behavioral disease, rather than an infectious one.

So, we still view many of these diseases of unknown etiology as multi-factorial, “complex” diseases. And undoubtedly, genetic predisposition does play a role in almost every infectious disease, so I’m not writing off any kind of host/pathogen interplay in the development of some of these more rare sequelae, such as HUS as a consequence of a STEC infection. But looking back over history, it’s amazing how many diseases which we view now as having a documented infectious cause were studied for years by researchers thinking that the disease was the result of exposure to a toxin, or diet, or behavior, or a combination of all three.

I’ve mentioned the example of multiple sclerosis in previous posts. Multiple sclerosis is an autoimmune disease; the body produces antibodies that attack and eventually destroy parts of the myelin sheath covering our nerves. The cause of MS, like HUS 40 years ago, is unknown, though it’s thought to be a combination of genetics and environmental influences. Going through the literature, it seems like almost everything has been implicated as playing a causal role at one point or another: pesticides, environmental mercury, hormones, various other “toxins,” and a whole host of microbes, including Chlamydia pneumoniae, measles, mumps, Epstein-Barr virus, varicella zoster (chickenpox), herpes simplex viruses, other herpes families viruses (HHV-6 and HHV-8), even canine distemper virus. They’ve done this looking at both microbe culture (from blood, brain tissue, CNS, etc.) as well as using serology and DNA/RNA amplification in various body sites. None have shown any strong, repeatable links to the development of MS–much like the spurious associations that were seen with adenovirus and HUS.

Although no microbial agent has been convincingly implicated to date, there are tantalizing hints that MS is caused by an infectious agent. There have been “outbreaks” of MS; the most famous occurred in the Faroe Islands in the 1940s. Studies of migrants show that the risks of developing MS seem to be tied to exposures in childhood, suggesting a possible exposure to an infectious agent as a kid. And one of the most common mouse models used to study MS has the disease induced by infection with a virus called Theiler’s murine encephalitis virus (TMEV). If it can happen in mice, why not humans?

It might seem implausible that infection with some microbe could lead to the eventual neurological outcomes of MS, but again, examples abound of weird connections between microbes and health outcomes. For STEC, it might not be intuitively obvious at first glance how a fecal organism could be a cause of kidney failure. The respiratory bacterium Streptococcus pyogenes usually causes throat infections (“strep throat”), but if left untreated, it can also cause kidney damage (glomerulonephritis) or even heart failure due to rheumatic heart disease. A microbial cause of MS could lie in a virus, bacterium, parasite, or fungus–maybe one that we haven’t even discovered yet, but that perhaps will pop up as we learn more and more about our metagenome. Perhaps 30 years down the road, the way we view many of these “complex” diseases will look as short-sighted as it does looking back at old HUS papers from today’s vantage point.

Can your pet dog make you sick? Multiple Sclerosis and Canine Distemper Virus

Student guest post by Raj Nair.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease that affects the central nervous system (CNS) consisting of the brain and the spinal cord [1]. It is thought to be an autoimmune disease since individual’s immune system attacks their own healthy tissues [1]. However, studies to ascertain triggering factors such as genetic, environmental, and infectious causes are still in progress [2]. So one wonders “Who is more susceptible to develop MS” Literature reveals that typically people between 20 and 50 years of age are commonly diagnosed with MS, affects more women than men, and Caucasians of Northern European ancestry are more prone to develop this disease [1, 2]. Knowledge on the pathophysiology of this disease is that immune system attacks myelin, which forms a protective coat surrounding the nerve fibers of the brain and the spinal cord [2]. The myelin sheath can be compared to insulation around an electrical wire. Loss of this protective layer impedes transmission of nerve signals [1]. Consequences of this damaged connection are the spectrum of symptoms seen in MS. Some of these symptoms are blurred vision, loss of balance, poor coordination, extreme fatigue, tremors, loss of sensation or odd sensations (pin and needle sensations), slurred speech, blindness, difficulty concentrating, poor memory and judgment, and in severe cases paralysis [1]. However, every person is wired differently and so these symptoms are not consistently seen in all patients with MS [1]. Considering all of the above facts my guess is symptoms may vary depending on a person’s immune system and the external or other internal factors governing their immune system. The disease is rarely fatal and most of the people are only mildly affected. Moreover, most of the affected people remit spontaneously [3].

Why should anyone care…. Because MS is unpredictable [1,3], there is no universal cure for the disease [3], can be a chronic condition [1], possibility of disease recurrence [4], and the most important being ‘a single cause’ for the disease has not been identified. As in all diseases with multiple interacting causes, in MS too there is no single pathogen or environment to complete its disease triad. Evidence has it that the disease is more common in Northern America and Canada demonstrating a north-south gradient [5]. Migration studies have established that risk for acquiring MS remains unchanged for those who move from a high prevalence area after age 15, while risk decreased for those who moved at an earlier age [5]. In addition, the genetic angle has been studied by conducting twin studies and studies on specific types of genes. Results yielded prove that genetics can lead to an increase in MS susceptibility but probably not cause MS [5]. In order to make more sense of all the above susceptibility factors and with my interest in infectious causes of diseases, I decided to probe into existing infectious perspectives on MS.

History has it that in 1868, Jean Marie Charcot described the first human demyelinating disease, Multiple Sclerosis. It was postulated then that the disease was a result of exposure to dampness or injuries or emotional stress. However, in the era of microbiological advances, one of Charcot’s students postulated an infectious etiology for MS [7]. Moreover, the CNS pathology and presence of IgG antibodies and oligoclonal bands are known to be consistent with an infectious or immune mediated neurological disorder [6]. Several infectious agents such as Epstein Barr virus, Canine Distemper virus (CDV), measles virus, Chlamydia pneumoniae, Varicella, Human Herpesvirus-6 (HHV-6), and mumps virus have been associated with MS. Viruses win hands down against bacteria in having a strong association with MS. Studies have a tilt towards a viral cause of MS due to the following reasons: low concordance of MS in monozygotic twins similar to what was seen in paralytic poliomyelitis (also a viral infection), spontaneous viral models of CNS demyelination, and increased titers of viral antibodies in MS patients (particularly measles virus). However, these associations can only be strengthened using criteria such as consistency of association across studies, biological plausibility, temporal association, specificity and dose -response relation (epidemiologists know these are the Bradford-Hills criteria!) I will briefly attempt to establish the causal role of CDV in development of MS. Reason I chose this virus? I lost my pet dog to Old Dog Encephalitis (ODE) due to chronic CDV infection. Now I am left thinking ‘Am I or any of my family member’s ideal candidates for developing MS later in life?”

CDV is an RNA virus belonging to the family of Paramyxoviridiae, is closely related to the measles virus in humans and is the most neurotropic form of morbillivirus. As observed in the measles virus, CDV can jump species [5] and causes fatal CNS demyelination in animals including primates [9]. However, the catch-22 is that there has not been one virus (measles or CDV) consistently detected in samples from MS patients to prove its causal role. To make things worse, there is a possibility of cross-reaction in testing for CDV and measles virus using molecular techniques in samples obtained from MS patients [10, 13]. Neutralization assay used to identify viral antibodies in patients have shown considerable variation in the CDV/measles antibodies ratio [10, 11]. This implies that there is a potential for CDV to produce undiagnosed or subclinical human infections [10]. To explain MS on the basis of owning dogs per se, several studies have observed that significantly higher proportion of dogs were kept indoors in the colder northern United States as compared to the southern and western region [12]. This may explain the north-south gradient noted in the prevalence of MS. So logically, greater exposure to dogs before onset of neurological symptoms was expected. However, this phenomenon could not be studied well using case-control studies owing to the higher exposure of humans to dogs in Western countries particularly the United States [6].

An interesting aspect studied was exposure to CDV infected dogs. Most of these studies yielded significant exposure to dogs with distemper-like illness at least 5-10 years before development of MS [12, 14]. Historically other studies have shown significant increase in MS incidence rates preceded by a CDV epidemic in locations such as Newfoundland [16], Key West [15], Sitka [17], and the Faroe Islands. One of the most interesting readings was a study conducted to determine environmental changes implemented that may have lead to a reduction in MS incidence in Key West [15]. An animal shelter on the island which was used to dump euthanized dogs was shut down. This change was said to have attributed to reduction in the MS incidence on the island.

With all of the above evidence and in context with the Hills criteria, I will conclude that there is biological plausibility of CDV playing a causal role in development of MS owing to the demyelinating nature of illness caused by this virus. In addition, this virus still causes disease in dogs despite the widespread use of vaccines [18]. This reinforces the possibility of contracting the virus via exposure to infected dogs (zoonotic disease). However, temporal association could not be established between the virus and occurrence of MS. This may be due to the fact that there are other viruses too causing demyelinating diseases such as measles and HIV, which have a well established role in human diseases. Similar symptoms of demyelinating diseases caused due to viruses other than CDV may have resulted in incorrect estimation of MS prevalence or incidence. There is some consistency among case-control studies which demonstrate exposure to CDV or dogs before the development of MS. However, owing to chronic nature of the CDV these studies do not really make a concrete argument for the role of this virus in MS causation. There does not seem to be any study conducted to examine a dose-response relation of the virus with respect to development of MS. In lieu of the above evidence, a criterion of specificity has been wasted and is best overlooked.

So one real conclusion from observations made so far is that CDV may be responsible for the causation of MS. However, it is definitely not the only factor in the causal pathway. This implies that CDV may be a necessary factor in the development of MS as could be other infectious agents (bacterial or viral). However, an individual’s environment, genetics and immune system are other sufficient factors crucial in disease causation. Also I take this opportunity to highlight the cause ‘Take good care of your pet dog and yourself’. It is the rule of nature, “What goes around, comes around”.

References

1. National Multiple Sclerosis Society. (n.d.). What is multiple sclerosis? Retrieved April 12, 2010.

2. The Journal of the American Medical Association. (2006). Multiple Sclerosis. Retrieved April 12, 2010.

3. National Institute of Neurological Disorders and Stroke. (2010). NINDS Multiple Sclerosis Information page. Retrieved April 12, 2010.

4. The Multiple Sclerosis Information Trust. (2008). All about multiple sclerosis. Retrieved April 12, 2010.

5. Cook, S.D. (1996). Epidemiology of multiple sclerosis: Clues to the etiology of a mysterious disease. Neuroscientist, 2, 172-80. Retrieved April 12, 2010.

6. Cook, S D, Rohowsky-Kochan, C, Bansil, S, et al. (1995). Evidence for multiple sclerosis as an infectious disease. Acta neurologica Scandinavica. Supplementum, 161, 34-42. Retrieved April 12, 2010

7. Johnson, R T. (1994). The virology of demyelinating diseases. Annals of neurology, 36 Suppl, S54-S60. Retrieved April 12, 2010.

8. Giovannoni, G, Cutter, G R, Lunemann, Jan, et al. (2006). Infectious causes of multiple sclerosis. Lancet Neurology, The, 5(10), 887-894.

9. Yoshikawa, Y, Ochikubo, F, Matsubara, Y, et al. (1989). Natural infection with canine distemper virus in a japanese monkey (macaca fuscata). Veterinary microbiology, 20(3), 193-205.

10. Hughes, R A, Russell, W C, Froude, J R, et al. (1980). Pet ownership, distemper antibodies and multiple sclerosis. Journal of the Neurological Sciences, 47(3), 429-432.

11. Rohowsky-Kochan, C, Dowling, P C, & Cook, S D. (1995). Canine distemper virus-specific antibodies in multiple sclerosis. Neurology, 45(8), 1554-1560.

12. Norman, J E, Cook, S D, & Dowling, P C. (1983). Household pets among veterans with multiple sclerosis and age-matched controls. pilot survey. Archives of neurology, 40(4), 213-214.

13. Haile, R, Smith, P, Read, D, et al. (1982). A study of measles virus and canine distemper virus antibodies, and of childhood infections in multiple sclerosis patients and controls. Journal of the Neurological Sciences, 56(1), 1-10.

14. Cook, S D, Natelson, B H, Levin, B E, et al. (1978). Further evidence of a possible association between house dogs and multiple sclerosis. Annals of neurology, 3(2), 141-143.

15. Macgregor, H S, & Latiwonk, Q I. (1992). Search for the origin of multiple sclerosis by first identifying the vector. Medical hypotheses, 37(2), 67-73.

16. Pryse-Phillips, W E. (1986). The incidence and prevalence of multiple sclerosis in newfoundland and labrador, 1960-1984. Annals of neurology, 20(3), 323-328.

17. Cook, S D, & Dowling, P C. (1982). Distemper and multiple sclerosis in sitka, alaska. Annals of neurology, 11(2), 192-194.

18. Cook, S D. (1987). Man, dogs, and hydatid disease. The Lancet, 1(8523), 21-22.