Can we “catch” breast cancer?

Third of five student guest posts by Dana Lowry

In 1911, Peyton Rous first discovered viruses can cause cancer.  A chicken with a lump in her breast had been brought to Rous by a farmer.  Rous prepared an extract that eliminated bacteria and tumor cells and injected this extract into other chickens—tumors grew.  Rous suggested “a minute parasitic organism” was causing the tumor growth, which is now known to be a virus.  However, Rous’ discovery remained very controversial, and it wasn’t until 1966 that he was awarded a Nobel Prize for his discovery.  Since Rous’s discovery, researchers have found an estimated 15 percent of all cancers worldwide are associated with viruses.  Some common virus and cancer associations are: human papilloma virus (HPV) and cervical cancer, hepatitis B and liver cancer and human T lymphotropic virus type 1 (HTLV-1) and T-cell leukemia.

Epstein-Barr virus (EBV), a member of the herpesvirus family, is one of the most common viruses worldwide.  Among 35 to 40 year olds in the U.S., up to 95% have been infected with EBV.  Oftentimes, children infected with EBV have no clinical signs or symptoms; however, 30% to 50% of adolescents and young adults exposed to EBV for the first time will develop infectious mononucleosis, commonly known as mono.  In the U.S., individuals are usually exposed to EBV in adolescence or young adulthood compared to developing countries, where oftentimes individuals are exposed as infants or young children.  EBV usually remains dormant in the body throughout an individual’s lifetime, similar to the varicella-zoster virus, the virus responsible for the chicken pox.  EBV is known to play a role in Burkitt ’s lymphoma (cancer of the immune cells), nasopharyngeal cancer (cancer of the upper throat) and Hodgkin’s lymphoma (cancer of the lymphatic system), but can EBV also play a role in breast cancer?

In 2010, James Lawson and Benjamin Heng reviewed 27 papers concerning EBV and breast cancer associations. EBV infections are universal in high and low risk breast cancer groups, making it unlikely that EBV is the sole contributor to forms of breast cancer [1].  However, the age at which EBV is contracted seems to play a role in the risk of developing breast cancer. Women in Western countries are at higher risk of developing breast cancer and tend to be infected with EBV during adolescence or young adulthood, whereas women from non-Western countries have a lower risk for developing breast cancer and tend be infected during infancy or early childhood.  Hodgkin’s lymphoma shares a similar correlation with higher rates in Western countries [2].  Although there seems to be a relationship between age of EBV infections and risk of breast cancer, potential confounders need to be considered.  Women in developing countries tend to have more children, have children at a younger age and breastfeed their children for longer periods of time.  Breastfeeding, having more children and having children earlier in life all seem to be protective factors against breast cancer.

Beyond epidemiological evidence, lies biological evidence.  Twenty two of the studies Lawson and Heng reviewed were based on polymerase chain reaction (PCR) techniques. Issues have been found with standard PCR procedures, but it is becoming widely accepted that EBV can be identified in breast cancer tissue through specific PCR techniques [1].  EBV genes have been found in breast cancers through polymerase chain reaction (PCR) analyses.  EBV has not only been shown to shed in human breast milk [3], but it has also been shown to stimulate growth of human breast-milk cells [4]. The mechanism by which EBV actually causes cell alterations is not known, but it is thought to be different from the mechanisms used in lymphomas and nasopharyngeal cancer [1].

It is unlikely that we can actually “catch” breast cancer, as EBV doesn’t seem to be the sole cause of breast cancer.  EBV may contribute to breast cancer by altering genes in the breast cells which eventually leads the uncontrolled cell division, known as cancer.  More importantly, it seems the age an individual is infected with EBV may play an even bigger role in the outcome of disease.  An EBV vaccination is in the works that will hopefully prevent infectious mononucleosis and EBV-associated cancers.  However, the vaccination may not prevent the EBV infection itself; it is targeted towards the most abundant protein on the virus and on virus-infected cells.  If the vaccination proves to be successful, it will be interesting to see if a reduction in breast cancer rates will follow, along with the known cancers associated with EBV. Only time will tell.

 

References:

  1. Lawson, J. and Heng, B. (2010). Viruses and Breast Cancer. Cancers 2010, 2(2), 752-772; doi: 10.3390/cancers2020752.

 

  1. Yasui et al. (2001). Breast cancer risk and “delayed” primary Epstein-Barr virus infection. Cancer Epidemiology, Biomarkers & Prevention, 10:9-16. http://cebp.aacrjournals.org/content/ 10/1/9.long.

 

  1. Junker et al. Epstein-Barr virus shedding in breast milk. (1991). The American Journal of the Medical Sciences, 302: 220–223. http://www.ncbi.nlm.nih.gov/pubmed/1656752.

 

  1. Xue et al. (2003). Epstein-Barr virus gene expression in human breast cancer: protagonist or passenger?. British Journal of Cancer, 89:113–119. http://www.nature.com/bjc/journal/ v89/n1/full/6601027a.html

 

 

The impact of HIV on Drug-Resistant Tuberculosis

Second of five student guest posts by Nai-Chung N. Chang

Tuberculosis (TB) is a major disease burden in many areas of the world. As such, it was declared a global public health emergency in 1993 by the World Health Organization (WHO). It is a bacterial disease that is transmitted through the air when an infected individual coughs, sneezes, speaks, or sings. However, not all individuals who contract the disease will display symptoms. This separates the infected into two categories, latent and active. Latent individuals are non-infectious and will not transmit the disease, whereas active individuals are able to transmit the disease.

TB is a significant concern in patients diagnosed with HIV, since individuals diagnosed with HIV and latent forms of TB infection is more likely to develop the disease, then the HIV negative individuals. In addition, in people living with HIV, TB is one of the leading causes of death. (CDC, 2012) The fact that latent forms of the disease are capable of becoming fully active forms given the right stimulus represents a high risk to individuals living in poor conditions, which is widely present in developing nations. It is of even greater concern to individuals who have immune system diseases, such as HIV. Individuals with latent TB infection depend on robust immune system responses to prevent the infection from going into active form. HIV and similar diseases targets and weakens immune systems so that the response to infections becomes weaker, providing increased risk of TB infections and the activation of latent forms.

TB is a major concern not only because of its status as a global epidemic. While there are many forms of prevention and treatment for the disease, such as antibiotics and vaccine, these treatments are not overly effective in combating and controlling the spread of the disease. TB is widespread and has a high chance of becoming resistant to any treatment that it is exposed to, especially antibiotics and other chemotherapeutic drugs such as isoniazid. Several of these strains already exist and each has varying levels of resistance, including Multidrug-Resistant (MDR) and Extensively Drug-Resistant (XDR). MDR is a strain that is resistant to two of the most often used and potent TB drugs, isoniazid and rifampin; whereas XDR is MDR strains that have developed resistance to any fluoroquinolone and at least one of three second-line drugs such as kanamycin or capreomycin. Also, the vaccine that has been developed for preventing TB is not overly protective, and sometimes fails to protect against infection. (CDC, 2012) The vaccine is not designed to prevent the infection of TB; instead, it is aimed towards boosting and speeding up the immune system response to any new infection so that the infected individual remains in latent forms. (Russell, et al., 2010)

The increasing trends in the resistance of TB to various treatments is a serious concern as it have major impacts in controlling the spread of the disease in many regions. This condition worsens with MDR and XDR TB. With regular, normal strains of TB, latent and early infections could be combated and controlled by a successful chemotherapeutic treatment even in patients with immune system diseases. However, with MDR and XDR TB, the strains are able to fully develop in an individual with weakened immune system, as evident in areas where incidence of TB and HIV is high, such as South Africa. (O’Donnell, et al., 2013) For cases with MDR and XDR strains, the weakened immune systems are not potent enough to prevent infections or keep them in latent form. Additionally, the active forms of these strains are resistant to common, and in some cases, advanced treatments.

With the increasing development of drug-resistant TB, the most effective way to combat TB is not only through vaccines and treatments. Instead, strict public health policy is needed to properly maintain control and combat the spread of TB. With a well-structured public health system, we can ensure that the long treatment of TB is complete, since most of the increase in the resistance to treatment often results from issues during treatment. Events such as patient non-compliance to the treatment and inadequate health-care supervision can all result in the development of new strains of the bacteria that have developed resistance to the treatments that was used. (Russell, et al., 2010) Also, a well-structured public health system can maintain better supply and quality of drugs throughout the treatment process, as well as the prevention and detection of possible new drug resistant strains. More importantly, it can maintain better surveillance and ensure patient compliance during the treatment process, which would help in reducing the development of drug resistant strains. The surveillance systems can also target comorbid diseases such as HIV to reduce risk factors for activating latent forms of the disease in patients with HIV and similar diseases.

References:
CDC, 2012. Tuberculosis (TB). [Online]
Available at: http://www.cdc.gov/tb/topic/basics/default.htm
[Accessed 13 2 2013].
O’Donnell, M. R. et al., 2013. Treatment Outcomes for Extensively Drug-Resistant Tuberculosis and HIV Co-infection. Emerging Infectious Disease [Internet], 19(3).
Russell, D. G., Barry 3rd, C. E. & Flynn, J. L., 2010. Tuberculosis: What We Don’t Know Can, and Does, Hurt Us. Science, 328(5980), pp. 852-856.

Treatment of Chronic Otitis Media: Guidelines versus Practice

First of five student guest posts by Kristen Coleman

Every morning as I prepare for class, I go through the same internal dialogue, “to wear or not to wear my hearing aide.” I am forced to do this because when I was a child I, like most American children (about 80% by age 3 as estimated by the American Academy of Family Practitioners, AAFP), suffered from otitis media and my treatment resulted in hearing loss. The treatment I underwent was called tympanostomy with ventilation tube insertion, which has rapidly become the most common reason for general anesthesia in children in the United States. However, the AAFP reports that meta-analysis of studies exploring the effectiveness of this procedure indicate that benefit is only marginal at best. So why is it that our children are being exposed to this potentially quality of life altering procedure, if there is little benefit? In order to explore the reasons, we must delve further into the disease in question.

Previously, it had been commonly thought that chronic otitis media was characterized by a virus-laden sterile effusion behind the ear drum; meaning that bacteria were not thought to be present and thus, antibiotic therapy was not indicated. Now we know that chronic otitis media is most commonly due to infection of the middle ear by Streptococcus pneumoniae, Haemophilus influenza, Moraxella catarrhalis, (all of which are bacteria) or respiratory viruses. The organisms contribute to the buildup of fluid and pus behind the ear drum that is characteristic of this disease. Dr. Kim Stol and collaborators have reported findings that demonstrate that immune inflammatory response, measured through the presence of immune mediators called cytokines, may play a role in the damage to the ear during bacterial infection that commonly results in hearing loss or diminishment. As demonstrated by the research of Dr. Lusk of the University of Iowa, this immune-mediated damage can persist even after surgical intervention if bacteria persist in the middle ear, making medical management of the bacteria through antibiotic therapy even more essential.

Due to this evidence, the AAFP and other leading organizations that publish guidelines for treatment recommend antibiotic therapy as the gold standard of care for children suffering from chronic otitis media. These guidelines indicate rigorous treatment with high doses of antibiotics such as amoxicillin/clavulanate, cephalosporins and macrolides. If these antibiotics do not offer relief, clindamycin and tympanocentesis (removal of fluid from behind the ear drum with a needle) are then warranted. It is only when all of these medical treatments fail that tympanostomy tubes may be an appropriate option. However, it has been reported by researchers at Mount Sinai School of Medicine in New York City that of the 682 children who received tympanostomy tubes as treatment for chronic otitis media in their study in 2002, only 7.5% did so in accordance to the guidelines set forth by these organizations, and that most of these operations occurred before adequate attempts at antibiotic management of the disease could be utilized. In the study performed by Dr. Stol, it was reported that of the 116 participants in the study who were suffering from chronic otitis media, only 6.9% had received a recent antibiotic prescription, despite the fact that 53% of these patients were suffering from a bacterial form of the disease that may have responded favorably to antibiotic therapy.

As for me and my story, I had an initial round of ventilation tubes places in my ear drums when I was 6 years old, along with an adenoidectomy which was thought to help diminish my ear infections. My family was told that my disease was due to a virus and I was not prescribed any antibiotics prior to my surgical procedure. These tubes fell out the next year, and my chronic otitis media still had not resolved. More permanent tubes were placed in my ears at age 8 and these became lodged in my ear drums until college, all the while I suffered from chronic fluid and pain in my ears. When I had the tubes removed at age 19, my ear drums were permanently scarred and I had to undergo a bilateral tympanoplasty in which a surgeon tried to patch the holes in my ear drums, to no avail. All of this resulted in me having to wear a hearing aide in order to hear adequately at the age of 28.

As the report from Mount Sinai Medical School indicates, the discrepancy between practice and guidelines, as well as the overuse of surgical management in lieu of less-invasive medical management cannot be in the best interest of the children suffering from this disease, and steps need to be taken in order to educate physicians and families alike as to the most appropriate steps for treatment of this chronic disease in order to save our children from having stories like mine.

References:

1. Stol, Kim et al. Inflammation in the Middle Ear of Children with Recurrent or Chronic Otitis Media is Associated with Bacterial Load. The Pediatric Infectious Disease Journal. Volume 31, Number 11, pages 1128-1134. November 2012.

2. Lusk, Rodney P. et al. Medical Management of Chronic Suppurative Otitis Media Without Cholesteatoma in Children. Layngoscope: February 1986.

3. Keyhani, et al. Overuse of tympanostomy tubes in New York metropolitan area: evidence from five hospital cohort. Mount Sinai Medical School. BMJ: 2008.

4. American Association of Family Practitioners. www.aafp.org/afp/2007/1201/p1650.html

Student guest posts: infectious causes of chronic disease

It’s that time again. I teach a class every other year on infectious causes of chronic disease, looking at the role various infections play in cancer, autoimmune disease, mental illness, and other chronic conditions. Each year, the students are assigned two writing assignments-–to be posted here on the blog. Over the next week or so, I will be putting up guest posts authored by students on various topics under the broad umbrella of infection and chronic disease.

Constructive comments on their posts are appreciated, but please keep in mind that they’re students doing this as an assignment and still learning. Finally, these posts are the students’ own; I’m formatting them for publication here, but beyond that their words (and opinions!) are theirs.

The emergence of “nodding disease”

The emergence of “new” diseases is a complicated issue. “New” diseases often just means “new to biomedical science.” Viruses like Ebola and HIV were certainly circulating in Africa in animal reservoirs for decades, and probably millenia, before they came to the attention of physicians via human infections. Hantavirus in the American southwest has likely infected many people, causing pneumonia of unknown origin, before the Four Corners outbreak led to the eventual identification of the Sin Nombre virus. Encroachment of humans into new areas can bring them into contact with novel infectious agents acquired via their food or water, or by exposure to new disease vectors such as mosquitoes or ticks. Occasionally, emerging diseases may be truly “new”–such as recombinant influenza viruses that resulted from a mixture of viruses from different host species to form a unique variant, different from either parent virus.

Nodding disease is one of those that has only recently appeared on the radar of those of us in public health, although it is not truly a “new” disease. It was first described 40 years ago, but this syndrome has been sufficiently rare as to not merit significant medical attention until 2010. Outbreaks of nodding disease have now occurred in South Sudan, Tanzania, and Uganda, affecting thousands of children. The disease first presents as cognitive difficulties; then the nodding starts, especially when children are provided food. They experience further cognitive decline, and ultimately regress to an almost infantile stage, where parents cannot leave them unattended for fear they may wander off or injure themselves by accident. Death appears to often be a result of such accidents: (drowning, falling into a cookfire) or starvation, as the seizures in the late stages of the disease seem to make it virtually impossible for the child to eat. No one is known to have recovered from the disease.

While the cause(s) still remain mysterious, studies have been done trying to determine risk factors for disease development. A recent CDC-assisted study, for example, was carried out in the new country of South Sudan. This examined 38 matched cases and controls and examined dietary as well as infectious disease factors, looking at issues such as vitamin deficiencies, a history of hunger, and current infection with the parasite Onchocerca volvulus.

This particular agent is interesting, as the nematode already causes a well-known disease, river blindness. Like many parasites, the life cycle of O. volvulus is fascinating and complicated. Humans are the main host, who are initially infected via the bite of the black fly, which was herself infected with O. volvulus from a previous human meal. After inoculation, the nematode larvae migrate to the subcutaneous tissue of their human host, where they multiply and mature over the course of 6-12 months, eventually mating and producing microfilariae–little baby worms, up to 3000 per day per female nematode. It’s this life stage that are then ingested by black flies during a daytime meal, when the microfilariae migrate to the host’s skin. Within the fly, they will mature through three larval stages, ready to infect another human host.

How then do these worms cause blindness, if they live mainly in the subcutaneous tissues and, sporadically, the skin? The microfilariae also migrate to the surface of the cornea, and when these organisms die, they cause an intense immune response. Interestingly, this response seems to be due not to the worms themselves, but to their Wolbachia symbionts–bacteria species notorious for infecting parasites (and insects) and causing all sorts of weird things to happen. Repeated episodes of this inflammation can lead to keratitis, and the cornea eventually becomes opaque. O. volvulus can also cause intense skin itching, leaving dead and discolored patches of skin in addition to the characteristic blindness. In all, it’s a nasty disease but one that is relatively simple to treat if caught early, either with antiparasitic drugs or even with antibiotics such as tetracycline to kill the Wolbachia. The disease can also be prevented by fly mitigation and preventative doses of anti-parasitic medicines.

Testing for O. volvulus is relatively simple. The MMWR study used a “skin snip”–just as it sounds, taking a small piece of skin from the patient and examining it for microfilariae. However, this has the limitation that it may miss early infections (where microfilariae have not yet developed and spread) or mild infections (where there are fewer organisms per square millimeter of skin sample). They note that they also took blood samples to examine antibody responses, but those data were not yet available.

What they found was interesting. In one village, Maridi, they found a matched odds ratio of 9.3 (with the cases being more likely to be currently infected with O. volvulus than the controls), which agrees with an earlier study done in Tanzania which found high levels of infections in cases. However, no healthy controls were tested for comparison in that publication. Furthermore, in the South Sudan study, no statistically significant difference in parasite infection was found between cases and controls in the second village, Witto. Why the dramatic difference between the two locations in the same country? Don’t know. It could simply be related to small sizes (only 25 pairs were examined in Maridi, a “semi-urban” area, and 13 in Witto, described as rural). We also don’t know anything about temporality–were the patients affected before they developed nodding disease, or subsequent to the start of symptoms? Even though many questions remain, the Ugandan government is taking steps that look as if they believe a cause of nodding disease has been found, and that O. volvulus is that cause. While additional measures to stop the spread of the parasite are probably a good idea in any case (reducing river blindness is also good), I certainly wouldn’t call this case closed, and neither did the individuals speaking on this issue recently at ICEID, where this outbreak was discussed in at least two sessions I attended.

There is biologic plausibility for O. volvulus to cause a seizure disorder. Several other types of parasites can cause epileptic conditions, including the tapeworm Taenia solium, which can originate in beef or pork products. Could it be that O. volvulus is getting into the brain and causing pathology, leading to seizures? The 2008 Tanzanian study suggests no, as the cerebral spinal fluid was tested in 42 patients and found to be negative for O. volvulus DNA in all patients.

With some emerging diseases, there is the risk that the incidence of a disease is increasing due only to awareness of an illness–the more doctors that recognize it, the more cases they will diagnose. However, there is anecdotal evidence that this isn’t the case with nodding disease:

Dr. Abubakar said in an interview that while the syndrome is known to have existed for some time in South Sudan, the recent spike in reported cases could only partially be explained by wider awareness and better surveillance. “It’s not only local authorities but local NGOs saying more children have been affected,” he said. Particularly striking, he said, is that in South Sudan “there are a number of displaced people from another location who did not have nodding. But after the displacement, when they moved to affected areas, after 2 years the children started developing the syndrome.”

Additional studies and more thorough surveillance are needed to confirm that this is true, which would suggest a localized focus of disease in multiple different areas (which does seem to be the case at this point in time).

The migration aspect is intriguing, suggesting some sort of environmental exposure–if it was simple genetics, where the children were living shouldn’t matter. However, this puts us back almost as square one, examining what is present in the local environment–both infectious and non-infectious agents including heavy metals and various toxins.

The work investigating nodding disease is still in its infancy, but already “nodding disease” has affected more individuals than all of the recorded cases of Ebola. Now that there is recognition of the disease, and some international support for research into its causes, hopefully better treatment and prevention efforts will follow.

Works cited

WInkler et al, 2008. The head nodding syndrome–clinical classification and possible causes. Epilepsia. 49(12):2008-15. Link.

CDC. 2012. Nodding Syndrome — South Sudan, 2011. MMWR. 61(03);52-54. Link.

Is the HPV vaccine “weak science?” (Hint: no)

Oh, Discover. You’re such a tease. You have Ed and Carl and Razib and Phil and Sean, an (all-male, ahem) cluster of science bloggy goodness. But then you also fawn over HIV deniers Lynn Margulis and Peter Duesberg. Why can’t you just stick with the science and keep the denial out?*

But no, now they’ve let it spill into their esteemed blogs. I was interested to see a new blog pop up there, The Crux, a group blog “on big ideas in science and how these ideas are playing out in the world. The blog is written by an outstanding group of writer/bloggers and scientist/writers who will bring you the most compelling thoughts throughout the world of science, the stuff most worth knowing.” Sounds ok, let’s see what stories are up…oh, one on HPV! Right up my alley. And hey, a woman! Bonus.

*Reads story*

Ohhhhh, it’s actually one on HPV vaccine misinformation, written by the author of the fawning Duesberg article referenced above. Faaantastic.
Continue reading “Is the HPV vaccine “weak science?” (Hint: no)”

Does bestiality increase your risk of penile cancer?

Aah, the things one learns when awake at 3AM on a Saturday night. Via a few different Tweeps, I ran across this article from Men’s Health magazine, titled “Urgent Warning: Sex with Animals Causes Cancer.”

I probably should have just stopped there.

But no, I read the magazine article, which states:

Brazilian researchers polled nearly 500 men from a dozen cities, and found that–we’re not joking around here–roughly 35 percent of the men had “made it” with an animal. That’s a problem, because screwing a horse, donkey, pig, or any other animal was found to up your likelihood of developing cancers of the penis by 42 percent.

Of course, this meant that now, I had to go dig up the actual journal manuscript. Though nothing is cited by Men’s Health, a quick PubMed search using the terms “sex with animals” and “Brazil” turned up Sex with Animals (SWA): Behavioral Characteristics and Possible Association with Penile Cancer. A Multicenter Study, published last month in The Journal of Sexual Medicine.

Though the MH write-up makes the research sound ridiculous, it’s not a bad paper overall. Starting out with the observation that penile cancer is common in impoverished regions in the world but relatively rare in developed areas, the authors wanted to examine one possible difference in this urban/rural divide: bestiality. So they enrolled 492 individuals who had spent their childhood in rural areas: 118 cases who had penile cancers and 374 controls who were seen at the same clinics for other issues, including check-ups and “cancer prevention” (though it’s not really defined what’s included in that catch-all). All participants were asked a variety of questions about their sexual history, including sex with animals and humans (frequency, number of partners, the usual drill), circumcision status, as well as other factors that might influence cancer outcomes, such as smoking status and history of sexually transmitted diseases and other health conditions.

The authors did find in the univariate analysis (basically, looking at one factor at a time) that there were several statistically significant differences between the cancer group and the control group. These included smoking, a history of sex with prostitutes, the presence of penile premalignant lesions (not surprising) and phimosis (NSFW), a condition where “the foreskin cannot be fully retracted over the glans penis.” As the title suggests, they also found that having sex with animals was significantly higher in the case than the control group (44.0 vs 31.6 percent, p<.008). When they combined risk factors into their multivariate analysis, a few factors still remained in the model. Phimosis was the big one, with an odds ratio of 10.41; SWA was down the list at 2.07 (95% CI: 1.21-3.52, p=0.007). Penile premalignant lesions and smoking also remained, with odds ratios in the middle of the other two. Finally, just because I know many of you out there are curious, they also break down those who have SWA by types of animals they, um, frequent:

The animal types most often cited were mares (N = 80), followed by donkeys (N = 73), mules (N = 57), goats (N = 54), chickens (N = 27), calves (N = 18), cows (N = 13), dogs (N = 10), sheep (N = 10), pigs (N = 6), and other species (N = 3).

Yes, chickens for 27 of them. I don’t even want to know, but I’m sure if I did, I could find out somewhere on the Internets. Please, don’t educate me on that one. They also note that almost a third of the men reported “SWA with a group of men.” I’m leaving that one alone as well (especially as that one wasn’t any different between cases and controls, so it didn’t seem to be an important variable for penile cancer development).

So how do they explain these findings? Their discussion is a bit odd, in my opinion, and narrows in on the SWA finding to the exclusion of their other significant risk factors. Of course, coming from my background, my first thought regarding SWA and cancer jumps to infectious agents. They acknowledge in the introduction that the human papillomavirus (HPV) is associated with about half of penile cancers. Other species of animals can also be infected with papillomaviruses, such as the rabbit of jackalope mythology. A previous study identified five potentially novel papillomaviruses in Australia, just by doing skin swabbing. As such, it’s certainly safe to say that we know very little about the diversity of these viruses that exist in other animal species, much less their cancer-causing potential. It would be fascinating to look at tumor samples from the men in this group who were known to have sex with animals, and see if any novel viruses (papillomas or otherwise) could be identified.

However, they don’t limit their suggestion to only zoonotic infections. That’s when it gets a bit weird to me, as they say things like:

Speculation exists regarding cancer status as an infectious disease in humans [24,25], as studies have suggested that tumor cells can be transmitted from one mammal host to another within the same species [26,27]. PC is frequent in equines [28], but transmission of malignancies between animals and humans has not been reported.Virology does not consider possible viral movement from animals to humans except in cases of zoonosis, such as rabies or pandemic forms of bird or swine flu. However, the hypothesis that the HIV epidemic resulted from simian-human virus transmission has not been fully explored.

Um, huh? First, the citation they use for the HIV claim is from 1999–indeed, at that point there was still a lot that was unknown about cross-species HIV transmission, but that was 12 years ago! The field has moved on since then. I’m baffled as to what they mean by their first sentence–as far as I know, “Virology” doesn’t consider anything–“Virologists” do, and why would this not be a zoonosis? Though I think direct transmission of cancer cells (like in the case of the Tasmanian devil transmissible cancer) would be unlikely, transmission of microbes which could lead to cancer development is certainly plausible and well within the realm of virology/bacteriology/etc. In my opinion, it’s infinitely more likely than the idea they also suggest of more directly carcinogenic animal secretions.

There were also a number of limitations in the paper. Though they grouped frequency of sex with prostitutes into a “more/less than ten times” dichotomous variable, I don’t see any similar “dose” analysis for the frequency of SWA in their models, even though they did ask the men about this. They make one statement that “long-term SWA (>3 years) was reported by 64% of the PC patients and 46.6% of the controls (P = 0.044).” This difference was statistically significant at the usual cutoff (p< .05), but it doesn't appear that they studied this further--why not? If you have a typical dose-response relationship (the more times the men had sex with animals, the more likely they were to develop cancer in the future), that would strengthen their case for a connection between the two. They also didn't ask about sexual orientation or the nature of the self-reported past STDs. Are any of these participants HIV positive, for example? Anyway, with these limitations in mind, it does appear that Men's Health got it mostly right: don't have sex with animals if you value your penis. But it's unfortunate that they just go for the sensationalism and ignore the more important variables from a public health standpoint, like "don't smoke" and "if you have abnormal penile conditions, you may want to get those checked out, k?" References

Zequi SD, Guimarães GC, da Fonseca FP, Ferreira U, de Matheus WE, Reis LO, Aita GA, Glina S, Fanni VS, Perez MD, Guidoni LR, Ortiz V, Nogueira L, de Almeida Rocha LC, Cuck G, da Costa WH, Moniz RR, Dantas Jr JH, Soares FA, & Lopes A (2011). Sex with Animals (SWA): Behavioral Characteristics and Possible Association with Penile Cancer. A Multicenter Study. The journal of sexual medicine PMID: 22023719

Antonsson and McMillan, 2006. Papillomavirus in healthy skin of Australian animals.

Hemolytic uremic syndrome (HUS): history and implications

Part One

It appears that the E. coli O104 sproutbreak is starting to wind down, with more than 3,500 cases diagnosed to date and 39 deaths. Though sprouts remain the key source of the bacterium, a recent report also documents that human carriers helped to spread the organism (via H5N1 blog). In this case, it was a food service employee working at a catering company, who spread infection to at least 20 people before she even realized she was infected.

As with many infectious diseases, there are potential lingering sequelae of infection, which can occur weeks to years after the acute infection has cleared up. Like almost 800 others involved in this outbreak, the woman who unwittingly infected others via food developed hemolytic uremic syndrome, or HUS. We now know that the most common cause of HUS are bacteria such as STEC (“shiga toxin-producing E. coli“); the “shiga toxin” that they produce inhibits protein synthesis in the host and cause cell death. This can have systemic effects, and leads to clotting in affected organs–most commonly the kidneys, but other organs can also be affected. Dialysis may be necessary, and the infection can lead to kidney failure and the need for organ transplantation. There is already concern that, because of the huge numbers of HUS cases, many patients will have long-term kidney damage, including the potential need for additional organs (and possibly, re-vamping the way donations are made as well):

In previous E. coli outbreaks, up to half of patients who developed the kidney complication were still suffering from long-term side effects 10 to 20 years after first falling sick, including high blood pressure caused by dialysis.

In addition to possible kidney problems, people who have survived serious E. coli infections may also suffer from neurological damage, as the bacteria may have eaten away at blood vessels in the brain. That could mean suffering from seizures or epilepsy years after patients recover from their initial illness.

While it’s common knowledge in the medical community now that STEC can lead to HUS, which can lead to chronic kidney issues, for many years, the link between E. coli and HUS was obscured. HUS first appears in the literature in 1955, but the link to STEC wasn’t confirmed until the early 1980’s. In the interim, myriad viruses and bacteria were examined, as well as genetic causes. (There are cases of HUS caused by host mutations and other etiologies, but they are much less common than HUS caused by STEC and related organisms). I’ll delve into the history of HUS and look at a few studies which examined alternative hypotheses of causation, until finally STEC was confirmed as the causative agent. I’ll also discuss what this means as far as discovering infectious causes of other “complex” and somewhat mysterious diseases whose causes are unknown, as HUS was a mere 30 years ago.

Part Two

The epidemiology of hemolytic uremic syndrome (HUS) was murky for several decades after it was first defined in the literature in 1955. In the ensuing decades, HUS was associated with a number of infectious agents, leading to the general belief that it was a “multifactorial disease”–one that had components of genetics and environment, much like we think of multiple sclerosis today, for example.

Several HUS outbreaks made people think twice about that assumption, and look deeper into a potential infectious cause. A 1966 paper documented the first identified outbreak of HUS, which occurred in Wales. The researchers examined a number of possible environmental factors the patients may have had in common–including food, water, and various toxins–but came up empty. They sum up:

Since it is almost invariably preceded by a gastrointestinal or respiratory illness, it seems probable that it represents a response to an infection. Although Gianantonio et al. (1964) have identified one possible causative virus, it may be that various infective agents can initiate the syndrome.

This idea held throughout the next 20-odd years, as numerous studies looked at both environmental and genetic effects that may be leading to HUS. A 1975 paper examined HUS in families, suggesting that there may be two types of HUS (which we now know to be true–the genetic form is less often associated with diarrhea, and tends to have a worse prognosis as I mentioned yesterday). But still, no definitive cause for either.

There were also a number of studies testing individuals for many different types of pathogens. A 1974 paper enrolled patients in the Netherlands between 1965 and 1970, but one of the inclusion criteria was a “history of a prodromal illness in which gastrointestinal or respiratory tract symptoms were present.” The respiratory tract symptoms are mentioned in a number of papers, and were probably a red herring that sent people in search of the wrong pathogens for awhile. In this particular paper, they examined children for infection with a number of viral and bacterial pathogens, using either culture or serological methods (looking for antibodies which may suggest a recent infection). In that portion of the paper, they note a possible association with adenoviruses, but state that the data don’t support a bacterial infection–a viral etiology was deemed more likely. Regarding basic epidemiology, they did note a few small clusters of cases in families or villages, as well as a peak in cases in spring/summer–as well as an increasing number of cases from the first year of their study to the last. The epidemiology of HUS was starting to become clearer, and the syndrome appeared to be on the rise.

Even as additional case reports occasionally targeted foods as a precursor to HUS outbreaks, it wasn’t until the late 1970s and early 1980s that HUS really started to come into focus. In 1977, a paper was published identifying the “Vero toxin”–a product of E. coli that caused cytotoxicity in Vero cells (a line of African green monkey kidney cells, commonly used in research). Researchers were closing in.

Part Three

I left off yesterday with the initial discovery of “Vero toxin,” a toxin produced by E. coli (also called “Shiga toxin” or “Shiga-like toxin”). Though this may initially seem unconnected to hemolytic uremic syndrome (HUS), the discovery of this cytotoxin paved the way for a clearer understanding of the etiology of this syndrome, as well as the mechanisms by which disease progressed. By the early 1980s, several lines of research pointed toward E. coli, and particularly O157:H7, as the main cause of HUS.

A 1982 Centers for Disease Control and Prevention MMWR report found a rare E. coli serotype, O157:H7, associated with hemorrhagic colitis following consumption of hamburgers. Similar results were reported in a 1983 Lancet paper, which found serotype O157 among their collection of verotoxin-producing strains. Another paper that same year from a Canadian group showed that O157:H7 was the second most common cytotoxic strain in their collection of over 2,000 E. coli isolates. The most common was serotype O26–more on that below. This paper also discussed an outbreak of hemorrhagic colitis that had occurred at a nursing home, with O157 identified as the cause. The evidence was mounting, but these were small studies and not always associated with HUS. Still, these papers collectively were suggestive of a connection between E. coli infection (especially with strains that produced the shiga/vero toxin), hemorrhagic colitis, and HUS.

In 1985, a new study came out which really helped to seal the deal. Rather than look only at cases in isolation, the authors designed a case-control study looking at patients with “idiopathic HUS” (in other words, HUS of unknown origin which started with diarrhea, rather than the other variant lacking this symptom). They ended up with 40 patients who qualified. They then picked a single control for each patient, matching them on age, sex, and season of the year. The controls were children either diagnosed with Campylobacter enterocolitis (and therefore, enterocolitis of a known cause) or were healthy children either from a local daycare center, or kids coming in for elective surgeries. Stools were collected from each group and tested for a variety of organisms, including vero toxin-producing E. coli (VTEC, also known as STEC for the shiga-like toxin nomenclature). They also tested for activity of the toxin itself in fecal samples. Finally, in the case patients, attempts were made to collect what are called “acute” and “convalescent” blood samples. These are samples taken when the patient is actually sick (“acute”), and then ones taken a few weeks later (“convalescent), to look at the presence of antibodies in the blood. If it was an infection by the suspected organism (in this case, STEC/VTEC), you should see a rise in antibodies the host produces that target the organism–for these kids, they were looking for antibodies to the shiga/vero toxin.

They found either vero toxin or VTEC in 60% of the case patients, but in none of the controls. Of the VTEC isolated, serotypes included O26, O111, O113, O121, and O157. For the latter, it was the most common type isolated (25% of the VTEC found). Of the patients who were negative for both VTEC and vero toxin, from those who had paired blood samples (12/16 of the remaining cases), 6 did show a rise in antibody titer against the vero toxin–suggesting they had been exposed and were producing antibodies to neutralize the toxin. So, for those keeping score, 75% of the cases had evidence of VTEC infection either by culture or serological techniques. It may not have been the nail in the coffin and there are certainly some flaws (the diversity of controls and lack of analysis of blood titers for the controls being two that pop out at me), but this paper went a long way toward establishing VTEC/STEC as the cause of HUS, which has been subsequently confirmed by many, many studies worldwide.

The most common vehicles of transmission of these organisms have also come into clearer focus since the 1950s, with almost all HUS/STEC outbreaks associated with food products; most common is still the O157:H7 serotype. O157 is a bit unique, in that this strain typically doesn’t ferment sorbitol–as such, this is often used as a diagnostic feature that sets it apart from “normal” E. coli. However, as I mentioned above (and as the current outbreak has shown), a number of other serotypes besides O157:H7 can also cause HUS. Most of these don’t appear to be as commonly associated with outbreaks–rather, they may more commonly cause sporadic disease where fewer people may become sick. Because these don’t have the unique sorbitol-non-fermenting feature, these may be overlooked at a diagnostic lab. There are assays that can detect the Shiga-like toxin directly (actually, we now know there are multiple families of related toxins), but not all labs use these routinely, so it’s likely that the incidence of infection due to non-O157 STEC is higher than we currently know.

HUS was once a mysterious, “complex” disease whose perceived etiology shifted almost overnight, as scientific advances go. What implications does this have for other diseases whose etiology is similarly described as HUS was 50 years ago? More on that tomorrow.

Part Four

As I’ve laid out in parts 1-3, 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.

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.

Hemolytic uremic syndrome (HUS) in history–part 3

I left off yesterday with the initial discovery of “Vero toxin,” a toxin produced by E. coli (also called “Shiga toxin” or “Shiga-like toxin”). Though this may initially seem unconnected to hemolytic uremic syndrome (HUS), the discovery of this cytotoxin paved the way for a clearer understanding of the etiology of this syndrome, as well as the mechanisms by which disease progressed. By the early 1980s, several lines of research pointed toward E. coli, and particularly O157:H7, as the main cause of HUS.

A 1982 Centers for Disease Control and Prevention MMWR report found a rare E. coli serotype, O157:H7, associated with hemorrhagic colitis following consumption of hamburgers. Similar results were reported in a 1983 Lancet paper, which found serotype O157 among their collection of verotoxin-producing strains. Another paper that same year from a Canadian group showed that O157:H7 was the second most common cytotoxic strain in their collection of over 2,000 E. coli isolates. The most common was serotype O26–more on that below. This paper also discussed an outbreak of hemorrhagic colitis that had occurred at a nursing home, with O157 identified as the cause. The evidence was mounting, but these were small studies and not always associated with HUS. Still, these papers collectively were suggestive of a connection between E. coli infection (especially with strains that produced the shiga/vero toxin), hemorrhagic colitis, and HUS.

In 1985, a new study came out which really helped to seal the deal. Rather than look only at cases in isolation, the authors designed a case-control study looking at patients with “idiopathic HUS” (in other words, HUS of unknown origin which started with diarrhea, rather than the other variant lacking this symptom). They ended up with 40 patients who qualified. They then picked a single control for each patient, matching them on age, sex, and season of the year. The controls were children either diagnosed with Campylobacter enterocolitis (and therefore, enterocolitis of a known cause) or were healthy children either from a local daycare center, or kids coming in for elective surgeries. Stools were collected from each group and tested for a variety of organisms, including vero toxin-producing E. coli (VTEC, also known as STEC for the shiga-like toxin nomenclature). They also tested for activity of the toxin itself in fecal samples. Finally, in the case patients, attempts were made to collect what are called “acute” and “convalescent” blood samples. These are samples taken when the patient is actually sick (“acute”), and then ones taken a few weeks later (“convalescent), to look at the presence of antibodies in the blood. If it was an infection by the suspected organism (in this case, STEC/VTEC), you should see a rise in antibodies the host produces that target the organism–for these kids, they were looking for antibodies to the shiga/vero toxin.

They found either vero toxin or VTEC in 60% of the case patients, but in none of the controls. Of the VTEC isolated, serotypes included O26, O111, O113, O121, and O157. For the latter, it was the most common type isolated (25% of the VTEC found). Of the patients who were negative for both VTEC and vero toxin, from those who had paired blood samples (12/16 of the remaining cases), 6 did show a rise in antibody titer against the vero toxin–suggesting they had been exposed and were producing antibodies to neutralize the toxin. So, for those keeping score, 75% of the cases had evidence of VTEC infection either by culture or serological techniques. It may not have been the nail in the coffin and there are certainly some flaws (the diversity of controls and lack of analysis of blood titers for the controls being two that pop out at me), but this paper went a long way toward establishing VTEC/STEC as the cause of HUS, which has been subsequently confirmed by many, many studies worldwide.

The most common vehicles of transmission of these organisms have also come into clearer focus since the 1950s, with almost all HUS/STEC outbreaks associated with food products; most common is still the O157:H7 serotype. O157 is a bit unique, in that this strain typically doesn’t ferment sorbitol–as such, this is often used as a diagnostic feature that sets it apart from “normal” E. coli. However, as I mentioned above (and as the current outbreak has shown), a number of other serotypes besides O157:H7 can also cause HUS. Most of these don’t appear to be as commonly associated with outbreaks–rather, they may more commonly cause sporadic disease where fewer people may become sick. Because these don’t have the unique sorbitol-non-fermenting feature, these may be overlooked at a diagnostic lab. There are assays that can detect the Shiga-like toxin directly (actually, we now know there are multiple families of related toxins), but not all labs use these routinely, so it’s likely that the incidence of infection due to non-O157 STEC is higher than we currently know.

HUS was once a mysterious, “complex” disease whose perceived etiology shifted almost overnight, as scientific advances go. What implications does this have for other diseases whose etiology is similarly described as HUS was 50 years ago? More on that tomorrow.