Atypical Typhus

This is the third of 16 student posts, guest-authored by Mary Egan.

Murine typhus has been in the news recently in Austin, TX, where in May of this year, two people were found to be positive and one died.  This rings a number of alarm bells for me, since I live in Texas, and specifically in Austin.  I know of another Austin veterinarian who got sick with murine typhus in 2008, when it was first noticed in Austin and investigated by the CDC.  I was also working as a relief vet at the Town Lake Animal Center, the municipal shelter, and at the Austin Humane Society, the main nonprofit adoption shelter which has a feral cat Trap-Neuter-Return surgery clinic, when the CDC investigators came to Austin.  They collected blood samples on local animals and also fleas.  Of course, at that time I wasn’t particularly interested in public health, just shelter medicine, and it didn’t really register.  Now I wish I could’ve gone back and tagged along to see more of what they were doing!

Murine typhus is an odd and off the radar disease.  It doesn’t help that murine and typhus are both words with multiple meanings.  Murine is a word that refers to mice, in Latin, murinus, or mouse, in Latin, mus.  It is also a type of eye drops and also a brand of ear wax remover.  How putting mice in your eyes or ears helps them is a mystery to me.  Murine also sounds very similar to marine, so it’s not unreasonable to start picturing typhus near the ocean, which is an odd coincidence, since murine typhus actually occurs primarily in coastal areas.

Typhus itself is a confusing word.  It comes from the Greek, and means hazy, which is how your brain feels if you’re infected.  It is not the same as typhoid fever, which is caused by Salmonella typhi, a bacteria that can cause food borne illness resulting in diarrhea and vomiting.  This is not that.

The typhus we are interested in is a tiny bacteria from the family Rickettsia.  And of course there is more than one type of typhus, to confuse the issue further.  Epidemic typhus is the ancient disease that has been a major player in history.  It was first noted in the Spanish blockade of Granada in 1489, and then killed more of Napoleon’s army than the Russians.   This is Rickettsia prowazekii, which is carried on lice and affects humans.  This is the typical typhus.  If you ever read just “typhus” it is referring to this type of typhus.  It has also been called jail fever, since many old jails were breeding grounds for lice, and the prisoners were more likely to die of infection than be hung for their misdeeds.  This typhus can cause a rash, fever, severe headache, joint pain, kidney failure, delirium, stupor, and even death in 10-60% of cases if it’s not treated.  A blood test will show if there are antibodies to typhus if you go to your doctor with these signs.  There is an effective treatment, a course of antibiotics that kills the rickettsia, and supportive care depending on how far along the disease had progressed.  It is possible for the agent to go underground, and then reappear later in life.  Then it is called Brill-Zinsser disease and is often a very mild form of epidemic typhus, still treated with antibiotics.

The typhus that showed up in Austin is murine typhus, also called Rickettsia typhi, and it is carried on fleas and primarily affects rats.  This is also called endemic typhus because it is pretty much always present on rats in the environment.  Humans historically get it as a side product of coming into contact with rats carrying the infected fleas.  This disease is usually not as severe as epidemic typhus, but can still cause all the same signs and symptoms, and rarely can lead to death if not treated.  Less than 2% die of murine typhus if it is not treated with antibiotics.

Murine typhus has a worldwide distribution, but in the United States it is usually seen near coastal areas in California, Hawaii, and Texas.  The 2008 cases were odd that they were in Austin, in central Texas.   In the previous 25 years, there had only been four cases total.  In 2008 there were 13 cases in the four months from March to July, and a total of 33 cases by October.  Of these, 70% of the people infected were hospitalized with myalgia, severe headache, and fever, and the most severe cases were treated for pneumonia, kidney failure, and coagulopathy.   There were no deaths.  This outbreak showed that aside from the normal rat-flea cycle, there are likely other cycles that involve domestic and feral cats, opossums, dogs, and the fleas that live on them.  And consequently, the fleas that live on domestic cats and dogs then live in the yards and homes of their owners, and then can live on the owners themselves.

The cases were clustered in the central Austin area, with a large percentage coming from one zip code that contains a large portion of the exceedingly popular Town Lake Hike and Bike Trail used by over 20,000 people daily, and the smaller but more wild Shoal Creek Trail.  There have been reports of coyote sightings and suspected killings of family pets in this zip code.  So there is ample space for wildlife within this urban environment.  This also means there are plenty of hosts for fleas.  And Austin in general and this neighborhood in particular is known for a slightly hippy, crunchy granola lifestyle preferring organic and natural everything, with easy access to the outdoors and hiking trails.  It is not surprising this outbreak occurred in this area.

So what does all this mean?  Diseases which were previously uncommon are now becoming more common due to changes in lifestyle.  People want to live close to nature and have trails to walk their dogs.  There is nothing wrong with that.  It’s the parasite hitchhikers their pets pick up and bring home that’s the problem.  And changes in behavior where dogs are now not only in the house, but often in the bed with their owners, means that those fleas have a chance to bite humans.  That doesn’t mean you shouldn’t walk your dog on the trail.  But it does mean you need to use protection.  Spray yourself and your clothes with a flea killing insecticide such as DEET when out walking.  Wear boots, long pants, and long sleeved shirts.  Use appropriate flea control on your pets.  Kill fleas in your yard or home with appropriate premises control measures.  It’s great to be one with nature, you just don’t want that nature to bite back with a case of murine typhus.

Bibliography

1.  Adjemian J, Parks S, McElroy K, Campbell J, Eremeeva ME, Nicholson WL, et al. Murine typhus in Austin, Texas, USA. Emerg Infect Dis. 2010 Mar.   Accessed June 13, 2012.  Available at: http://wwwnc.cdc.gov/eid/article/16/3/09-1028.htm

2.  James C.  Two cases of typhus in Travis County.  KXAN web site.  Accessed June 13, 2012.  Available at: http://www.kxan.com/dpp/news/local/austin/2-cases-of-typus-in-travis-county

3.  Typhus.  Wikipedia website.  Accessed June 13, 2012.  Available at: http://en.wikipedia.org/wiki/Typhus.

4.  Murine typhus.  Texas Department of State Health Services website.  Accessed June 13, 2012.  Available at: http://www.dshs.state.tx.us/idcu/disease/murine_typhus/information/

5.  Conlon J.  The historical impact of epidemic typhus.  Accessed June 13, 2012.  Available at: http://entomology.montana.edu/historybug/typhus-conlon.pdf.

6.  Google map of 78703 zip code.  Google maps website.  Accessed June 13, 2012.  Available at: http://maps.google.com/maps?oe=utf-8&rls=org.mozilla:en-US:official&client=firefox-a&q=78703&um=1&ie=UTF-8&hq=&hnear=0x8644b55c47d7dc5f:0x717c8b7186632905,Austin,+TX+78703&gl=us&ei=i7DTT9vPJsLQ2AX54riFDw&sa=X&oi=local_group&ct=image&ved=0CHQQtgM

7.  Gonzales R.  Santa Ana announces flea-borne typhus alert.  Orange County Register website.   Accessed June 13, 2012.Available at: http://www.ocregister.com/news/santa-356066-control-typhus.html

8.  Roving pack of coyotes mauls pets.  KXAN website.  Accessed June 13, 2012.  Available at: http://www.kxan.com/dpp/news/local/austin/roving-pack-of-coyotes-maul-pets

What you don’t see can hurt your cat…and you too

This is the second of 16 student posts, guest-authored by Eileen Ball.

The beauty of dogs and cats as companions is that we don’t have to raise them to go out into the world and be successful.  As pet parents we can set the household “rules” according to what works for us and get on with enjoying our pets; hopefully for many years.   According 2011-2012 APPA National Pet Owners Survey cats have now surpassed dogs as the most common household pets in the United States.  Despite this fact  the same survey reports that in 2010 only 30% of US veterinary patients were cats.  As a companion animal veterinarian I find these statistics alarming and I fear that many well-intentioned pet owners are simply unaware of the risks that can accompany the joys of cat ownership.

A common perception is that indoor cats don’t need veterinary care.  In this sentence there two big factors that need to be addressed.  The first, and for me the most obvious, is that indoor cats need veterinary care too!  In a bit I’ll get to explaining that even without outdoor threats,  such as motor vehicles and big dogs, indoor cats and their owners face almost as many dangers as their outdoor brethren.    The other part of the eleven word sentence at the start of this paragraph that requires definition is the concept of “indoor cat.”    During my ten years as a practicing veterinarian I had many a conversation with an owner that started with the question “Is Fluffy indoor or outdoor?”  Followed by the owner confidently responding “indoor.”  As we moved forward in our discussion and I asked more about how Fluffy spent her day I’d often learn that Fluffy had access to the yard or deck and often spent long periods of time there.  There were alternative versions of the discussion where Fluffy didn’t physically go outside but the dog did as well as scenarios where mice, birds or bats came indoors even though they weren’t invited.  The reality is that In order for a cat to be considered 100%  indoor it would need to live in a biosphere.

So why should you take your indoor cat to the veterinarian on at least a yearly basis?   The first and most important reason is that your cat has the potential to carry parasites and diseases that can be transmitted to you and your family.  These include but are not limited to:  hookworms, roundworms, fleas, ticks, ringworm and Rabies.  According to the CDC approximately 14% of the US population has been infected with a type of roundworm called Toxocara.  Indoor cats are a potential source of exposure as they generally use litter boxes and they frequently contact surfaces such as countertops, bathroom vanities, kitchen tables and bedding.  Many cat owners have the misunderstanding that because their cats do not go outdoors they are not at risk.  This is simply not true.  There are lots of indoor/outdoor parasite sources such as mice, rats, other pets and people.  Hookworm and roundworm infections are easily and safely prevented with a variety of medications.  Your veterinarian can run a simple fecal test to see if your cat is infected with these or other parasites.  Another concern for cat owners is the transmission of a type of bacteria called Bartonella.   In most cases infected cats will show no symptoms, although in some it may cause gum disease, conjunctivitis (swollen membranes around the eyes) or respiratory disease.  Bartonella can spread from cats to humans.  It is the causative agent of Cat Scratch Disease in people.  Cats often get this bacteria from fleas and they can transmit it to humans via bites and scratches.  While parasites and Bartonella are a significant risk for healthy humans in those who don’t have a fully functioning immune system the risk is magnified even further.

The most important disease that you can protect your indoor cat from is Rabies.  This is a virus that is spread via saliva and is almost always deadly.  Rabies infection is common in skunks, raccoons, foxes and bats.  A bat getting into the house through an open window or a chimney is a very real risk for any animal or person in your house.  If you should happen to find a bat in the house with your cat (or other pets) you must assume that they were bitten.  Because of the thick fur that cats have it can be impossible to see a small bite wound.  Depending on local laws you may be required to vaccinate your cat for Rabies every 1-3 years.

There are other conditions such as ringworm and toxoplasmosis that cats can have without showing any signs.  People with healthy immune systems are not likely to show symptoms if they are exposed to these parasites but for others with HIV, cancer, pregnancy or a suppressed immune system serious consequences can occur.  When I think of ringworm without symptoms I always recall one of my patients, Miss Kitty, who was loved and adored by her entire family.  Miss Kitty and her humans were originally from Hawaii and had moved to Virginia where I was in practice.  Since Miss Kitty couldn’t travel from mainland US to Hawaii without quarantine the relatives in Hawaii decided to come to Virginia for Christmas.  Miss Kitty’s human grandmother happened to have breast cancer and was undergoing radiation.  The family had a great holiday.  Shortly after her return to Hawaii the grandmother developed circular, itchy scabs on her skin.  Her MD diagnosed it as ringworm and asked if she had any pets.  The grandmother said “no” and the MD presumed she had picked it up from the environment and started treating her.  It was a couple months later in conversation with Miss Kitty’s owner that I’d inquired about the holiday visit and the grandmother’s health.  Miss Kitty’s owner described the wonderful time that they’d had and mentioned that the grandmother had enjoyed the trip except for her persistent skin lesions.  A bell went off in my head and I decided to test Miss Kitty’s hair for ringworm.  Sure enough even though she’d never had a problem with her skin Miss Kitty was positive for ringworm.  Based on the species we cultured the grandmother’s MD was able to change treatment and get her skin cleared up quickly.

Finally, as most people who have shared their lives with both dogs and cats will agree, cats are not small dogs.  While the process of domestication for both dogs and cats has been ongoing for thousands of years it is estimated that the dog started the process 9-10,000 years before the cat.  For this reason cats tend to display a “survival of the fittest” instinct that we don’t see in dogs. Because of this instinct cats generally aren’t transparent when they don’t feel well.  Some cats are prone to chronic heart, thyroid  and kidney diseases that can often be detected with a thorough examination and some bloodwork.  Although most of these chronic conditions can’t be cured, with good veterinary guidance they can be well managed and allow you to share many happy years with your cat.

If your cat hasn’t been to the veterinarian in awhile I hope you will consider scheduling an appointment.  This can not only make life longer and better for your cat it can also protect you and your family from serious disease.

References:

American Pet Products Association 2011-2012 Pet Owners Survey

http://www.americanpetproducts.org/pubs_survey.asp

http://www.cdc.gov/parasites/toxocariasis/epi.html

http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002581/

http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002310/

http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002411/

http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001661/

http://catvets.com/cfpandpractitionersearch/

Bartonella Spp. In Pets and Effect on Human Health,  Chomel et al. Vol. 12 number 3, March 2006,  www.cdc.gov/eid

 

 

 

 

 

 

 

 

 

 

 

 

The human origins of “pig” Staph ST398

I recently gave a talk to a group here in Iowa City, emphasizing just how frequently we share microbes. It was a noontime talk over a nice lunch, and of course I discussed how basically we humans are hosts to all kinds of organisms, and analysis of our “extended microbiome” shows that we share not only with each other, but also with a large number of other species. We certainly do this with my particular organism of interest, Staphylococcus aureus. There are many reports in the literature showing where humans have apparently spread their strains of S. aureus to their pets (dogs, cats, hamsters)–and sometimes the pets have been nice enough to share it right back. My own research looks at S. aureus in pigs and the humans who care for them, and many studies have shown that a “pig” type of MRSA, dubbed sequence type 398 (ST398), can be transmitted from pig carriers to their human caretakers. The assumption has been that this is truly a “pig” strain, originating in swine, and has spread to humans (and other animals, including cattle, poultry, dogs and horses) from pig hosts, either directly or indirectly via contaminated meat products.

According to a new study (open access in mBio), it seems that there has been more sharing of ST398 than we’d realized. Led by Lance Price at TGEN (full disclosure–I’m a coauthor on the paper), his group analyzed 89 ST398 isolates from China, Europe, and North America, including isolates from humans and animals as well as both methicillin-susceptible and -resistant strains. Using whole genomic sequence typing, the evolutionary history of these isolates was reconstructed.

The findings throw the ST398 story a bit on its head. Instead of being a true pig strain, ST398 appears to have originated as a methicillin-susceptible human strain which was transferred into the pig population, picked up antibiotic resistance genes (including resistance to methicillin and tetracyclines), and then has been passed back to farmers as more resistant organisms. Some prophages were also gained or lost along the way, probably due to selection by host factors.

This also suggests that there is still likely a low level of “native human” ST398 circulating in people. There have been a few case reports of ST398 colonization and/or infection in people without any known livestock contact. Some of these have been resistant to methicillin and/or tetracycline, which are more frequently associated with livestock-adapted strains. Are these truly “human” strains which aren’t involved in livestock at all, or are these ST398 findings in people lacking livestock contact still due to some livestock exposure along the chain of transmission (farmer neighbors? Transmission via food?) We still don’t know, but carrying out more of this WGST will give us better targets in order to be able to differentiate true “human” ST398 strains from those that have been hanging out in animals, and then transmitted back to people.

Now, for long-time science blog readers, this story may sound a bit familiar. Indeed, it looks like ST398 has taken a very similar path to that of another animal-associated S. aureus strain, ST5. As Ed Yong described back in 2009, humans are also the ultimate origin of a “chicken” type of S. aureus ST5, which spread around the world in broiler chicken flocks. In Ed’s article, the first author of the chicken ST5 paper, Bethan Lowder, notes that the change in chicken farming from small farms to multinational corporations likely aided the spread of this organism–and the exact same thing has happened with pig farming.

One difference between the two is that ST5 causes disease in chickens, whereas ST398 seems to be a very rare cause of illness in pigs. This is likely one reason that ST398 in pigs went undetected until relatively recently–it’s simply not much of an economic issue for pig producers, whereas in chickens, S. aureus can cause several nasty diseases (such as bumblefoot and BCO) leading to animal loss (and thus, less money for the farmer).

So, where do we go from here? Clearly studies like this show the utility of using WGST to examine the evolution and spread of these strains. If you look at how spa types are distributed throughout the tree, you can see that those alone don’t tell you much about where the strain came from, or if it’s fully “human” or a pig-adapted lineage. Ideally, a set of simple markers could be found to distinguish ancestral human strains from livestock strains (as methicillin-sensitive ST398 can also be found in pigs, so methicillin resistance alone isn’t enough of an indicator that it’s a “pig” strain). We’ll be working on this in ST398 and other strains we see being shared between animals and humans, in order to better understand this generous sharing we’re doing amongst species.

Reference:

Lance B. Price, Marc Stegger, Henrik Hasman, Maliha Aziz, Jesper Larsen, Paal Skytt Andersen, Talima Pearson, Andrew E. Waters, Jeffrey T. Foster, James Schupp, John Gillece, Elizabeth Driebe, Cindy M. Liua, Burkhard Springer, Irena Zdovc, Antonio Battisti, Alessia Franco, Jacek Żmudzki, Stefan Schwarz, Patrick Butayej, Eric Jouy, Constanca Pomba, M. Concepción Porrero, Raymond Ruimy, Tara C. Smith, D. Ashley Robinson, J. Scott Weese, Carmen Sofia Arriola, Fangyou Yu, Frederic Laurent, Paul Keima,, Robert Skov, & Frank M. Aarestrup (2012). Staphylococcus aureus CC398: Host Adaptation and Emergence of Methicillin Resistance in Livestock mBio, 3 (1), 305-311 : 10.1128/mBio.00305-11

Castrating sheep with teeth: not a good idea (with video!)

Just a quick post as I’m in end-of-semester hell. Via Maryn McKenna on Twitter, the CDC has released a report of Campylobacter illnesses due to not food consumption, but because of castrating lambs. With their teeth.

On June 29, 2011, the Wyoming Department of Health was notified of two laboratory-confirmed cases of Campylobacter jejuni enteritis among persons working at a local sheep ranch. During June, two men had reported onset of symptoms compatible with campylobacteriosis. Both patients had diarrhea, and one also had abdominal cramps, fever, nausea, and vomiting. One patient was hospitalized for 1 day. Both patients recovered without sequelae.

During June, both patients had participated in a multiday event to castrate and dock tails of 1,600 lambs. Both men reported having used their teeth to castrate some of the lambs.

Among the 12 persons who participated in the event, the patients are the only two known to have used their teeth to castrate lambs.

Sadly, this wasn’t the first time I’ve heard of such a procedure. This was on Dirty Jobs a few years back (and yes, Mike Rowe participated–not for the squeamish).

On a related note, my grandma always had sheep on her farm. I helped to shear but never castrate. Now I’ll have to ask my dad and uncles what method they used…

MRSA found in Iowa meat

I’ve blogged previously on a few U.S. studies which investigated methicillin-resistant Staphylococcus aureus in raw meat products (including chicken, beef, turkey, and pork). This isn’t just a casual observation as one who eats food–I follow this area closely as we also have done our own pair of food sampling investigations here in Iowa, and will be doing a much larger, USDA-funded investigation of the issue over the next 5 years.

Let me sum up where the field currently stands. There have been a number of studies looking at S. aureus on raw meat products, carried out both here in North American and in Europe. In a study from the Netherlands, a large percentage of samples were found to harbor MRSA (11.9% overall, but it varied by meat type–35.3% of turkey samples were positive, for example). Most of there were a type called ST398, the “livestock” strain. This was also found in one Canadian study (5.5% MRSA prevalence, and 32% of those were ST398), but no ST398 were found in a second study by the same group.

Here in the US, prevalence has found to be lower than in that Dutch study (from no MRSA found, up to 5% of samples positive). Furthermore, in the previously-published studies, no MRSA ST398 was found in samples of US meat, though this paper did find plenty of methicillin-sensitive S. aureus (MSSA) ST398 strains. Instead, most of the MRSA isolates have been seemingly “human” MRSA types, like USA100 (a common hospital-associated strain) and USA300 (a leading community-acquired strain).

Why am I rehashing all of this? We have a new paper out examining S. aureus in Iowa meats–and did find for the first time MRSA ST398, as well as MRSA USA300 and MSSA strains including both presumptive “human” and “animal” types. This was just a pilot study and numbers are still fairly small, but enough to say that yes, this is here in the heart of flyover country as well as in the other areas already examined.

As I mentioned, this is one of two studies we’ve completed examining MRSA on meat; the other is still under review and much more controversial, but I will share that as soon as I’m able. And with the USDA grant, we’ll be working on better understanding the role that contaminated meats play in the epidemiology and transmission of S. aureus for the next several years, so expect to see more posts on this topic…

References

Hanson et al. Prevalence of Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA) on retail meat in Iowa. J Infect Public Health. 2011 Sep;4(4):169-74. Link.

Waters et al. Multidrug-Resistant Staphylococcus aureus in US Meat and Poultry . Clin Infect Dis. 2011 May;52(10):1227-30. Link.

Weese et al. Methicillin-resistant Staphylococcus aureus (MRSA) contamination of retail pork. Can Vet J. 2010 July; 51(7): 749-752. Link.

De Boer et al. Prevalence of methicillin-resistant Staphylococcus aureus in meat. Int J Food Microbiol. 2009 Aug 31;134(1-2):52-6. Link.

Pu et al. Isolation and characterization of methicillin-resistant Staphylococcus aureus strains from Louisiana retail meats. Appl Environ Microbiol. 2009 Jan;75(1):265-7. Link.

Bhargava et al. Methicillin-resistant Staphylococcus aureus in retail meat, Detroit, Michigan, USA. Emerg Infect Dis. 2011 Jun;17(6):1135-7. Link.

Scarlet fever–past and present

While “flesh-eating infections” caused by the group A streptococcus (Streptococcus pyogenes) may grab more headlines today, one hundred and fifty years ago, the best known and most dreaded form of streptococcal infection was scarlet fever. Simply hearing the name of this disease, and knowing that it was present in the community, was enough to strike fear into the hearts of those living in Victorian-era United States and Europe. This disease, even when not deadly, caused large amounts of suffering to those infected. In the worst cases, all of a family’s children were killed in a matter of a week or two. Indeed, up until early in the 20th century, scarlet fever was a common condition among children. The disease was so common that it was a central part of the popular children’s tale, The Velveteen Rabbit, written by Margery Williams in 1922.

Luckily, scarlet fever is much more uncommon today in developed countries than it was when Williams’ story was written, despite the fact that we still lack a vaccine for S. pyogenes. Is it gone for good, or is the current outbreak in Hong Kong and mainland China a harbinger of things to come? More below…
Continue reading “Scarlet fever–past and present”

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.

Hemolytic uremic syndrome (HUS) in history–part 2

As I mentioned yesterday, 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.