Tuesday, June 28, 2011

Rocky Mountain Spotted Fever


The last rickettsial disease I will cover at Infection Landscapes is Rocky Mountain spotted fever. This is not a collection of diseases as was the case with typhus and ehrlichiosis. Rather, it is a single and quite severe condition. Indeed, it is the most severe of all the rickettsial diseases.

Rocky Mountain spotted fever (RMSF) is caused by Rickettsia rickettsii, and is vectored by yet another tick. We will look at the pathogen and vector in turn before coming back to the clinical manifestations and the epidemiology of the disease.

The Pathogen: Rickettsia rickettsii  is an obligate intracellular parasitic organism, as are all other Rickettsia and Rickettsiales bacteria:

Rickettsia rickettsii

This bacterium's target are endothelial cells, which it invades by a rather remarkable mechanism. The organism first adheres to the surface of the host endothelial cell and subsequently induces structural changes within, which causes the cell to phagocytize the Rickettsia organism. Since endothelial cells are not phagocytes, this bacterium has evolved a mechanism of entry into host cells by coercing them to perform functions they are not evolved to perform. This invasion of, and subsequent proliferation in, endothelial cells results in vascular damage and can lead to widespread organ failure.

The Vector: This rickettsial disease is again vectored by ticks. Dermacentor variabilis is the primary vector in the eastern and southern US, while D. andersoni is more common in the northwest:

Dermacentor variabilis

Amblyomma cajennense is the primary vector in Central and South America:

Amblyomma cajennense

To see how these ticks (Dermacentor in particular) compare to the other species we have covered at Infection Landscapes, here is the familiar scaled image:


Dermacentor is somewhat larger than the Ixodes species, but is similar in size to the Amblyomma species, though the Amblyomma are slightly more stout in appearance during their nymphal and adult life cycle stages. A. americanum and A. cajennense are similar in size, even though their dorsal markings can be quite different.

Here are the distributions of the three important tick vectors for RMSF:

Dermacentor variabilis distribution

Dermacentor andersoni distribution

Amblyomma cajennense distribution

The life cycles of the Dermacentor species and A. cajennense are quite similar to Ixodes and other Amblyomma species, in that they are 3 host ectoparasites, requiring a blood meal during the larval, nymphal, and adult life stages, which typically take approximately 2 years to complete. Rather than review the general life cycle for a third time, I will simply refer the reader to the Lyme disease or ehrlichiosis descriptions.

Importantly, tick hosts are not necessary for the maintenance of R. rickettsii in nature, as this pathogen is transmitted transovarially between ticks (you'll recall we saw transovarial maintenance before with mite-borne scrub typhus). Therefore, the ticks are the primary reservoir for this rickettsial disease. Nevertheless, transstadial transmission of this pathogen from ticks to rodents and dogs is also significant. This creates additional natural reservoirs of these mammals that, while not necessary for maintaining R. rickettsii in nature, do amplify the pathogen's transmission capacity. Humans, as is the case with most tick-borne infections, are dead-end hosts. Therefore, once infected, humans are not capable of transmitting the pathogen to non-infected ticks.

The Disease: This is the definitive rickettsial disease. It is characterized by the sudden onset of fever, chills, severe headache and myalgia, reddening of the eyes, and often debilitating malaise. This acute illness typically lasts 2 to 3 weeks when untreated. During the first week of illness a maculopapular rash often presents on the extremities, usually sometime between day 3 and 5. This rash can quickly spread to the palmar and plantar surfaces and subsequently extends to the trunk:


You will recall this is the opposite pattern to the rash observed in the typhus forms we discussed, which begins on the trunk and moves out to the extremities. In 40% to 60% of adults, or 90% of kids, the rash can become petachial exanthematous toward the end of the first week. Because R. rickettsii  invades and damages endothelial cells, widespread organ damage involving the gut, lung, kidneys and the central nervous system can ensue. Thrombocytopenia and elevated liver enzymes can be important findings preceding these more extended systemic sequelae. The case-fatality ranges between 20% and 80% in untreated individuals, with older individuals being at significantly higher risk. With quick diagnosis and treatment the case-fatality is reduced to 3%-5%.

Although distributed throughout the Americas, the greatest number of cases of RMSF occur in the US. In addition, RMSF is the most commonly reported rickettsial disease in the US. Here is a map from the Centers for Disease Control and Prevention (CDC) showing the incidence of RMSF by state in 2008:


Notice the greatest incidence occurs in the south-central and southeastern seaboard regions of the country, despite the "Rocky Mountain" in the common name.

This CDC graph below, shows that rather than improving, RMSF has actually been increasing in incidence over the last two decades:

Given the similar incidence trends with other tick-borne infections, such as Lyme disease, we may do well to consider that more encounters between humans and ticks follow as urban development encroaches on natural habitat.


Control and prevention of RMSF is, of course, similar in approach to that outlined for both Lyme disease and ehrlichiosis. Still, it is worth restating here. The focus must be on the human point of contact with ticks. Attempts to intervene at the level of any of the other organisms (i.e. tick hosts) will, almost certainly, meet with failure because of the transovarial transmission of the pathogen between ticks. In addition, and as with other tick-borne infections, attempts to control favored host species of the relevant tick (whether Dermacentor or Amblyomma ticks) are extremely difficult because the secondary rodent and dog reservoirs are ubiquitous, highly adaptive, and can exploit a wide range of habitat. Moreover, because dogs can act as reservoirs, they have the capacity to bring the pathogen and its primary reservoir and vector (i.e. the tick) directly into the human domestic environment. Thus elimination of the bacteria is highly unlikely. Therefore, control and prevention is best aimed at human points of contact. Use of long-sleeved shirts and long pants are very effective control measures as these eliminate tick access to human skin. However, this approach may not be realistic for those that live, or work outdoors in endemic areas during the summer months. As such, individuals who do spend time outside during the summer months and are at risk of exposure to ticks, should practice regular body tick checks.

Here is a nice video on the proper way to remove ticks from the skin:




This concludes the short series on the rickettsial diseases. The series is by no means exhaustive, but I think it has served as a good introduction. Next week I will also be concluding the extended series on arthropod-borne infections, which began almost 6 months ago. It has been a fun and exciting series, and it will be concluded next week with yellow fever.


Following this, we will focus on two important airborne infections: measles and tuberculosis.

29 comments:

  1. The light spots on the map are interesting to me. I wonder if that is simply an artifact of mapping process, or if there is more to it. There's a big difference in real life between 1.5 and 19. Also there are a lot of different types of land use in each state, so clusters could be more regionally located, and the division could make it seem like there's a blank area just by chance. But if its not an artifact of mapping, development/human behavior might have a role. For instance, there might be less playing outside in Louisiana versus neighboring states, or more concrete, and less tick habitat. It'd be interesting to see some more maps with a smaller scale and more variables to explore this.

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  2. Usually when one thinks of ticks, dark wooded areas come to mind. However, when I was looking at the map it seems to have occurrences almost all over the US including states with a lot of cities. As cities expand and forests decline.. are cities part of the landscape of ticks and subsequently their infections? If not do you see them becoming part of their habitat?

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  3. I find it fascinating that Rickettsia rickettsii "tricks" endothelial cells into phagocytosing the organism, since endothelia are, by and large, barrier cells. Are the mechanisms known for this conversion of function?

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  4. Interesting question, Deanna. From what I understand, Dermacentor variabilis have been known to hang out in more residential settings (particularly in shrubs, tall grass, weeds, etc. since that's where their hosts congregate). But I don't know if truly urban settings, where such vegetation is spotty, could really sustain the appropriate disease ecology as we know it, with the proper hosts and all.

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  5. Matt- I would say that there is a lot more tall grass/overgrown vegetation in the urban areas than you might think at first. Backyards, empty lots, overgrown medians, busted down buildings that have been reclaimed by nature. Downtown Manhattan is for sure a different beast than the rest of this city we live in, we just choose not to explore the overgrown areas mostly.

    That said, you're probably right. The habitats would be so fragmented anyway.

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  6. Matt-

    The exact mechanism of how Rickettsia rickettsii tricks endothelial cells is not fully understood. However, it is hypothesized that Phospholipase A2 is involved in the mechanism.

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  7. This is kind of off topic but I feel the need to express my frustration with naming diseases after places. First, it ends up being very confusing. These bugs turn up in other regions after the original "discovery" and you have yourself a misleading misnomer. Second, and this is less the case with RMSF, but this sort of naming can have racist implications. When a disease gets associated with a place, its a not so subtle way of placing blame. For example, when H1N1 first emerged it was being referred to as “Mexican” Swine flu and as a result Mexico lost a lot of tourism and income.

    So these are just some thoughts on a topic that comes up a lot in science and medicine. Unfortunately the alternative isn't ideal either, naming everything with unmemorable numbers and letters. I wonder if anyone has any thoughts about other naming approaches that might work moving forward?

    -Becca

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  8. Speaking of urban environments, i found a paper that basically says its been found in NYC parks and IV drug users and homeless people are at an elevated risk of acquiring R.ricettsii infections in urban environments...Perhaps as these people might be hanging out in overgrown lots, abandoned areas, and other areas Robin mentioned earlier.
    http://www.ncbi.nlm.nih.gov/pubmed/10403316

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  9. Deanna,

    That seems a plausible reason that there is an increased risk in urban areas. Aside from this, the increased levels in IV drug users may be a cause of the IV drug use itself, rather than a sign of an increased presence of R. ricettsii. The sharing and passing of needles will lead to an increase in infection transmission and, potentially, skew the data because of it. Just a thought.

    Chris

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    1. Its interesting to think that urban drug use can spread the disease. It makes one wonder what are the risks of human to human transmission. Is it only transmittable through blood? or are we at risk from other body fluids.

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  10. I was very surprised to learn about how this bacterium infects host cells. As previous comments have pointed out, endothelial cells act as a protective barrier for the body. It is remarkable that a bacterium has developed an ability to bypass this defense mechanism. I was curious about the genetics of this ability by the bacterium. Since the spread of bacterial antibiotic resistance is such a big issues, I was wondering if there is also potential for this ability to induce phagocytosis to spread. If this ability is controlled by one or a few genes, I think there would be potential for this feature to spread. I wonder also what the impact on disease burden would be if many forms of bacteria gained an ability to access humans through the endothelium.

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    1. Diana (as well as to Matt and Jamal),

      I agree with you all with regard to how interesting it is that Rickettsia rickettsii can induce phagocytosis among endothelial cells (particularly in this case, vascular endothelium). However, though the mechanism is not flushed out entirely in this case, I do think that this ability of a pathogen to coerce cells to do things that are not in their normal nature (in this case, instigate the cytoskeletal structure to alter, so as to phagocytose the bug) is not a extremely rare trait among clever pathogens (nor does necessarily involve genetic alteration of the host cell in order to accomplish).

      In the end, I think these little intracellular parasites are just adept at taking advantage of certain capacities that most (or all) cells have in common. In this case, if I were to hazard a guess, it seems that the endothelium creates an endosome in order to eventually bind with a lysosome, lyse the bug, and use the bug's parts for immunization purposes. Now, this property is not part of endothelial cells everyday main function; however, like most cells, I would guess that they are capable of taking in an attached item which it recognizes as foreign, and trying to kill it. The only problem is that rickettsia is too intelligent, and uses this local defense mechanism to gain entry into the cell; it busts out of the endosome before it can get lysed, energizes itself on the host cell's ATP, replicates, and commandeers the host's cytoskeletal structure to move about and eventually spread. So though endothelial cells are performing functions they are not specifically evolved to perform, I hazard to guess that rickettsia is simply instigating and taking advantage of some of the host cell's lesser known capabilities to achieve its own goals.

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  11. Is urban development the only reason we are seeing an increase in Rocky Mountain Spotted Fever (RMSF) cases? I am curious to see if the changing weather patterns have anything to do with the increase in RMSF Cases. Particularly when there are periods of drought in the south central and southeastern regions of the US, do more cases of RMSF arise?? In 2008, there was a drought in these regions and others throughout the US, which might explain why the number of RMSF Cases peeked to over 2500. Currently, the Southern and Midwestern regions are experiencing an extreme drought I wonder if the number RMSF Cases will increase and exceed the 2008 numbers. If so what is being done or what can be done (other than a few rain storms) to combat this disease??

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    1. As the two main reservoirs for Rocky Mountain spotted fever are rodents and dogs,the prevalence of RMSF depends on the growth of tick population. And the tick populations depend upon the seasonality of environmental factors such as temperature, humidity, and vegetation. Optimally, climate must be warm enough to promote progression through the life cycles, humid enough to prevent the drying out of eggs, and cold enough in winter to initiate the resting stage. Therefore, drought do not seem to be a key factor for the rapid growth of tick population.

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  12. I looked up seasonal patterns for RMSF transmission and found a good summary on the CDC's website:

    http://www.cdc.gov/rmsf/stats/index.html (I'm assuming that this is the same site from which some of the images on this page were taken?).

    Given that the majority of cases are reported to the CDC during the summer months [nationwide], I'm assuming that RMSF transmission tends to occur during the more humid parts of the year, since the south-east portion of the United States can get pretty humid. However, the south-central portion of the United States can get pretty dry (as you point out) during these months, so this might be an interesting factor for analysis. However, I can't imagine that the tick species dominating these parts of the country would vary significantly in their temperature preferences. Maybe the drought period that met the RMSF peak was just coincidental?

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    1. In response to the previous post:
      According to CDC, the highest incidence rates, ranging from 19 to 63 cases per million persons were found in Arkansas, Delaware, Missouri, North Carolina, Oklahoma, and Tennessee. This June-and-July- seasonality varies for different regions of the country due to the climate and the tick vectors involved. The frequency of reported cases of Rocky Mountain spotted fever is highest among males, American Indians, and people at least 40 years old. Individuals with frequent exposure to dogs and who reside near wooded areas or areas with high grass may be at increased risk of infection. For example some people are infected by brown dog ticks in which the peak months of illness onset are April through October but not just June and July. Therefore the seasonality of RMSF varies according to States and tick population.

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  13. I never knew that diseases in ticks such as this was still such a common problem, especially in the U.S. It is also interesting that though there is no way to ameliorate the disease, can it be better controlled via a vaccination during the season? Also, does correct tick removal diminish the chances of getting the disease? How amazing it is to see how a bacteria can essentially turn a cell again itself.

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    2. Personally, I do not think vaccination is a practical solution to this problem. With a recorded maximum of 2500 cases (within the US) in 2008, resources could be better spent promoting safety techniques. Not only will this be cheaper, but it could reach many more people at one time.

      But you are right about the last part. I found it astounding that the bacteria can force a cell to carry out an action it has not yet evolved to perform. I am curious to know if this ability could be farmed and turned into a treatment method for something.

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  15. I am just curious about why the disease is commonly known as “Rocky Mountain Spotted Fever”, while its incidence in US is higher in seaboard regions. Is it more common to find this disease in mountain regions in other countries? Also, I find it interesting that a lot of diseases have different patterns of how the rash spreads, and I wonder the biological mechanism behind this phenomenon. I am not surprised by the fact that the incidence of RMSF has been increasing in recent years as we have been constantly invading the natural habitat, but I wonder why there was a big jump in the incidence between 2003 and 2004 (showed in the graph). Was it a true increase due to more transmission of RMSF, or was it due to improved diagnosis/reporting of RMSF at that time?

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  16. To tag on to Pui Ying Chan's comment above, I also wonder why there's an increasing incidence of RMSF in the last two decades. With urban sprawl in the last several decades, are ticks becoming more domesticated like Aedes aegypti that act as a vector in spreading dengue, chikungunya and yellow fever?

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  17. There were a couple of things that stood out to me while reading this article. First, the case fatality rate of 20-80% among those untreated seems very high. Similar diseases like typhus, the case fatality rate is 10-40% and for Ehrlichiosis it is only 1-3%. I wonder why Rocky Mountain spotted fever has such a higher fatality rate. The second thing that stood out to me was the fact that there are additional reservoirs aside from humans for transmissions of the pathogen, these being rodents and dogs. As we learned in class the fact that there are non-human reservoirs means eradication/elimination of this disease would be near to impossible. This is concerning since it has such a high case fatatlity rate and humans are frequently in contact with rodents and dogs.

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  18. What I find interesting about Rocky Mountain Spotted Fever, RMSF, is that this is the first time I've heard of the disease and with such a wide case fatality range, you would think this tick and the illness it spreads would be more well- know. I am originally from an area that is in the medium to high (1.5-19) incidence range and spend a lot of time outdoors, but again still never heard of this type of disease or which tick specifically it is carried in. After reading this information, and the lack of treatment, I've realized that prevention is key to stopping RMSF. However, prevention can only be key if people are aware of how to protect themselves from these ticks. Outdoor recreation centers such as hiking trails, playgrounds, and camping grounds should have information posted with every tick and disease they can carry as well as handouts available detailing proper protective clothing and detaching/removal of tick (if unlucky enough to find a tick on yourself) information for each individual that comes through. Local news stations, newspaper, and social media could also detail this protective information during the summer season, or all year-round if you live in a warmer climate. Putting the information out there is just one way to slow and eventually (hopefully) eliminate the incidence of RMSF, but more action would of course be needed to see if the information is having impact on the rate of RMSF.

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  19. Considering that humans have been coming into more frequent contact with ticks as a result of urban development encroaching on natural habitats, it isn't surprising that the incidence of Rocky Mountain Spotted Fever has been increasing over the past 20 years. It was interesting to learn that the case-fatality ranges between 20% to 80% in untreated individuals as I had not known it was that high. More awareness and education are needed for the effective control and prevention of RMSF, Lyme disease, and other tick-borne infections. Education should be targeted not just to adults, but to children as well. Children should be taught how to properly protect themselves when outdoors in endemic areas and need to be taught how to check for ticks.

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  20. After hearing so much about Lyme disease, it was very interesting to read about another tick related disease that I does not receive as much attention. I was surprised to also learn that unlike Lyme Disease, it is the most common fatal tick-borne disease in the United States. IF RMSF is not treated correctly in the first eight days of symptoms it can be fatal even in previously healthy people. This factor makes it crucial for clinicians to consider this diagnosis even when full symptoms have not appeared yet. Considering the complexities of this disease and it ability to appear similar to other diseases, misdiagnosis can occur more often than not. Why is there still no test available that can provide a conclusive result in time to make crucial decisions about treatment?

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  21. It was interesting to read about the most severe of all the rickettsial diseases in which the bacterium has evolved a mechanism of entry into host cells by forcing them “to perform functions they are not evolved to perform.” Given that the pathogen is transmitted transovarially between ticks, ticks are the primary reservoir for this rickettsial disease, meaning that ticks should be the focus when promoting prevention. Even though the pathogen can cause potentially fatal human illness in North and South America, in the US common ticks such as the American dog tick (Dermacentor variabilis) and the brown dog tick (Rhipicephalus sanguineus) and of course the Rocky Mountain wood tick (Dermacentor andersoni), can be vectors. It was also interesting to read that despite its “Rocky Mountain” name, the greatest incidence occurs in the south-central and southeastern seaboard regions of the country. In addition, a great concern is that the incidence of Rocky Mountain Spotted Fever (the number of RMSF cases for every million persons) has increased during the last years, “from less than 2 cases per million persons in 2000 to over 6 cases per million in 2010” (CDC 2013). For those who live and/or work outdoors in endemic areas during the summer months and cannot be wearing long-sleeved shirts or pants, besides having regular body tick checks, using appropriate tick repellents and wearing white or light colors might also help since it would make it easier to see and remove the ticks. If bitten, to get rid of the infection, antibiotics such as doxycycline or tetracycline need to be taken, given that with quick diagnosis and treatment the case-fatality is reduced to 3%-5%. However, many cases are not quickly diagnosed since for example, infection may be confirmed by specialized laboratory procedures where the bacterium is isolated but few laboratories undertake such diagnostic procedures in endemic areas. Thus, attention to tick exposure is imperative for diagnosis especially knowing that symptoms like rash are often not present when affected individuals initially seek medical attention.

    Works Cited: http://www.cdc.gov/rmsf/stats/


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  22. Recently, various changes in organisms' behaviors (ex: flowers blooming or birds migrating) have been correlated with slight changes in their respective environments brought on by global climate change. In particular, average seasonal temperatures are rising, and the differences between summer and winter conditions are becoming less stark. It was stated that the ticks responsible for RMSF transmission require a 2 year (8 season) life cycle. How may less distinct seasons (or longer summer seasons and shorter winter seasons) affect the life cycle and transmission abilities of these specific ticks?

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  23. I have never heard of Rocky Mountain Spotted Fever, I have always just associated ticks with adventuring into the woods and with possible Lyme disease. How interesting that urban development has increased the incidence of this infection. As a hiker I am certainly cautious about becoming a carrier of ticks through wearing appropriate attire and performing tick checks; however, as a resident in an urban environment ticks are far removed from my conscious as bed bugs, roaches, mice and rats have taken over. An earlier post mentioned that urban habitats would be fragmented due to the spotty patches of nature that cities host. I wonder, if coming in contact with tick reservoirs would be more common with the growth of tackling those empty lots with overgrown vegetation in order to create more natural habitats such as urban gardens and farms increases. Additionally, dogs and rodents are typical reservoirs for the pathogen and greatly facilitate transmissions, which it is not uncommon to come in contact with either of these species. Should dog owners be more cautious when taking their pets out to the parks to play? As we have read prevention education is the key and not elimination, so it seems as urban environments grow so should prevention education especially for urban residents who, like me is far removed from this concern.

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