Tuesday, June 21, 2011

Ehrlichiosis


The next rickettsial disease we are covering is ehrlichiosis. This disease, or rather set of diseases, is caused by several different species, comprising two distinct genera, in the Anaplasmataceae family. Ehrlichia chaffeensis, E. ewingii, and E. canis are the Ehrlichia species that cause human monocytic ehrlichiosis, Anaplasma phagocytophilum causes human granulocytic anaplasmosis, and Neorickettsia sennetsu causes sennetsu fever. These five bacteria species, causing their three distinct disease forms, comprise the ehrlichiosis disease constellation. (Because, much of the epidemiology and ecology of sennetsu fever is unknown, I will not cover this disease here.) While these causative bacteria are in the order Rickettsiales and thus are typically considered "rickettsial" disease agents, as you can see these bacteria are not members of the Rickettsia genus.

Here are the players:

Ehrlichia chaffeensis

Ehrlichia ewingii

Ehrlichia canis

Anaplasma phagocytophilum


Ehrlichiosis, in at least four of its forms (the mode of transmission for sennetsu fever remains unknown), is vectored by ticks. The four bacteria pictured above are not all vectored by the same tick, but they are vectored by ticks, nonetheless. The vector for A. phagocytophilum consists of several Ixodes species, which were described previously when we covered Lyme disease. I will recap Ixodes ecology below.

Vector 1

For A. phagocytophilum transmission, the relevant vectors are Ixodes scapularis, the deer tick, AKA blacklegged tick, in the northeastern United States:




Ixodes pacificus in the western US:






and Ixodes ricinus in Europe, the Mediterranean, the Middle East, and parts of Central Asia:






These are hard-bodied ticks of the family Ixodidae. Each of these three tick species can transmit the anaplasmosis form of ehrlichiosis. Here is a picture of one species:



 Ixodes scapularis

An important characteristic of Ixodes spp. for infection transmission is that these ticks are quite small. Moreover, while Ixodes is small in each of its developmental stages, it is barely visible in its nymphal stage until it reaches the point where it is completely engorged with blood. Here is a look at some scaled pictures of each of the developmental stages of this tick:


The top row of ticks represent I. scapularis and are scaled to a ruler and other ticks below.


The above picture compares engorged and non-engorged nymph and adult ticks. The two ticks on the left are both nymphs with the far left non-engorged and the one to its right an engorged nymph. The two ticks on the right are both adults with the one on the left a non-engorged adult and the one on the right an engorged adult.

The above picture shows just how difficult it can be to identify these ticks, particularly before they have become engorged with blood. If they are obscured by hair, one has little hope of identifying them to prevent infection, unless one employs active tick inspection.

Ixodes species have a complex life cycle that, unlike most arthropod vectors we have covered, requires MULTIPLE seasons across two years to complete. In comparison, most mosquito species can complete several generations of life cycles within one season, depending on their local geography and climate. Ixodes (and Amblyomma) species require two years to complete their life cycle, with different developmental stages needing to transition through 8 distinct seasonal changes. This adds levels of complexity and layers of dependencies to the tick life cycle that we did not encounter with other arthropod life cycles. Let's take a closer at this life cycle:



The life cycle proceeds as follows: First, the eggs hatch in the spring and the new larvae need to feed by taking a blood meal. The preferred host for this blood meal is the white-footed mouse. After this first, and single, blood meal, the larvae rest and overwinter. During this time they develop into dormant nymphs. Next,the nymphs emerge in the following spring, and they do so before the newly emerging larvae, which will be hatching from the eggs later in the spring. Are you still with me? Good, because the nymphs, now newly emerged, again require a blood meal to continue the life cycle of the tick. Once again the preferred host is the white-footed mouse. Following this blood meal and another period of rest, the adult ticks emerge in late summer or early fall and will require a second blood meal to reproduce, which is taken from a large mammal (typically the white-tailed deer, thus the common name, "deer tick"). The male and female ticks mate on the host mammal, the males dies and falls off, and the female overwinters for the second time in her life cycle. When the female emerges for the last time in the spring, she lays her eggs, which will hatch later that spring after the nymphs emerge. We can now appreciate the complex ecologically-driven evolution of these ticks, which pass through several levels of climate and weather variation, and multiple host population dynamics across two years of time. Impressive.

When we discussed Lyme disease, we saw that the white-footed mouse was the primary reservoir for the B. burgdorferi bacterium. This host, along with other rodents, is again an important reservoir for A. phagocytophilum, but ruminants (especially cattle and deer) also serve as significant reservoirs.

Vector 2

Ehrlichia species, on the other hand, are transmitted by Amblyomma americanum, the lone star tick. This tick can be recognized by the distinctive white spot on its back:

Amblyomma americanum

This tick is somewhat larger than the Ixodes spp. covered aboved. For comparison, here again is the scaled image with both species:


The life cycle of A. americanum is quite similar to I. scapularis, in that it is a 3 host ectoparasite, requiring a blood meal during the larval, nymphal, and adult life stages, which typically takes approximately 2 years to complete:


The distribution of A. americanum, however, is concentrated more in the southeastern US, compared to the northeastern, upper midwestern, and west coast distributions of I. scapularis and I. pacificus as mapped here by the Centers for Disease Control and Prevention (CDC):


Do notice, though, that despite the distribution of the lone star tick being concentrated in the Southeast and Texas, the range of the tick does indeed extend up along the eastern seaboard as far north as New York and Massachusetts.

Finally, here is a map that depicts the geographical ranges across the US of both the important Ixodes and Amblyomma ticks:



Clinical Disease

The various rickettsial organisms that I have included in this discussion (as well as some that I have not included) do indeed cause distinct disease within the ehrlichiosis spectrum. Nevertheless, the spectrum is narrow, and the clinical manifestations of these organisms are quite similar and thus they are considered together as ehrlichioses.

E. chaffeensis invades macrophages and dendritic cells, causing human monocytotropic ehrlichiosis across the western hemisphere. E. ewingii targets the host's neutrophils, which causes ehrlichiosis ewingii and is limited to North America. These ehrlichioses typically present with non-specific symptoms such as headache, myalgia, and fever. Nausea and vomiting with associated loss of appetite are also common. Leukopenia and thrombocytopenia are both common, as are elevated liver enzymes. More severe disease with meningoencephalitis presents in about 20% of people with clinical disease. While not typically lethal, this ehrlichiosis does have a broad range of experience in populations, ranging from rather minor disease to a serious, life-threatening condition. The case-fatality associated with E. chaffeensis infections is almost 3% (Deaths have not been reported in E. ewingii infections).

The CDC has reported the distribution of ehrlichiosis caused by E. chaffeensis in humans in the Morbidity and Mortality Weekly Report (MMWR), published in 2008

Number of cases of ehrlichiosis caused by Ehrlichia chaffeensis (i.e., human monocytotropic ehrlichiosis)

And here is a CDC map showing the distribution of ehrlichiosis caused by E. ewingii, again published in 2008 in the MMWR:

Number of cases of ehrlichiosis caused by Ehrlichia ewingii (i.e., ehrlichiosis ewingii)

A. phagocytophilum also targets neutrophils. This Anaplasma infection causes human granulocytotropic anaplasmosis and has a broader geographic distribution across Asia, Europe and North America than do the other ehrlichioses. The clinical disease associated with anaplasmosis is also typically non-specific in nature, yet is generally milder than the other ehrlichioses. Presentation includes headache, myalgia and fever. Laboratory findings are also similar, with leukopenia, thrombocytopenia and elevated liver transaminases. However, meningoencephalitis is quite uncommon in anaplasmosis and the case-fatality is less than 1%.

The CDC's 2008 MMWR report on the distribution of anaplasmosis in humans is mapped here:

Number of cases of ehrlichiosis caused by Anaplasma phagocytophilum (i.e., human granulocytotropic anaplasmosis)

The distribution of this condition is quite similar to that of Lyme disease with the northeastern and upper-midwestern US primarily affected. This is not surprising since the two diseases share the same primary tick vector.

Notice how these maps of disease distribution correspond to the map of the distribution of ticks above. The geography of ehrlichiosis closely overlays the geography of ticks, and thus, as with Lyme disease, the ecology of the relevant tick largely determines the disease ecology of ehrlichiosis. When humans encroach upon tick habitat, increases in the incidence of ehrlichiosis can be expected to follow. The ecology is obviously even more complex for ehrlichiosis than for Lyme disease, however, because there are several ticks invloved in ehrlichiosis transmission. These varied ticks, while similar in life cycle development, nevertheless exploit different ecological niches and exhibit different host preferences, which adds further nuance to the landscape epidemiology of this spectrum of disease.


Control and prevention of ehrlichiosis is very similar in approach to that which I outlined for Lyme disease. Nevertheless, I will reiterate 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 is likely to consistently meet with failure because of the complex ecologies involved. For example, control of the favored host species of the relevant tick (whether Amblyomma or Ixodes ticks) is extremely difficult because these reservoir animals are ubiquitous, highly adaptive, and can exploit a wide range of habitat. In addition, the wide variety of hosts available to the ticks at the larval, nymphal, and adult stages makes controlling the ticks, themselves, quite difficult. And finally, the complex life cycles of the Amblyomma and Ixodes ticks, which maintains the reservoir status of the rodent and ruminant species for the bacteria, as well as the competency of these primary hosts to serve as reservoirs, ensure that the rickettsial pathogens that cause the spectrum of ehrlichiosis will persist. Thus elimination of the bacteria is also 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:

10 comments:

  1. Considering the similarities in clinical presentations between E.chaffeensis and E.ewingii infections, their overlapping geographic ecologies in the Midwestern US, and the fact that one appears more lethal than the other (given the difference in case-fatality rates), are there any ways to clinically differentiate one from the other without waiting for the lab results to come back? It seems that there may be times when one might want to act faster for E.chaffeensis than E.ewingii, and knowing what differences to look for might be helpful in that respect.

    -Matt T-N

    ReplyDelete
  2. Similar to what Matt said, is there a "classic" antibiotic treatment used for these patients? Or is a broad spectrum antibiotic used until the lab susceptibility reports come back? Also, I wonder if doctors are familiar with tick borne infections that are not Lyme disease... because I can see if they are not familiar with them misdiagnosis could occur.
    -Deanna

    ReplyDelete
  3. I am going to intervene on this one before the Wednesday replies, because I don't think anyone will be able to provide feedback. Doxycycline is the go to drug for these ehrlichioses, UNLESS the person is under 8 years of age or has another contraindication. When you see something that clinical presentation and a good history suggest is a rickettsial disease, you treat empirically. You don't wait for the labs to come back on the specific organism.

    ReplyDelete
  4. Has there been any resistance seen in certain strains of Ehrlichia?
    -Deanna

    ReplyDelete
  5. Deanna-
    I came across an article on PubMed looking at the antibiotic susceptibilities in the different ehrlichia and anaplasma species. It seems that they have varying susceptibilities to different antibiotics and show resistance to some antibiotics. It seems that in 2004 scientists found for the first time point mutation in these bacteria that are known to provide antibiotic resistance in other bacteria and this has caused some concern.

    Here is the article if you want to check it out:

    http://www.ncbi.nlm.nih.gov/pubmed/15561862

    Max

    ReplyDelete
  6. Max
    Thank you so much for the link to the article.. I found it to be very interesting; especially since rifampin and doxycline were found to be very effective. Also, the 4 different point mutations that they found to be the cause of resistance is very interesting as well.
    Thanks again
    Deanna

    ReplyDelete
  7. This is a very interesting article! I am a RN in Ky and one night in late April in 2006,I thought I had a stomach virus. As the night progressed from 10pm to 4 am my condition deteriorated very fast, I knew I was running a fever, I knew I had a headache but quite honestly I was sleeping on the bathroom floor I was so sick that it was hard to care. By noon I was in a coma. I had been graced by a nymph lone star tick sometime between 2 days and 12 days earlier and never knew it was on me. I had the HME and was treated with doxycycline. I was in the ICU at a major hosp. for 1 week and another unit for another week. Thank God for good Dr's and quick blood work tests.. Ticks are really nothing to mess with.. more people need to be aware of the dangers they carry.

    ReplyDelete
  8. Very interesting. Ehrlichia infection seems difficult to determine since diagnosis is based on Clinical signs and symptoms where the symptoms vary from person to person and morulae in WBC's which is indicative of infection, can be confused with other WBC inclusions. Also, Detection of antibodies will be negative for the first 7 to 10 days of illness and it is not detected in routine blood cultures.

    ReplyDelete
  9. I agree with Cadia that clinical signs and symptoms are so non-specific that diagnosis would be difficult at times especially if you weren’t looking in the right places. But I think this is where a very thorough history taking would be essential to elicit possible tick contact or recent activities in the woods. On another note, since A. phagocytophilum which causes human granulocytotropic anaplasmosis shares the same vector as B. burgdorferi which causes Lyme disease, I wonder how likely it is to be infected by both and if there are any synergistic effects from having simultaneous infections. Lastly, the youtube video made a point that pathogen transmission only occurs after 24 hours of attachment. That seems peculiar to me; what are the mechanisms whereby the tick does not transmit the pathogen in the first 24 hours? How is that evolutionarily advantageous? I feel like the mosquito-plasmodium model moreso evolutionarily favors the pathogen but I guess it ultimately depends on where the bacteria is within the tick?

    ReplyDelete
  10. The specificity and intricacy of the Ixodes and Amblyomma species is indeed quite impressive. Based on our knowledge of disease's geographic variation, and high prevalence in Southeastern and South-central parts of the United States, perhaps special attention needs to be paid to patients traveling across states. Interestingly, reported cases of Ehrlichiosis is observed to be highest among men and people over 50 years of age. Are societal factors contributing to this gender-specific trend? Gender-based norms in which mostly men are working outdoors and are at an increased risk of getting infected?

    ReplyDelete

Note: Only a member of this blog may post a comment.