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This week I'll be describing Lyme disease, which is another vector-borne infection. The vector is once again an arthropod although this time it is a tick rather than a mosquito. The arthropod-borne pathogen for Lyme disease is a now bacterium, rather than a virus, as was the case for both of the two previous arthropod-borne infections we covered. This discussion will proceed a little differently than have the previous two arthropod-borne infections. First we'll cover the clinical disease itself, then we'll discuss the primary vector and it's ecology, then the bacterial organism, Borrelia burgdorferi, and finally the epidemiology. I think this discussion flow will feel more natural to the particular circumstances of Lyme disease.
Lyme disease can be a very debilitating disease, particularly if it is not identified and treated early. Lyme disease can be roughly categorized into three chronological stages, or manifestations, although all three stages do not necessarily manifest even in untreated individuals. In early Lyme disease, a red macule or papule will often appear on the skin followed later by a lesion with an erythematous border and clearing center. It looks like this:
This rash is very distinctive for Lyme disease and is very useful for diagnosis in the early stage, however the rash does not present in every person who becomes infected unfortunately. The lesion is not typically painful or itchy (pruritic), but can be warm to the touch. Early Lyme disease is also often accompanied by flu-like symptoms: headache, fever, chills, malaise, and body ache. Interestingly, it is only at this early stage that the bacterium causing infection, B. burgdorferi, can be isolated from blood and cultured, so unless the clinical symptoms are caught early the opportunity will be missed. Symptoms associated with the early stage will generally resolve in 3 to 4 weeks.
The second stage, known as disseminated Lyme disease, can occur 1 to 6 months after initial exposure. Disseminated Lyme disease can present with more generalized lesions (as opposed to the localized lesion of the early stage), myocarditis, and neurologic disease. More specifically, when disseminated Lyme disease is present, it will often occur with multiple lesions on the body, intense lethargy, encephalopathy, muscle pain, lymphadenopathy, and splenomegaly. Myocarditis will occur in approximately 5% of untreated persons who develop disseminated Lyme disease, while the neurologic complications will occur in about 15% of untreated persons that go on to develop disseminated disease. These neurologic complications can include meningitis, meningoencephalitis, cranial nerve neuropathies, radiculitis, and distal neuropathies. The symptoms of disseminated Lyme disease will typically resolve in about 6 weeks.
Finally the late stage of disease, if it occurs, can appear months to years after initial infection. The most common manifestation of late Lyme disease is arthritis in one or multiple joints. Approximately 60% of infections will develop Lyme disease-associated arthritis if the infection is untreated. Arthritic attacks can last from weeks to months and the episodes can recur over many years. This condition can cause long-term ongoing disability and diminished quality of life. Generalized encephalopathy and distal polyneuropathy can also accompany late Lyme disease, further contributing to dysfunction and disability.
Diagnosis of infection depends on when in the clinical course the disease is identified. Clinical presentation is very important in early stage Lyme disease. In particular, a thorough history that captures recent outdoor activity is absolutely critical and should be regular practice for physicians practicing in endemic areas. Identification of the erythematous (EM) rash is usually sufficient for diagnosis of infection in early Lyme disease, but this EM rash is not present in all persons infected and so, while it is quite specific it is not sensitive enough for consistent diagnosis. This is precisely why a detailed history of all outdoor activity is essential. Simply inquiring about tick bites is not enough because often the tick and it's bite are very small and go unnoticed. B. burgdorferi can be cultured, but only during this stage of early Lyme disease, so effective microbiology, in the absence of the EM rash, also depends on a thorough history. In disseminated and late Lyme disease the opportunity to identify the pathogen directly is lost. In secondary, or disseminated, Lyme disease clinical presentation is again very important. In particular the combination of meningitis and cranial or distal neuropathy are very informative and suggestive of Lyme disease. However, detailed history is again very important, though one must remember that the time point of exposure and initial infection will be further removed from clinical presentation of disseminated Lyme disease. Antibody response is measurable only several weeks after initial infection, as IgM is typically not detectable in early disease. On the other hand, IgG is often present (but not always) in disseminated disease so this can be a viable marker of infection in many (but not all) people.
The vector. So, we are switching from the mosquito vectors we have talked about in the last several weeks to a very different organism altogether: ticks. In particular we are talking about 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 ticks are hard-bodied ticks of the family Ixodidae. Each of these three tick species can transmit Lyme disease. Additionally, I. scapularis is responsible for transmitting not only Lyme disease, which is caused by the bacterium B. burgdorferi, but also babesiosis and anaplasmosis. Because of the endemic nature of Lyme disease in parts of the northeastern and midwestern US, I. scapularis has been the most studied tick in relation to Lyme disease and so this discussion will focus on this species:
An important characteristic of I. scapularis for infection transmission is that this tick is quite small. Moreover, while it 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 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 without active tick inspection.
This tick has a complex life cycle that, unlike mosquitoes, is NOT completed with the passing of a single season (even though many mosquitoes are capable of overwintering). In fact, most mosquito species can complete several generations of life cycles within one season, depending on their local geography and climate. In contrast, Ixodes 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 mosquito 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.
There are a some important features of this life cycle that are relevant to the transmission of the pathogen, B. burgdorferi. First, the staggered appearance of the nymphs before the larvae each spring ensures the maintenance of the mouse reservoir for B. burgodorferi. Larvae that hatch in the spring are NOT infected with B. burgdorferi because this bacterium is not transmitted vertically from the adult female tick to her eggs. However, the larvae can become infected when they take their blood meal from an infected white-footed mouse, and they will remain infected as they develop into nymphs. When the nymphs emerge, if they became infected as larvae then they will now have the potential to infect any uninfected white-footed mouse if they happen to select such a mouse for their blood meal. Because the nymphs emerge in the spring before the larvae, and thus bite and infect mouse hosts before the larvae get to the mice, the nymphs replenish and maintain the mouse reservoir for B. burgdorferi, which can subsequently infect the pathogen-naive larvae emerging later that spring. This is a superb example of the co-evolution of this pathogen with it's vector and host species, and highlights the fine ecological balance required for its survival.
This brings us to the second important feature of the tick life cycle: human encroachment on this delicate ecology. Notice how humans are included as incidental hosts for both nymphal and adult ticks:
Humans are not natural hosts for either stage of the tick. Humans are also not the natural hosts for the bacterium. Humans are incidental hosts for both the vector and pathogen. Human contact with the tick results primarily from expanded land use development into areas that were previously undeveloped. For example, expansion of suburban residential communities and commercial zones into forest areas encroaches on the forest habitat. This encroachment brings humans into contact with the ticks in transition habitat areas (known as ecotones), which were previously comprised of the unmolested habitat of deer and mice. This is represented in the picture above by including humans in the host boxes along with the natural hosts at both the nymphal and adult stages of the tick life cycle.
Humans, like deer, are dead end hosts for B. burgdorferi, and so these large mammals cannot infect ticks with the bacterium. The mouse is the primary reservoir, therefore, while both the mouse and deer are necessary for the survival of I. scapularis, it is the mouse and the tick that are necessary for the survival of B. burgdorferi.
That brings us back to the agent of Lyme disease itself: the bacterium, Borrelia burgdorferi. Here's a look at it:
This is a gram negative spirochete bacterium. This motile organism's cellular structure is comprised of an inner and outer membrane and a flagellum. B. burdorferi's outer surface proteins are very important for the organism's infectivity and pathogenicity. There are two outer surface proteins that are of particular relevance: outer surface protein A (OspA) and outer surface protein C (OspC). While B. burgdorferi is in the tick gut, it expresses OspA, which allows the spirochete to attach to the wall of the tick gut. When the tick takes a blood meal, the host blood changes the environment inside the tick's gut. The spirochete senses this change in chemistry and temperature, which stimulates the bacterium to stop expressing OspA and to start expressing OspC. In the absence of OspA B. burgdorferi detaches from the stomach wall of the tick and is free moving. At this point the OspC expressing B. burgdorferi crosses the epithelium of the midgut and migrates to the salivary glands via the hemolymph. Here is a graphic depiction of the process:
This migration is a relatively SLOW process. It takes approximately 60 hours of this gradual accumulation of the organism in the salivary glands of the tick to produce sufficient numbers of the bacteria to infect a new host. This, of course, has very important implications for the prevention of Lyme disease in humans. Because infectivity requires a couple days of feeding, if you can identify a tick on the body early and remove it you can prevent it from transmitting the Borrelia pathogen.
The incidence of Lyme disease closely reflects the distribution of Ixodes ticks, as we would expect:
This week I'll be describing Lyme disease, which is another vector-borne infection. The vector is once again an arthropod although this time it is a tick rather than a mosquito. The arthropod-borne pathogen for Lyme disease is a now bacterium, rather than a virus, as was the case for both of the two previous arthropod-borne infections we covered. This discussion will proceed a little differently than have the previous two arthropod-borne infections. First we'll cover the clinical disease itself, then we'll discuss the primary vector and it's ecology, then the bacterial organism, Borrelia burgdorferi, and finally the epidemiology. I think this discussion flow will feel more natural to the particular circumstances of Lyme disease.
Lyme disease can be a very debilitating disease, particularly if it is not identified and treated early. Lyme disease can be roughly categorized into three chronological stages, or manifestations, although all three stages do not necessarily manifest even in untreated individuals. In early Lyme disease, a red macule or papule will often appear on the skin followed later by a lesion with an erythematous border and clearing center. It looks like this:
This rash is very distinctive for Lyme disease and is very useful for diagnosis in the early stage, however the rash does not present in every person who becomes infected unfortunately. The lesion is not typically painful or itchy (pruritic), but can be warm to the touch. Early Lyme disease is also often accompanied by flu-like symptoms: headache, fever, chills, malaise, and body ache. Interestingly, it is only at this early stage that the bacterium causing infection, B. burgdorferi, can be isolated from blood and cultured, so unless the clinical symptoms are caught early the opportunity will be missed. Symptoms associated with the early stage will generally resolve in 3 to 4 weeks.
The second stage, known as disseminated Lyme disease, can occur 1 to 6 months after initial exposure. Disseminated Lyme disease can present with more generalized lesions (as opposed to the localized lesion of the early stage), myocarditis, and neurologic disease. More specifically, when disseminated Lyme disease is present, it will often occur with multiple lesions on the body, intense lethargy, encephalopathy, muscle pain, lymphadenopathy, and splenomegaly. Myocarditis will occur in approximately 5% of untreated persons who develop disseminated Lyme disease, while the neurologic complications will occur in about 15% of untreated persons that go on to develop disseminated disease. These neurologic complications can include meningitis, meningoencephalitis, cranial nerve neuropathies, radiculitis, and distal neuropathies. The symptoms of disseminated Lyme disease will typically resolve in about 6 weeks.
Finally the late stage of disease, if it occurs, can appear months to years after initial infection. The most common manifestation of late Lyme disease is arthritis in one or multiple joints. Approximately 60% of infections will develop Lyme disease-associated arthritis if the infection is untreated. Arthritic attacks can last from weeks to months and the episodes can recur over many years. This condition can cause long-term ongoing disability and diminished quality of life. Generalized encephalopathy and distal polyneuropathy can also accompany late Lyme disease, further contributing to dysfunction and disability.
Diagnosis of infection depends on when in the clinical course the disease is identified. Clinical presentation is very important in early stage Lyme disease. In particular, a thorough history that captures recent outdoor activity is absolutely critical and should be regular practice for physicians practicing in endemic areas. Identification of the erythematous (EM) rash is usually sufficient for diagnosis of infection in early Lyme disease, but this EM rash is not present in all persons infected and so, while it is quite specific it is not sensitive enough for consistent diagnosis. This is precisely why a detailed history of all outdoor activity is essential. Simply inquiring about tick bites is not enough because often the tick and it's bite are very small and go unnoticed. B. burgdorferi can be cultured, but only during this stage of early Lyme disease, so effective microbiology, in the absence of the EM rash, also depends on a thorough history. In disseminated and late Lyme disease the opportunity to identify the pathogen directly is lost. In secondary, or disseminated, Lyme disease clinical presentation is again very important. In particular the combination of meningitis and cranial or distal neuropathy are very informative and suggestive of Lyme disease. However, detailed history is again very important, though one must remember that the time point of exposure and initial infection will be further removed from clinical presentation of disseminated Lyme disease. Antibody response is measurable only several weeks after initial infection, as IgM is typically not detectable in early disease. On the other hand, IgG is often present (but not always) in disseminated disease so this can be a viable marker of infection in many (but not all) people.
The vector. So, we are switching from the mosquito vectors we have talked about in the last several weeks to a very different organism altogether: ticks. In particular we are talking about 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 ticks are hard-bodied ticks of the family Ixodidae. Each of these three tick species can transmit Lyme disease. Additionally, I. scapularis is responsible for transmitting not only Lyme disease, which is caused by the bacterium B. burgdorferi, but also babesiosis and anaplasmosis. Because of the endemic nature of Lyme disease in parts of the northeastern and midwestern US, I. scapularis has been the most studied tick in relation to Lyme disease and so this discussion will focus on this species:
Ixodes scapularis
An important characteristic of I. scapularis for infection transmission is that this tick is quite small. Moreover, while it 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 without active tick inspection.
This tick has a complex life cycle that, unlike mosquitoes, is NOT completed with the passing of a single season (even though many mosquitoes are capable of overwintering). In fact, most mosquito species can complete several generations of life cycles within one season, depending on their local geography and climate. In contrast, Ixodes 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 mosquito 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.
There are a some important features of this life cycle that are relevant to the transmission of the pathogen, B. burgdorferi. First, the staggered appearance of the nymphs before the larvae each spring ensures the maintenance of the mouse reservoir for B. burgodorferi. Larvae that hatch in the spring are NOT infected with B. burgdorferi because this bacterium is not transmitted vertically from the adult female tick to her eggs. However, the larvae can become infected when they take their blood meal from an infected white-footed mouse, and they will remain infected as they develop into nymphs. When the nymphs emerge, if they became infected as larvae then they will now have the potential to infect any uninfected white-footed mouse if they happen to select such a mouse for their blood meal. Because the nymphs emerge in the spring before the larvae, and thus bite and infect mouse hosts before the larvae get to the mice, the nymphs replenish and maintain the mouse reservoir for B. burgdorferi, which can subsequently infect the pathogen-naive larvae emerging later that spring. This is a superb example of the co-evolution of this pathogen with it's vector and host species, and highlights the fine ecological balance required for its survival.
This brings us to the second important feature of the tick life cycle: human encroachment on this delicate ecology. Notice how humans are included as incidental hosts for both nymphal and adult ticks:
Humans are not natural hosts for either stage of the tick. Humans are also not the natural hosts for the bacterium. Humans are incidental hosts for both the vector and pathogen. Human contact with the tick results primarily from expanded land use development into areas that were previously undeveloped. For example, expansion of suburban residential communities and commercial zones into forest areas encroaches on the forest habitat. This encroachment brings humans into contact with the ticks in transition habitat areas (known as ecotones), which were previously comprised of the unmolested habitat of deer and mice. This is represented in the picture above by including humans in the host boxes along with the natural hosts at both the nymphal and adult stages of the tick life cycle.
Humans, like deer, are dead end hosts for B. burgdorferi, and so these large mammals cannot infect ticks with the bacterium. The mouse is the primary reservoir, therefore, while both the mouse and deer are necessary for the survival of I. scapularis, it is the mouse and the tick that are necessary for the survival of B. burgdorferi.
That brings us back to the agent of Lyme disease itself: the bacterium, Borrelia burgdorferi. Here's a look at it:
This is a gram negative spirochete bacterium. This motile organism's cellular structure is comprised of an inner and outer membrane and a flagellum. B. burdorferi's outer surface proteins are very important for the organism's infectivity and pathogenicity. There are two outer surface proteins that are of particular relevance: outer surface protein A (OspA) and outer surface protein C (OspC). While B. burgdorferi is in the tick gut, it expresses OspA, which allows the spirochete to attach to the wall of the tick gut. When the tick takes a blood meal, the host blood changes the environment inside the tick's gut. The spirochete senses this change in chemistry and temperature, which stimulates the bacterium to stop expressing OspA and to start expressing OspC. In the absence of OspA B. burgdorferi detaches from the stomach wall of the tick and is free moving. At this point the OspC expressing B. burgdorferi crosses the epithelium of the midgut and migrates to the salivary glands via the hemolymph. Here is a graphic depiction of the process:
This migration is a relatively SLOW process. It takes approximately 60 hours of this gradual accumulation of the organism in the salivary glands of the tick to produce sufficient numbers of the bacteria to infect a new host. This, of course, has very important implications for the prevention of Lyme disease in humans. Because infectivity requires a couple days of feeding, if you can identify a tick on the body early and remove it you can prevent it from transmitting the Borrelia pathogen.
The incidence of Lyme disease closely reflects the distribution of Ixodes ticks, as we would expect:
Lyme disease in the United States is most concentrated in the Northeast and upper Midwest where the deer tick is well-established, as can be seen in the two maps above. Incidence rates can be greater than 1 per 100 persons per year in some areas of New York and Connecticut. Here is the New York incidence depicted below:
Publications by the Morbidity and Mortality Weekly Report show that Lyme disease incidence rates vary greatly by state:
But there is also great variation within states by counties:
Control and prevention of Lyme disease must focus 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 tick (i.e. the white-footed mouse and the white-tailed deer) is extremely difficult as these animals are ubiquitous, highly adaptive, and can exploit a wide range of habitat. In addition, the wide variety of hosts available to the tick at the larval, nymphal, and adult stages make controlling Ixodes quite difficult. And finally, the complex life cycle of the tick, which maintains the reservoir status of the white-footed mouse, as well as the competency of this primary host to serve as a reservoir, ensure that B. burgdorferi will persist in concert with the mouse's persistence. Thus elimination of the bacterium 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:
Next week I will begin an extended series on malaria, so be sure to follow the posts.