Table of Contents
Description of Borrelia burgdorferi associated Lyme Disease
The spirochete bacterium Borrelia burgdorferi (hereafter referred to as B. burgdorferi) sensu lato is the agent that causes Lyme disease or borreliosis. This disease is known as one of the most prevalent tick-borne infection in the United States (US), Europe and is reported to be endemic in various areas in Asia. However, in the US, B. burgdorferi is the only causative agents of Lyme disease which differs from the causative agents in other countries.
The B. burgdorferi is a helically shaped spirochaete bacterium that has different genospecies that can cause Lyme disease. The envelope of the cell of B. burgdorferi contains two lipid membranes that cover a protoplasmic cylinder and between the outer and inner membrane lies the periplasmic spaces that are comprised of flagellar filaments and a peptidoglycan layer. Lyme disease Borrelia is classified as a non-toxic pathogen due to the Borrelia not producing toxins that cause tissue damage.
Although B. burgdorferi stains as Gram-negative, the stain is too weak to be classified as such, according to sources. This is due to the typical structure of the envelope, which significantly differs from other Gram-negative bacteria. The lipopolysaccharides generally are components of the outer membrane in Gram-negative bacteria; differing from B. burgdorferi which membrane lacks lipopolysaccharides and consists of immunoreactive glycolipids and the flagella are located in the periplasmic space, conversely to other bacteria which have flagella outside the cell.
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The enveloped flagella do the basic function of providing motility but also confines the cell shape in B. burgdorferi. B. burgdorferi is pleomorphic, which means that the bacterium is able to alter its shape in response the environmental conditions. The optimum growth temperature for B. burgdorferi ranges from 30-37°C; however, 28°C was also observed to be a good growth temperature.
Symptoms of B. burgdorferi associated Lyme Disease
There are three major divisions into which Borrelia burgdorferi has been classified: erythema migrans, arthritis, and neurological complications (central nervous system or CNS). The most common and widely recognized classification is erythema migrans. This manifestation of Borrelia burgdorferi starts with individuals not having any noticeable symptoms– asymptomatic — and the spirochete is confined skin lesions. Due to an individual being asymptomatic, the infection that Borrelia burgdorferi causes tend to progress and physiological symptoms being to arise: headaches, fever, fatigue, malaise, and a stiff neck.
The further the infection is left untreated more symptoms start to arise, and after the milder effects observed the infection spreads quickly, even in an early phase of the disease. When the disease spreads throughout the entire body — disseminated Lyme disease– more dramatic symptoms start to manifest: hepatitis, arthritis, acute meningitis, generalized lymphadenopathy, myocarditis, and neuropathies. The symptoms of this phase are diverse and can range from mild to profound depending on the speed of the infectious load.
As Borrelia burgdorferi disseminates into the blood, the infection invades the central nervous system. During the first 2-3 months of infection, symptoms such has cranial neuritis and painful radiculitis occur in about 15% of the patients diagnosed with Lyme disease. Cranial neuropathy causes abnormalities in the cerebrospinal fluid and chronic nervous system diseases are more difficult to assess. Other common manifestations of early disseminated Lyme disease are cranial nerve palsies, especially facial nerve palsy, and meningitis. The most severe effects of the dissemination of B burgdorferi in the CNS is encephalitis and meningopolyneuritis. The severity of the disease in the later stages causes one to bring into question, how does B burgdorferi cause such severe disease.
Significance
B. burgdorferi associated Lyme disease, is known as the most prevalent vector-borne disease in the United States. Although most of the cases of Lyme disease are in less than 70 countries the dissemination of the infections are increasing, and the number of reported cases has increased to 25,000 to 30,000 per year. Of these reported cases, the group of people most affected is children between the ages of 5 and 10 years, which is almost twice as high as the adults that were reportedly affected. The risk of developing Lyme disease is increased for those that are exposed to tick-infested areas: woodlands and fields. The exposure may be due to people that work in high grassy areas (occupational), those that play sports (recreational), or people that simply live in highly infested areas (residential).
The significance of a disease is not only determined by the number of people it affects but also the severity of the disease. In the event that Lyme disease goes untreated or undetected, the symptoms become more severe. The aforementioned symptoms, when B. burgdorferi invades the bloodstream, it begins to affect the central nervous system; and the symptoms go beyond skin lesions, fever, and fatigue.
Conditions and such as encephalitis and meningopolyneuritis should not be overlooked. Encephalitis, inflammation of the brain, has long-term effects such as paralysis, loss of brain function, and issues involving behavior, speech, memory, and balance. Meningopolyneuritis is mainly caused by B. burgdorferi associated Lyme disease and the most severe symptom of this condition is malignant lymphoma, cancer that starts in the lymphatic system. These are only two examples of the dangerous manifestations of Lyme disease. There are some symptoms that are able to be treated; however, some are treatable but not curable.
When Lyme disease reaches the final stages of the disease, it may persist and only a few symptoms can be treated, which means that flare-ups and recurrence of harmful symptoms may appear in various stages of an infected person’s life. In addition, significant Lyme disease may go unreported or is misdiagnosed which limits the reliability of using past cases to predict potential risk to humans. Complications with laboratory tests are discussed further; however, it is also another reason that Lyme disease causes further discussion and research surrounding the disease.
Pathogenesis
The pathogenesis of a disease is a significant area of discussion because it describes the mechanisms by which the disease can develop, how it progresses and persists in a given system. Most importantly, by understanding the cellular levels of pathogenesis, researchers can develop techniques and methods that can either prevent or improve the condition of an infected person. By deducing which microbial molecules cause the disease and infection and which receptors they bind to in order to enter the cells or tissues, researchers are able to acquire vaccines against tick-borne illness or Lyme disease.
In humans, the tick bite (of an infected tick) is the first step in the introduction of the pathogen through a healthy person’s skin. The dermal tissue is the area in which the extracellular pathogen adapts to the living conditions in the human or mammalian host; it is able to adapt by altering the expression of the glycoproteins on its surface. Simultaneously, the inflammatory cells and mediators secreted by the cells cause the erythema migrans lesion; this process is stimulated by the bacterium, B. burgdorferi.
Proteases and other induced host cell molecules are also activated by the bacterium, and the activation allows for dissemination through the blood, which then travels to the joints, the heart, tissues such as nervous tissue and secondary skin lesions. The essential element of infection is complex plasmid content which is characterized by B. burgdorferi. The proteins that are located on the outer surface, allow for selective interaction with the extracellular matrix, endothelial cells, and platelets through specific interactions with integrins, glycosaminoglycans, and collagen.
One of the essential roles of pathogenesis depends on the response of the host to B. burgdorferi. The damage of tissue due to colonization is not due to the B. burgdorferi producing toxins and proteases; instead, various molecules that can cause localized inflammatory pathogenic responses are activated by B. burgdorferi. The host response, normally, is activated to contain infections and are apart of the inflammatory response; however, if continuously stimulated, lesions will develop and disease will arise.
The persistent infection of B. burgdorferi is caused by the immune response of the host being evaded. The downregulation of OspA, a protein antigen which is important for the life cycle of B. burgdorferi, during which, a tick is affixed to its host, is a mechanism used to keep the infection persistent. Another important mechanism is the innate immune response being inhibited; inhibiting bacterial surface-exposed proteins. Antigenic variation is the third mechanism and stimulates an alteration in a surface structure that occurs more often than other mutations.
Laboratory Diagnosis
The laboratory methods that are currently available for Lyme disease diagnosis are categorized as either direct and indirect methods. The direct method is used to detect B. burgdorferi, while the indirect methods are used to detect antibodies against B. burgdorferi. The main direct test used are PCR and culture. At present, no antigen assays are recommended for the diagnosis of Lyme disease.
Although culture is one of the main direct methods, it is not a routine method due to low sensitivity, long incubation periods (8-12 weeks) and special media and expertise that is required for that media. The probability of B. burgdorferi ability to be cultured depends on the stages of the disease, the expertise of the researchers, genotype and most importantly the specimen.
However, isolating and culture B. burgdorferi has proven to be essential when researching Lyme disease and it remains to be the superior method when diagnosing the disease. A complex growth media needed for B. burgdorferi, as a result of B. burgdorferi having a limited metabolic capacity. The complex media used for B. burgdorferi culture include the variations of the Barbour-Stoenner-Kelly (BSK) medium and a modified variation of the Kelly–Pettenkofer (MKP) medium[1]. During the examination of the cultures, dark-field or fluorescent microscopy are used after acridine orange staining of aliquots. A setback of this method was the low sensitivity of the aliquots; however, by using PCR methods the sensitivity is improved.
An assay that uses broad-range PCR and electrospray ionization mass spectrometry are new methods and are speculated to be promising. The PCR assay is currently being used to examine synovial fluids in infected patients with Lyme arthritis. This is an essential method because B. burgdorferi DNA can be detected in up to 85% of infected patients. However, a positive PCR does not specify whether an infection is active due to low sensitivity to fluid samples, such as cerebrospinal fluids, especially in early stages of infection.
The indirect methods are those that examine the antibody response of a host against the organism causing the infection, B. burgdorferi, by testing serum. The main tests used for indirect methods are an enzyme immunoassay (EIA) or an indirect immunofluorescence assay (IFA); testing does not continue following a negative result. Following a positive result or borderline result, the serum is rested by using IgM and IgG Western Blots. Negative results can occur when an infected person is in the early stages of the disease and patients with erythema migrans have less than a 50% chance of having positive; in this case, these patients receive treatment based on a clinical diagnosis.
In the early stage of Lyme disease, an infected person may not have an erythema migran rash. The occurrence of a difficult diagnosis should be followed by serologic testing for Lyme disease. However, ELISA type tests may be negative and a Western Blot, testing for IgM reactivity, is performed in this event. Clinicians presented with patients with neurological symptoms may need to perform a lumbar puncture and examination of cerebrospinal fluid are required for appropriate evaluation of these patients or any patient suspected of having central nervous system involvement.
The assays that are currently being used are not able to distinguish between infections that are inactive or active; therefore, years may pass and patients will unknowingly be seropositive, even after treatment with antibiotics. Hopefully, with further studies utilizing new, promising immunoassay techniques, a combination of multiple antigens can be developed that will help in early diagnosis, inform on the stage and disease manifestations, and on the presence of active versus past infection.
Xenodiagnosis is a test used to detect Lyme disease by using Ixodes scapularis – a natural tick vector. This particular test, however, is experimental and whether it has clinical uses depend on future results. One practical use of Xenodiagnosis may be to aid in developing new tests for Lyme disease.
Treatments for Lyme Disease
The treatment for B burgdorferi associated Lyme disease depends on if a tick has been embedded for a long period of time, the severity of the infection, the phases of infection and the symptoms. If a tick has been embedded for 48 hours or more the tick would need to be analyzed. A negative test (PCR-DNA or IFA) indicates that no treatment needs to be given to the patient; however if the tests are positive, the recommended treatment would be antibiotics used to treat infections such as the amoxicillin, cefuroxime, or doxycycline.
If there are no symptoms the recommended time of treatment is about 1-2 weeks; if rashes are observed on the infected person the recommended time is 2-4 weeks. In the event that the tick is not analyzed or tested, a patient must wait for symptoms, such as rashes, to appear or they are prescribed with doxycycline, which is considered an illogical approach to treating a patient with no prior knowledge if the patient has an infection. However, if treated this way patients are told to look for any symptoms that may arise in the months following treatment.
Although doxycycline is an effective treatment for the early phases of Lyme disease, the antibiotic is not as effective with persisting Lyme disease. When treating patients with relapsing or chronic Lyme disease, clinicians combine the medications, erythromycin, and hydroxychloroquine, in order to successfully treat an infected individual. Clinicians also approach treatment by using symptom-based medications, gabapentin, anti-depressants, and trazodone, to relieve symptoms patients are experiencing, such as neuropathy, any localized pain, or difficulty sleeping. When treating patients, clinicians do not prescribe narcotics due to the possibility of addiction, which causes treatment to become increasingly difficult when an underlying illness is present.
Prevention of B. burgdorferi associated Lyme Disease
Preventing a tick bite is one of the first and obvious steps of preventing LD. Aforementioned in the previous texts LD is localized to certain geographical areas and people in those areas have to take preventative measures to ensure that the risk of tick bites are reduced or eliminated. When in areas that are known to be areas where ticks reside, people working or traveling through those areas can create protective barriers, long-sleeved shirts with gloves and long pant legs that are tucked into socks, and wearing light-colored clothes to ensure that dark-colored ticks are visible.
Another safety measure is using insect or repellents containing DEET (diethyl-3-methylbenzamide), which are the most commonly used and effective repellents. Products containing DEET are usually topically applied to the skin. Although high concentrations are known to be harmful to children, causing serious neurological complications and seizures, most commercially available insect repellents do not contain doses higher than about 30%, and the reported cases of children negatively affected are low[9].
Insecticides and acaricides are effective ways to prevent tick bites without application of insect repellents on the skin; this method is used by applying the product to clothing. Permethrin, an insecticide not only used to treat human lice, its most common use but is also be used to prevent tick bites by application of the substance to bedding and clothing. Permethrin can be applied by spraying the clothing or by immersing the clothing in a permethrin and water mixture for 3-5 hours. The efficacy of applying this substance to clothing, clothing was greater than DEET products against Ixodes ticks.
Targeting the areas where ticks are found by using acaricides such as carbaryl and deltamethrin, can also be an effective way to reduce the risk of tick bites, but only for an allotted period of time. Using the acaricide, deltamethrin, is 100% effective in reducing ticks for 11 weeks at a time. Although this method may be effective in its goal, it is not widely used due to the drawbacks of using harsh chemicals; and can pose a threat not only to human health and safety but to other arthropods that are not being targeted.
The methods listed above are known to be effective in protecting against tick bites, which in turn helps prevent LD; however, there are times when tick bites are unavoidable and repellants may fail. When in areas where ticks are prevalent, it is imperative for each individual to conduct tick checks, even if repellents and insecticides have been used. This safety precaution is helpful in preventing LD because this allows for tick embedding to be spotted before a B. Burgdorferi infected ticks can transmit the disease into the human, which is before 36 hours have passed.
In summary, there are various techniques that have been proven to be efficacious in preventing Lyme disease in humans. However, there has been no success in the reduction of the spread or increasing incidence of human LD in terms of population levels. Although there no available human vaccine for B. burgdorferi associated Lyme disease, research is underway, investigating vaccinations for B. burgdorferi. Unfortunately, vaccinations, no matter how efficacious, cannot alter the dynamics of the disease. Future developments should focus on reducing reservoirs of disease in uncultivated regions.
