Lyme Disease: A Review of Evidence-Based Practices in Diagnosis Treatment and Prevention

Abstract

Lyme borreliosis (LB) is a multifaceted inflammatory illness that is increasingly encroaching on areas with higher altitudes and latitudes. This disease predominantly occurs in temperate regions, with the US Centers for Disease Control and Prevention (CDC) documenting over 30,000 cases annually. Lyme disease can be found in diverse locales across North America, Europe, the Middle East, Australia, Southeast Asia, and certain regions of the former Soviet Union, depending on the habitat of Ixodes ticks. It is caused by several species within the Borrelia burgdorferi sensu lato (sl.) complex, which thrive in complex networks involving ixodid ticks and various hosts. The pathogens, identified within the genus Borrelia, are transmitted via bites from Ixodes Ricinus ticks. Ticks undergo three developmental stages: larva, nymph, and adult, with each stage lasting between one to two years. Adult ticks have a capacity to harbor the infection at a rate that is twice that of nymphs, with transmission needing 36 to 48 hours for nymphs and 48 to 72 hours for adults. Clinically, Lyme disease is typically characterized by a distinct lesion known as erythema migrans, which manifests as a homogeneous, reddish, ring-like rash.

Keywords

Introduction

Lyme disease, also known as Lyme borreliosis (LB), is a multifaceted inflammatory disorder that results from the immune response to the pathogenic strains of Borrelia burgdorferi sensu lato (sl)^[1]. These pathogens are transmitted by the bites of Ixodes Ricinus ticks. Despite considerable progress in the detection and management of LB in recent years, it remains the most prevalent arthropod-borne disease in temperate regions of the northern hemisphere. The effect of improvements in diagnostic practices and disease reporting on present prevalence rates is unclear. Nonetheless, it is widely recognized that the geographical distribution of LB is expanding, particularly into areas of higher elevation and latitude. Additionally, due to complex interactions among various environmental and socio-economic elements, LB is expected to represent an increasingly serious health concern in the future, affecting various aspects of disease ecology and epidemiology, as outlined in the subsequent sections^[2].

ECOLOGY OF LYME DISEASE:

Ecological Dynamics And Disease Transmission:

The ecological context of Lyme disease (LB) is fundamentally influenced by the interactions involving the pathogen Borrelia burgdorferi sensu lato (sl) (figure No. 1), its vector, the Ixodes ticks, and the vertebrate reservoir hosts^[3]. The B. burgdorferi sl complex is recognized to encompass at least 18 distinct genospecies, several of which are pathogenic to humans including B. afzelii, B. garinii, B. burgdorferi sensu stricto (ss), B. bavariensis (previously designated as B. garinii OspA serotype 4), and B. spielmanii. The pathogenic capabilities of other genospecies, such as B. lusitaniae, B. valaisiana, and B. bissettii, remain somewhat ambiguous^[4]. It is significant to note that multiple genospecies can exist within a single tick vector. While all pathogenic genospecies can lead to erythema migrans, each is associated with different clinical presentations: B. burgdorferi ss is closely linked to arthritis and neuroborreliosis, B. garinii primarily with neuroborreliosis, and B. afzelii with the chronic skin condition acrodermatitis chronica atrophicans^[5].

Figure No. 1: Borrelia burgdorferi sensu lato

The distribution and prevalence of these genospecies vary considerably on both local and regional scales, shaped by temporal and spatial dynamics. A notable increase in biodiversity of genospecies is observed between 4 °W and 20 °E, correlating with a higher prevalence of Borrelia-infected ticks. Moreover, certain Borrelia genospecies are typically associated with specific reservoir hosts; for example, B. afzelii and B. bavariensis are commonly related to rodents, B. valaisiana and several B. garinii serotypes to birds, B. lusitaniae to lizards, and B. spielmanii to dormice. The genetic structuring of Borrelia genospecies has been shown to be influenced by host migration patterns, as demonstrated through the analysis of housekeeping gene sequences^[6]. Specifically, genospecies associated with avian hosts tend to have a broader distribution compared to those linked to mammals. Furthermore, Borrelia can be classified based on the sequences of outer surface proteins (Osp), with 21 major OspC groups identified. Recent research reveals that these genotypes exhibit considerable ecological and epidemiological diversity. However, despite the critical role of this information in the creation of preventive strategies and treatments, our comprehension of the distribution and clinical outcomes associated with each genospecies and genotype remains incomplete. Progress is being made in understanding the genetic mechanisms related to Borrelia transmission and virulence^[7,8].Ticks undergo three developmental stages: larva, nymph, and adult, each lasting one to two years. Hard ticks locate hosts through a behaviour known as 'questing,' where they climb grass blades or leaf edges, raising their forelegs in response to thermal and chemical cues. Subsequently, they either drop or crawl onto hosts that brush past their forelegs. Larvae, nymphs, and female adult ticks each take a single blood meal over several days from a vertebrate host, while adult males mate with the feeding females. Between blood meals, larvae and nymphs remain in leaf litter until they undergo the molting process, while adult females lay a clutch of eggs in the litter before dying. Borrelia can be transmitted to a tick through feeding on an infected host, by co-feeding with an infected tick on the same host, or from the site where an infected tick has recently fed, a process referred to as localized extended co-feeding^[9]. Once a tick becomes infected, certain species are capable of retaining the pathogen even during moulting, thereby transmitting it to subsequent feeding stages or directly to a host. The ability of ticks to convey Borrelia to a variety of hosts is affected by multiple factors, both internal to the ticks such as questing behavior, duration of diapause, host preferences, mating strategies, and population density and external biotic and abiotic elements, which include climate conditions, types of vegetation, management practices, and the behaviour, abundance, susceptibility, tick burden, and reservoir competence of hosts. Research indicates that ticks infected with Borrelia may exhibit enhanced abilities in locating hosts^[10]. The interaction between ticks and their hosts plays a crucial role in the dynamics of Borrelia infection, as feeding ticks release salivary vasoactive mediators and immunomodulators that aid the pathogen's transfer between the tick and the host. Additionally, the efficiency of transmission may vary depending on the specific Borrelia genospecies and the duration of host infectivity. Tick nymphs are primarily responsible for transmitting Borrelia to humans, displaying heightened questing activity from spring to autumn in environments with over 85% relative humidity, including deciduous or mixed woodlands with elevated ecotonal indices, suburban and urban areas, as well as along roadsides^[11]. The risk of exposure for humans in known tick-infested regions can reach levels of one infected tick per person for each hour of exposure, or approximately 0.25 infected ticks for every 100 meters traversed. Transmission typically does not happen within the first 24 hours after a tick has taken a blood meal, making the prompt removal of ticks a highly advised preventive action (refer to the details below). The identified competent reservoir hosts those that can carry Borrelia and pass it to previously uninfected ticks—include various common small and medium-sized rodents (such as mice, rats, squirrels, hares, and rabbits), along with multiple bird species (notably passerines), reptiles, and insectivores. In contrast, numerous larger wild and domestic vertebrates, including deer and sheep, are classified as non-competent reservoirs. This means that ticks feeding on these animals do not acquire Borrelia^[12]. Non-competent reservoir hosts can potentially diminish the transmission likelihood of Borrelia, thereby lowering its prevalence within the vector and subsequent disease risk to humans a phenomenon referred to as a dilution effect. Research by Ogden and Tsao indicates that any host capable of sustaining enough ticks to decrease overall infection rates in nymphs by diverting them from feeding on competent host species could ultimately promote a higher tick population density by enhancing the likelihood of successful tick feeding. However, the comprehensive impacts of biodiversity alterations on the emergence of Lyme borreliosis remain insufficiently explored^[13].

EPIDEMIOLOGY:

Lyme disease is predominantly found in temperate regions, with over 30,000 cases reported to the US Centers for Disease Control and Prevention (CDC) annually. This disease also occurs in various parts of North America, Europe, the Middle East, Australia, Southeast Asia, and the former Soviet Union, depending on the habitat of Ixodes ticks. The rising incidence of Lyme disease has been linked to factors such as reforestation, increasing populations of deer and ticks, and heightened tick exposure due to urban encroachment into forested and deer-rich areas. Individuals such as hikers, workers in wildlife parks, and those traveling in endemic regions face a greater risk^[14]. While large and white-tailed deer, small rodents, domestic cattle, and some birds serve as natural reservoirs for Borrelia burgdorferi, the disease primarily occurs incidentally in humans. In India, cases of Lyme disease, including instances of Lyme disease-associated monoarthritis and neuroretinitis, have been documented in states such as Himachal Pradesh, Haryana, Bihar, Uttarakhand, Uttar Pradesh, Maharashtra, and certain areas of southern India. Additionally, Praharaj et al. reported a seroprevalence of Borrelia in 13% of the population in northeastern Indian states, and the presence of Ixodes ticks has also been noted in the Himalayan region^[15].

Figure No. 2: Egg Stage of Ticks

PATHOGENESIS:

B. burgdorferi colonizes and infects Ixodes ticks, which subsequently transmit the infection to various hosts, including humans. The typical life cycle of these ticks spans approximately two years. Adult ticks lay eggs in the spring (Figure No. 2), which hatch into larvae during the summer. These larvae develop into nymphs, which then molt into adults by autumn, feeding on infected host animals. While adult ticks are known to carry the infection at a rate twice that of nymphs, it is the nymph stage that accounts for 90% of human cases. This is largely due to their greater prevalence and the increase in human outdoor activities in summer, coinciding with peak feeding times for both nymphs and adult female ticks. Their small size often leads to difficulties in detection and removal, allowing them to attach for sufficient durations typically 36 to 48 hours for nymphs and 48 to 72 hours for adults necessary for transmission of the infection. The progression of the disease is fundamentally influenced by how B. burgdorferi adapts to both environmental factors and host conditions, which involves alterations in the composition of spirochete membrane proteins or variations in gene expression, alongside the response elicited by the host's immune system^[16]. The spirochetes located in the midgut of an infected tick are conveyed to the salivary glands and then introduced into the skin during a bite. Following this introduction, the host's immune response may eradicate the spirochetes or allow them to persist and localize in the skin, resulting in the typical erythema migrans (EM) lesion(s) (Figure No.3). Within one to two weeks (averaging 3–30 days), the spirochetes may disseminate through the bloodstream or lymphatic system, become latent, or develop into disseminated disease in approximately 50% of untreated cases^[17]. These spirochetes exhibit a notable preference for the skin, joints, central nervous system, heart, and eyes. However, during early disseminated spread, they have also been identified in lymph nodes, bone marrow, liver, spleen, testes, and placenta. In around 10% of patients experiencing EM without systemic symptoms, B. burgdorferi or its genetic material can be found in the bloodstream or cerebrospinal fluid (CSF), indicating the presence of spirochetemia and early involvement of the central nervous system. Notably, only a limited number of B. burgdorferi genotypes are linked to most cases of disseminated or chronic disease. Clinically, B. afzelii is primarily associated with acrodermatitis chronica atrophicans (ACA), while B. garinii is linked to neurological manifestations. In contrast, arthritis and neuroborreliosis are generally associated with B. burgdorferi sensu stricto^[18]. Moreover, antibodies targeting spirochetal membrane protein epitopes may cross-react with neural and connective tissues, potentially triggering an autoimmune inflammatory response and clinical symptoms due to molecular mimicry¹⁹.

Figure No. 3: Erythema Migrans

CLINICAL FEATURES:

Early Localized Infection:

Lyme disease frequently manifests with a distinct lesion resembling a bull’s-eye or target, referred to as erythema migrans. This rash appears as a uniform, reddish, ring-shaped lesion that may show partial central clearing as the disease progresses. Typically, the lesions exhibit a slow, expanding growth pattern. The central area may develop ecchymosis, and necrosis can occur in advanced cases. Common sites of involvement include the thigh, groin, buttocks, and armpits²⁰. This characteristic rash is often accompanied by flu-like symptoms such as fever, chills, muscle aches, fatigue, headaches, and general malaise, which can arise a few days before the rash develops. The incubation period from the initial infection to the appearance of the erythema migrans rash generally ranges from 7 to 14 days, though it can present as early as 3 days or delayed up to 1 month following tick exposure. Notably, some individuals may be asymptomatic, and approximately 20% might not exhibit the typical skin manifestations. Additionally, many patients present with a mild fever and minimal systemic symptoms. A significant fever may indicate a co-infection with babesiosis. Lyme disease propagates from the tick bite site through cutaneous, lymphatic, and hematogenous pathways¹⁴.

DIAGNOSIS OF LYME DISEASE:

The diagnosis of Lyme disease can frequently be missed, particularly in areas where it is not commonly found, as the distinctive skin lesions may mimic several other dermatological conditions. Due to the vague nature of histological findings, skin biopsies are rarely required for diagnosis, although they may assist in excluding other conditions. Culturing Borrelia burgdorferi in the laboratory poses considerable difficulties, resulting in challenges in confirming its existence within affected tissues. Consequently, diagnosing Lyme disease typically depends on a patient’s history of tick exposure or travel to areas where the disease is endemic, along with clinical signs that are consistent and positive serological tests. Patients in the early stages may recall a tick bite, which highlights the importance of the epidemiological history for accurate diagnosis²¹. Typical laboratory results may show an increased erythrocyte sedimentation rate (ESR), while leukocyte counts and complement levels (C3, C4) usually remain normal or only mildly elevated. Serum transaminases may be elevated, and tests for rheumatoid factor and antinuclear antibodies (ANA) tend to be negative. Additional assessments, such as electrocardiograms, echocardiograms, cerebrospinal fluid (CSF) analyses, and imaging studies, are vital when needed. In instances where characteristic skin lesions are subtle or absent, the examination of cranial neuritis, lymphocytic meningitis, radicular pain alongside dermatomal sensory-motor neuropathy, carditis, or joint swelling may serve as important indicators, necessitating positive serological or immunoblot tests for confirmation. The diagnosis of Lyme neuroborreliosis is deemed definitive when there are compatible neurological symptoms, lymphocytic pleocytosis, and intrathecal antibodies against B. burgdorferi present⁵.

TREATMENT:

Guidelines from the Infectious Diseases Society of America recommend doxycycline as the first-line antibiotic for Lyme disease in nonpregnant patients aged 9 years and older, administered at a dosage of 100 mg orally twice daily. For patients younger than 9 years, amoxicillin is advised at a dosage of 50 mg/kg per day orally, which has proven effective in early-stage infections²². As an alternative for adults, amoxicillin can be given at 500 mg orally three times a day. For individuals with penicillin allergies or those unable to take tetracyclines, cefuroxime axetil (500 mg orally twice daily, or 30 mg/kg per day divided into two doses with a maximum of 2 g/d) or erythromycin (250 mg orally four times a day, or 30-50 mg/kg per day divided into three or four doses with a maximum of 2 g/d) may be prescribed. Oral antibiotic therapy should be maintained for a duration of 14 to 21 days^23,22. Treatment for pregnant patients mirrors that of nonpregnant individuals, although tetracycline should be avoided. The duration of treatment is contingent upon the stage and severity of the infection. Localized skin infections warrant a 14-day treatment period; early disseminated infections require 21 days; acrodermatitis, which is predominantly found in Europe, necessitates 30 days of treatment; and Lyme disease-related arthritis should be treated for 30 to 60 days. Severe late-stage disease, especially with neurologic (neuroborreliosis) or cardiovascular symptoms, necessitates intravenous antibiotic administration (ceftriaxone at 2 g/day, cefotaxime at 2 g every 8 hours, or penicillin G at 5 million units every 6 hours), each for a minimum of 4 weeks. For patients experiencing interventricular delay, oral therapy can commence once high-degree atrioventricular block is resolved and should be continued for at least 30 days. Retreatment may be required in cases of late disease where treatment failures are observed. Approximately 15% of patients may experience a Jarisch-Herxheimer reaction within 24 hours of beginning therapy, characterized by a temporary exacerbation of symptoms such as fever, sweating, chills, headache, and general malaise. This reaction is typically less severe than reactions associated with other spirochete infections. In 1998, a recombinant vaccine named LYMErix (SmithKline Beecham Biologicals, Philadelphia, PA) targeting a Borrelia burgdorferi surface protein (outer-surface lipoprotein A) was developed and recommended for individuals at heightened risk of contracting Lyme disease. However, in February 2002, the manufacturer announced that LYMErix would no longer be available commercially due to low demand, limited efficacy, high costs, and potential concerns regarding its association with autoimmune arthritis or Lyme disease itself, despite insufficient evidence to substantiate these claims. New vaccines are anticipated in the future²⁴.

PREVENTION:

The most effective way to prevent B. burgdorferi infection is to avoid tick bites. Individuals who need to be outdoors in regions where Ixodes ticks are present should wear protective clothing and apply tick repellents containing N, N-diethyl-m-toluamide (DEET). Regular inspection of the skin and timely removal of ticks can also help reduce the risk of infection. Nonetheless, evidence on the effectiveness of these preventive measures is limited. Additional strategies, such as clearing or burning vegetation in tick-infested areas, employing acaricides, and managing deer populations, can lead to reductions of up to 94% in I. scapularis tick numbers. Research indicates that despite awareness of Lyme disease, only 40% to 50% of adults take steps to protect against tick bites. Prompt removal of attached ticks is crucial in preventing Lyme disease. Therefore, a thorough examination of the skin and scalp, particularly in children, is advisable following outdoor activities in areas where the disease is endemic²⁵.

CONCLUSION:

Lyme disease is increasingly recognized outside of its traditional endemic areas. The habitats of tick vectors are expanding to higher altitudes and latitudes, indicating that Lyme borreliosis will likely continue to be a significant health issue in the future. Implementing preventive strategies to reduce the risk of tick bites is regarded as one of the most effective methods to prevent Borrelia infection. Early treatment with suitable antibiotic therapies typically results in a positive outcome for patients, although the possibility of recurrent infection exists. While recent studies have provided insights into how B. burgdorferi avoids detection by the immune system, there remains much to discover. Further research is essential to clarify the specific ways in which B. burgdorferi engages with and circumvents various components of the immune response. A deeper comprehension of how B. burgdorferi undermines the host's immune system is crucial for developing new therapeutic and preventive strategies.

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