1. Introduction
Globally, tick-borne infections (TBIs) are increasingly recognized as an important cause of zoonotic diseases [
1]. In fact, tick-derived pathogens contribute to the bulk of vector-borne infections in Europe, Asia, and the temperate regions of North America [
2]. Global warming is a significant driver of tick population growth, enabling their migration to higher altitudes and latitudes [
3,
4,
5]. With the exception of Lyme borreliosis, tick-borne diseases are sometimes overlooked among vector-borne diseases [
1]. Complex vector–pathogen–host interactions make an estimation of the national incidence challenging [
5,
6,
7]. Tick-borne diseases can be concentrated in rural or agricultural settings [
5,
7], which might not receive adequate public health attention [
1]. With a broad spectrum of microorganisms within ticks [
6,
7], further research into TBIs is crucial to improve diagnosis, treatment, and eradication.
The focus of research has mainly centered around the
Borrelia burgdorferi sensu lato complex, which causes Lyme disease; the most prevalent tick-borne disease world-wide [
3,
4]. Within the
B. burgdorferi sensu lato complex, the main pathogenic species are
B. burgdorferi sensu stricto and
B. mayonii in North America, and
B. afzelii and
B. garinii in Europe and Asia [
8]. More recent surveillance data from the US estimated that 476,000 patients were treated for Lyme disease annually from 2010 to 2018 [
9]. Within Europe, a systematic review by Vandekerckhove and colleagues [
10] discovered a rising trend in the national incidence of Lyme disease in Norway and Finland. In another study, three countries, Switzerland, Belgium, and the Netherlands, recorded a national incidence of more than 100 per 100,000 population per year [
7]. Limited data are available from countries such as Ireland, Portugal, and Spain [
7,
10]. A retrospective cohort study by Forde and co-workers [
11] from 2012 to 2016 estimated the incidence to be 1.15 per 100,000 population per year for those between the ages of 2 and 18 in Ireland. In Ireland, the national incidence of tick-borne illnesses, such as Lyme disease, can be hard to estimate, as only Lyme Neuroborreliosis is a notifiable disease [
12]. There were four notifications in 2021 in Ireland and the national neuroborreliosis notification rate is 0.08 per 100,000 population [
12].
Lyme disease symptoms can be categorized as early localized, early disseminated, or late disseminated [
13]. Initial symptoms of Lyme borreliosis usually appear 2–30 days after a tick bite [
5]. Constitutional symptoms such as fever, malaise, muscle and joint aches, and
erythema migrans rash, are described in the early stages of the disease [
2,
4,
7,
8,
13]. An
erythema migrans rash is a circular or ovoid erythematous lesion with a central clearing that resembles a target sign. It develops on average 7 days after a tick bite, but studies have reported the appearance of
erythema migrans from 1 to up to 36 days after a Borrelia infection [
8,
14]. While
erythema migrans is a classic sign of Lyme disease, it is not seen in all patients [
4,
7,
8]. The early-disseminated stage usually begins within days to weeks and can manifest as multiple
erythema migrans, Lyme carditis, or neurological deficits [
4,
7,
8,
13]. Bannwarth syndrome, a meningoradiculoneuritis due to Lyme neuroborreliosis, is one of the most common disease manifestations after
erythema migrans [
8,
15,
16]. Lyme carditis can lead to complications like atrioventricular blocks, including third-degree heart blocks, which can be fatal if untreated [
8,
17]. Lyme arthritis is among the most common late symptoms of Lyme disease [
8]. Another late manifestation of Lyme borreliosis is
acrodermatitis chronica atrophicans, a bluish-red dermatological discoloration of the extremities that can lead to tissue atrophy if untreated [
18].
The diagnosis of Lyme disease is aided by clinical manifestations, such as
erythema migrans and a positive patient history of exposure to tick-endemic areas or tick bites [
8]. Careful evaluation is advised, as several publications have found that only about 14–32% of patients in the US recalled receiving a tick bite, and some patients do not present with
erythema migrans [
4,
7,
8,
14]. Serological testing with a standard or modified two-tier testing protocol can support a diagnosis. Standard two-tier testing involves an initial enzyme immunoassay and the subsequent utilization of Western blotting [
8]. In the modified two-tier testing protocol, two enzyme immunoassays are used [
8]. Both immunoassays need to be positive to support the diagnosis of Lyme disease [
8]. The modified two-tier testing protocol is more sensitive at detecting early infections and less labor-intensive [
8].
Ticks can concurrently carry other Borrelia subspecies or microbes in addition to
B. burgdorferi [
19,
20,
21,
22,
23]. Rickettsiosis, Ehrlichiosis, Babesiosis, and Bartonellosis are other notable TBIs [
2,
6]. An important consideration is that infections with these pathogens give rise to vague and non-specific symptoms, unlike
erythema migrans with Lyme disease [
6]. Clinical presentations cannot reliably distinguish co-infections from mono-infections or uninfected patients [
24]. In the eastern United States, the majority of tick-borne co-infections are Lyme disease and human babesiosis, which can have confounding impacts on the disease course and severity [
6,
14,
21,
23]. Co-infections with both
B. burgdorferi and
B. microti can increase the duration and severity of Lyme disease in the early phase of illness [
6].
B. burgdorferi and
B. microti also have a synergistic relationship that causes the higher parasitemia of
B. microti in mice [
6]. Another study in Switzerland found co-infections of
B. burgdorferi with the spotted fever group Rickettsiae [
25]. These patients are more likely to present with non-specific symptoms, such as myalgia and fatigue. The authors recommended co-infections to be ruled out during diagnosis, especially in endemic areas [
25].
The antibiotic treatment for Lyme disease is determined by multiple factors, such as age, antibiotic tolerance and hypersensitivity, the type of symptoms, and the presence of co-infections [
8,
26,
27]. Doxycycline, amoxicillin, or cefuroxime are all recommended for the first-line treatment of Lyme disease [
26,
27]. However, using combination antibiotics to treat long-term Lyme disease symptoms is controversial [
16,
28]. Debilitating chronic symptoms, such as pain, fatigue, and neurological symptoms, can arise from a Lyme borreliosis infection [
26,
29,
30]. One possible cause is persistent
B. burgdorferi infection, as the bacteria possess immune-evasion mechanisms, such as hindering complement activation and phagocytosis [
29], existing as metabolically inactive forms like round bodies, and bacterial biofilm creation [
31]. Prolonged inflammation, autoimmunity, or permanent physiological damage from an infection are other proposed mechanisms for chronic symptoms [
26,
30]. Post-treatment Lyme disease syndrome has been used to describe the chronic symptoms that persist even with antibiotic treatment, and without clinical or laboratory evidence of infection [
26,
28]. The most widely debated hypothesis is “Chronic Lyme disease (CLD)”, which shares many similarities with post-treatment Lyme disease syndrome. There are two categories proposed for CLD: untreated CLD (CLD-U) and previously treated (CLD-PT), where the latter demands that CLD symptoms remain present continuously or in a relapsing/remitting pattern for a period of six months or more after therapy [
32]. To date, there is no consensus on the suitability and duration of antibiotic treatment for the chronic symptoms of Lyme disease [
16,
28].
Given the increasing global prevalence of tick-borne illnesses, further research could help improve the management of infections and co-infections. Currently, there is a lack of updated research on the incidence of different TBIs within Ireland. In this study, we aimed to investigate the types of TBIs and symptoms within a cohort of 301 patients from an Irish infectious disease clinic. We categorized the types of single and multiple tick-borne infections faced in this cohort. Secondly, we investigated the efficacy and safety of using prolonged combination antibiotics for relieving chronic symptoms in this cohort. We focused on the most common symptoms faced by this patient cohort: muscle and joint pain, fatigue, and neurological symptoms.
4. Discussion
Our findings (
Table 2 and
Table 3) support the notion that infection from the
Borrelia burgdorferi species is the most predominant TBI in Ireland, with most of the antibody-positive cases (59.29%) in this cohort being solely infected with Borrelia. A total of 42 out of 140 patients (30.00%) had co-infections of Borrelia with other TBIs, such as Babesia, Bartonella, Ehrlichia, and Rickettsia. This is notable, as earlier publications have established that co-infections with Ehrlichiosis and Babesiosis can complicate the disease course and treatment [
6,
14,
21,
23]. Furthermore, past research has also noted that
B. burgdorferi can cause immune dysfunction and hinder the development of IgG-producing plasma cells [
47]. One study also demonstrated that
B. burgdorferi has immunosuppressive effects, as mice who were infected had less capability to produce antibodies against influenza [
47]. Immune system derangements in TBIs could also impact the pathogenesis of tick-borne co-infections, as seen in the synergistic relationship between
B. burgdorferi and
B. microti co-infections, which cause higher serum levels of
B. microti in mice [
6]. It is important to consider and test for co-infections, especially in endemic areas and for those with unusual non-specific symptoms, or abnormal investigation results [
25,
27].
From our first assessment questionnaire results, only 52.14% of all the antibody-positive patients recalled receiving a tick bite. Some publications from the US found that only about 14–32% of patients recalled a tick bite [
14]. Additionally, our questionnaire showed that 46.43% of the patients did not experience a bull’s-eye rash, and 22.14% were unsure if they had developed a rash. Only 28.57% of all the antibody-positive patients could confirm they had a rash. From the past literature,
erythema migrans are not seen in all patients [
4,
7,
8]. Our study thus highlights the importance of not relying solely on a positive tick bite or positive
erythema migrans to consider a Lyme disease diagnosis.
Based on this patient cohort, we believe there is merit in using prolonged combination antibiotics to relieve the lingering symptoms from TBIs. For this patient cohort, the three most commonly reported patient symptoms were pain, fatigue, and neurological symptoms, such as a tingling sensation in the limbs and memory defects. These three symptoms were among the most reported persisting symptoms by others [
26,
30]. A total of 94.06% of the patients who returned to the clinic at both T1 and T2 had been prescribed three antibiotics, and the remaining 5.94% were given two antibiotics from T0 to T2. Although current guidelines by the IDSA (Infectious Diseases Society of America) and ILADS (International Lyme and Associated Diseases Society) sometimes differ on the optimum duration of antibiotic treatment, both do not recommend treatment beyond 6 weeks without clinical reassessment [
27,
48]. These guidelines also recommended single antibiotic treatment for Lyme disease in most circumstances [
27,
48]. Earlier studies were inconclusive for determining the efficacy of long-term combination antibiotics [
16,
28]. However, our study illustrated that treatment with prolonged combination antibiotics is effective and has a good safety profile (
Supplementary Materials, Table S1). From the results of our questionnaire, many patients had a general improvement in symptom severity from T0 to T1 and subsequently from T1 to T2. We also demonstrate a statistically significant difference in the incidence of pain and neurological symptoms between T1 and T2. Most antibody-positive patients who returned for both follow-ups tolerated the prolonged use of combination antibiotics, and only two (1.98%) discontinued the antibiotic treatment. Other publications have also found combination antibiotics effective in clearing persister forms of
B. burgdorferi [
49]. Current guidelines should consider prolonged combination antibiotics as a treatment for Lyme disease and co-infections.
This study was a retrospective analysis of patients presenting in a clinical setting who were prescribed, on a case-by-case basis, an antibiotic regimen. With close monitoring, the individuals were assessed with regards to antibiotic tolerability, allergies, safety, and potential efficacy. As this was a preliminary study to highlight treatment safety and the improvement in patient well-being and symptoms, further research should be conducted to find the most effective combination antibiotic regimen for the various clinical manifestations of Lyme disease.
We discovered no statistically significant difference in the incidence of fatigue between T1 and T2. An earlier randomized controlled trial of 55 patients with severe fatigue 6 months after antibiotic treatment for Lyme disease by Krupp and colleagues [
50] showed that IV ceftriaxone for 28 days improved symptoms. In our study, we used the incidence of fatigue, instead of assessing the reduction in fatigue severity, with a 11-item questionnaire like Krupp and colleagues [
50]. Another difference is the route of administration, as patients were managed in an outpatient setting and were not given IV antibiotics. This could mean that fatigue is a chronic symptom of Lyme disease that requires specific management and a more sensitive assessment tool to monitor treatment effect.
A limitation of this study is the lack of validated patient-reported symptom questionnaire specific for Lyme disease or other tick-borne infections. Our questionnaires were created based on the existing research literature on the common clinical manifestations of Lyme disease and the clinical experience of specialists in this area. Using the questionnaires to monitor patient-reported symptoms, our study assessed the most important clinical symptoms in our patient cohort.