The Role of Borrelia Burgdorferi in the Etiology of Chronic Urticaria

Abstract

Background:

Lyme borreliosis/European borreliosis (LB/EB) is a multisystemic infection caused by the bacterium Borrelia burgdorferi, which is transmitted to humans by the bite of ticks and other hematophagous insects. Transmitted borrelia can occupy any organ where it causes a silent inflammation, which in sensitive persons is intermittently repeated chronically.

Objective:

The aim of this paper was to determine how much Borrelia burgdorferii participates in the occurrence of chronic urticaria in children and adults.

Methods:

In the 13-year period from January 1, 2013 to December 31, 2025, a study of all manifestations of Lyme borreliosis was conducted on a sample of 1,059 patients, treated and monitored in the Private practice of an infectious disease specialist. The research was retrospective-prospective, descriptive, clinical and analytical. It was carried out in three phases: the first retrospective phase and the second two prospective phases. The diagnosis of LB was established on the basis of anamnestic-epidemiological data, clinical picture, clinical findings of new borreliosis markers and performed examinations. Serological confirmation of borreliosis was done using ELISA, WB and Immunoblot methods, as well as the ex-yuvantibus method, and in the last six months of 2025, additionally, the finding of bacteria Borreliosis in a dark field with a light microscope.

Results:

The results showed that 92.1% of the patients in the study group had intermittent migratory redness with itching. In the majority of patients, redness was without exudation or with little or no exudation. In 4.8% of patients, typical urticarial changes were found that occurred occasionally or daily. In all subjects, we serologically confirmed the presence of Borrelia burgdorferi. All patients had intermittent itching of the skin, which lasted for years.

Conclusion:

Based on the results, it can be concluded that Borrelia burgdorfrii is one of the most important factors in the development of chronic urticaria in monitored patients with 96.9%. Due to its persistence in the macroorganism, it causes reduced tolerance to food. Only 3.1% of cases of urticaria are caused by some other factors. In all cases of chronic urticaria, new clinical markers should be sought on the patients’ skin. Serologically look for antibodies to Borrelia protein sequences in an immunoblot. In the active phase, look for Borrelia with a light microscope in the dark field. Administer antibiotic therapy together with antihistamines. Exclude food to which the intolerance test confirmed hypersensitivity greater than „2“.

1. BACKGROUND

Lyme borreliosis or European borreliosis (LB, EB) is today the most significant unsolved health problem in the world (1–3). Due to the prevalence of vectors, borreliosis is the most widespread vector-borne disease in the world. The disease is caused by a spirochete bacterium of the genus Borrelia–Borrelia burgdorferii (B.b.), and is transmitted by the bite of ticks and all hematophagous insects. B.b. can occupy every organ and cause inflammation that is intermittently repeated chronically in sensitive people (3). It has been said for years that Borrelia is the greatest imitator, that it can imitate any disease. It is true that, in most cases, Borrelia is the cause of many diseases from different fields of medicine, the etiology of which is unknown (2,3). The prevalence of Borrelia in the world and the possibility of transmission from animals to humans is not the same everywhere; it depends on the biotope, climatic conditions, the proliferation of small rodents, the close connection between man and nature, the genetic hypersensitivity of certain human organs, and possibly some other unknown factors (4,5). The genus Borrelia has a large number of types, but only some are pathogenic for humans. In Europe, the dominant pathogens are B. burgdorferi, B. afzelii and B. garinii (6) For the last 25 years, B. spielmanii types have been equally represented in Southeast Europe, B. bavarienzis is somewhat rarer (3.) In Americas, Borrelia burgdorferii is the only pathogen for humans. In Asia, B. afzeli, B. garinii, B. valasiana, B. japonica are dominant. (1,6). Depending on the genus, Borrelia have a special affinity for certain organs: B. burgdoferi. has a special affinity for joints. B. garinii is found exclusively in Europe and has selectivity for causing encephalitis in the white matter of the brain. B. afzelli has an affinity for the skin and is present at the site of infection, especially in acrodermatitis chronica atrophicans (ACA) (6). Lyme disease occurs in humans in three stages: primary stage–localized infection, secondary stage–early dissemination and tertiary stage–late dissemination–persistent infection (1). The first and second stages represent the acute/subacute form of the disease. The first stage–a skin localized infection occurs in 70% of patients within 5-7 days after a tick bite if Borrelia was transmitted, and it can occur from 3-45 days after the transmission of the bacteria. The third stage is a permanent infection, which in sensitive people has an undulating course and if not recognized and treated, affects organ by organ in a slow course (3).

Erythema migras (EM) is considered the basic clinical diagnostic marker in the transmission of Borrelia from animals to humans. and there is no need for additional laboratory tests (7,8) It occurs in several clinical variants: in stages I and II it has a ring or target-like shape. In stage III, it appears in a round or oval shape with continuous redness, and in the form of dotted red changes (1,9,10,11). In endemic areas, patients with a typical rash can start treatment without waiting for serological testing. New clinical markers that can be found on the skin are white borreliosis striae in about 72.2% of patients, pink borreliosis striae in 24.6% of patients, borreliosis palms and soles in 5.8% of cases associated with the first two, and migrating redness on the skin in 92.1% of cases + typical urticaria that recurs in 4.8% of cases associated with white borreliosis striae (1).

Borrelia can affect any organ and cause different syndromes: neuroborreliosis (CNS, PNS, ANS) borreliosis arthritis, carditis and damage to the conduction system of the heart, scledoderma of different areas can affect all segments of the eye: cause neuritis, conjunctival suffusion, uveitis, retinitis, retinal ablation, (2,3), persistent recurrent inflammation of the external ear canal, tinnitus, cause generalized vasculitis or regional,(10,12) , Epy attacks, MS, M.Parkinson, motor neuron disease, ALS, clonic muscle twitches of different regions, urinary system, various forms of dermatitis on the skin (2,3,10,12–16).

The diagnosis of a chronic disease depends on a clinical assessment based on a comprehensive history, findings of new clinical markers on the skin, and is confirmed by laboratory tests. Enzyme-linked immunosorbent assay (ELISA) and confirmatory WB tests are used to detect Lyme disease immunoglobulin in younger children and young adults, because the specific antibodies they detect are short-lived. (2,3). In older children and adults, it is necessary to perform an advanced Immunoblot test, which detects antibodies to Borrelia protein sequences and, additionally, the detection of Borrelia in a dark field with a light microscope (3).

Microbiological isolation of Borrelia by cultivation or detection of its DNA by PCR method from tissues and body fluids is done rarely or for scientific purposes. The Ex yuvantibus method confirms LB based on the effect of the treatment in cases of false negative results due to Borrelia biofilm coating. (9). Repeated episodes of rash in borreliosis can be experienced by 20% of patients, and multiple lesions are common. Approximately 30% of patients who have a rash do not show further progression of symptoms (1,10).

According to the definition, chronic urticaria is a heterogeneous group of diseases that have in common the formation of urticarial lesions on the skin in the form of swellings/skin plaques that itch or, less often, a burning sensation occurs. Chronic urticaria can be caused by autoimmune inflammation, intolerance to food, medicine, or an infectious disease. During their lifetime, 20% of people develop acute urticaria, while chronic urticaria occurs less often in about 3% of patients.

2. OBJECTIVE

The aim of this research was to investigate how much the spirochete Borrelia burgdorferi can be important in the development of chronic urticaria, which is very widespread in the population of Bosnia and Herzegovina.

3. MATERIAL I METHODS

Study area

This research was conducted in Bosnia and Herzegovina, a country located in Southeast Europe, in order to investigate the progress of knowledge and practice in the diagnosis and treatment of all clinical forms of Borrelia infection.

Studio design

This is a retrospective-prospective clinical study in which the study lasted 13 years, from 2013 to 2025.

Inclusion criteria

This study included patients with borreliosis who had a clinical picture of chronic borreliosis during the year 2025. Inclusion criteria are a) A clear clinical picture of erythema migrans (EM) as a solitary or disseminated form at the first visit to an infectious disease specialist, with normal routine results; b) Positive results of white and/or pink stretch marks in predilection places (groin, underarm, L-S and gluteal part, lower third/half of the back, lateral part of the chest and back and front part of the shoulder, on the back side of the knee and the inner side of the thigh/calf) with data on chronic intermittent complaints from several organs for more than eight months, with regular laboratory findings; and c) Positive results of ELISA/WB/Immunoblot for Borreliae with multiorgan intermittent symptoms or negative results of the same tests at the arrival of the patient, who became positive for Borreliae in 4-6 months during antibiotic therapy.

Exclusion criteria

Exclusion criteria were: a) Patients with evidence of malignancy or blood disease and patients who refused treatment because they received several months/years of biological, corticosteroid or homeopathic therapy; and b) To reduce the risk of hematological abnormalities, pregnancy and malignant tumors were excluded from the study.

Data collection

Patient data were collected, including medical history, clinical findings at the time of visit to the infectious disease specialist, and laboratory results. Routine blood tests (CBC, DCS, GUK, urea, creatinine, CRP, fibrinogen, hepatogram, transaminases, gamma-GT) were performed in all patients, as well as Borrelia serology (ELISA, WB, Immunoblot). Additional tests for immune diseases and thyroid hormone tests were performed as needed. Data were maintained in Microsoft Excel. All patients signed informed consent forms to participate in the study.

Data analysis

Data collected from patients were analyzed using SPSS, and GraphPad prism was used for better visualization of the results. Descriptive statistics, such as means, percentages, and standard deviations, were used to summarize the data.

Ethical approval

This study was approved by the Ethics Committee of the General Hospital „Prim. Dr. Abdulah Nakaš“, Sarajevo, Bosnia and Herzegovina (No. 26-35/23).

4. RESULTS

All patients included in this study had previously undergone diagnostic clinical treatment through medical institutions in the system–state owned institutions. The patients then, after several months or years, reported to a private infectious disease specialist’s office. They felt that they were not taken seriously by their family doctor, that they were not given the right diagnosis by the specialists to whom they were referred because all routine findings were normal, and the disease had progressed. In the end, they were referred to a psychiatrist who treated them as an anxiety-depressive disorder.

A Retrospective and Prospective study (I+II research phase) + III phase of a prospective study was conducted on the distribution of patients with LD based on the appearance of skin changes in the acute, subacute and chronic phases.

Table 2. Skin changes in patients with chronic relapsing symptoms.

Skin changes	Percentage
Migrating erythema nodosum or erythema nodosum	92.10%
White Lyme disease striae	72.20%
Pink Lyme disease striae	24.60%
Lyme disease palms and soles	5.60%
Urticarial generalized changes with marked exudation	4.80%
Seal-like psoriatic changes with scaling and often secondary infection	7.10%
Acrodermatitis chr.atrophicans with white striae borreliosis	2.50%
Erythema nodosa on both lower legs	2.50%
Granuloma annulare	2.50%
Scleroderma circumscripta (Morphae)	2.50%
Vitiligo	2.50%
Alopetia areata	4.80%
Alopetia totalis	2.50%
Lichen striatus et atrophicans extrem. inf.l.dex.	0.80%

Table 1 shows summarized data from the retrospective-prospective study Phase I+II (conducted from 2013 to 2021), and the prospective study Phase III (conducted in 2022-2025), providing insight into the characteristics of patients with Lyme disease.

Table 1. Distribution of Lyme Disease patients in the investigated period from 2013-2025. according to age, gender and duration of the disease.

Characteristics	Number of patients	Number of patients Total number Odrasli			Children
Research phase	I+II Phase	III Phase	I+II+III Phase		120
Patients	509	1095	975		120
Age	28.7(1.8-77.)	39.6 (0.8-89)	34.15(0.8-89)	50,1(18-89)	1.82 (0.4-17)
Sex (M:F)	189:320	247: 339	436:659	365:610	71:49
Duration of illness	8.3 (9 d.- 45 y.)	-	-	8.2 (9 d. - 45y.)	2.2 (0.8-10y)

The average duration of disease across all three phases of the study in adults was 8.2 years (0.8 to 45 years) and in children it was 2.2 years (8 months to 10 years) as shown in Table 1.

Table 4. Relationship between migrating erythema, white borreliosis striae, and pink borreliosis striae in the study group and the control group.

Characteristics	Research group	Control group
EM + white borreliosis striae	92.10%	5%
Pink borreliosis striae	24.60%	10%
White borreliosis striae	72.20%	70.50%

Skin changes in patients with Lyme disease with chronic relapsing symptoms are numerous, and five of them were taken as new clinical markers that are essential for the diagnosis of chronic borreliosis.

The most common observed skin changes, which occur in 92.1% of cases, manifest as redness in the form of small, dotted or larger spots like beaches on the skin. This redness is with little or no pronounced exudation, but always with pronounced itching, so in more pronounced forms, certain parts of the body are covered in scabs. Typical urticarial changes with pronounced exudation were observed in 4.8% of cases and together with migrating redness, they account for 96.9% of changes in the studied group of patients. Urticaria is always characterized by locally raised and inflamed skin with a strong feeling of itching. All patients had negative total IgE antibodies, or rarely slightly above the normal limit. White borreliosis striae were present in about 72.20% of patients, pink in 24.6%, and borreliosis palms and soles in 5.60% of patients. The above data are graphically presented in Figure 1.

Figure 1. Frequency of skin changes in patients with chronic relapsing symptoms of Lyme disease.

Table 3 shows a large number of patients, both adults and children, who contacted an infectious disease specialist during 2025: 147 adults and 20 children, which is more than in previous years. In childhood, the prevalence is boys, and in adulthood there are more women than men, which is the same as in earlier years.

Table 3. Distribution of Lyme disease patients according to age, gender and duration of the disease for the year 2025.

Characteristics	Total number of patients	Adults	Children
Patients	167	147	20
Age	29.7 (1.8-76.)	50.1 (18-76)	9.29 (0.8-16)
Sex (M:F)	70:97	59: 98	11:9
Duration of illness (years)	8.3 (0.1-35)	-	2.6 (0.1-8)

During the year 2025, we treated 20 children on an outpatient basis who came to the office of a private infectious disease specialist for the first time: eight came under the diagnosis of Urticaria, three as suspected EM- Dermatitis, five had a diagnosis of Sy Anxsioso-Depressivum and another five children with individual diagnoses: Nightmare-Somnabulismus, Alopetia areata, Paresis facialis, Epylepsio-Convulsiones, Autismus. The presence of borrelia burgdorferi was confirmed serologically in all of them, as shown in Figure 2.

Figure 2. Distribution of children with previously established diagnoses and subsequently serologically confirmed diagnosis of Morbus Lyme during 2025.

One of the children diagnosed with Suspected EM-Dermatitis was a two-month-old male baby, who was breastfed and in whom the suspicion of vertically transmitted Borrelia from the mother was confirmed serologically. Additionally, Borrelia was found in the serum of both the mother and the baby in the dark field.

5. DISCUSSION

Transmitted Borrelia burgdorferi remains dormant in the human body for a long time, without causing any disturbances in the clinical picture and laboratory findings: CBC and WBC, liver and kidney tests (2,3). When activated, Borrelia initially does not cause any clinical or laboratory disorders. Considering that B.b. has a long biorhythm, the disease develops very slowly, without giving any symptoms in the beginning (1,3). Unlike most other bacteria that spread actively in the skin or soft tissues, B. burgdorferi does not have its own proteases for the degradation of extracellular matrix proteins, but uses human proteases. At the site of a vascular injury, caused by the bite of a tick or other hematophagous insect, this bacterium binds the created human plasmin to itself, in order to use it to destroy the proteins of the host›s extracellular matrix (20). This mechanism of pathogenic „stealth“ gives spirochetes a powerful immune mechanism for undetected spread and invasion (21). In our patients with symptoms of chronic borreliosis, with the involvement of multiple organs and recurrent skin changes, migrating erythema was monitored for several years, although some of them were previously treated with antibiotic therapy for primary EM for 7-15 days. On prescribed antibiotic therapy, these continuous red oval, round, irregular or dotted skin changes disappeared after several months of intermittent antibiotic therapy (1,3). In children, who had primary dissemination of unrecognized and untreated skin borreliosis–Erythema chr.migrans, the therapy also lasted several months intermittently, because the redness recurred. (9). The appearance of walking erythema with itching of the skin always meant the reactivation of chronic persistent borreliosis. (1), In the case of worsening of the disease–relapse in our patients with skin changes, as well as in relapses, the first symptom was most often severe itching of the skin and walking erythema, of various shapes and sizes, before symptoms appeared in other organs, or in the peripheral nervous system, joints, heart, and disturbances of vision, hearing, and urinary tract (1,12).

This is easy to understand if we consider that the spread of Borrelia through the skin and other tissues is facilitated by the binding of human plasminogen and its activators to the surface of the spirochete. (20), because B.b is found in the skin in small blood vessels where it causes vasculitis (10).

In Acrodermatitis ch.atrophicans, the Borrelia spirochete was isolated from skin lesions even 10 years after the onset of the disease (16). One study showed that the infiltrates of T cells and macrophages in such lesions had a restrictive cytokine profile, with little or no production of gamma interferon (21–23), which can explain why the immune system is ineffective in eradicating the spirochete and that skin changes recur.

In order to clarify the pathogenesis of Lyme disease, mechanisms have been described: avoidance of the host›s immune response due to the biofilm and cystic transformation of Borrelia, hiding of B. burgdorferi inside cells due to an error in cellular classification or due to its characteristics, release of inflammatory mediators, formation of antibodies and others (17,18). Electron microscopy has proven that the presence of spirochetes causes changes in phagocytes, which probably leads to an inadequate immune response [23,24]. The results of the aforementioned research are sufficient evidence that borreliosis is a permanent infection in the macroorganism. Borrelia burgdorferi remains in us, as do the viruses HSV, CMV, VZV and others, and in sensitive persons, the reactivation of Borrelia burgdorferi is repeated, i.e. it recurs whenever it is triggered by one of the triggers (3,25,26,27,28).

Patients constantly ask why they have such itching, why some people feel like something is crawling under their skin. If you look at a native preparation of Borrelia in a dark field, you can see that in some patients the Borrelia are very long, twisted like a whip and more mobile than in other patients, similar to a 2-month-old baby with vertical transmission of Borrelia (3). Also, in some patients the native preparation is flooded with Borrelia, in others they are single, not so multiplied and less mobile (3). The unbearable feeling of itching in some patients is probably genetically determined due to skin sensitivity. Etiologically untreated, these patients scratch themselves to the point of bleeding, and constantly have more or less pronounced scabs on the lower legs, upper arms, back. Some patients have a constant feeling of internal cold, without an elevated temperature, and occasionally have shivering that they cannot stop voluntarily. The reason for this may be that borrelia is found in the epithelial cells of the small blood vessels of the skin (10), so they can easily enter the blood stream and, depending on the organ in which it causes vasculitis, it causes characteristic changes. This is how the skin quickly becomes red, and in some cases burning, after a new transmission of Borrelia through a bite, because they trigger and reactivate the old, previously transmitted Borrelia that remained in the epithelial cells of the small blood vessels of the skin. The described migrating redness is actually erythema migrans after the second dissemination. This redness is never ring-shaped, nor does it have the shape of a target, but is always a continuous dotted or spotty redness (1,10). It can be of different shape and size, as a single redness, and more often multiple changes occur on the face, neck, trunk or extremities. Redness in sensitive people occurs every time they are exposed to direct sunlight, in the spring but also throughout the year (1) (personal experience of the author). Strong heat and strong cold are also triggers for the appearance of erythema migrans, such as showering with hot water, sitting next to a heat source, but also severe psychological stress (death of a loved one, divorce, serious illness of a family member, failure in an exam at university), physical stress (complicated broken arm, leg, shoulder dislocation, excessive strain, carrying loads), taking sugar (sweets), alcohol, a lot of coffee, especially on an empty stomach (1,3). Walking erythema resolves on antibiotic therapy, and usually leaves no trace of hyperpigmentation except in rare patients on the lower extremities, such as after the appearance of the first EM after tick/mosquito bites and other hematophagous insects.

Bearing in mind that 30% of the examined adult patients all had a positive food intolerance test for several foods (qualitative and quantitative), that during intermittent antibiotic therapy this sensitivity decreases and disappears, it can be assumed that this is an acquired food intolerance and that it was caused by Borrelia. As we did HLA B27 in a small number of patients, we cannot say how much genetic predisposition is responsible for food intolerance, it is possible that some other unknown factors are involved.

In an earlier study, we confirmed that 80.5% of subjects in the control group had Borrelia, serologically confirmed as a persistent infection without clinical manifestations (1), but only some, probably genetically susceptible patients, had chronic Lyme disease (2,3). If in the investigated group, 92.1% of subjects had atypical migrating erythema, and 4.8% had typical urticaria (1). then the frequency of urticaria in the population of the examined group was 96.9%, which is an incredible figure. This could mean that only 3.1% of our patients› cases of chronic urticaria are caused by other agents such as drugs, pollen, and that the rest are caused by Borrelia burgdorferi!!

6. CONCLUSION

Based on the research results, it can be concluded that:

• Borrelia burgdorfrii is, with 96.9%, one of the most important factors in the development of chronic urticaria.

• Due to its persistence in the macro-organism, it causes reduced tolerance to food and other external allergens.

• Only 3.1% of cases of urticaria in the research group were caused by some other factors.

• In all cases of chronic urticaria, one should look for new clinical markers on the patient›s skin.

• Serologically look for antibodies to Borrelia protein sequences in an immunoblot.

• In the active phase, look for Borrelia with a light microscope in a dark field.

• Administer antibiotic therapy together with antihistamines.

• Exclude food to which the intolerance test confirmed hypersensitivity greater than “2”.

• To improve cooperation between doctors of different specialties and infectious disease specialists.

Patient consent form:

All participants were informed about the subject of the research.

Author's Contribution:

The author has agreed to be responsible for all aspects of the work to ensure that questions relating to the accuracy or integrity of any part of the work are adequately investigated and resolved.

Conflict of interest:

There are no conflict of interest.

Financial support and sponsorship:

None.