Clinical Manifestations of Borrelia Species Infections

Borrelia species are responsible for multiple zoonotic diseases transmitted to humans via ticks, particularly Ixodes species. The most prominent among these are Lyme borreliosis (LB) and tick-borne relapsing fever (TBRF). Emerging infections like Borrelia miyamotoi disease also contribute to the expanding clinical spectrum. The geographic distribution of Borrelia species significantly influences the clinical manifestations of these diseases.

Lyme Borreliosis (LB)

Lyme borreliosis is the most common vector-borne disease in the Northern Hemisphere. It is caused by several Borrelia species, mainly Borrelia burgdorferi sensu lato, B. afzelii, and B. garinii. Each of these species presents unique clinical characteristics and epidemiology. The disease progresses through three distinct stages: early localized, early disseminated, and late disseminated. Each stage exhibits specific symptoms that may vary depending on the infecting species.

Cutaneous Manifestations

Erythema Migrans (EM)

The earliest and most recognized manifestation of Lyme disease, erythema migrans, occurs at the site of the tick bite. This rash develops in approximately 70-80% of patients, typically within 3-30 days of infection. EM is often described as a “bull’s-eye” lesion, with a red, expanding center. In Borrelia burgdorferi sensu stricto infections, this is the hallmark of early Lyme disease. However, EM can be absent or atypical in certain cases, particularly in Borrelia afzelii infections.

Acrodermatitis Chronica Atrophicans (ACA)

ACA is a rare, late-stage skin manifestation associated primarily with Borrelia afzelii in Europe. This progressive skin condition can lead to significant tissue atrophy and scarring, usually seen in the extremities. It often develops months or even years after initial infection and is more common in elderly individuals.

Musculoskeletal Manifestations

Lyme Arthritis

A prominent feature of late-stage Lyme borreliosis, Lyme arthritis commonly involves large joints, especially the knees. In North American cases caused by Borrelia burgdorferi sensu stricto, this can manifest as a recurring or persistent form of arthritis, with joint effusion and swelling being common signs. Patients may experience significant discomfort but usually respond well to antibiotics. Untreated cases, however, can lead to chronic joint damage.

Joint Effusion

Persistent joint effusion is particularly common in Borrelia burgdorferi infections, where swelling in the synovial fluid leads to noticeable joint enlargement, often without much pain. This is a key differentiator in diagnosing Lyme arthritis as opposed to other arthritic conditions.

Neurological Manifestations

Neuroborreliosis

One of the more severe manifestations of Lyme disease is neuroborreliosis, which occurs when the Borrelia spirochete infects the nervous system. B. garinii, prevalent in Europe, is most commonly associated with this condition, making neuroborreliosis more common in Europe than in North America.

Meningitis

Inflammation of the membranes surrounding the brain and spinal cord, leading to headaches, fever, and stiff neck, is a common presentation. In untreated cases, this can progress to more severe neurological deficits.

Encephalopathy

Cognitive impairments, including memory loss and difficulty concentrating, are characteristic of Lyme encephalopathy. This manifestation may persist even after antibiotic treatment, contributing to the controversy surrounding post-treatment Lyme disease syndrome.

Peripheral Neuropathy

Patients with neuroborreliosis can also experience peripheral nervous system involvement, characterized by numbness, tingling, or burning sensations in the extremities. This is due to inflammation of the peripheral nerves and can lead to significant disability if untreated.

Cranial Nerve Palsies

Facial nerve palsy, often affecting the seventh cranial nerve, is a hallmark of early Lyme neuroborreliosis, especially in children. Bilateral facial nerve palsy is highly suggestive of Lyme disease, though it can occur unilaterally as well.

Cardiac Manifestations

Lyme Carditis

Lyme carditis occurs in approximately 1-5% of Lyme disease cases, and it primarily manifests as atrioventricular (AV) block. This condition is particularly concerning because it can progress rapidly to high-degree AV block, requiring temporary pacemaker insertion if not promptly diagnosed.

Ocular Involvement

Conjunctivitis, Keratitis, Uveitis

Ocular manifestations of Lyme disease are rare but can include conjunctivitis in early infection and keratitis or uveitis in later stages. Uveitis, an inflammation of the middle layer of the eye, can cause vision disturbances and may lead to more serious complications if untreated.

Tick-Borne Relapsing Fever (TBRF)

Tick-borne relapsing fever is another significant disease caused by various Borrelia species, including Borrelia hermsii and Borrelia duttonii. TBRF is primarily seen in regions where soft ticks (Ornithodoros species) are present. The disease is characterized by recurring episodes of fever due to the unique ability of Borrelia to evade the immune system through antigenic variation.

Recurrent Fever

Cyclical Fever Spikes

A hallmark of TBRF is the periodic recurrence of fever, which typically follows a 3–7-day cycle. During febrile episodes, Borrelia spirochetes are detectable in the blood, but they decrease to undetectable levels as the fever subsides. The spirochetes alter their surface proteins to evade the host’s immune response, allowing them to persist and cause recurrent illness.

Neurological Involvement

Meningitis

In severe cases of TBRF, especially in immunocompromised patients, the infection can invade the central nervous system, leading to meningitis and altered mental status. This is often accompanied by severe headaches, photophobia, and neck stiffness.

Hematological Issues

Anemia and Thrombocytopenia

High levels of spirochetes in the bloodstream can lead to hematological abnormalities, including anemia, thrombocytopenia (low platelet count), and leukopenia. These conditions are often seen during the febrile episodes of TBRF​.

Complications

Hepatosplenomegaly

Enlargement of the liver and spleen, or hepatosplenomegaly, is a common complication of TBRF, especially in children. This occurs due to the body’s immune response to the high spirochetemia seen during the disease. Myocarditis and end-organ damage can also occur in severe cases, contributing to the morbidity of the disease.

Borrelia miyamotoi Disease

Borrelia miyamotoi is an emerging pathogen that shares similarities with both Lyme borreliosis and tick-borne relapsing fever (TBRF). It was first identified in 1995 and has since been recognized as a distinct species, causing a disease with symptoms resembling both Lyme disease and relapsing fever. Unlike Borrelia burgdorferi, which primarily causes Lyme borreliosis, Borrelia miyamotoi is more closely related to relapsing fever Borrelia species, though transmitted by the same Ixodes tick vectors.

Clinical Presentation

Patients infected with Borrelia miyamotoi typically present with a non-specific flu-like illness, characterized by fever, chills, fatigue, headache, and muscle pain. Symptoms often resemble early Lyme borreliosis but without the characteristic erythema migrans rash. The absence of this hallmark symptom can delay diagnosis, making laboratory confirmation crucial.

Recurrent Fever

One of the key differences between Borrelia miyamotoi infection and Lyme disease is the presence of recurring fever spikes, similar to tick-borne relapsing fever. This is caused by the organism’s ability to undergo antigenic variation, allowing it to evade the host’s immune system and cause recurrent febrile episodes​.

Neurological Involvement

In rare cases, Borrelia miyamotoi can cause meningoencephalitis, particularly in immunocompromised patients. This severe form of the disease may lead to altered mental status, headaches, and stiff neck, mimicking the central nervous system involvement seen in neuroborreliosis caused by Borrelia burgdorferi. Diagnostic challenges often arise due to overlapping symptoms with other tick-borne infections.

Immunocompromised Patients

Patients with weakened immune systems are at greater risk of developing severe disease, including prolonged relapsing fever and neurological complications. These patients may also be more likely to experience chronic symptoms, such as fatigue and cognitive disturbances, after the acute infection has resolved.

Geographical Distribution and Epidemiology

Although first described in Japan, Borrelia miyamotoi infections have been documented across the Northern Hemisphere, including Europe, North America, and parts of Russia. The geographic distribution of Borrelia miyamotoi overlaps with that of Ixodes ticks, which are also vectors for Lyme disease. Infected ticks can transmit multiple pathogens simultaneously, leading to co-infections that complicate clinical presentation and management.

Geographical and Species-Specific Manifestations

The clinical presentation of Borrelia infections varies significantly depending on the geographic region and the specific Borrelia species involved. The following sections will explore the regional variations in disease manifestations and the reasons for these differences.

European Lyme Borreliosis

Neuroborreliosis

In Europe, neuroborreliosis is more common due to the prevalence of Borrelia garinii, a species known to have a neurotropic affinity. Symptoms include facial palsy, meningitis, and peripheral neuropathy. Acrodermatitis chronica atrophicans (ACA), caused primarily by Borrelia afzelii, is also more common in European populations​

Chronic Skin Conditions

In addition to ACA, European patients may experience other chronic skin conditions associated with Borrelia infections, such as borrelial lymphocytoma. This condition is characterized by a benign proliferation of lymphoid tissue, typically presenting as a bluish-red swelling near the site of the tick bite​.

North American Lyme Disease

Lyme Arthritis

In North America, Borrelia burgdorferi sensu stricto is the predominant species, and Lyme arthritis is the most common late-stage manifestation. It typically affects large joints, such as the knees, and can result in long-term joint damage if not treated​.

Lower Incidence of Neuroborreliosis

Neuroborreliosis is less common in North American Lyme disease compared to Europe, likely due to the differences in Borrelia species. When it does occur, the most common neurological manifestation is facial nerve palsy, often unilateral.

Co-Infections and Mixed Manifestations

Co-infections with other tick-borne pathogens significantly complicate the clinical presentation, diagnosis, and treatment of Borrelia infections. These co-infections occur when a tick transmits multiple pathogens to the human host during a single bite, leading to overlapping or more severe symptoms. Common co-infections include Anaplasma phagocytophilum, Babesia microti, and Ehrlichia chaffeensis, which can modify the clinical course of Lyme borreliosis or relapsing fever and contribute to a more chronic or severe illness.

Anaplasma Co-Infection

Anaplasmosis, caused by Anaplasma phagocytophilum, is a bacterial infection transmitted by the same Ixodes ticks that carry Borrelia species. This co-infection is common in North America, particularly in regions where Lyme disease is endemic, such as the northeastern United States and parts of Europe.

Clinical Impact

Patients co-infected with Anaplasma and Borrelia often present with more severe systemic symptoms, including high fever, chills, headaches, and myalgia. This can lead to diagnostic confusion as these symptoms overlap with early Lyme disease. Additionally, Anaplasma infection can suppress the immune response, making it more difficult for the body to clear Borrelia, which may lead to more persistent or relapsing forms of Lyme disease.

Hematologic Complications

Anaplasma infection often results in hematologic abnormalities, including leukopenia (low white blood cell count), thrombocytopenia (low platelet count), and elevated liver enzymes, complicating the clinical picture. These features can help differentiate co-infection from a typical Lyme disease presentation.

Babesia Co-Infection

Babesiosis is a parasitic infection caused by Babesia microti, a protozoan that infects red blood cells and is transmitted by Ixodes ticks. Co-infection with Babesia and Borrelia is particularly problematic because Babesia affects the red blood cells, while Borrelia impacts multiple organ systems, including the joints and nervous system.

It is important to note that different regions of the world have distinct species of Babesia, making accurate diagnosis nearly impossible without microscopic examinations by local laboratories and hospitals.

Clinical Impact

Babesia co-infection increases the severity of symptoms in patients with Lyme borreliosis. Common symptoms of babesiosis include fever, chills, sweating, fatigue, and hemolytic anemia. When co-infected with Borrelia, patients may experience an exacerbation of these symptoms, along with more intense fatigue, muscle pain, and cognitive disturbances.

Immune Suppression and Disease Persistence

Babesia co-infection is associated with immune suppression, particularly in patients who are immunocompromised or have had a splenectomy. This immune suppression allows Borrelia to persist longer in the host, making the infection more difficult to eradicate and potentially leading to chronic symptoms such as fatigue and joint pain even after treatment.

Diagnosis and Treatment Challenges

Diagnosing Babesia co-infection can be challenging because the symptoms often mimic those of Lyme disease. Blood smears and PCR testing are required to identify Babesia microti. Treatment for babesiosis typically involves a combination of atovaquone and azithromycin, but patients co-infected with Lyme disease often require additional antibiotics such as doxycycline for the Borrelia infection.

Ehrlichia Co-Infection

Ehrlichiosis, caused by Ehrlichia chaffeensis, is another tick-borne infection that often co-occurs with Lyme disease. This intracellular bacterial pathogen primarily infects white blood cells and can cause a range of symptoms, from mild fever and headache to severe multi-organ failure in immunocompromised individuals.

Clinical Impact

Patients co-infected with Borrelia and Ehrlichia may experience more acute onset of symptoms, including high fever, muscle pain, headaches, and gastrointestinal symptoms like nausea and vomiting. Severe cases can lead to renal failure, respiratory distress, and sepsis-like syndromes.

Diagnostic Considerations

Co-infection with Ehrlichia complicates the diagnosis of Lyme borreliosis due to overlapping symptoms. Serological testing and PCR for Ehrlichia DNA are necessary for confirmation. Treatment usually involves doxycycline, which is effective against both Borrelia and Ehrlichia species.

Immune Suppression and Persistent Borrelia Infections

The presence of co-infections can modify the host immune response, allowing Borrelia to evade the immune system more effectively. This is due to several factors:

Immunomodulation by Co-Infecting Pathogens

Co-infecting pathogens, such as Babesia and Anaplasma, can alter the immune system’s response, leading to a suppressed or delayed immune reaction. This makes it harder for the host to clear Borrelia from the system, increasing the likelihood of chronic or relapsing disease​.

Altered Pathogen Dynamics

Co-infections can lead to altered pathogen dynamics, where one pathogen facilitates the persistence of another. For example, Babesia infection can lead to long-term parasitemia, which in turn creates a favorable environment for Borrelia to evade the immune system and persist for extended periods.

Chronic Neuroborreliosis

Patients co-infected with neurotropic pathogens like Borrelia garinii and Anaplasma or Babesia are at higher risk for developing chronic neurological symptoms. These may include persistent headaches, cognitive dysfunction, mood disturbances, and peripheral neuropathies.

Reported Symptoms

This is a list of common symptoms reported by individuals with infections.

Cardiovascular Symptoms

• Anemia
• Chest pain
• Elevated blood pressure
• Heart block on EKG
• Heart murmurs
• Heart palpitations or extra beats
• Low blood pressure
• Mitral valve prolapse
• Vasculitis (inflamed blood vessels)

Gastrointestinal Symptoms

• Abdominal pain, cramps
• Anorexia
• Bloating
• Constipation
• Frequent heartburn
• Frequent need to urinate
• Irritable bladder
• Reflux (acid reflux, GERD)
• Upset stomach, nausea, vomiting

Ear and Eye Symptoms

• Buzzing, clicking, or ringing in ears
• Conjunctivitis
• Decreased hearing in one or both ears
• Double or blurry vision
• Dry eyes
• Eye floaters
• Flashing lights
• Pain in ears without a clear cause
• Eye pain
• Pressure in eyes
• Sensitivity to sound
• Tearing eyes
• Vision loss or blindness

Skin and Infections

• Any type of rash
• Frequent infections (sinus, kidney, yeast, bladder, etc.)
• Cracks around the sides of the mouth
• Itching
• Low body temperature
• Scalp rash
• Sore soles
• Swollen glands

Respiratory and ENT Symptoms

• Difficulty swallowing
• Drippy nose (unexplained)
• Hoarseness
• Persistent head congestion
• Sore throat
• Shortness of breath, “air hunger”

Systemic Symptoms

• Extreme or persistent fatigue
• Malaise
• Night sweats (drenching)
• Unexplained chills
• Unexplained fevers
• Unexplained sweating
• Unexplained weight gain or loss
• Increased sensitivity to allergens
• Painful gums

Musculoskeletal Symptoms

• Aches or burning in palms or soles of feet
• Arthritis or arthritis-like symptoms
• Back pain
• Bone sensitivity, especially the spine
• Creaking, popping, or cracking joints
• Foot pain (ankle, heel, plantar fasciitis)
• Generalized muscle pain and tenderness
• Joint pain or swelling
• Joint stiffness, especially in the back or neck
• Muscle pain or cramps
• Rib soreness
• Shin splints
• Pain or swelling that moves to different joints

Neurological and Cognitive Symptoms

• Abnormal blood flow in the brain
• Abnormalities in taste or smell
• Aggression, rage, road rage
• Becoming lost in familiar places
• Bipolar disorder
• Burning or stabbing pains
• Clumsiness
• Cold or heat intolerance
• Confusion
• Declining performance at school or work
• Dementia
• Depersonalization
• Difficulty falling or staying asleep
• Difficulty walking
• Diminished reflexes
• Disorientation
• Distorted memory
• Dizziness
• Dyslexia (letter, number, or word reversals)
• Easy frustration
• Facial paralysis (usually one side)
• Fainting
• Forgetting how to perform simple tasks
• Gait disturbance
• Going to the wrong place (disorientation)
• Headache (persistent, severe, intermittent)
• Increased motion sickness
• Long-term memory loss
• Mood swings, irritability
• Muscle weakness
• Napping during the day
• Numbness in parts of the body or extremities
• Obsessive-compulsive behavior
• Odor or taste hallucinations
• Overly emotional reactions (crying easily)
• Panic or anxiety attacks
• Paranoia
• Pins and needles
• Poor balance
• Pressure in the head
• Psychosis-like disorders
• Restless legs syndrome
• Seizures
• Sensitivity to light
• Short-term memory loss
• Sleeping too much
• Speech difficulty (slurred, slow, or hesitant)
• Stammering or stuttering
• Stiff or painful neck
• Sudden lightning-like jabs
• Suicidal thoughts
• Tingling sensations (like insects crawling on skin)
• Tremors or unexplained shaking
• Trouble finding the right word
• Twitching of facial muscles
• Muscle twitching
• Unusual depression
• Visual or auditory hallucinations
• Weakness or partial paralysis
• “Brain fog” (difficulty concentrating, inattention)

Reproductive and Sexual Health Symptoms

• Loss of sex drive
• Sexual dysfunction
• Testicular or pelvic pain
• Unexplained breast or nipple pain, discharge
• Unexplained menstrual pain, irregularity, flooding