| disease | Lyme Disease |
| alias | Lyme Disease |
Lyme disease is a systemic, chronic inflammatory tick-borne spirochetal illness. The initial stage [first stage] of the disease is often characterized by erythema migrans. The condition is typically disseminated, leading to cardiac, neurological, or joint disorders. In 1975, the disease was first identified in a cluster of cases among children in Lyme, Connecticut, USA, from which it derives its name.
bubble_chart Epidemiology
Lyme disease has now been detected in 43 states in the United States and dozens of countries across continents worldwide. However, as of 1989, 97% of the 7,402 reported cases in the U.S. originated from nine states, indicating the disease still has a regional distribution. This distribution is primarily linked to the geographic range of certain hard ticks. The deer tick (Ixodes dammini) is the main vector in the northeastern U.S., from Massachusetts to Maryland, as well as in the Midwest states of Wisconsin and Minnesota. In California and Oregon, the primary vector is the western black-legged tick (Ixodes pacificus). Sporadic cases may be transmitted by the black-legged tick (Ixodes scapularis) or the lone star tick (Amblyomma americanum). Lyme disease is widespread in Europe, from France to Scandinavia and the former Soviet Union, where the castor bean tick (Ixodes ricinus) serves as the primary vector. Cases have also been reported in Australia, Japan, and Africa. In China, patients with Lyme disease have been identified in Heilongjiang, Xinjiang, Anhui, and Jiangsu provinces. A survey of 1,332 individuals in forested areas of Heilongjiang found that among 483 people bitten by ticks, 43 were diagnosed with Lyme disease. The disease occurs primarily from May to August, with a slightly higher incidence in males than females, affecting individuals of all ages, from children to the elderly. On certain islands in the northeastern U.S., the infection rate of ticks with spirochetes can reach 50–100%.
bubble_chart EtiologyIn 1948, Lenhoff discovered spirochetes in skin tissue samples from patients with chronic migratory erythema. A year later, Hellerström proposed that ticks might be carriers of the spirochetes, which could be the causative agents of chronic migratory erythema. In 1981, American microbiologist Burgdorfer dissected 126 Ixodes dammini ticks from Shelter Island near New York, an area endemic for Lyme disease, and found spirochetes in 77 of them, primarily concentrated in the midgut. Infected ticks were transferred to eight New Zealand white rabbits, and within 10–12 weeks, all rabbits developed skin erythema. Serum tests confirmed that all infected rabbits had positive anti-spirochete antibodies. Concurrently, Lyme disease patients were also found to have positive serum antibodies against these spirochetes. Based on these findings, Burgdorfer proposed that the spirochetes isolated from Ixodes dammini ticks might be the causative agents of Lyme disease and named them Borrelia burgdorferi. Subsequently, spirochetes resembling B. burgdorferi were detected in the blood, cerebrospinal fluid, and skin lesions of a few Lyme disease patients. B. burgdorferi was also identified in the synovium and synovial fluid of Lyme arthritis patients, in the eye tissues of Lyme uveitis patients who had undergone enucleation due to blindness, and in the myocardial tissues of patients who died from pancarditis. Similar spirochetes were later isolated from Ixodes ricinus ticks in Switzerland. B. burgdorferi belongs to the genus Borrelia, with a length of 11–38 μm and 7–11 flagella. It is a microaerophilic, catalase-negative bacterium. Obtaining primary isolates from patients' blood or other samples is challenging.
bubble_chart PathogenTicks lay their eggs in dark, damp soil crevices, grass roots, and similar locations. Larvae, nymphs, and adults all rely on blood-sucking for growth and development. Immature ticks often parasitize small animals such as rodents, insectivores, and birds, while adults frequently infest cattle, sheep, horses, dogs, deer, and hares. Ticks become active in spring and begin overwintering in nature or on hosts by autumn. Overwintering in nature occurs in habitats consistent with their living environment, such as the leaf litter layer in forested areas or the burrows of small wild animals and ground cracks. In the forested regions of Heilongjiang Province, China, ticks inhabiting tender leaves on branches or grass often bite people working or passing through the area after the ice melts in early May each year. Spirochetes develop in the midgut of infected ticks. When ticks bite a host, pathogens can be transmitted through the backflow of gut contents containing spirochetes, saliva, or feces.
When an infected tick bites a host, it injects Borrelia burgdorferi into the skin. After local incubation, the spirochete can migrate to the epidermis, forming chronic migratory erythema at the bite site. The spirochete can also enter local lymph nodes via lymphatic vessels and disseminate hematogenously to the eyes, heart, nervous system, joints, and reticuloendothelial system, subsequently spreading to the skin and causing various lesions.
The distinct regional and seasonal distribution and occurrence of Lyme disease, with ticks as the transmission vector and Borrelia burgdorferi as the pathogen; the isolation of spirochetes from patients' blood, cerebrospinal fluid, and affected tissues; the detection of anti-spirochete antibodies in patients' serum and cerebrospinal fluid; and the effectiveness of antibiotic treatment at all stages of the disease suggest that this is an infectious disease and that the pathogen invades and persists in affected tissues throughout the course of the illness.
However, long-term clinical observations reveal that only a minority of patients' cultured specimens and tissues contain the pathogen, creating a discrepancy with the diverse clinical manifestations. Given that patients' serum cryoglobulin-common bletilla tuber complex levels are elevated, certain autoantibodies (such as anti-phospholipid and anti-Fab antibodies) may appear, and some patients experience transient symptom exacerbation after antibiotic treatment, many researchers hypothesize that factors other than infectious agents contribute to the pathogenesis of Lyme disease. The immune system may play the following roles: ① Immune complexes formed by spirochete antigens, antibodies, and complement deposit in patients' joints. Neutrophils phagocytose these immune complexes and release various enzymes, leading to arthritis and damage to joint cartilage and bone. ② Macrophages produce IL-1, participating in immune regulation and exerting nonspecific defense effects. Lipopolysaccharide (LPS), a potent stimulator of IL-1 release, is present in the outer membrane of all Gram-negative bacteria. Borrelia burgdorferi is a Gram-negative bacterium, and LPS has been extracted from its cultures. Injecting the extracted LPS into subjects causes chronic migratory erythema-like rashes at the injection site; intravenous injection of the extracted LPS into rabbits induces fever within hours. Cultured macrophages secrete large amounts of IL-1 when exposed to Borrelia burgdorferi. Injecting rabbits with IL-1, extracted LPS, or Borrelia burgdorferi and performing skin biopsies at the injection sites all show acute inflammatory reactions. When purified spirochete LPS or spirochetes are added to cultured synovial membrane cells from Lyme disease patients, IL-1 is released. Experimental results suggest that fever, chronic migratory erythema, and arthritis in Lyme disease patients are all associated with IL-1 release.bubble_chart Clinical Manifestations
Lyme disease typically begins with chronic migratory erythema as the initial symptom (the initial stage [first stage]), with some patients developing neurological or cardiac manifestations (the intermediate stage [second stage]) and arthritis (the late stage [third stage]). Chronic migratory erythema is the characteristic skin manifestation of the disease, occurring in 75% of patients. It usually appears 3 to 32 days after a tick bite. Initially presenting as an erythematous patch, it gradually expands outward in a circular pattern, with a bright red border and a paler center, appearing flat or slightly raised, smooth, and occasionally with scale. Patients may experience grade I burning and cutaneous pruritus. The center of the rash may sometimes show darker erythema, induration, vesicles, or necrosis. The diameter ranges from 8 to 52 mm, and it can occur anywhere on the body, with the trunk, thighs, groin, and armpits being common sites. The palms, soles, and mucous membranes are rarely affected. Some patients develop secondary chronic migratory erythema days after the initial rash, caused by hematogenous dissemination of the spirochete. These secondary rashes resemble the primary rash but are smaller and multiple. Other skin manifestations in Lyme disease include malar rash, diffuse erythema, or urticaria. Chronic atrophic acrodermatitis usually develops years after onset, initially appearing as red or yellowish rashes, sometimes progressing to sclerotic or atrophic lesions. Early skin manifestations are often accompanied by severe headache, grade I neck stiffness, fever, chills, myalgia, arthralgia, extreme malaise, and fatigue. Less common systemic manifestations include generalized lymphadenopathy, splenomegaly, hepatomegaly, sore throat, irritative cough, proteinuria, testicular swelling, conjunctivitis, iritis, or panophthalmitis. Untreated patients may see early symptoms improve or resolve within weeks.
Approximately 15% of patients develop neurological symptoms simultaneously with the rash or 1 to 6 weeks after its disappearance (or even in those without a rash history). These symptoms include meningitis, cranial neuritis (especially facial nerve palsy and optic atrophy), motor and sensory radiculitis, plexitis, mononeuritis multiplex, chorea, cerebellar ataxia, myelitis, or pseudotumor cerebri (benign intracranial hypertension). These manifestations may occur alone or in combination. Typical cerebrospinal fluid findings include lymphocytic pleocytosis, often with elevated protein. Symptoms may persist for months, but most cases fully recover. Recent reports suggest that Borrelia burgdorferi can cause chronic central nervous system infections, presenting as organic mental syndrome or multiple sclerosis-like syndrome.
Within weeks of onset, about 8% of patients develop cardiac involvement. The most common manifestation is atrioventricular block (first-degree, Wenckebach phenomenon, or complete heart block). Some cases exhibit more diffuse cardiac lesions, such as cardiomyopathy and heart failure, or rare conditions like myocardial hypertrophy or pancarditis. The course lasts only weeks, and most cases recover, though severe cases can be fatal.
Musculoskeletal symptoms in the early stage typically present as migratory pain in joints, tendons, bursae, or muscles, usually without joint swelling, lasting hours or days. About 60% of patients develop joint involvement weeks to 2 years after onset, typically as intermittent monoarthritis of large joints, especially the knees, but also the shoulders, elbows, wrists, hips, ankles, and small joints of the limbs. Monoarthritis or oligoarthritis is most common, though some cases progress to symmetric polyarthritis, with symptoms lasting weeks, months, or even years. In 10% of patients, recurrent arthritis may become chronic, leading to cartilage and bone erosion. Rare cases may develop osteomyelitis, panniculitis, or myositis.
Lyme disease-related eye diseases have become less common. 11% of early-stage patients may develop conjunctivitis. Sporadic ocular lesions are more frequently observed in second-stage or late-stage [third-stage] patients, with clinical manifestations including interstitial keratitis, diffuse choroiditis, panophthalmitis, ischemic optic neuropathy, optic neuritis, papilledema with normal intracranial pressure or pseudotumor cerebri, cortical blindness, and ocular motor paralysis.
There are reports that mother-to-infant transmission of Borrelia burgdorferi can cause congenital infection. Infants born to mothers with Lyme disease have adverse outcomes such as syndactyly, cortical blindness, premature labor, stillbirth, or skin rashes.
Before the disease cause of Lyme disease was determined, clinical diagnosis mainly relied on typical erythema chronicum migrans and epidemiological history. However, diagnosis was more difficult for patients lacking skin rashes but presenting with neurological, cardiac, or joint disorders. The discovery of Borrelia burgdorferi provided specific diagnostic evidence for this disease. However, the detection rate of spirochetes from patient fluids or other specimens was extremely low, making this test unsuitable as a routine clinical diagnostic procedure. Since 1982, international studies have used whole-cell proteins or whole-cell smears of Borrelia burgdorferi as antigens, employing enzyme-linked immunosorbent assay (ELISA) or indirect immunofluorescence (IIF) to measure serum antibodies against Borrelia burgdorferi in patients. The positive rate was 53–67% in early-stage erythema chronicum migrans patients and 90–100% in advanced-stage patients. ELISA was more sensitive than IIF. Measuring serum antibodies against Borrelia burgdorferi has become an essential test for the clinical diagnosis of Lyme disease. Specific IgM antibodies against Borrelia typically peak 3–6 weeks after onset. Specific IgG antibody levels rise more slowly, peaking during the neurological and joint involvement stages and often persisting for a long time. Elevated anti-spirochete antibody levels in the cerebrospinal fluid of patients with chronic meningitis are valuable for diagnosing Lyme meningoencephalitis.
The U.S. Centers for Disease Control and Prevention proposed the following diagnostic criteria for Lyme disease: In endemic areas, erythema chronicum migrans (a single lesion must be at least 5 cm in diameter and confirmed by a physician) or an anti-Borrelia burgdorferi antibody titer ≥1:256, plus involvement of one or more organ systems; in non-endemic areas, erythema chronicum migrans plus an anti-Borrelia burgdorferi antibody titer ≥1:256, or erythema chronicum migrans plus involvement of one or more organ systems, or an antibody titer ≥1:256 plus involvement of one or more organ systems. Meeting any one of these criteria qualifies for a diagnosis of Lyme disease.
bubble_chart Treatment Measures
Choosing appropriate antibiotics and treating early-stage Lyme disease promptly can quickly control symptoms and prevent advanced stage lesions. For early-stage erythema chronicum migrans, the first-line drug for adults is tetracycline, 250mg, taken orally four times daily. Pregnant women, lactating women, and children under 8 years old should be treated with penicillin. For children, the dosage is 30–50mg per kilogram of body weight per day, divided into three doses. For those allergic to penicillin, erythromycin can be used, with children taking 30mg per kilogram of body weight per day, divided into three doses. The treatment course lasts 10–20 days. Approximately 15% of patients may experience a Jarisch-Herxheimer-like reaction within the first 24 hours of treatment. Late-stage [third stage] disease usually requires parenteral antibiotic therapy.
(1) For Lyme carditis, third-generation cephalosporins such as ceftriaxone, 2g daily via intravenous drip, can be used for a 14-day course. Other similarly effective drugs include penicillin, 20 million U daily via intravenous drip for 14 days; amoxicillin 500mg orally three times daily for 14–21 days; or doxycycline 100mg orally twice daily for 14–21 days. Patients with high-grade atrioventricular block or prolonged P–R interval require cardiac monitoring. For complete atrioventricular block or congestive heart failure, adding glucocorticoids may be beneficial if no improvement is observed after 24 hours of antibiotic therapy alone.
(2) For Lyme neuropathies such as facial nerve palsy, oral antibiotic regimens (as mentioned above) can be used for at least 21 days. For Lyme meningitis, ceftriaxone 2g daily via intravenous drip for 14–21 days or penicillin 20 million U daily in divided doses via intravenous drip for 10–21 days is recommended.
(3) For Lyme arthritis, doxycycline 100mg orally twice daily for 30 days; or amoxicillin 500mg four times daily plus probenecid 500mg four times daily for 30 days; or penicillin 20 million U daily in divided doses via intravenous drip for 14–21 days can be used. About 50% of arthritis patients achieve a cure after treatment. Intra-articular steroid injections are not only ineffective for arthritis but may also lead to antibiotic treatment failure. For severe arthritis unresponsive to antibiotics, synovectomy may be successful.
(4) For pregnant patients, in the early stage, amoxicillin 500mg orally three times daily for 21 days is recommended; in the advanced stage, penicillin 20 million U daily via intravenous drip (either as a single dose or in divided doses) for 14–21 days is advised.
(5) Asymptomatic individuals with positive serum antibodies do not require treatment.
Initially, the clusters of Lyme disease cases in children in Lyme town were misdiagnosed as juvenile wind-dampness arthritis. Based on the seasonal and regional occurrence of Lyme disease, the early appearance of chronic migratory erythema, arthritis duration generally less than 6 weeks, negative serum wind-dampness factors, positive specific anti-Borrelia burgdorferi antibodies, and responsiveness to antibiotic treatment, Lyme disease can be distinguished from juvenile inflammatory wind-dampness arthritis. Adult Lyme arthritis primarily affects large joints, exhibits symmetric distribution, lacks morning stiffness, shows rare bone erosion, has negative wind-dampness factors, and an increased frequency of HLA-DR4. These characteristics contrast with those of wind-dampness arthritis, which involves both large and small joints of the limbs symmetrically, presents with morning stiffness, frequent bone erosion, negative wind-dampness factors, and an increased frequency of HLA-DR4, allowing for differentiation.
Both Lyme disease and syphilis involve skin, heart, nervous system, and joint lesions, and due to shared antigenicity between Borrelia and Treponema pallidum, syphilis patients may also exhibit cross-reactive antibodies against Lyme disease spirochetes. However, a negative syphilis serological test result aids in distinguishing Lyme disease from syphilis.
