Lyme disease, or Lyme borreliosis, is an emerging infectious disease caused by at least three species of bacteria belonging to the genus Borrelia. Borrelia burgdorferi sensu stricto is the main cause of Lyme disease in the United States, whereas Borrelia afzelii and Borrelia garinii cause most European cases. The disease is named after the town of Lyme, Connecticut, USA, where a number of cases were identified in 1975. Although Allen Steere realized Lyme disease was a tick-borne disease in 1978, the cause of the disease remained a mystery until 1981, when B. burgdorferi was identified by Willy Burgdorfer.
Lyme disease is the most common tick-borne disease in the Northern Hemisphere. Borrelia is transmitted to humans by the bite of infected ticks belonging to a few species of the genus Ixodes ("hard ticks"). Early symptoms may include fever, headache, fatigue, depression, and a characteristic circular skin rash called erythema migrans. Left untreated, later symptoms may involve the joints, heart, and central nervous system. In most cases, the infection and its symptoms are eliminated by antibiotics, especially if the illness is treated early. Delayed or inadequate treatment can lead to the more serious symptoms, which can be disabling and difficult to treat. Lyme disease is a biosafety level 2 disease.
Signs and symptoms
Lyme disease can affect multiple body systems and produce a range of symptoms. Not all patients with Lyme disease will have all symptoms, and many of the symptoms are not specific to Lyme disease, but can occur with other diseases, as well. The incubation period from infection to the onset of symptoms is usually one to two weeks, but can be much shorter (days), or much longer (months to years). Symptoms most often occur from May through September, because the nymphal stage of the tick is responsible for most cases. Asymptomatic infection exists, but occurs in less than 7% of infected individuals in the United States. Asymptomatic infection may be much more common among those infected in Europe.
Early localized infection
The classic sign of early local infection with Lyme disease is a circular, outwardly expanding rash called erythema chronicum migrans (also erythema migrans or EM), which occurs at the site of the tick bite three to thirty days after the tick bite. The rash is red, and may be warm, but is generally painless. Classically, the innermost portion remains dark red and becomes indurated; the outer edge remains red; and the portion in between clears, giving the appearance of a bullseye. However, partial clearing is uncommon, and the bullseye pattern more often involves central redness.
EM is thought to occur in about 80% of infected patients. Patients can also experience flu-like symptoms, such as headache, muscle soreness, fever, and malaise. Lyme disease can progress to later stages even in patients who do not develop a rash.
Early disseminated infection
Within days to weeks after the onset of local infection, the Borrelia bacteria may begin to spread through the bloodstream. EM may develop at sites across the body that bear no relation to the original tick bite. Another skin condition, which is apparently absent in North American patients, but occurs in Europe, is borrelial lymphocytoma, a purplish lump that develops on the ear lobe, nipple, or scrotum. Other discrete symptoms include migrating pain in muscles, joint, and tendons, and heart palpitations and dizziness caused by changes in heartbeat.
Various acute neurological problems, termed neuroborreliosis, appear in 10–15% of untreated patients. These include facial palsy, which is the loss of muscle tone on one or both sides of the face, as well as meningitis, which involves severe headaches, neck stiffness, and sensitivity to light. Radiculoneuritis causes shooting pains that may interfere with sleep, as well as abnormal skin sensations. Mild encephalitis may lead to memory loss, sleep disturbances, or mood changes. In addition, some case reports have described altered mental status as the only symptom seen in a few cases of early neuroborreliosis.
Late persistent infection
After several months, untreated or inadequately treated patients may go on to develop severe and chronic symptoms that affect many parts of the body, including the brain, nerves, eyes, joints and heart. Many disabling symptoms can occur, including permanent paraplegia in the most extreme cases.
Chronic neurologic symptoms occur in up to 5% of untreated patients. A polyneuropathy that involves shooting pains, numbness, and tingling in the hands or feet may develop. A neurologic syndrome called Lyme encephalopathy is associated with subtle cognitive problems, such as difficulties with concentration and short-term memory. These patients may also experience profound fatigue. However, other problems, such as depression and fibromyalgia, are no more common in people who have been infected with Lyme than in the general population.Chronic encephalomyelitis, which may be progressive, can involve cognitive impairment, weakness in the legs, awkward gait, facial palsy, bladder problems, vertigo, and back pain. In rare cases untreated Lyme disease may cause frank psychosis, which has been mis-diagnosed as schizophrenia or bipolar disorder. Panic attack and anxiety can occur, also delusional behavior, including somatoform delusions, sometimes accompanied by a depersonalization or derealization syndrome, where the patients begin to feel detached from themselves or from reality.
Diffuse white matter pathology can disrupt grey matter connections, and could account for deficits in attention, memory, visuospatial ability, complex cognition, and emotional status. White matter disease may have a greater potential for recovery than gray matter disease, perhaps because neuronal loss is less common. Resolution of MRI white matter hyperintensities after antibiotic treatment has been observed.
Lyme arthritis usually affects the knees. In a minority of patients, arthritis can occur in other joints, including the ankles, elbows, wrist, hips, and shoulders. Pain is often mild or moderate, usually with swelling at the involved joint. Baker's cysts may form and rupture. In some cases, joint erosion occurs.
Acrodermatitis chronica atrophicans (ACA) is a chronic skin disorder observed primarily in Europe among the elderly. ACA begins as a reddish-blue patch of discolored skin, often on the backs of the hands or feet. The lesion slowly atrophies over several weeks or months, with the skin becoming first thin and wrinkled and then, if untreated, completely dry and hairless.
Cause
Lyme disease is caused by Gram-negative, spirochetal bacteria from the genus Borrelia. At least 11 Borrelia species have been discovered, three of which are known to be Lyme-related. The Borrelia species that cause Lyme disease are collectively known as Borrelia burgdorferi sensu lato, and show a great deal of genetic diversity.
The group Borrelia burgdorferi sensu lato, made up of three closely related species, are probably responsible for the large majority of cases: B. burgdorferi sensu stricto (predominant in North America, but also present in Europe), B. afzelii, and B. garinii (both predominant in Eurasia). Some studies have also proposed B. bissettii and B. valaisiana may sometimes infect humans, but these species do not seem to be important causes of disease.
Transmission
Lyme disease is classified as a zoonosis, as it is transmitted to humans from a natural reservoir among rodents by ticks that feed on both sets of hosts. Hard-bodied ticks of the genus Ixodes are the main vectors of Lyme disease.Most infections are caused by ticks in the nymphal stage, as they are very small and may feed for long periods of time undetected. Larval ticks are very rarely infected. Tick bites often go unnoticed because of the small size of the tick in its nymphal stage, as well as tick secretions that prevent the host from feeling any itch or pain from the bite. However, transmission is quite rare, with only about 1% of recognized tick bites resulting in Lyme disease; this may be because an infected tick must be attached for at least a day for transmission to occur.
In Europe, the vector is Ixodes ricinus, which is also called the sheep tick or castor bean tick. In China, Ixodes persulcatus (the taiga tick) is probably the most important vector. In North America, the black-legged tick or deer tick (Ixodes scapularis) is the main vector on the east coast. The lone star tick (Amblyomma americanum), which is found throughout the Southeastern United States as far west as Texas, is unlikely to transmit the Lyme disease spirochete Borrelia burgdorferi, though it may be implicated in a related syndrome called southern tick-associated rash illness, which resembles a mild form of Lyme disease. On the West Coast of the United States, the main vector is the western black-legged tick (Ixodes pacificus). The tendency of this tick species to feed predominantly on host species such as lizards that are resistant to Borrelia infection appears to diminish transmission of Lyme disease in the West.
While Lyme spirochetes have been found in insects as well as ticks, reports of actual infectious transmission appear to be rare. Lyme spirochetes have been found in semen and breast milk,but transmission has not been known to take place through sexual contact. Transmission across the placenta during pregnancy has not been demonstrated, and no consistent pattern of teratogenicity or specific "congenital Lyme borreliosis" has been identified. As with a number of other spirochetal diseases, adverse pregnancy outcomes are possible with untreated infection; prompt treatment with antibiotics reduces or eliminates this risk. Pregnant Lyme-disease patients cannot be treated with the first-choice antibiotic, doxycycline (see below), as it is potentially harmful for the fetus. Instead, erythromycin is usually given; it is less effective against the disease but harmless for the fetus.
Tick-borne coinfections
Ticks that transmit B. burgdorferi to humans can also carry and transmit several other parasites, such as Theileria microti and Anaplasma phagocytophilum, which cause the diseases babesiosis and human granulocytic anaplasmosis (HGA), respectively. Among early Lyme disease patients, depending on their location, 2–12% will also have HGA and 2–40% will have babesiosis. Ticks in certain regions, including the landscapes along the eastern Baltic Sea, also transmit tick-borne encephalitis.
Coinfections complicate Lyme symptoms, especially diagnosis and treatment. It is possible for a tick to carry and transmit one of the coinfections and not Borrelia, making diagnosis difficult and often elusive. The Centers for Disease Control studied 100 ticks in rural New Jersey, and found 55% of the ticks were infected with at least one of the pathogens.
Pathophysiology
Borrelia burgdorferi can spread throughout the body during the course of the disease, and has been found in the skin, heart, joint, peripheral nervous system, and central nervous system. Many of the signs and symptoms of Lyme disease are a consequence of the immune response to the spirochete in those tissues.
B. burgdorferi is injected into the skin by the bite of an infected Ixodes tick. Tick saliva, which accompanies the spirochete into the skin during the feeding process, contains substances that disrupt the immune response at the site of the bite. This provides a protective environment where the spirochete can establish infection. The spirochetes multiply and migrate outward within the dermis. The host inflammatory response to the bacteria in the skin causes the characteristic circular EM lesion. Neutrophils, however, which are necessary to eliminate the spirochetes from the skin, fail to appear in the developing EM lesion. This allows the bacteria to survive and eventually spread throughout the body.
Days to weeks following the tick bite, the spirochetes spread via the bloodstream to joints, heart, nervous system, and distant skin sites, where their presence gives rise to the variety of symptoms of disseminated disease. The spread of B. burgdorferi is aided by the attachment of the host protease plasmin to the surface of the spirochete. If untreated, the bacteria may persist in the body for months or even years, despite the production of B. burgdorferi antibodies by the immune system. The spirochetes may avoid the immune response by decreasing expression of surface proteins that are targeted by antibodies, antigenic variation of the VlsE surface protein, inactivating key immune components such as complement, and hiding in the extracellular matrix, which may interfere with the function of immune factors.
In the brain, B. burgdorferi may induce astrocytes to undergo astrogliosis (proliferation followed by apoptosis), which may contribute to neurodysfunction. The spirochetes may also induce host cells to secrete products toxic to nerve cells, including quinolinic acid and the cytokines IL-6 and TNF-alpha, which can produce fatigue and malaise. Both microglia and astrocytes secrete IL-6 and TNF-alpha in the presence of the spirochete. This cytokine response may contribute to cognitive impairment.
A developing hypothesis is that the chronic secretion of stress hormones as a result of Borrelia infection may reduce the effect of neurotransmitters, or other receptors in the brain by cell-mediated proinflammatory pathways, thereby leading to the dysregulation of neurohormones, specifically glucocorticoids and catecholamines, the major stress hormones. This process is mediated via the hypothalamic-pituitary-adrenal axis. Additionally tryptophan, a precursor to serotonin, appears to be reduced within the central nervous system (CNS) in a number of infectious diseases that affect the brain, including Lyme. Researchers are investigating if this neurohormone secretion is the cause of neuropsychiatric disorders developing in some patients with borreliosis.
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