Excerpt from Lyme Disease

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Background

Lyme disease is a systemic infection caused by the spirochete Borrelia burgdorferi. The bacteria are inoculated into the skin by a tick bite, nearly always from hard-bodied ticks of the genus Ixodes.

The original descriptions of the dermatologic manifestations of Lyme disease date back to 1883 in Europe, when a German physician, Alfred Buchwald, described what is now termed acrodermatitis chronica atrophicans (ACA). Several decades later in 1912, a Swedish dermatologist, Arvid Afzelius, described erythema chronicum migrans (ECM), which currently is referred to simply as erythema migrans (EM).

It was not until 1975, when a statistically improbable cluster of childhood arthritis occurred in and around the town of Lyme, Connecticut, that the full spectrum of the disease began to be elucidated. This outbreak stimulated intense clinical and epidemiologic research that led to the discovery of the causative agent and its ecology and an expanding geographic range and list of clinical manifestations. In addition, the initial antibiotic responsiveness of the cutaneous manifestations that had been described in the 1950s in the European literature was confirmed, and the findings were extended.

In 1998, the US Food and Drug Administration (FDA) approved a protective vaccine, but the manufacturer pulled it from the market a few years later.

Pathophysiology

The pathophysiology of Lyme disease is incompletely understood. Many of its manifestations are caused by active infection by the spirochete; others may be driven by immunopathogenetic mechanisms. While any part of the body can be affected, the organism shows a distinct tropism for the skin, heart, central nervous system (CNS), joints, and eyes.

The bacteria are introduced into the skin by a bite from an infected Ixodes tick. In the northeastern and upper midwestern United States, Ixodes scapularis (sometimes termed Ixodes dammini) is the vector. In the northwestern United States, Ixodes pacificus is the vector. In other parts of the world, other Ixodes ticks serve this function. Other tick species (eg, Amblyomma americanum) and insects can carry B burgdorferi, but the vast majority of cases are believed to be caused by bites by Ixodes ticks. Note that in the southern and midcentral United States, a Lyme-like disease has been reported for which the vector appears to be A americanum.

Patients with EM from Missouri and those from New York have different clinical and microbiological aspects of the disease. B burgdorferi has not been isolated from the southern patients, although a closely related spirochete is suspected to be involved. At least one culture-positive case has been documented with this new spirochete, called Borrelia lonestari.

Once in the skin, the spirochete can be overwhelmed and eliminated by host defense mechanisms, can remain viable but localized at the site of inoculation, or may disseminate via blood and lymphatics. Hematogenous dissemination can occur within days or weeks of the initial infection. The organism can travel to other parts of the skin, the heart, joints, the CNS, and other parts of the body.

Early studies showed that in roughly 10% of patients with isolated EM and no systemic symptoms, B burgdorferi or its DNA, can be detected in the bloodstream. In addition, early in the course of disease and while EM still is present, spirochetal DNA has been detected in cerebrospinal fluid, indicating early CNS penetration. This can occur even in the absence of neurologic symptoms.

Importantly, one 2005 study found that if large-volume cultures (9 mL of plasma) were performed in early presenting patients with EM, 93 (43.7%) of 213 had spirochetemia. Some of these patients had only isolated EM and no systemic symptoms.

The organism also can persist in the skin for very long periods of time. Experimentally, the spirochete can penetrate human fibroblasts and live intracellularly, even when the extracellular medium contains ceftriaxone at concentrations well above bacteriocidal levels. While intracellular organisms have never been demonstrated in vivo, this may be one mechanism by which the organism eludes host defense mechanisms. Clinically, B burgdorferi has been cultured from skin lesions of patients with ACA 10 years after initial infection.

Similar to syphilis, Lyme disease classically has been divided into stages; however, in individual patients, no rigid cutoffs exist between stages.

• Early localized Lyme disease refers to isolated EM and patients who present with an undifferentiated febrile illness.
• Early disseminated disease refers to the secondary (hematogenously spread) skin lesions and to the extracutaneous manifestations that occur during the initial weeks to months of infection. The more common of these include lymphocytic meningitis, cranial neuropathy (usually of the seventh nerve), radiculoneuritis (more common in Europe), and carditis (often with fluctuating degrees of arteriovenous block). Borrelial lymphocytoma (BL) usually occurs during this stage (see Media File 6).
• Late Lyme disease refers to manifestations, primarily rheumatologic and neurologic, that occur months to years after initial infection. ACA develops during this phase.

Note that while many patients present with EM, others first present with extracutaneous symptoms, either because EM never occurred or because it was not recognized by the patient or correctly diagnosed by the physician.

The last important phenomenon to appreciate is co-infection by other organisms transmitted by the same tick bite. Co-infection by ehrlichial species and Babesia microti are reported with increased frequency; in some studies, in as many as 10-15% of patients with Lyme disease. When Lyme disease is strongly suggested but some of the manifestations are atypical, these other tick-borne infections must be considered.

Frequency

United States

The US Centers for Disease Control and Prevention (CDC) track cases of Lyme disease by using strict surveillance criteria (not designed for diagnosis of individual cases). The incidence has been increasing over time. This is not simply a result of increased recognition, since in states that perform active surveillance, true incidence and geographic range have increased. The likely causes of this increase are expansion of deer herds and the expanded range of the vector.

• In 2001, the CDC reported 17,029 cases. In 2002, that number rose to 23,763 (40% increase). Year-to-year variation can be significant. More than 95% of cases come from 12 states (Connecticut, Delaware, Maine, Maryland, Massachusetts, Minnesota, New Hampshire, New Jersey, New York, Pennsylvania, Rhode Island and Wisconsin). Even within these states, incidence can be quite variable from county to county and even neighborhood to neighborhood.
• Overall in the United States, the prevalence is 6.0-8.2 cases per 100,000 population (2001 and 2002 data). However, in Connecticut in 2001, the rate was nearly 134 cases per 100,000 population, and, on the island of Nantucket, Massachusetts, the rate exceeds 1000 cases per 100,000 population.
• Epidemiologic data suggest that the actual incidence of Lyme disease could be as much as 10 times higher than the CDC data indicate. This probably is a result of a restrictive case definition from the CDC, inevitable misdiagnosis, and the fact that physicians tend to underreport reportable diseases of all kinds.
• BL has not been described in North America. Only a handful of cases of ACA have been reported in North American patients.

International

Lyme disease exists throughout much of the world including Scandinavia, Central Europe, Southern Europe, and Western Europe, the former Soviet Union, Japan, and China. Occasionally, cases are reported in more tropical locales, and Lyme diseases may exist in Australia. The ecology of Lyme disease differs in various parts of the world. In addition, different strains of the organism exist in Europe that account for differences in clinical manifestations and have implications for diagnostic testing and vaccine strategies. Even in Europe, BL occurs only in approximately 1% patients with Lyme disease, and ACA occurs in 10%.

Mortality/Morbidity

• Very rarely are fatalities reported associated with Lyme disease. Many of the fatalities have been in patients co-infected with other tick-borne pathogens such as Ehrlichia species and B microti, and in Europe, tick-borne encephalitis.
• Morbidity usually is neurologic and rheumatic. Patients with neurologic disease who are not diagnosed and treated promptly can suffer from neurologic and cognitive dysfunction that can be difficult to treat. Some patients may have fixed neurologic deficits that are unresponsive to antibiotics. Patients with cardiac disease rarely exhibit chronic morbidity from their heart involvement.
• Similarly, some genetically predisposed individuals with arthritis may have ongoing joint inflammation that is not responsive to further antibiotic therapy.

Race

Lyme disease occurs in individuals of all races; however, it is diagnosed much more frequently in whites. No genetic explanation is known for this, and likely, the frequency stems from social or environmental factors (ie, whites have a higher exposure rate to ticks than do other races) and possibly to the fact that EM is more difficult to diagnose in dark-skinned individuals.

Sex

No strong preponderance of Lyme disease is noted in either sex. Risk is a function of tick exposure rather than any intrinsic difference in susceptibility.

Age

• Epidemiologically, a bimodal peak in incidence of Lyme disease is seen; 1 peak occurs in patients aged 5-14 years, and the other occurs in patients aged 30-49 years. Roughly 25% of cases occur in children younger than 14 years (see Media File 8).
• The likelihood of contracting Lyme disease is related primarily to exposure to ticks, not to age, sex, or race. Therefore, the epidemiology is very important. Ascertaining where patients live, work, or vacation and what kind of activities they pursue in those locations is an important part of the history.
• Age has some effect on the location of BL, since children tend to develop lesions on the ears, while adults develop lesions on the nipples. Acrodermatitis tends to occur more commonly in older patients.

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