Allen C. Steere

The Clinical Assessment, Treatment, and Prevention of Lyme Disease, Human Granulocytic Anaplasmosis, and Babesiosis: Clinical Practice Guidelines by the Infectious Diseases Society of America

Evidence-based guidelines for the management of patients with Lyme disease, human granulocytic anaplasmosis (formerly known as human granulocytic ehrlichiosis), and babesiosis were prepared by an expert panel of the Infectious Diseases Society of America. These updated guidelines replace the previous treatment guidelines published in 2000 (Clin Infect Dis 2000; 31[Suppl 1]:1-14). The guidelines are intended for use by health care providers who care for patients who either have these infections or may be at risk for them. For each of these Ixodes tickborne infections, information is provided about prevention, epidemiology, clinical manifestations, diagnosis, and treatment. Tables list the doses and durations of antimicrobial therapy recommended for treatment and prevention of Lyme disease and provide a partial list of therapies to be avoided. A definition of post-Lyme disease syndrome is proposed.

The Spirochetal Etiology of Lyme Disease

We recovered a newly recognized spirochete from the blood, skin lesions (erythema chronicum migrans [ECM]), or cerebrospinal fluid of 3 of 56 patients with Lyme disease and from 21 of 110 nymphal or adult lxodes dammini ticks in Connecticut. These isolates and the original one from l. dammini appeared to have the same morphologic and immunologic features. In patients, specific IgM antibody titers usually reached a peak between the third and sixth week after the onset of disease; specific IgG antibody titers rose slowly and were generally highest months later when arthritis was present. Among 40 patients who had early disease only (ECM alone), 90 per cent had an elevated IgM titer (greater than or equal to 1:128) between the ECM phase and convalescence. Among 95 patients with later manifestations (involvement of the nervous system, heart, or joints), 94 per cent had elevated titers of IgG (greater than or equal to 1:128). In contrast, none of 80 control subjects had elevated IgG titers, and only three control patients with infectious mononucleosis had elevated IgM titers. We conclude that the I. dammini spirochete is the causative agent of Lyme disease.

The emergence of Lyme disease

Since its identification nearly 30 years ago, Lyme disease has continued to spread, and there have been increasing numbers of cases in the northeastern and north central US. The Lyme disease agent, Borrelia burgdorferi, causes infection by migration through tissues, adhesion to host cells, and evasion of immune clearance. Both innate and adaptive immune responses, especially macrophage- and antibody-mediated killing, are required for optimal control of the infection and spirochetal eradication. Ecological conditions favorable to the disease, and the challenge of prevention, predict that Lyme disease will be a continuing public health concern.

The Clinical Evolution of Lyme Arthritis

To determine the clinical evolution of Lyme arthritis, 55 patients who did not receive antibiotic therapy for erythema chronicum migrans were followed longitudinally for a mean duration of 6 years. Of the 55 patients, 11 (20%) had no subsequent manifestations of Lyme disease. From 1 day to 8 weeks after disease onset, 10 of the patients (18%) began to have brief episodes of joint, periarticular, or musculoskeletal pain for as long as 6 years, but they never developed objective joint abnormalities. From 4 days to 2 years after disease onset, 28 (51%) had one episode or began to have intermittent attacks of frank arthritis, primarily in large joints; a few had polyarticular movement. The total number of these patients who continued to have recurrences decreased by 10% to 20% each year. The remaining 6 patients (11%) developed chronic synovitis later in the illness; of these, 2 (4%) had erosions, and 1 (2%), permanent joint disability. The spectrum of Lyme arthritis ranges from subjective joint pain, to intermittent attacks of arthritis, to chronic erosive disease.

Vaccination against Lyme Disease with Recombinant Borrelia burgdorferi Outer-Surface Lipoprotein A with Adjuvant

BACKGROUND The risk of acquiring Lyme disease is high in areas in which the disease is endemic, and the development of a safe and effective vaccine is therefore important. METHODS We conducted a multicenter, double-blind, randomized trial involving 10,936 subjects who lived in areas of the United States in which Lyme disease is endemic. Participants received an injection of either recombinant Borrelia burgdorferi outer-surface lipoprotein A (OspA) with adjuvant or placebo at enrollment and 1 and 12 months later. In cases of suspected Lyme disease, culture of skin lesions, polymerase-chain-reaction testing, or serologic testing was done. Serologic testing was performed 12 and 20 months after study entry to detect asymptomatic infections. RESULTS In the first year, after two injections, 22 subjects in the vaccine group and 43 in the placebo group contracted definite Lyme disease (P=0.009); vaccine efficacy was 49 percent (95 percent confidence interval, 15 to 69 percent). In the second year, after the third injection, 16 vaccine recipients and 66 placebo recipients contracted definite Lyme disease (P<0.001); vaccine efficacy was 76 percent (95 percent confidence interval, 58 to 86 percent). The efficacy of the vaccine in preventing asymptomatic infection was 83 percent in the first year and 100 percent in the second year. Injection of the vaccine was associated with mild-to-moderate local or systemic reactions lasting a median of three days. CONCLUSIONS Three injections of vaccine prevented most definite cases of Lyme disease or asymptomatic B. burgdorferi infection.

The Early Clinical Manifestations of Lyme Disease

Lyme disease, caused by a tick-transmitted spirochete, typically begins with a unique skin lesion, erythema chronicum migrans. Of 314 patients with this skin lesion, almost half developed multiple annular secondary lesions; some patients had evanescent red blotches or circles, malar or urticarial rash, conjunctivitis, periorbital edema, or diffuse erythema. Skin manifestations were often accompanied by malaise and fatigue, headache, fever and chills, generalized achiness, and regional lymphadenopathy. In addition, patients sometimes had evidence of meningeal irritation, mild encephalopathy, migratory musculoskeletal pain, hepatitis, generalized lymphadenopathy and splenomegaly, sore throat, nonproductive cough, or testicular swelling. These signs and symptoms were typically intermittent and changing during a period of several weeks. The commonest nonspecific laboratory abnormalities were a high sedimentation rate, an elevated serum IgM level, or an increased aspartate transaminase level. Early Lyme disease can be diagnosed by its dermatologic manifestations, rapidly changing system involvement, and if necessary, by serologic testing.

Erythema chronicum migrans and Lyme arthritis. The enlarging clinical spectrum.

Thirty-two patients with the onset of erythema chronicum migrans, Lyme arthritis, or both in mid-1976 were studied prospectively. The skin lesion (24 patients) typically lasted about 3 weeks, beginning as a red macule or papule that expanded to form a large ring with central clearing. Associated symptoms ranged from none to malaise, fatigue, chills and fever, headache, stiff neck, backache, myalgias, nausea, vomiting, and sore throat. Three patients had been bitten by ticks at the site of the initial lesion 4 to 20 days before its onset. Nineteen patients suddenly developed a monoarticular or oligoarticular arthritis 4 days to 22 weeks (median, 4 weeks) after onset of the skin lesion; eight developed arthritis without a preceding skin lesion. Seven of these 27 experienced migratory joint pains. Arthritis attacks, most commonly in the knee, were typically short (median, 8 days) but sometimes persisted for months. Other manifestations included neurologic abnormalties, myocardial conduction abnormalities, serum cryoprecipitates, elevated serum IgM levels, and elevated erythrocyte sedimentation rates. The diagnostic marker is the skin lesion; without it, geographic clustering is the most important clue.

Detection of Borrelia burgdorferi DNA by Polymerase Chain Reaction in Synovial Fluid from Patients with Lyme Arthritis

BACKGROUND Borrelia burgdorferi is difficult to detect in synovial fluid, which limits our understanding of the pathogenesis of Lyme arthritis, particularly when arthritis persists despite antibiotic therapy. METHODS Using the polymerase chain reaction (PCR), we attempted to detect B. burgdorferi DNA in joint-fluid samples obtained over a 17-year period. The samples were tested in two separate laboratories with four sets of primers and probes, three of which target plasmid DNA that encodes outer-surface protein A (OspA). RESULTS B. burgdorferi DNA was detected in 75 of 88 patients with Lyme arthritis (85 percent) and in none of 64 control patients. Each of the three OspA primer-probe sets was sensitive, and the results were moderately concordant in the two laboratories (kappa = 0.54 to 0.73). Of 73 patients with Lyme arthritis that was untreated or treated with only short courses of oral antibiotics, 70 (96 percent) had positive PCR results. In contrast, of 19 patients who received either parenteral antibiotics or long courses of oral antibiotics (> or = 1 month), only 7 (37 percent) had positive tests (P < 0.001). None of these seven patients had received more than two months of oral antibiotic treatment or more than three weeks of intravenous antibiotic treatment. Of 10 patients with chronic arthritis (continuous joint inflammation for one year or more) despite multiple courses of antibiotics, 7 had consistently negative tests in samples obtained three months to two years after treatment. CONCLUSIONS PCR testing can detect B. burgdorferi DNA in synovial fluid. This test may be able to show whether Lyme arthritis that persists after antibiotic treatment is due to persistence of the spirochete.

The triad of neurologic manifestations of Lyme disease Meningitis, cranial neuritis, and radiculoneuritis

We studied 38 patients with Lyme meningitis, a newly recognized spirochetal infection. The patients characteristically had intermittent attacks of severe headache, mild meningismus, and a predominantly lymphocytic pleocytosis. In addition to meningitis, 11 patients experienced subtle encephalitic signs, 19 had cranial neuritis, most commonly unilateral or bilateral facial palsy, and 12 developed peripheral radiculoneuritis, plexitis, or mononeuritis multiplex. Without antibiotic therapy, the duration of neurologic involvement was 3 to 18 months. Although sometimes incomplete, the triad of neurologic manifestations of Lyme disease— meningitis, cranial neuritis, and radiculoneuritis—presents a unique clinical picture.

Lyme Carditis: Cardiac Abnormalities of Lyme Disease

We studied 20 patients, mostly young adult men, with cardiac involvement of Lyme disease. The commonest abnormality (18 patients) was fluctuating degrees of atrioventricular block; eight of them developed complete heart block. Thirteen patients had evidence of more diffuse cardiac involvement: electrocardiographic changes compatible with acute myopericarditis (11 patients), radionuclide evidence of mild left ventricular dysfunction (five of 12 patients tested), or frank cardiomegaly (one patient). Heart involvement was usually preceded by erythema chronicum migrans and sometimes accompanied by meningoencephalitis, facial palsy, arthritis, elevated serum IgM levels, or cryoglobulins containing IgM. The duration of cardiac involvement was usually brief (3 days to 6 weeks). The clinical picture in these patients has similarities to acute rheumatic fever; but in Lyme disease, complete heart block may be commoner, myopericardial involvement tends to be milder, and valves seem not to be affected.