Diagnosis and Management of Tickborne Rickettsial Diseases: Rocky Mountain Spotted Fever and Other Spotted Fever Group Rickettsioses, Ehrlichioses, and Anaplasmosis - United States.

Tickborne rickettsial diseases continue to cause severe illness and death in otherwise healthy adults and children, despite the availability of low-cost, effective antibacterial therapy. Recognition early in the clinical course is critical because this is the period when antibacterial therapy is most effective. Early signs and symptoms of these illnesses are nonspecific or mimic other illnesses, which can make diagnosis challenging. Previously undescribed tickborne rickettsial diseases continue to be recognized, and since 2004, three additional agents have been described as causes of human disease in the United States: Rickettsia parkeri, Ehrlichia muris-like agent, and Rickettsia species 364D. This report updates the 2006 CDC recommendations on the diagnosis and management of tickborne rickettsial diseases in the United States and includes information on the practical aspects of epidemiology, clinical assessment, treatment, laboratory diagnosis, and prevention of tickborne rickettsial diseases. The CDC Rickettsial Zoonoses Branch, in consultation with external clinical and academic specialists and public health professionals, developed this report to assist health care providers and public health professionals to 1) recognize key epidemiologic features and clinical manifestations of tickborne rickettsial diseases, 2) recognize that doxycycline is the treatment of choice for suspected tickborne rickettsial diseases in adults and children, 3) understand that early empiric antibacterial therapy can prevent severe disease and death, 4) request the appropriate confirmatory diagnostic tests and understand their usefulness and limitations, and 5) report probable and confirmed cases of tickborne rickettsial diseases to public health authorities.

Long-term Assessment of Post-Treatment Symptoms in Patients With Culture-Confirmed Early Lyme Disease.

BACKGROUND: Lyme disease patients with erythema migrans are said to have post-treatment Lyme disease symptoms (PTLDS) if there is persistence of subjective symptoms for at least 6 months following antibiotic treatment and resolution of the skin lesion. The purpose of this study was to characterize PTLDS in patients with culture-confirmed early Lyme disease followed for >10 years. METHODS: Adult patients with erythema migrans with a positive skin or blood culture for Borrelia burgdorferi were enrolled in a prospective study beginning in 1991 and followed up at 6 months and annually thereafter to determine the long-term outcome of this infection. The genotype of the infecting strain of B. burgdorferi was evaluated in subjects with PTLDS. RESULTS: One hundred twenty-eight subjects with culture-confirmed early Lyme disease, of whom 55% were male, were followed for a mean ± SD of 14.98 ± 2.71 years (median = 15 years; range = 11-20 years). Fourteen (10.9%) were regarded as having possible PTLDS, but only 6 (4.7%) had PTLDS documented at their last study visit. Nine (64.3%) had only a single symptom. None of the 6 with PTLDS at their last visit was considered to be functionally impaired by the symptom(s). PTLDS was not associated with a particular genotype of B. burgdorferi. CONCLUSIONS: PTLDS may persist for >10 years in some patients with culture-confirmed early Lyme disease. Such long-standing symptoms were not associated with functional impairment or a particular strain of B. burgdorferi.

Long-term assessment of health-related quality of life in patients with culture-confirmed early Lyme disease.

The health-related quality of life of 100 subjects with culture-confirmed early Lyme disease enrolled in a prospective study with annual follow-up visits was evaluated using the 36-Item Short Form General Health Survey version 2 (SF-36v2) questionnaire at 11-20 years after diagnosis. The mean summary scores of physical and mental health were similar to those of the general population.

Differentiation of reinfection from relapse in recurrent Lyme disease.

BACKGROUND: Erythema migrans is the most common manifestation of Lyme disease. Recurrences are not uncommon, and although they are usually attributed to reinfection rather than relapse of the original infection, this remains somewhat controversial. We used molecular typing of Borrelia burgdorferi isolates obtained from patients with culture-confirmed episodes of erythema migrans to distinguish between relapse and reinfection. METHODS: We determined the genotype of the gene encoding outer-surface protein C (ospC) of B. burgdorferi strains detected in cultures of skin or blood specimens obtained from patients with consecutive episodes of erythema migrans. After polymerase-chain-reaction amplification, ospC genotyping was performed by means of reverse line-blot analysis or DNA sequencing of the nearly full-length gene. Most strains were further analyzed by determining the genotype according to the 16S-23S ribosomal RNA intergenic spacer type, multilocus sequence typing, or both. Patients received standard courses of antibiotics for erythema migrans. RESULTS: B. burgdorferi isolates obtained from 17 patients who received a diagnosis of erythema migrans between 1991 and 2011 and who had 22 paired episodes of this lesion (initial and second episodes) were available for testing. The ospC genotype was found to be different at each initial and second episode. Apparently identical genotypes were identified on more than one occasion in only one patient, at the first and third episodes, 5 years apart, but different genotypes were identified at the second and fourth episodes. CONCLUSIONS: None of the 22 paired consecutive episodes of erythema migrans were associated with the same strain of B. burgdorferi on culture. Our data show that repeat episodes of erythema migrans in appropriately treated patients were due to reinfection and not relapse. (Funded by the National Institutes of Health and the William and Sylvia Silberstein Foundation.).

Public health impact of strain specific immunity to Borrelia burgdorferi.

BACKGROUND: Lyme disease, caused by Borrelia burgdorferi, is the most common tick-borne infection in the United States. Although humans can be infected by at least 16 different strains of B. burgdorferi, the overwhelming majority of infections are due to only four strains. It was recently demonstrated that patients who are treated for early Lyme disease develop immunity to the specific strain of B. burgdorferi that caused their infection. The aim of this study is to estimate the reduction in cases of Lyme disease in the United States that may occur as a result of type specific immunity. METHODS: The analysis was performed based on three analytical models that assessed the effects of type specific immunity. Observational data on the frequency with which different B. burgdorferi strains cause human infection in culture-confirmed patients with an initial episode of erythema migrans diagnosed between 1991 and 2005 in the Northeastern United States were used in the analyses. RESULTS: Assuming a reinfection rate of 3 % and a total incidence of Lyme disease per year of 300,000, the estimated number of averted cases of Lyme disease per year ranges from 319 to 2378 depending on the duration of type specific immunity and the model used. CONCLUSION: Given the assumptions of the analyses, this analysis suggests that type specific immunity is likely to have public health significance in the United States.

Evidence for strain-specific immunity in patients treated for early lyme disease.

Lyme disease, caused by Borrelia burgdorferi, is the most commonly reported vector-borne disease in the United States. Many patients treated for early Lyme disease incur another infection in subsequent years, suggesting that previous exposure to B. burgdorferi may not elicit a protective immune response. However, identical strains are almost never detected from patients who have been infected multiple times, suggesting that B. burgdorferi exposure may elicit strain-specific immunity. Probabilistic and simulation models assuming biologically realistic data derived from patients in the northeastern United States suggest that patients treated for early Lyme disease develop protective immunity that is strain specific and lasts for at least 6 years.

Differences and similarities between culture-confirmed human granulocytic anaplasmosis and early lyme disease.

Lyme disease is transmitted by the bite of certain Ixodes ticks, which can also transmit Anaplasma phagocytophilum, the cause of human granulocytic anaplasmosis (HGA). Although culture can be used to identify patients infected with A. phagocytophilum and is the microbiologic gold standard, few studies have evaluated culture-confirmed patients with HGA. We conducted a prospective study in which blood culture was used to detect HGA infection in patients with a compatible clinical illness. Early Lyme disease was defined by the presence of erythema migrans. The epidemiologic, clinical, and laboratory features of 44 patients with culture-confirmed HGA were compared with those of a convenience sample of 62 patients with early Lyme disease. Coinfected patients were excluded. Patients with HGA had more symptoms (P = 0.003) and had a higher body temperature on presentation (P < 0.001) than patients with early Lyme disease. HGA patients were also more likely to have a headache, dizziness, myalgias, abdominal pain, anorexia, leukopenia, lymphopenia, thrombocytopenia, or elevated liver enzymes. A direct correlation between the number of symptoms and the duration of illness at time of presentation (rho = 0.389, P = 0.009) was observed for HGA patients but not for patients with Lyme disease. In conclusion, although there are overlapping features, culture-confirmed HGA is a more severe illness than early Lyme disease.

Babesiosis in Lower Hudson Valley, New York, USA.

Although Lyme disease has been endemic to parts of the Lower Hudson Valley of New York, United States, for >2 decades, babesiosis has emerged there only since 2001. The number of Lower Hudson Valley residents in whom babesiosis was diagnosed increased 20-fold, from 6 to 119 cases per year during 2001-2008, compared with an ≈1.6-fold increase for the rest of New York. During 2002-2009, a total of 19 patients with babesiosis were hospitalized on 22 occasions at the regional tertiary care center. Concurrent conditions included advanced age, malignancies, splenectomy, and AIDS. Two patients acquired the infection from blood transfusions and 1 from perinatal exposure, rather than from a tick bite. One patient died. Clinicians should consider babesiosis in persons with fever and hemolytic anemia who have had tick exposure or have received blood products.

Scientific evidence and best patient care practices should guide the ethics of Lyme disease activism.

Johnson and Stricker published an opinion piece in the Journal of Medical Ethics presenting their perspective on the 2008 agreement between the Infectious Diseases Society of America (IDSA) and the Connecticut Attorney General with regard to the 2006 IDSA treatment guideline for Lyme disease. Their writings indicate that these authors hold unconventional views of a relatively common tick-transmitted bacterial infection caused by the spirochete Borrelia burgdorferi. Therefore, it should come as no surprise that their opinions would clash with the IDSA's evidence-based guidelines for the diagnosis and treatment of Lyme disease. Their allegations of conflict of interest against the IDSA resemble those made against the National Institutes of Health, the Food and Drug Administration and the Centers for Disease Control and Prevention in 2000, which were found to be baseless. It is the responsibility of all physicians and medical scientists to stand up to antiscientific, baseless and unethical attacks on those who support an evidence-based approach to caring for patients.

Efficacy of antibiotic prophylaxis for the prevention of Lyme disease: an updated systematic review and meta-analysis.

BACKGROUND: The clinical value of antibiotic prophylaxis in preventing Lyme disease remains uncertain, owing to a meta-analysis lacking sufficient power to demonstrate efficacy and a more recent trial showing effectiveness but lacking precision. Our objective was to update our prior meta-analysis on antibiotic prophylaxis for the prevention of Lyme disease, to obtain a more precise estimate of treatment effect. METHODS: Clinical trials were identified by searching MEDLINE, Embase, the Cochrane Library and trial registries, and by an assessment of the bibliographies of retrieved articles and reviews. Trials were selected if their patients were randomly allocated to a treatment or placebo group within 72 h following an Ixodes tick bite and had no clinical evidence of Lyme disease at enrollment. Details of the trial design, patient characteristics, interventions and outcomes were extracted from each article. Study quality was assessed using the Jadad scale. RESULTS: Four placebo-controlled clinical trials were included for review. Among 1082 randomized subjects, the risk of Lyme disease in the placebo group was 2.2% [95% confidence interval (CI), 1.2%-3.9%] compared with 0.2% (95% CI, 0.0%-1.0%) in the antibiotic-treated group. Antibiotic prophylaxis significantly reduced the odds of developing Lyme disease compared with placebo (pooled odds ratio=0.084; 95% CI, 0.0020-0.57; P=0.0037). CONCLUSIONS: The available evidence to date supports the use of antibiotic prophylaxis for the prevention of Lyme disease in endemic areas following an Ixodes tick bite. Pooled data from four placebo-controlled trials suggests that one case of Lyme disease is prevented for about every 50 patients who are treated with antibiotics.

Blood cultures for patients with extracutaneous manifestations of Lyme disease in the United States.

Spirochetemia in US patients with extracutaneous manifestations of Lyme disease is not well documented. In this study, blood culture results were positive for 5 (19.2%; 95% confidence interval, 6.6%-39.4%) of 26 untreated adult patients with extracutaneous manifestations but only for patients with clinical evidence for a short duration of infection.

Relationship between population density of attorneys and prevalence of methicillin-resistant Staphylococcus aureus: is medical-legal pressure on physicians a driving force behind the development of antibiotic resistance?

We performed a hypothesis-generating study evaluating the perceived threat of lawsuits among physicians and methicillin resistance in Staphylococcus aureus. We found a correlation between the prevalence of methicillin resistance among clinical S. aureus isolates and both antibiotic prescriptions per capita and density of attorneys in countries in Europe and North America. We did not find a correlation between prevalence of methicillin resistance and physician density. Further investigation is warranted to study whether physicians' perceived fear of lawsuits, of which attorney density may be a crude surrogate marker, results in antibiotic prescription practices that contribute to the emergence of antimicrobial resistance among virulent pathogens such as S. aureus, with global implications on the ethics of the delivery of quality health care to all members of society.

Erythema migrans.

Erythema migrans (EM) is the most common objective manifestation of Lyme disease, accounting for about 90% of cases. Establishing the diagnosis of EM is important because appropriate treatment with oral antibiotics at an early stage of infection with Borrelia burgdorferi results in excellent outcomes. This article includes a discussion of the epidemiology of EM and its clinical, differential, and laboratory diagnosis. The treatment of EM and the prevention of Lyme disease are also discussed.

Reinfection in patients with Lyme disease.

Lyme disease is the most common tick-borne infection in the United States and Europe. A surprising number of patients experience a subsequent episode of Lyme disease after the first episode has resolved. Reinfection has been well-documented only after successfully treated early infection (nearly always erythema migrans) and can often be recognized clinically by the development of a repeat episode of erythema migrans occurring at a different location on the skin during months when the principal tick vectors are abundant in the environment. Limited data suggest that the clinical and laboratory manifestations of reinfection in patients with Lyme disease with erythema migrans are not very different from those of initial infection. Patients with recurrent infections afford an opportunity to study the role of the immune response in this illness. Because patients with early Lyme disease continue to remain at high risk for reinfection, this population should be targeted for education about prevention of Lyme disease.

Human granulocytic anaplasmosis during pregnancy: case series and literature review.

We describe the clinical and laboratory manifestations and pregnancy outcomes of 6 women who received a diagnosis of human granulocytic ehrlichiosis during pregnancy. Human granulocytic ehrlichiosis did not seem to present in a fulminant fashion, and all treated patients had excellent responses to rifampin or doxycycline therapy. Perinatal transmission was documented in 1 neonate, who responded well to treatment. There do not appear to be any long-term adverse sequelae in children born from these pregnancies (mean follow-up duration, 21 months).

The impact of strain-specific immunity on Lyme disease incidence is spatially heterogeneous.

Lyme disease, caused by the bacterium Borrelia burgdorferi, is the most common tick-borne infection in the US. Recent studies have demonstrated that the incidence of human Lyme disease would have been even greater were it not for the presence of strain-specific immunity, which protects previously infected patients against subsequent infections by the same B. burgdorferi strain. Here, spatial heterogeneity is incorporated into epidemiological models to accurately estimate the impact of strain-specific immunity on human Lyme disease incidence. The estimated reduction in the number of Lyme disease cases is greater in epidemiologic models that explicitly include the spatial distribution of Lyme disease cases reported at the county level than those that utilize nationwide data. strain-specific immunity has the greatest epidemiologic impact in geographic areas with the highest Lyme disease incidence due to the greater proportion of people that have been previously infected and have developed strain-specific immunity.

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.

Brief communication: hematogenous dissemination in early Lyme disease.

BACKGROUND: Bloodstream invasion in Lyme disease has been difficult to study because until recently blood culture methods were too insensitive to detect spirochetemia. OBJECTIVE: To evaluate the clinical and laboratory features of spirochetemic patients. DESIGN: Cross-sectional study. SETTING: Lyme Disease Diagnostic Center in Valhalla, New York, 1997 to 2002. PATIENTS: 213 untreated adults with erythema migrans. INTERVENTION: Blood culture for Borrelia burgdorferi. MEASUREMENTS: Symptom scores and selected laboratory measures. RESULTS: Spirochetemia was found in 93 (43.7%) patients. Spirochetemic patients were more often symptomatic (89.2% vs. 74.2%; P = 0.006) and more often had multiple erythema migrans lesions (41.9% vs. 15.0%; P < 0.001) than patients without spirochetemia. However, 8 (22.9%) of the 35 asymptomatic patients with a single skin lesion nevertheless had a positive blood culture. Risk for spirochetemia was present the day the patient noticed the lesion and continued for more than 2 weeks. LIMITATIONS: Long-term outcome data were not available. CONCLUSIONS: The high rate, early onset, and prolonged duration of risk for spirochetemia explain why untreated patients with erythema migrans are at risk for dissemination of B. burgdorferi to anatomic sites beyond the lesion site. Differences in the strain of the infecting spirochete, as well as host factors, may be important determinants of hematogenous dissemination.

Identification of Dietzia spp. from Cardiac Tissue by 16S rRNA PCR in a Patient with Culture-Negative Device-Associated Endocarditis: A Case Report and Review of the Literature.

The genus Dietzia was recently distinguished from other actinomycetes such as Rhodococcus. While these organisms are known to be distributed widely in the environment, over the past decade several novel species have been described and isolated from human clinical specimens. Here we describe the identification of Dietzia natronolimnaea/D. cercidiphylli by PCR amplification and sequencing of the 16S rRNA encoding gene from cardiac tissue in a patient with culture-negative device-associated endocarditis.