 |
|
The Cost-effectiveness of Vaccination Against Lyme Disease
Nancy A. Shadick, MD, MPH;
Matthew H. Liang, MD, MPH;
Charlotte B. Phillips, MPH;
Karin Fossel, MA;
Karen M. Kuntz, ScD
Arch Intern Med. 2001;161:554-561.
ABSTRACT
| |
Background Vaccination against Lyme disease appears to be safe and effective; however,
the cost per quality-adjusted life-year (QALY) gained with vaccination is
unknown.
Methods We developed a decision-analytic model to evaluate the cost-effectiveness
of vaccination compared with no vaccination in individuals living in endemic
areas of Lyme disease. Our analysis encompassed a 10-year time horizon including
a 2-year vaccination schedule with an additional year of vaccine effectiveness.
The costs and probabilities of vaccination risk, compliance and efficacy,
and Lyme disease clinical sequelae and treatment were estimated from the literature.
Health-related quality-of-life weights of the various clinical sequelae of
Lyme disease infection were obtained from a sample of 105 residents from Nantucket
Island, Massachusetts.
Results Vaccinating 10 000 residents living in endemic areas with a probability
of Lyme disease per season of 0.01 averted 202 cases of Lyme disease during
a 10-year period. The additional cost per QALY gained compared with no vaccination
was $62 300. Vaccination cost $12 600/QALY gained for endemic areas
with an attack rate of 2.5% per season, and $145 200/QALY gained for
an attack rate of 0.5%. Vaccinating individuals over an accelerated 2-month
vaccination schedule improved the cost-effectiveness to $53 700/QALY
gained. If a yearly booster shot is required for persisting efficacy, the
marginal cost-effectiveness ratio increases to $72 700/QALY. The cost-effectiveness
of vaccination was most sensitive to the Lyme disease treatment efficacy and
assumptions about the persistence of vaccination effect.
Conclusion Vaccination against Lyme disease appears only to be economically attractive
for individuals who have a seasonal probability of Borrelia
burgdorferi infection of greater than 1%.
INTRODUCTION
LYME DISEASE is a multisystem disorder of the skin, nervous system,
cardiovascular system, and joints that is transmitted by the Ixodes tick carrying Borrelia burgdorferi.1, 2 The incidence of Lyme disease has increased
dramatically since its initial description in 1977, with more than 80 000
cases reported to the Centers for Disease Control and Prevention3
since 1980. Although tick bite precautions can be effective in preventing
Lyme disease and other tick-borne illnesses, these behaviors, such as the
use of tick repellents, avoidance of tick-infested areas, use of protective
clothing, habitat modification, and doing daily tick checks, are not routinely
practiced by residents of endemic areas.4, 5, 6
Although antibiotics are generally effective in treating Lyme disease, long-term
morbidity can occur with significant costs and impact on health-related quality
of life.7, 8, 9
A vaccine against Lyme disease using a recombinant outer-surface lipoprotein
has been shown to reduce the risk of Lyme disease by 79% to 92% with minimal
adverse effects.10, 11 As the risk
of Lyme disease varies widely between regions from zero in areas of the West
and Hawaii to up to 2% to 3% in highly endemic areas such as certain areas
in the Northeast,3 understanding the relative
impact of the vaccine by risk of infection has important policy implications.
Previously, Meltzer and colleagues12 reported
a net cost of vaccination of $4467 per case of Lyme disease averted when the
annual cost of vaccination was $100. To place Lyme disease vaccination in
the context of other preventive interventions competing for limited health
care resources, we evaluated the cost-effectiveness of vaccination against
Lyme disease in terms of cost per quality-adjusted life-year (QALY) gained
among residents in an endemic area with an annual attack rate of 1% per season.
We also varied the rate of seasonal risk to help practitioners generalize
to areas of higher or lower endemicity.
METHODS
THE MODEL
We developed a decision-analytic model to evaluate the cost-effectiveness
of vaccination compared with no vaccination for persons living in areas of
moderate to high risk of Lyme disease (Figure
1). The seasonal attack rate for the vaccine efficacy trials10, 11 incorporated subjects living in the
northeastern and upper midwestern United States, with yearly attack rates
of approximately 1%, which roughly corresponds to the high to moderate risk
areas in Figure 1. We constructed
a Markov model to simulate a cohort of individuals through 10 seasons (Figure 2 and Figure 3).13 Each year (1 cycle length),
an unvaccinated person faces a 1% chance of contracting Lyme disease. Persons
with Lyme disease may or may not present with erythema migrans and may or
may not present subsequently with disseminated disease. Dissemination was
modeled according to the primary organ system involvement: rheumatological,
cardiac, or neurologic manifestations. Vaccinated persons face a reduction
in the probability of contracting Lyme disease. We assume that the course
of Lyme disease among vaccinated persons is the same as that among unvaccinated
persons. The model allows for full, partial, or no (1 shot) compliance with
the 3-shot vaccination series with its concomitant protection evaluated in
the context of the seasonal probability of Lyme disease. We assumed that partially
compliant persons were only protected for the first season.10, 11
Noncompliant persons were assigned the cost of 1 shot and received no benefit.
Although the length of follow-up of the clinical trials used to evaluate the
vaccine was 2 years, we assumed a persistence of vaccination effect of an
additional year for fully compliant persons in our base-case analysis, and
varied this assumption as a sensitivity analysis.
|
|
|
|
Figure 1. National Lyme disease risk map.
This map demonstrates an approximate distribution of predicted Lyme disease
risk in the United States. The true relative risk in any given county compared
with other counties might differ from that shown here and might change from
year to year. Information on risk distribution within states and counties
is best obtained from state and local public health authorities. Source: Durland
Fish, MD, and Howard Carrie, MD, Department of Epidemiology and Public Health,
Yale University School of Medicine, New Haven, Conn. Reprinted with permission.
|
|
|
|
|
|
|
Figure 2. Markov model of the decision tree
outlining vaccination of a cohort of 10 000 individuals. The circles
represent chance outcomes and the triangles represent the health states of
individuals. M indicates Markov node.
|
|
|
|
|
|
|
Figure 3. The decision tree. The clinical
sequelae and treatment strategies for Lyme disease. Patients who end in a
"success" outcome (triangles) transition to one of the nonfailure states.
The circles represent chance outcomes.
|
|
|
The model outputs were number of cases of Lyme disease, QALYs, and direct
medical costs over a 10-year period. We also considered indirect costs in
a sensitivity analysis. Incremental cost-effectiveness ratios for vaccination
compared with no vaccination was calculated by dividing the additional cost
by the additional benefit (measured in QALYs) of vaccination compared with
no vaccination. We adopted a societal perspective and followed the reference-case
recommendations of the Panel on Cost-Effectiveness in Health and Medicine.14 Costs and life-years were discounted at an annual
rate of 3%. All analyses were performed using DATA software (TreeAge Software,
Inc, Williamstown, Mass).
DATA
The probabilities and costs used in the model were estimated from the
literature (Table 1). For each
variable in the model, we assigned a best estimate to use in the base-case
analysis as well as a clinically plausible range to use in sensitivity analyses.
|
|
|
|
Table 1. Model Estimates and Ranges
|
|
|
Vaccine-Related Effects
The efficacy, compliance, and risk of adverse effects associated with
vaccination were obtained from 2 recent clinical trials.10, 11
The vaccination schedule included an initial dose at time 0, with 2 subsequent
doses 1 month and 12 months later. Pooling the results from these trials showed
efficacies of 62% for partially vaccinated (compliant) persons and 85% for
fully vaccinated (compliant) persons. In our model, we assumed an efficacy
of 62% for the first year, 85% for years 2 and 3, and no efficacy thereafter.
The overall percentage of subjects in the 2 trials who received the first
2 inoculations was 98%, while only 83% of subjects received all 3 injections
(73% in one trial; 92% in the other). The percentage of vaccine recipients
who reported adverse effects was about 4% to 10% greater than that of placebo
recipients. Typical adverse effects reported were pain or tenderness at the
injection site and systemic symptoms of myalgias, achiness, fever, or chills.
Symptoms lasted from 3 to 7 days.
Lyme Disease Sequelae and Treatment
In our model, 70% of patients who contract Lyme disease present with
and are treated for erythema migrans.15, 16, 17
If this early treatment is successful, then disseminated Lyme disease will
be prevented. Among patients who do not present with or do not receive treatment
for erythema migrans or in whom treatment for early Lyme disease has failed,
we assumed that they might then develop disseminated Lyme disease that manifests
itself as arthritic, cardiac, or neurologic sequelae.12, 18
Patients in whom initial antibiotic treatment for disseminated manifestations
has failed were subsequently retreated with another 3 weeks of intravenous
antibiotics. We assumed that a small fraction of patients who were retreated
and in whom treatment failed developed a syndrome of arthralgias, fatigue,
and cognitive difficulties that persisted for 5 years (modeled via a tunnel
state).8, 32 Persons are at risk
for subsequent Lyme disease except for the small percentage who spend 5 years
in the failure state.
Doxycycline and ceftriaxone sodium were the oral and parenteral antibiotics
used in the model, respectively (Table 1). Doxycycline was used for patients with erythema migrans, first-degree
atrioventricular block, Bell palsy, and arthritis. Parenteral ceftriaxone
was used for patients with meningitis, radiculoneuritis or cranial neuritis,
and arthritis resistant to an initial course of oral antibiotics. When there
was a failure to respond to ceftriaxone therapy, individuals were retreated
once more with a 3-week course. Treatment efficacies varied from 85% to 95%
(Table 1). We also incorporated
both minor and major reactions associated with antibiotic treatment in terms
of cost.
Costs
The costs of management and treatment of Lyme disease were derived primarily
from a previous cost-effectiveness analysis by Magid and et al18
and updated to 1998 US dollars using the medical care component of the consumer
price index. The cost of the 3-shot series was estimated at $150 for fully
compliant persons, partially compliant persons were assigned two thirds of
this cost, and noncompliant persons were assigned one third of this cost.
Persons experiencing adverse effects associated with vaccination, such as
soreness, redness, and swelling at the site with myalgias and/or influenzalike
symptoms, were assigned the cost of ibuprofen, 400 mg 3 times daily, for 2
days and a visit to the physician in approximately 10% of cases. The cost
of erythema migrans included the costs of an antibody test ($57), an office
visit ($41), doxycycline for 3 weeks ($23), minor reactions to treatment (4%
chance of incurring a cost of $81), and major reactions to treatment (0.01%
chance of incurring a cost of $5933). Total medical costs associated with
disseminated Lyme disease were based on previously published estimates.18 When intravenous therapy failed in these individuals,
they were retreated with 3 weeks of parenteral ceftriaxone at a cost of $3612.
The annual cost of management of the post–Lyme disease fatigue syndrome
included naproxen sodium therapy (500 mg twice daily) and amitriptyline hydrochloride,
50 mg, based on consensus opinion of 3 rheumatologists and tabulated using
1998 pharmacy costs at the Brigham and Women's Hospital outpatient pharmacy.
One of the assumptions in a reference case analysis is that morbidity costs
are incorporated in the quality-of-life estimates. We challenged this assumption
in a sensitivity analysis by incorporating morbidity costs from a cost-of-illness
study by Maes et al.9
Health-Related Quality of Life
The health-related quality-of-life weights were estimated from a random
sample of 105 residents from Nantucket Island, Massachusetts, an area with
one of the highest incidences of Lyme disease in the United States (Table 2). Subjects rated a visual analogue
scale that ranged from death (0) to perfect health (1) for each hypothetical
clinical scenario. Each question was phrased in lay terms to approximate clinical
manifestations of Lyme disease, including erythema migrans, facial palsy,
heart block, arthritis, and meningitis, lasting for 30 days2
and a syndrome of fatigue, arthralgias, and difficulty concentrating, which
was labeled as a post–Lyme disease "failure state" (Table 2). For example, the following descriptions were used to classify
patients' clinical state: "A large, red expanding rash for the rest of your
life" (erythema migrans), "Your mouth droops and you drool" (facial paralysis),
and "You have a swollen, painful knee . . . it is hard to walk" and " . .
. joint and muscle aches . . . you forget things and cannot concentrate .
. . " (failure state). Prior to administration, the questions were pretested
for clarity among 16 subjects. Rating scores33
(r) were converted to utilities (u) using a power transformation: u = 1 -
(1 - r)1.6. The estimated utilities
were multiplied by the expected duration in each health state to estimate
QALYs over a 10-year period.
|
|
|
|
Table 2. Health-Related Quality-of-Life Adjustments*
|
|
|
SENSITIVITY ANALYSIS
We performed sensitivity analyses on all variables to assess the robustness
of the results. Clinical probabilities, treatment efficacy, vaccine efficacy,
and cost estimates were varied over a plausible range according to estimates
from the literature. Utilities and seasonal attack rates were varied over
a range that reflected the variation in the subjects' responses. We also varied
the cost of the vaccination series from $50 to $300 for a 3-shot series as
well as an annual booster scenario.
RESULTS
BASE-CASE ANALYSIS
In the base-case analysis, which assumes an infection rate of 0.01 for
Lyme disease per season, we predict that 202 cases of Lyme disease will be
averted during a 10-year period for every 10 000 persons vaccinated who
live in an endemic area. This translates into an additional 0.7 quality-adjusted
days (undiscounted) per person over the 10-year period, at an incremental
cost of $62 300/QALY gained and cost per case averted of $5300 for vaccination
compared with no vaccination (Table 3).
|
|
|
|
Table 3. Base-Case Analysis*
|
|
|
SENSITIVITY ANALYSIS
Seasonal Infection Rate of Lyme Disease
The cost-effectiveness ratio of vaccination compared with no vaccination
was sensitive to the probability of Lyme disease, with a seasonal infection
rate of 2.5% resulting in a cost-effectiveness ratio of $12 600/QALY
saved for vaccination. If the annual probability of Lyme disease were less
than 0.50%, the incremental cost-effectiveness ratio was greater than $100 000/QALY
gained (Figure 4). If a booster
shot is required yearly and the efficacy persists for the 10 years of the
model, the marginal cost-effectiveness ratio increases to $72 700/QALY.
Because the persistence of the vaccination efficacy has not been demonstrated,
we present a 2-way sensitivity analysis of the Lyme disease attack rate and
the amount of time for which the vaccine is effective (Figure 4). Furthermore, a map of the United States based on level
of risk for Lyme disease published by the American College of Immunization
Practices demonstrates the variability in risk across the continent based
on reports to the Centers for Disease Control and Prevention.34
Extrapolating the highest risk areas to seasonal probabilities of greater
than 1%, moderate risk to between 0.5% and 1%, and minimal risk to less than
0.5%, one can estimate the range of incremental cost-effectiveness ratios
by state (Figure 1).
|
|
|
|
Figure 4. Incremental cost-effectiveness
of vaccination vs nonvaccination in a cohort of individuals according to the
yearly probability of infection and the length of efficacy of the vaccine.
QALY indicates quality-adjusted life-year.
|
|
|
Vaccination Effects
Using clinically reasonable bounds on vaccination efficacy, compliance
rate, and adverse effect rate, the incremental cost-effectiveness ratio of
vaccination ranges between $56 400/QALY and $88 700/QALY saved.
If vaccination efficacy were only 0.43 for partially compliant persons, and
0.67 for fully compliant persons, then the incremental cost-effectiveness
ratio increased to $88 700/QALY gained (Table 4). Using the base-case estimates for both vaccine efficacy
and compliance results in a cost-effectiveness ratio of $51 900/QALY
saved. Vaccinating individuals during an accelerated 2-month vaccination schedule
(assuming that the 2-year efficacy could be achieved at 1 year) improved the
cost-effectiveness of vaccination to $53 700/QALY gained.
|
|
|
|
Table 4. Sensitivity Analysis of the Cost-effectiveness Ratio of Vaccination*
|
|
|
Lyme Disease Prognosis
We varied the probability that a person infected with B burgdorferi would present with erythema migrans. Patients who do
not present with erythema migrans fail to receive early treatment and thus
are more likely to experience disseminated disease. As the probability of
presenting with erythema migrans varied from 0.6 to 0.8, the incremental cost-effectiveness
ratio for vaccination varied from $46 400/QALY to $87 500/QALY gained.
We also varied the probability of experiencing disseminated disease among
patients whose conditions were not diagnosed, who did not present with erythema
migrans, or who were not adequately treated. If there was only a 50% probability
of dissemination, the cost-effectiveness ratio was $106 800/QALY gained.
With 100% probability of dissemination, the incremental cost-effectiveness
ratio was $49 500/QALY gained (Table
4).
Patients with erythema migrans who fail treatment are at risk of disseminated
Lyme disease. If we decreased all of the Lyme disease treatment efficacies
by 20% of their base-case estimates, the cost-effectiveness ratio of vaccination
decreased to $18 800/QALY gained. Alternatively, if all treatments were
100% efficacious (and patients were 100% compliant with treatment), then the
cost-effectiveness of vaccination increased to $301 900/QALY gained.
Note that because we assumed that patients would be 100% compliant with their
Lyme disease treatment, the base-case analysis is biased against vaccination.
Health-Related Quality of Life
Varying all quality-of-life weights over the interquartile range of
responses yielded a substantial variation in the incremental cost-effectiveness
ratio of vaccination from $39 600/QALY to $124 600/QALY gained.
The model was most sensitive to the utility assigned to the small percentage
of patients with persisting arthralgias and fatigue. As this utility was varied
within its observed interquartile range (Table 2), the incremental cost-effectiveness of vaccination varied
from $42 900 to $97 800.
Costs
The results were most sensitive to the cost of vaccination for the 3-shot
series. If vaccination costs were only $50, then the cost-effectiveness ratio
for vaccination was only $6900/QALY saved. If vaccination costs were as high
as $300, then the cost-effectiveness ratio of vaccination was $145 300/QALY
gained. Varying the treatment costs of disseminated Lyme disease by 50% of
the base-case estimates varied the cost-effectiveness of Lyme disease vaccination
to between $52 400/QALY and $72 100/QALY gained. When we incorporated
the indirect costs of Lyme disease, the incremental cost-effectiveness ratio
for vaccination decreased by approximately $10 000/QALY gained.
COMMENT
Little is known about whom to vaccinate against Lyme disease. In this
study, we used established methods to evaluate the cost-effectiveness of Lyme
disease vaccination. In an area with a probability of 0.01 per year of contracting
Lyme disease, 202 cases of Lyme disease would be averted over 10 years for
every 10 000 residents vaccinated, at an incremental cost-effectiveness
ratio of $62 300/QALY saved and $5300 per case of Lyme disease averted.
Because Lyme disease is usually nonfatal, the benefit of vaccination expressed
in terms of QALYs reflects the relative impact on the patients' time with
symptoms.
The incremental cost-effectiveness ratio of vaccination compared with
no vaccination varied substantially depending on the rate of endemicity of
Lyme disease. The annual probability of contracting Lyme disease depends on
host-parasite interactions, such as rates of B burgdorferi tick infection, cumulative exposure to tick-infested areas, the use
of precautionary behaviors, and environmental factors such as seasonal rainfall
and temperatures. In highly endemic areas, annual attack rates have been reported
between 2.5% to 10%.35 Incidence rates collected
from larger endemic areas, including the areas in 2 vaccine studies, showed
annual rates averaging approximately 1%. Areas with lower attack rates (0.5%)
raise the cost-effectiveness of vaccination to more than $100 000/QALY
gained for a wide range of assumptions regarding the persistence of vaccine
efficacy.
Our results were also sensitive to assumptions about the persistence
of vaccine efficacy. Although the available clinical trials report efficacy
for a 2-year time horizon, this is because of the 2-year timing of the vaccination
series. Using a time horizon of only 2 years, Lyme disease vaccination cost
$105 000/QALY gained. However, the incremental cost-effectiveness ratio
decreased substantially to $29 600/QALY gained under the assumption that
the vaccine effectiveness persisted for an additional 3 years.
Our results were also sensitive to the treatment effectiveness associated
with Lyme disease. In our base-case analysis, we assumed that patients would
be 100% compliant. Lower compliance with treatment would effectively lower
the treatment effectiveness. If the base-case treatment efficacies were reduced
by 20%, then the cost-effectiveness ratio of vaccination decreased to only
$18 800/QALY saved. Alternatively, if treatment for Lyme disease (for
both the early and disseminated states) were 100% effective and compliance
with these treatments were 100%, then the cost-effectiveness ratio of vaccination
increased to more than $300 000/QALY saved.
The results were also sensitive to the utility weights assigned to the
Lyme disease clinical states. We compared our results with those of Nichol
and coworkers.19 Although there were similar
results for rheumatologic sequelae (0.68 vs 0.69), our utility weights were
somewhat lower for erythema migrans (1.0 vs 0.80). The utility questionnaires
were filled out by residents of Nantucket Island, which is highly endemic
for Lyme disease. Nearly half of the 105 individuals who completed our questionnaire
previously had Lyme disease. In the study by Nichol and coworkers,19 utility states were calculated via a time trade-off
task by an expert panel. Our model was sensitive to the utility values varying
between $38 500/QALY and $122 300/QALY, when the values were varied
to within the 25th and 75th percentiles. Lower utility values would bias our
analysis in favor of vaccination.
In a recent cost-effectiveness analysis, Meltzer et al12
examined the Lyme disease vaccination in terms of cost per case averted. There
were a number of differences between the 2 studies including Meltzer and coworkers'12 inclusion of indirect costs in the base-case analysis,
higher treatment costs, and assumptions that included higher probabilities
of dissemination, for example. Our cost per case averted was $5300 for a seasonal
attack rate of 0.01, which was not too different from Meltzer and coworkers.
Our results in terms of QALYs allow comparison with other medical interventions
(eg, other vaccinations). A recent Institute of Medicine36
report estimates the incremental cost-effectiveness of Lyme disease vaccination
to be greater than $100 000/QALY if given to residents of a highly endemic
area, making it one of the lowest priority vaccinations. Our study presents
somewhat lower cost-effectiveness ratios for vaccination in endemic areas.
While many vaccinations are cost saving, there are immunizations and accepted
medical interventions that have incremental cost-effectiveness ratios in excess
of $50 000/QALY gained (Table 5).37 Table 5 provides a league table to place our analysis in the context of other preventive
interventions.
|
|
|
|
Table 5. League Table of Selected Cost Utility Analyses, With Ratios
Converted to 1998 US Dollars
|
|
|
Although our model may not encompass all costs in treating patients
with Lyme disease, such as other less frequent long-term sequelae, the resulting
loss of work from disability, and the pain incurred from the illness, these
costs would favor vaccination over no vaccination. For example, incorporating
costs due to loss of work decreased the cost-effectiveness ratio of vaccination
by about $10 000/QALY saved. In addition, the model does not incorporate
the cost of imperfect diagnostic capabilities of the clinician and laboratory
tests or address the general fear and anxiety that residents of an endemic
area experience as a result of their risk for Lyme disease.
Vaccination against Lyme disease does not protect against other tick-borne
illnesses such as babesiosis and ehrlichiosis.38, 39, 40, 41, 42
Although the seasonal risk of these other tick-borne illnesses are currently
less than that for Lyme disease, vaccination may increase the incidence of
these illnesses since individuals may be less likely to take precautions.
The use of precautionary behavior is an important aspect in determining the
cost-effectiveness of a Lyme disease vaccine. For the purposes of this analysis,
the attack rate estimates the current level of precautions taken by individuals
in varying areas. If precautionary behavior were to increase, this would be
reflected in the yearly attack rate (Figure
4). The cost of an intervention to change tick bite precautionary
behavior is unknown at this time.
Lyme disease vaccination is approved for a 3-injection series over a
1-year period. Data suggest that an accelerated vaccination series during
a 6-month and 2-month series may also be effective.43, 44
This accelerated vaccination series increased the cost-effectiveness of the
vaccination since there is a smaller likelihood that there will be an episode
of Lyme disease between the second and third shot series if one assumes that
full (2-year) efficacy shown in the trials can be achieved in the first year.
Little is known about the duration of protection against Lyme disease
with the vaccination. We assumed in this model that there would be adequate
protection for 1 year after the series is completed. In a sensitivity analysis,
the cost-effectiveness increased to $72 700/QALY if a yearly booster
shot is required for persisting efficacy. One study shows that individuals
vary in their ability to mount an immune response against the OspA protein,
particularly with regard to age.10 It is likely
that both the duration and strength of protection against B burgdorferi varies on an individual basis and additional information
is necessary to determine the true duration of protection.
The availability of the Lyme disease vaccination is an important adjunct
in managing the increasing risk of Lyme disease in endemic areas. Guidelines
are necessary for appropriate use of vaccination, both from an individual
and societal point of view. Our analysis, which incorporates health state
utilities and factors in management costs of the late sequelae of Lyme disease,
demonstrated that in areas with a seasonal rate of Lyme disease of greater
than 1%, vaccination of individuals compares somewhat favorably with other
preventive treatments. Residents living in these areas may be appropriate
recipients for vaccination against Lyme disease.
AUTHOR INFORMATION
Accepted for publication August 15, 2000.
This work was supported in part by grants AR-43653, AR 02033, and AR-36308
from the National Institutes of Health (National Institute of Arthritis and
Musculoskeletal and Skin Diseases). Dr Shadick is the recipient of a KO8 Mentored
Clinical Scientist Award.
Reprints are not available from the authors.
From the R. B. Brigham Multipurpose Arthritis and Musculoskeletal Diseases
Center (Drs Shadick and Liang and Mss Phillips and Fossel), the Department
of Medicine, Division of General Medicine and Primary Care (Drs Liang and
Kuntz), Division of Rheumatology, Immunology and Allergy (Drs Shadick and
Liang), Brigham and Women's Hospital, Harvard Medical School, and the Department
of Health Policy and Management (Dr Kuntz), Harvard School of Public Health,
Boston, Mass. Dr Shadick has received research support from SmithKline Beecham.
REFERENCES
| |
1. Steere AC, Grodzicki RL, Kornblatt AN, et al. The spirochetal etiology of Lyme disease. N Engl J Med. 1983;308:733-740.
ABSTRACT
2. Steere AC. Lyme disease. N Engl J Med. 1989;321:586-596.
ABSTRACT
3. Centers for Disease Control and Prevention. Lyme disease—United States, 1996. MMWR Morb Mortal Wkly Rep. 1997;46:531-535.
PUBMED
4. Cartter ML, Farley TA, Ardito HA, Hadler JL. Lyme disease prevention: knowledge, beliefs, and behaviors among high
school students in an endemic area. Conn Med. 1989;53:354-356.
PUBMED
5. Herrington JEJ, Campbell GL, Bailey RE, et al. Predisposing factors for individuals' Lyme disease prevention practices:
Connecticut, Maine, and Montana. Am J Public Health. 1997;87:2035-2038.
FREE FULL TEXT
6. Shadick NA, Daltroy LH, Phillips CB, Liang US, Liang MH. Determinants of tick-avoidance behaviors in an endemic area for Lyme
disease. Am J Prev Med. 1997;13:265-270.
ISI
| PUBMED
7. Shadick NA, Phillips CB, Logigian EL, et al. The long-term clinical outcomes of Lyme disease: a population-based
retrospective cohort study. Ann Intern Med. 1994;121:560-567.
FREE FULL TEXT
8. Asch ES, Bujak DI, Weiss M, Peterson MG, Weinstein A. Lyme disease: an infectious and postinfectious syndrome. J Rheumatol. 1994;21:454-461.
ISI
| PUBMED
9. Maes E, Leconte P, Ray N. A cost of illness study of Lyme disease in the United States. Clin Ther. 1998;20:993-1008.
FULL TEXT
|
ISI
| PUBMED
10. Steere AC, Sikand V, Meurice F, et al. Vaccination against Lyme disease with recombinant Borrelia burgdorferi outer-surface lipoprotein A with adjuvant. N Engl J Med. 1998;339:209-215.
FREE FULL TEXT
11. Sigal LH, Zahradnik JM, Lawrence DA. A vaccine consisting of recombinant Borrelia burgdorferi outer-surface protein A to prevent Lyme disease. N Engl J Med. 1998;339:216-222.
FREE FULL TEXT
12. Meltzer MI, Dennis DT, Orloski KA. The cost-effectiveness of vaccinating against Lyme disease. Emerg Infect Dis. 1999;5:321-328.
ISI
| PUBMED
13. Sonnenberg FA, Beck JR. Markov models in medical decision making: a practical guide. Med Decis Making. 1993;13:322-338.
14. Gold MR, Siegel J, Russell LB, Weinstein MC. Cost Effectiveness in Health and Medicine. New York, NY: Oxford University Press; 1996.
15. Steere AC, Bartenhagen NH, Craft JE, et al. The early clinical manifestations of Lyme disease. Ann Intern Med. 1983;99:76-82.
16. Steere AC, Taylor E, Wilson ML, Levine JF, Spielman A. Longitudinal assessment of the clinical and epidemiological features
of Lyme disease in a defined population. J Infect Dis. 1986;154:295-300.
ISI
| PUBMED
17. Hanrahan JP, Benach JL, Coleman JL, et al. Incidence and cumulative frequency of endemic Lyme disease in a community. J Infect Dis. 1984;150:489-496.
ISI
| PUBMED
18. Magid D, Schwartz B, Craft J, Schwartz JS. Prevention of Lyme disease after tick bites: a cost-effectiveness analysis. N Engl J Med. 1992;327:534-541.
ABSTRACT
19. Nichol G, Dennis DT, Steere AC, et al. Test-treatment strategies for patients suspected of having Lyme disease:
a cost-effectiveness analysis. Ann Intern Med. 1998;128:37-48.
FREE FULL TEXT
20. Steere AC, Schoen RT, Taylor E. The clinical evolution of Lyme arthritis. Ann Intern Med. 1987;107:725-731.
21. Shrestha M, Grodzicki RL, Steere AC. Diagnosing early Lyme disease. Am J Med. 1985;78:235-240.
FULL TEXT
|
ISI
| PUBMED
22. McAlister HF, Klementowicz PT, Andrews C, Fisher JD, Feld M, Furman S. Lyme carditis: an important cause of reversible heart block. Ann Intern Med. 1989;110:339-345.
23. Steere AC, Taylor E, McHugh GL, Logigian EL. The overdiagnosis of Lyme disease. JAMA. 1993;269:1812-1816.
ABSTRACT
24. Rubin D, Sorbera C, Nikitin P, McAllister A, Wormser GP, Nadelman RB. Prospective evaluation of heart block complicating early Lyme disease. Pacing Clin Electrophysiol. 1992;15:252-255.
FULL TEXT
| PUBMED
25. Reik L, Burgdorfer W, Donaldson JO. Neurologic abnormalities in Lyme disease without erythema chronicum
migrans. Am J Med. 1986;81:73-78.
ISI
| PUBMED
26. Pachner AR, Duray P, Steere AC. Central nervous system manifestations of Lyme disease. Arch Neurol. 1989;46:790-795.
ABSTRACT
27. Clark JR, Carlson RD, Sasaki CT, Pachner AR, Steere AC. Facial paralysis in Lyme disease. Laryngoscope. 1985;95:1341-1345.
ISI
| PUBMED
28. Lui NY, Dinerman H, Levin RE. Randomized trial of doxycycline vs amoxicillin/probenecid for the treatment
of Lyme arthritis: treatment of non-responders with IV penicillin or ceftriaxone
[abstract]. Arthritis Rheum. 1989;32:S46.
29. Logigian EL, Steere AC. Clinical and electrophysiologic findings in chronic neuropathy of Lyme
disease. Neurology. 1992;42:303-311.
FREE FULL TEXT
30. Dattwyler RJ, Halperin JJ, Volkman DJ, Luft BJ. Treatment of late Lyme borreliosis—randomised comparison of ceftriaxone
and penicillin. Lancet. 1988;1:1191-1194.
ISI
| PUBMED
31. Karlsson M, Hammers-Berggren S, Lindquist L, et al. Comparison of intravenous penicillin G and oral doxycycline for treatment
of Lyme disease: recognition and management. Neurology. 1994;44:1203-1207.
FREE FULL TEXT
32. Dinerman H, Steere AC. Lyme disease associated with fibromyalgia. Ann Intern Med. 1992;117:281-285.
33. Torrance GW, Boyle MH, Horwood SP. Application of multi-attribute utility theory to measure social preferences
for health states. Oper Res. 1982;30:1043-1069.
FULL TEXT
|
ISI
| PUBMED
|
