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The Positive Predictive Value of Borrelia burgdorferi serology in the light of symptoms of patients sent to an outpatient service for tick-borne diseases
Inflammation ResearchDOI 10.1007/s00011-010-0209-1
Running head: Predictive Value of Lyme tests
András Lakos, M.D., PhD,1 Jenő Reiczigel PhD2 and Norbert Solymosi D.V.M. PhD3
(1) The Centre for Tick-borne Diseases, Budapest, Hungary
(2) Szent István University, Faculty of Veterinary Science, Budapest, Hungary
(3) Adaptation to Climate Change Research Group, Hungarian Academy of
Sciences, Budapest, Hungary
Address for correspondence: András Lakos, The Centre for Tick-borne Diseases, Budapest,
Hungary, H-1132 Budapest, Visegrádi 14, Hungary, email: [email protected] Tel: 3630-
961-9134; Fax: 361-2505860
Keywords: Borrelia burgdorferi antibody testing, false positivity, positive predictive value,
specificity of Lyme serology
Word count of the text: 2753
Word count of the abstract: 140
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Abstract
Objective
By using the published incidence of Lyme borreliosis in endemic regions of the World and
the sensitivity and specificity data of the best Lyme serological tests, we computed the
positive predictive value of Borrelia burgdorferi antibody testing.
Methods
The calculation of predictive value was based on Bayes’ theorem. We also analyzed the
frequency distribution of the specific and non-specific symptoms and complaints of 27,194
patients sent to the Centre for Tick-borne Diseases in Budapest from 1986 to 2008.
Results
This evaluation demonstrated that practitioners often use Lyme serology in a “trial and error”
way, without any reasonable ground. According to our calculation the positive predictive
value of the best Lyme antibody tests if applied in this way is <9.1%.
Conclusion
Our study suggests that the present practice of applying Lyme serological tests may result in
more harm than benefit.
3
Abbreviations:
ACA - acrodermatitis chronica atrophicans
BL - Borrelia lymphocytoma
ELISA – enzyme linked immunosorbent assay
EM - erythema migrans
Lb - Lyme borreliosis
LMR - lymphocytic meningoradiculitis
TIBOLA - tick-borne lymphadenopathy
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Introduction
Lyme borreliosis is the most frequent vector-borne disease in the temperate zone of the
Northern hemisphere. Borrelia burgdorferi infection is often suspected to be the cause of
many different complaints and symptoms and, even when the symptoms are not typical for
Lyme borreliosis (Lb), antibody testing is ordered by general practitioners as well as
specialists. The more serious and long-lasting is the disease, the higher the chance of testing
for Borrelia burgdorferi antibody. Abundant use of serology tests is supported by recent
numbers reported by Binnicker et al. that Borrelia serology was performed at the Mayo Clinic
more than 75,000 times in one year, and about 2.5 million times per year in the USA [1].
Already more than a decade ago, Tugwell et al. warned against testing patients with
nonspecific signs and symptoms (headache, fatigue, myalgia, arthralgia etc.) when the pretest
probability is <0.20 or >0.80 (ie. in cases with reasonable suspicion of EM). They described
that testing patients with low pre-test probability may result in more false than true positives
[2].
The present study consists of two parts. First we present the data of some relevant
publications dealing with the incidence of Lb and sensitivity/specificity of the best Borrelia
burgdorferi antibody tests [3-8] These data are needed for the calculation of positive
predictive value of a B. burgdorferi antibody test. In the second part, we analyze the
composition of symptoms of patients visiting our outpatient service specializing in Lb
diagnostics to check what proportion of Lyme serology tests are ordered in case of non-
specific symptoms and how this influences its predictive values.
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Materials and methods
We collected the most relevant incidence data for Lb and sensitivity/specificity of the most
sensitive and specific Borrelia antibody tests as they were published [3-8]. Based on this
information, the positive predictive value, or post-test probability after a positive test result, of
a Borrelia antibody test result was calculated according to equation (1),
(1)
where A, and B denote Lb, lack of Lb, and positive test result, respectively, is the
positive predictive value, is the sensitivity, is 1–specificity, and is the
pre-test probability of Lb [9]. We considered the yearly incidence rate of Lb as pre-test
probability, which is the usual way in case of curable diseases with relatively short mean
duration [10-12]. Note that for Lb this might result in an optimistic (higher than true) positive
predictive value because the mean duration of the disease is less than one year.
The leading symptoms and/or complaints of patients who were advised to visit the Centre for
Tick-borne Diseases, Budapest in the period from 1986 to 2008 with the suspicion of having
Lb were identified and ranked by frequency. Patients, including children as well as adults,
were sent by family doctors and specialists from all over Hungary. We handled complaints
and symptoms together. When we mention “musculoskeletal” symptom arthralgia, myalgia,
small and large joint arthritis are covered by the same term. We did not separate paraesthesia
and ENG-proven neuritis.
We divided the patients into two groups. The first group consisted of patients with specific
clinical symptoms that enable to set up the diagnosis without serology. Typical signs of
Borrelia burgdorferi infection included erythema migrans (EM), Borrelia lymphocytoma
(BL), lymphocytic meningoradiculitis (LMR), acrodermatitis chronica atrophicans (ACA).
Another recently described rickettsial illness, the tick-borne lymphadenopathy – TIBOLA
[13] with characteristic clinical symptoms was also allocated to this group.
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The second group consisted of patients with other, non-specific symptoms and/or complaints
like musculoskeletal pain, headache, etc. Patients having both specific and non-specific
symptoms and/or complaints (e.g. EM with accompanying arthralgia), were enrolled in the
group with specific symptoms. The number of patients suspected to have Central European
tick-borne encephalitis or tularaemia was very low (<5 per year for both diseases together),
therefore these patients were disregarded.
During the 22-year study period we applied different serological methods with diverse
sensitivity/specificity characteristics, but in the present work we do not use the serological
results obtained in our laboratory. We focus on the specific and non-specific clinical signs
present in our patients.
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Results
Incidence of Lyme borreliosis in endemic areas
The maximal incidence of Lb in the United States is 100 reported cases per 100,000 people
per year. The average incidence in the endemic region (in the 10 “reference states”) is about
30/100,000 per year [3]. Except for the southern region of Europe (Greece, Italy, Spain,
Portugal) and Great Britain, the published incidence of Lb is >10/100,000 per year throughout
Europe [7]. In Hungary, the reported incidence of Lb is 20/100,000 per year. We estimate that
the actual incidence in Hungary is five times higher than the reported incidence. Our estimate
is supported by the incidence data of Lb in neighbouring countries (Austria and Slovenia)
where they are >100/100,000 per year .The range of Lb incidence in the endemic part of the
world is reported as 10 to 206/100,000 per year [7, 8]. The true incidence is probably higher
because 10% of Borrelia infections remain asymptomatic or unrecognized [14].
Sensitivity of B. burgdorferi sl. antibody tests
The typical initial sign of Lb, EM, appears in 60-80% of infected people [15, 16]. The
sensitivity of the test depends on many inherent components, but the most important factor is
the number of early infections (EM patients) among those examined. If these patients visit the
medical service shortly after the appearance of EM, the antibody response is still
undetectable. Therefore, the maximal sensitivity is likely to be <90% [4, 17]. In these cases, if
the infection is not generalized, most patients have no detectable antibody response shortly
after presenting this early clinical sign. The intensity of the immune response depends mainly
on the time elapsed between the onset of clinical symptoms and serological testing/antibiotic
treatment [18,19]. In a European immunoblot study, the maximal accessible sensitivity was
only 66% with a specificity of 99% [5]. The same results have been published in a US study
with C6 IgG ELISA [4]. In another report the performance of C6 ELISA was better, with 87%
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sensitivity and 99% specificity [17]. To our knowledge this is the best performance of Lyme
diagnostic test that has ever been published.
The specificity of B. burgdorferi sl. antibody tests
Detection of Borrelia antibody may be related to a past or convalescent infection, therefore
seropositivity does not imply that a current clinical symptom is actually due to Lb. This is the
most important reason (beside cross reactivity) why no serological test for actual Lb can have
a specificity of 100% in an endemic region. Ninety-nine percent specificity is a generally
accepted threshold for a high standard Borrelia antibody test. Higher specificity than 99% has
never been published. In many studies, serological tests with 98% specificity are considered
to be excellent [6, 20-22].
A positive Borrelia antibody test has been reported in >5% of the healthy population in many
seroprevalence studies [23, 24]. Recently, the Food and Drug Administration accepted a new
serodiagnostic test (C6 ELISA) with similar sensitivity and specificity than two-tier testing
(sensitive ELISA followed by a more specific immunoblot if the ELISA is positive or
borderline) [4, 6]. According to the package insert of the C6 ELISA kit, the prevalence of a
positive antibody reaction among healthy blood donors was 3% in an endemic region [21].
This means that the specificity of this test in an endemic region is only 97%.
The positive predictive value of Lyme borreliosis antibody testing
Assume that we have a high standard serology test with 90% sensitivity and 99% specificity.
As noted above, these limits are the most optimistic ones at present. The average incidence of
Lb is expected to be about 1/1000 per year in the endemic region of the World (probably for
Hungary, too). Under these assumptions, considering a one-year period 10 Lb cases are
expected among 10,000 people examined. The 90% sensitivity implies that nine of these
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patients will be test positive. Based on the 99% specificity, there will be about 100 false
positives (0.01*9990=99.9), so altogether 109 positive results will be registered. Therefore,
the probability that a positive result reflects to an actual Borrelia burgdorferi infection is only
9/109 = 8.3%. Even with a sensitivity of 100%, the positive predictive value turns out to be as
low as 9.1%.
To illustrate the calculation, Figures 1 and 2 show the positive predictive values assuming
99% and 98% specificities, respectively. A test with 98% specificity will have half of the
predictive value of a test with 99% specificity. We developed a simple computer program
based on formula (1) for the calculation of the positive predictive value of a diagnostic test
given the incidence, specificity, and sensitivity (available at http://kullancs.hu/orvosoknak).
Analysis of patients of the Centre for Tick-borne Diseases, Budapest
We considered 21,614 complaints/symptoms of 19,659 patients with non-specific symptoms
thought to be suggestive for Lb and 7696 typical Lb symptoms of 7293 patients, as well as
242 patients with TIBOLA which is a newly recognized Rickettsia slovaca infection with
characteristic clinical symptoms [13]. The number of symptoms was higher than the number
of patients due to repeated visits of the same patient with new symptoms. Following EM, the
second most frequent type of symptom and/or complaint was musculoskeletal (Figure. 3).
Five percent of these patients had a well-supported diagnosis of juvenile rheumatoid arthritis,
rheumatoid arthritis, primer chronic polyarthritis, gout, or psoriasis. Nevertheless, the
practitioners requested the B. burgdorferi antibody tests. The clinical characteristic and
serology (very strong antibody reaction for B. burgdorferi) supported Lyme arthritis in only
2% of this group). The third most frequent type of symptom was dermatological. Nearly half
of the dermatological patients had a clinically characteristic dermatological illness, such as
morphea, granuloma anulare, erythema nodosum, microsporiasis, urtica, psoriasis, eczema,
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contact dermatitis, fixed drug eruption, Schamberg’s purpura, vitiligo, or foreign body
reaction after tick bite. No one in this group proved to have B. burgdorferi infection based on
clinical symptoms and serology.
Polyneuropathy/paraesthesia, headache, and fever were the next most frequent complaints that
motivated clinicians to request a Lyme serology test. Among the reported
psychological/psychiatric diseases, panic syndrome and memory disturbances were the most
frequent, but major depressive disorder, bipolar psychosis, and even schizophrenia were given
as reasons for Borrelia antibody examination. Proportion of patients having positive Lyme
serological result in the above mentioned groups was < 2%, similarly to the general
population. The category “no clinical symptoms/complaints” in Figure 3 refers to screening
tests of healthy people who were at high risk for tick bites (forestry workers, orienteer, and
hunters).
The proportion of specific symptoms that reflect tick-borne diseases (i.e., EM, ACA, BL,
LMR, TIBOLA) among all symptoms was 26.0%.
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Discussion
Huge numbers of serology tests performed in low-risk groups imply masses of false positives.
Aguero-Rosenfeld et al. [18], calculating with about 2.7 million tests done per year in the
United States, concluded that each 1% reduction in test specificity would produce
approximately 27,000 false positive results per year, while the incidence of disease is about
20,000 cases/year. In particular, a decrease of specificity from 99% to 98% doubles the
number of false positives. It should be stressed that a specificity of 98% for a Borrelia
antibody test is still very good; none of the seven commercial ELISA kits and two
immunoblot tests we examined fulfilled this (unpublished data). In a European multicenter
Lyme immunoblot study, in which the most acknowledged six laboratories participated, only
one reached the 99% specificity at the expense of very low sensitivity (56%) [5].
Targeted Lyme serological testing of EM patients is unnecessary because if a patient has
typical EM that fulfills the case definition, treatment for Lb should be started immediately,
without waiting for the serological result. Moreover, many of the EM patients are still
serologically negative. Thus, the serological result does not influence treatment in this patient
group. If physicians recognize this fact and do not request Borrelia antibody testing for EM
patients, sensitivity theoretically can approach 100% due to the exclusion of such patients
who might probably be false negatives if tested (i.e. the later forms of Lb are usually
serologically positive). Since early and later forms of Lb usually accompanied by
musculoskeletal symptoms, it is not surprising that the second main complaint of patients
visiting our Centre was of musculoskeletal type. Neck and low back pain occur in 31% of the
adult population [25], frank arthritis in 21% [26], and any type of musculoskeletal pain in
>50% of adults [27]. Fifty percent means the incidence of 500/1000 per year and it is 500
times more frequent than Lb (1/1000 per year). Therefore, on the basis of these complaints
alone, physicians might erroneously suspect Lb in more than half of the population.
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In Figure 3, grey bars represent non-specific symptoms. With the exception of facial palsy,
which has a higher-than-average Borrelia etiology (>9.4% in our previous study) [28], test for
B. burgdorferi antibodies in these cases can be considered as a screening test in the general
population. Although our data cannot be considered representative of all laboratories in which
Lb testing is a frequent task, we believe that most Borrelia antibody testing is performed to
clarify the etiology of non-specific symptoms. Our view is also supported by data from other
countries [1]. Patients and their doctors would like to change the diagnosis of an incurable
disease (e.g., multiple sclerosis, rheumatoid arthritis) to a curable one (i.e., Lb) or a disease of
unknown origin to a disease with a clear-cut etiology. Therefore, there is a strong pressure on
doctors to test for Borrelia antibodies in patients suffering from diseases of serious course
and/or unknown origin. This pressure leads to the substantial consumption of B. burgdorferi
antibody tests. We experienced that physicians regularly order Borrelia antibody tests for
anybody who has any kind of symptoms which may resemble to Lyme borreliosis. They test
patients with any type of musculoskeletal symptoms, round like dermatological eruption
autoimmune or neurodegenerative illnesses, psychiatric and psychological diseases, headache,
fever, memory loss, and even after the faint suspicion of a tick bite. Our study suggest that
occurrence of Borrelia sl. infection in this population is equal to the average population, that
means 0.1%, which 200 times smaller than the “lower” prevalence given in the example of
Brown et al. [29]
In the interpretation of a test result, the clinician should use the available epidemiological and
clinical data. Bayes’ theorem [9] allows the incorporation of the pre-test probability of a
particular disease and the specificity and sensitivity of a test into the quantitative estimation of
the post-test probability of a disease. If a Borrelia burgdorferi antibody reaction is used in an
endemic population with average incidence of Lb, or, equivalently, among people with
nonspecific signs of Lb, the positive predictive value is surprisingly low. Our study
13
demonstrated that the maximum positive predictive value is <9.1% even when the sensitivity
is 100%. Most clinicians find it unbelievable that a high standard diagnostic test may result in
predictive values as low as these [30, 31].
Although use of these tests in the absence of high pre-test probability (ie. specific symptoms
of Lb) has long been discouraged, our study is the first illustrating that the positive predictive
value of Borrelia burgdorferi antibody tests, as they are usually applied in everyday praxis, is
surprisingly low. Moreover, there is no reason for using such tests in cases of high pre-test
probability (i.e. in cases of EM) when the clinical symptom is more specific and sensitive
than the serological result could be. Our study suggests that consuming Lyme serological tests
in the recent practice results in more harm than benefit. A false-positive Borrelia antibody test
results in repeated and unnecessary antibiotic treatments, and additionally, in delayed
recognition of the correct diagnosis. Moreover, subsequent complaints will suggest the
possibility of Lb “relapse.” Most patients with falsely diagnosed Lb do not heal after repeated
courses of antibiotic treatments, or their symptoms will relapse, which augments the false
belief of chronic and incurable Lb.
One can ask whether we should discard B. burgdorferi antibody testing in the light of the
above results. Surely not. The solution could be sample pair examinations. When the clinical
symptoms are not suggestive for Lb and the serology shows reaction above the cut-off,
instead of antibiotic treatment a second sample drawn a few weeks or months later should be
tested in parallel with the previous one. If a serological progression is seen, an actual B.
burgdorferi infection is proven, otherwise the diagnosis can be ruled out. We are working on
defining the rules and characteristics of the serological progression in untreated Lb.
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Ethics
A part of this study is a retrospective epidemiological evaluation of our patients’ data going
back over 22 years; consequently, written informed consent has not been sought from the
patients. All examination and intervention was a part of the routine clinical practice. The
study was approved by the Expert Committee of the Hungarian Society for Infectious
Diseases.
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The corresponding author had full access to all of the data in the study and takes
responsibility for the integrity of the data and the accuracy of the data analysis and has final
responsibility for the decision to submit the manuscript for publication.
Dr. Lakos designed the study, provided the clinical data and wrote the manuscript, Dr.
Solymosi computed the statistical analysis and made the graphs. Dr. Reiczigel checked the
statistical analysis and provided valuable suggestion for rewriting the text after reviewer
comments.
The study has not been supported financially by any source.
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Figure legends
Figure 1. Positive Predictive Value of a Borrelia Antibody Test assuming 99%
Specificity. The curves illustrate the positive predictive value in percents depending on
sensitivity and pre-test probability. E.g. if the test has 90% sensitivity and the examined
patients live in an endemic area where Lyme borreliosis incidence is 1/1000 per year
(intersection of the dashed lines), then the positive predictive value of the test is 8.3%.
Figure 2. Positive Predictive Value of a Borrelia Antibody Test assuming 98%
Specificity. The curves illustrate the positive predictive value in percents as a function of
sensitivity and pre-test probability. E.g. if the test has 90% sensitivity and the examined
patients live in an endemic area where Lyme borreliosis incidence is 1/1000 (intersection of
the dashed lines), then the positive predictive value of the test is 4.3%.
Figure 3. Frequency of Main Symptoms as the Reason for Borrelia burgdorferi
Antibody Testing in Patients Who Visited the Centre for Tick-borne Diseases in
Budapest from 1986 to 2008. The graph is based on 29,552 symptoms of 27,194 patients. A
patient could have more symptoms due to repeated visits. Grey bars represent non-specific
symptoms, whereas black bars show specific symptoms that are diagnostic for tick-borne
diseases.
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