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: alakos@t-online.hu 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.

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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

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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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