In this study, we evaluated the clinical impact of IgM reactivities in Borrelia testing of serum and CSF, and whether the results actually enhance the clinicians’ way to a proper diagnosis or rather misguide them. By looking at all positive Borrelia-specific antibody tests in serum in Jönköping County during the year 2017, we found that merely 30% of the tests were taken according to current guidelines. The proportion of borrelia tests taken in accordance with the recommendations is presumably even lower in the group with negative test results (n = 3700), but this has not been investigated here. This finding is similar to what has been shown in other studies where as much as up to 82% of tests had been taken in contradiction with current guidelines [10, 11] Most certainly, this fact emphasizes that serological testing without distinct clinical signs/symptoms consistent with LB contributes to most misdiagnoses.
When looking at the results of the tests taken according to recommendations, there is no clinical enhancement for dual IgM and IgG positivity compared to isolated IgG positivity to be seen when it comes to establishing a correct diagnosis (Fig. 2). Hence, no added value of IgM detection in serum could be seen in this group.
Furthermore, the proportion of patients receiving a LB diagnosis was higher in the group with both IgM and IgG positivity compared to the group with isolated IgG positivity, and as seen during our review of the patients’ medical records, clinicians tend to believe that a present IgM response is required for an active infection, whereas the lack of IgM positivity rather speaks against an active infection. In several cases with IgG positivity alone, the physicians had decided not to treat the patient with antibiotics even though the LB diagnosis seemed quite obvious with specific symptoms and correct serologic findings. As an example, ACA was ruled out in a patient because the lack of IgM antibodies even though a long-standing skin rash and high Borrelia-specific IgG levels were present.
Isolated IgM positivity in serum is quite rare in the group of patients tested in accordance with the recommendations. Isolated IgM showed very limited clinical value and needs further assessment in order to offer any guidance at all. The analyzing laboratory should either have a routine of confirming specificity with an immunoblot, or instead recommend a follow-up test 4– weeks later. In suspected LNB cases, a lumbar puncture should be performed and the presence of intrathecally produced Borrelia-specific antibodies should be investigated.
When analyzing the borrelia tests taken without proper indication, we noticed the same pattern regarding the presence of IgM positivity and its effect on whether a LB diagnosis was made or not. Clinicians connect a positive IgM with an active infection and are more inclined to interpret it as an actual and on-going infection, regardless of the lack of specific symptoms. The result is that patients acquire a very doubtful diagnosis and receive treatment with antibiotics on incorrect grounds. Isolated IgM reactivities in the group of patients tested outside current recommendations, EM patients excluded, were more frequently assessed as unspecific in this study.
In this perspective, IgM reactivities, as well as lack of them, seem to be more harmful than helpful in LB diagnosis, causing both over- and underdiagnosis, overuse of antibiotics and delay of proper diagnosis and treatment. For the patients, delay of correct diagnosis may be associated with prolonged suffering and anxiety, and for the healthcare system, with increased costs.
In our patients with paired serum and CSF analyses, we noticed that among 15 patients with positive Borrelia-specific CSF/serum AI, 3/11 confident diagnoses of LNB would have been missed if IgM AI analyses had not been performed. All three patients were children, two with symptoms of meningitis and one with a one sided facial palsy, and all had elevated IgM AI only. Thus, determination of Borrelia-specific IgM AI increased the diagnostic sensitivity for the IDEIA Lyme neuroborreliosis assay. Furthermore, two of these three children had no detectable levels of Borrelia-specific antibodies in serum, which underscores the necessity of performing CSF analysis in suspected LNB cases.
Our findings suggest that IgM testing in serum is potentially more harmful than helpful in LB diagnosis. However, the main problem seems to be the large amount of tests taken outside the current recommendations, i.e., with very low pre-test-probability, and our suspicion is that many clinicians lack the proper knowledge regarding how to use and interpret serologic findings in LB diagnosis, and have very high faith in especially IgM positivity. Based on our assessments in this study, our conclusion is that IgM testing in serum causes more unreliable diagnoses and mistreatments, and should therefore be excluded in future testing, except when the analysis is paired with a simultaneous CSF analysis. Perhaps, another possibility could be that the laboratory would demand explicit and distinct clinical information on the referral and only perform IgM testing in cases where it actually could be useful, such as early LNB, LC, and BL as suggested by Dessau et al . At least, isolated IgM reactivities in serum samples should not be reported uncritically by the laboratory without further confirmation, either with immunoblot or another EIA with different antigen composition.