When do symptoms mean Lyme disease?

Is it Possible to Make a Valid Diagnosis of Lyme Disease Based on Symptoms Alone?

Lyme disease has been defined historically in the United States as a tick-borne infectious disease caused by a bacterial spirochete, Borrelia burgdorferi sensu stricto (1). It was named for the town of Old Lyme, Connecticut, near where it was discovered in the U.S. in the mid-1970s. It also has been called “the great imitator” because its symptoms are said to resemble those associated with several unrelated medical conditions.

However, the fact that there are more than 350 medical conditions with symptoms very similar to those often attributed to Lyme disease (2), renders it extremely difficult—if not impossible—to make a valid diagnosis of Lyme disease based on symptoms alone, even in situations where the diagnosis of Lyme disease might seem to be most likely.

For example, individuals living in endemic areas and exposed to ticks may develop a “bulls-eye” or erythema migrans (EM) rash that may be sufficiently pathognomonic for Lyme disease to justify antibiotic therapy with no additional testing; however, such a rash is present in 70-80% — not 100%– of those who acquire Lyme disease, and is sometimes mistaken for other types of skin reactions (3, 4).

Although some consider the appearance of facial palsy a hallmark feature of Lyme disease, it is sometimes expressed in patients with other medical conditions, including several common viral infections (5). Even in regions where Lyme disease is endemic, 3 of 4 facial palsies are unrelated to Lyme disease (6).

The Centers for Disease Control and Prevention (CDC) conducts annual surveys of undiagnosed symptoms that commonly occur in the general population of the U.S. They report that about 15% of women and 10% of men in the general population of the United States felt exhausted or extremely tired (fatigued) either every day or most days of the preceding 3 months (7), and that about 16% of men and 22% of women experienced pain in the past 3 months (8). It is estimated that nonspecific irritable bowel symptoms affect about 11% of the general population (9).

Subjective cognitive decline (SCD) is a form of impairment in which more frequent or worsening confusion or memory loss can affect the ability to care for oneself. Among adults aged > 45 years, 11.2% reported SCD, including 10.4% of adults aged 45-54 years (10). In a 2016 study, the CDC noted that about 20% of U.S. adults (approximately 20 million) had high-impact chronic pain linked to restrictions in mobility and daily activities, dependence on opioids, anxiety and depression, and poorly perceived health or reduced quality of life (11).

The Institute of Medicine (IOM) reports that nonspecific chronic pain affects 100 million Americans, about 30% of the general population; such individuals go from one physician to another, unable to find anyone who can identify the cause of their pain or suggest a remedy (12). Individuals who believe that they have “chronic Lyme disease”, a poorly defined condition that occurs in about 10-15% of patients previously treated for Lyme disease, might well be included in the above noted study groups, simply based on the presence of symptoms that are widely prevalent in the general population and occur with about the same frequency.

Although the diagnosis of Lyme disease is sometimes described as a “clinical judgement”, this can mean different things to different people. The term generally implies a clinical judgement based on the results of a large body of evidence derived from peer-reviewed research, i.e., evidence that is generally accepted by well-informed physicians in the medical community at large. To date, a PubMed search of the scientific literature reveals more than 12,000 publications dealing with practically every aspect of Lyme disease.

Since its discovery in the United States in the mid-1970s, we have learned much about the cause, diagnosis, and treatment of Lyme disease. It is not the strange and mysterious disease that uninformed individuals imagine it to be, nor is it “a disease without a cure” as some have proclaimed falsely. A physician who is board certified in the specialty of infectious diseases surely is “Lyme literate” and should know how to diagnose and treat Lyme disease; the same is true for general practitioners in endemic areas with much experience treating patients with Lyme disease.

Lyme disease conforms to the same fundamental rules and principles that apply to other infectious diseases. This likewise applies to the host immune response to B. burgdorferi and/or its various cell surface antigens. There are no “special rules” that apply only to Lyme disease, and one does not need to acquire “special training” or insights in medical school — or anywhere else for that matter — just to learn how to diagnose and treat Lyme disease. Although there is abundant knowledge upon which to base a rational clinical judgement, the results of an approved and correctly performed objective laboratory test certainly are invaluable in making a valid diagnosis of Lyme disease.

Two-tier testing has long been accepted as the standard procedure for the laboratory diagnosis of Lyme disease (13, 14). Unfortunately, there is much false and misleading information about its accuracy and reliability. For example, it is often stated that the criteria used for the interpretation of Western blots used in the second step of the two-step procedure were selected arbitrarily. Instead, they were based on the results of a rigorous statistical analysis of Western blots for hundreds of patient and control specimens that revealed 8 IgM bands associated with early infection, and 10 IgG bands detected 4-6 weeks after infection (15).

When receiver operating characteristic (ROC) curves, which are plots of sensitivity vs specificity, were constructed for the most common IgM bands detected in early infection, as well as for the most common IgG bands detected after several weeks of infection, the area under each optimal ROC curve indicated that the minimum number of bands required to obtain 99% specificity, was at least 2 for IgM bands, and at least 5 for IgG bands; this gave the greatest incidence of unequivocal positive values in combination with the lowest incidence of false positive values (15).

These objective findings provide the foundation for the criteria recommended by the CDC for Western blots now being used in two-tier testing for Lyme disease (14). Note that recombinant proteins now have replaced undefined whole-cell sonicates as ligands in Western blots; this has not only increased sensitivity and precision, but also has considerably reduced intra-laboratory variation in the results obtained.

Comparisons were made between the results obtained using the standard two-tiered test procedure vs those obtained using ELISA tests performed with whole-cell sonicates (WCS) or different well-defined and highly specific peptides (C6 or VlsE) as ligands (16). They showed that, in assays of specimen samples collected 4-6 weeks or longer after infection, there was complete agreement in all cases, thereby confirming the reliability of standard two-tier testing done late after infection (16). However, for comparisons made using specimens from patients with acute EM and during early infection, greater sensitivity (25-50%) was noted for ELISAs using the defined ligands than for ELISAs using whole-cell sonicates (16-38%).

Since Borrelia replicate (divide) at a slow rate (once every 12 hours), it may not be possible to realize much greater gains in sensitivity and the earlier detection of antibody; it simply takes time for enough antibodies to be generated by the host immune system in response to Borrelia antigens, even when these extremely sensitive methods are used for their detection (13).

The results of other comparative studies also suggest that the use of two ELISAs conducted with defined ligands (C6 and VlsE) give results comparable to those obtained using the conventional two-tier procedure.   Although this suggests that the use of two ELISAs using defined ligands might obviate the need for doing Western blots (16), additional studies are needed to establish that point.

A major disadvantage of using Western blots is that the results obtained are qualitative, rather than quantitative in nature. The use of quantitative ELISAs and specific peptides as ligands should enable one to distinguish between high levels of serum antibody characteristic of active infection from the low levels of background antibodies often detected in patients cured of infection.

Since low levels of background antibody often persist for several years after an infection has been cured by antibiotic therapy, this makes it difficult to distinguish between active infection and past exposure by means of Western blots (13). The use of quantitative ELISAs should be more fully evaluated for routine use, since ELISA plate readers with relevant software have been commercially available for many years at low cost.

A second misconception about two-tier testing is the notion that its reliability is no better than that of “a coin toss” (17). This false claim is due to misinterpretation of the results obtained early after infection — at the time an EM is present – and when sensitivity is known to be at or less than 50%; in contrast, the situation is quite different 4-6 weeks after infection by which time the full array of Borrelia specific antigens is expressed and antibodies specific for most — if not all — of these antigens can be detected in blood.

There is ample evidence to indicate that individuals infected for 4 or more weeks in duration — unless immunocompromised — are seropositive by the CDC IgG Western blot criteria (13). Therefore, one must seriously question whether individuals who claim that they have suffered from Lyme disease for long periods of time or years and are seronegative by two-tier testing, really have Lyme disease. Even the most specific and sensitive diagnostic test for Lyme disease that one can imagine will not give a positive result for an individual who does not have Lyme disease.

A third major misconception is the view that the post treatment symptoms that some patients experience after receiving recommended treatment for Lyme disease (PTLDS), are due to a persistent infection termed “chronic Lyme disease” that requires longer antibiotic therapy with other kinds of antibiotics — given singly or in combination– to cure.

It should be noted that the results of five placebo-controlled clinical trials on the efficacy of extended antibiotic therapy for the treatment of PTLDS, provided no evidence of a persistent infection in such patients by culture and/or other laboratory tests; the results of all of these clinical studies showed no significant lessening of symptoms which one would expect to occur if such symptoms were due to a persistent infection (18-21). Furthermore, most seronegative individuals who believe that they have “chronic Lyme disease” seldom — if ever — have evidence of a persistent infection by culture or any other laboratory test.

Some believe that reports indicating the ability of Borrelia survive antibiotic treatment in vitro mimic what occurs in vivo during “chronic Lyme disease” and suggests the likelihood of a persistent infection in patients previously treated with antibiotics. However, such in vitro studies fail to compensate for the protective effects attributed to the host immune system in vivo.

More important, there is no evidence that such in vitro findings have any clinical relevance (22). The presence of antibiotic resistant “persisters” may very well be an in vitro laboratory artifact that can be explained by basic biochemical kinetics since the ability to detect “persisters” in vitro is influenced greatly by both the numbers of Borrelia and concentration of antibiotics used (23).

What are the implications for those who believe that they have Lyme disease based on symptoms alone, but are seronegative by two-tier testing? There are several that could have serious consequences:

First, the inability to make a valid diagnosis of Lyme disease based on symptoms alone, means that the decision to treat with antibiotics for prolonged periods of time until symptoms disappear — in the absence of any evidence of active infection — is unwise to say the least. Since some antibiotics (e.g., tetracyclines) are known to have anti-inflammatory properties, they may provide temporary relief against chronic pain, thus creating the false impression that this is the result of eliminating a persistent infection.

However, when symptoms return after antibiotic therapy is discontinued, as often occurs when most pain relievers are discontinued, this is interpreted to be a “relapse” of infection, thereby requiring longer antibiotic therapy — sometimes for years — perhaps using different antibiotic given singly or in combination. The situation resembles what occurs when one is taking non-steroidal anti-inflammatory agents for chronic pain such as that caused by osteoarthritis.

There is relief while one is taking such medication; unfortunately, the pain returns after the medication is discontinued and once the effects of the medication subside. With respect to the conditions ascribed to “chronic Lyme disease”, subsequent rounds of antibiotic are no more effective than the first. Thus, there is no true and lasting benefit attributable to extended antibiotic therapy, simply because there is no persistent infection to begin with.

Second, being dissatisfied with the failed results of extended antibiotic therapy, some pursue various unorthodox remedies that falsely claim to cure the Lyme disease that they do not have. Many of these unproven approaches not only have no demonstrable benefit but also may even be harmful (24). Often, this is done at great personal expense—sometimes for as much as $70K-$80K per year—since health insurance companies will pay only for remedies known to be beneficial and safe for the treatment of correctly diagnosed illnesses.

In contrast, the cost of a recommended course of treatment for Lyme disease with an oral, generic antibiotic (doxycycline) is about $40. Obviously, it would not be in the best interest of the public health to pass legislation requiring health insurance companies to pay for unorthodox remedies of no proven benefit. That would increase the costs of medical care for all, making it even more difficult for those who can least afford it to obtain the medical care they need.

Here, the solution is to demand to see published, peer-reviewed evidence showing that such unorthodox treatments are indeed beneficial and safe. Testimonials are no substitute for such rigorous proof, since for every patient claiming to have benefited from such therapy, there may be many, many more who derived no benefit whatsoever and perhaps have experienced adverse consequences.

Third, the fixation on Lyme disease—and only on Lyme disease—as the sole cause of their symptoms prevents one from seeking medical advice to consider other possible causes for their symptoms. When correctly diagnosed and treated, such symptoms may be resolved promptly, with an almost miraculous return to normal good health. In such cases, health insurance companies will cover the costs involved.

Fourth, the dissatisfaction resulting from the failure of various unproven and unorthodox remedies, as well as the dissemination of false and misleading information about Lyme disease on the internet and in the media, have generated much dissatisfaction and distrust. Unfortunately, many competent scientists and physicians, who have just the expertise needed to address key issues related to Lyme disease have become the targets of such negativity and distrust (25).

To make matters worse, a concerted effort is being made to discredit the recommendations made by the Infectious Diseases Society of America (IDSA) in its guidelines for the treatment of Lyme disease (3). These guidelines are universally accepted by experts on Lyme disease throughout the world, and the treatment recommended has been demonstrated to be both beneficial and safe (25). No other set of guidelines has been subjected to such independent and intense scrutiny and critical review — and survived the process intact with no revisions recommended (26).

If we chose to abandon the rational and disciplined approaches historically associated with evidence-based science and the practice of medicine, then all we are left with is magic, superstition, and quackery. Obviously, the solution is to seek information, not from blogs and the social media, but from only reliable sources such as websites managed by the CDC, the National Institute of Allergy and Infectious Diseases, the IDSA and the American Lyme Disease Foundation. One will find that the information derived from these sources is consistent as would be expected for information that is factually correct. Only a fool would consider that to be evidence of a conspiracy.

Finally, the IOM published a comprehensive report advocating a multidisciplinary rational approach for dealing with chronic pain and other nonspecific symptoms that occur in the general population and that often are incorrectly attributed to Lyme disease (12). Here, the goal is to identify specific biomarkers so that individuals with chronic pain can be assigned to appropriate treatment groups where they are most likely to derive tangible benefit. Its recommendations make good sense and deserve to be given serious consideration and implemented.

References

1.  Halperin JJ, et al. Common misconceptions about Lyme disease. Am J Med. 2013;126(3):264.e1-7.

2.  ALDF: List of Symptoms Reported to be Associated with Lyme Disease

3. Wormser GP, et al. The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2006;43(9):1089-134.

4. CDC: Signs and Symptoms of Untreated Lyme Disease

5. National Institute of Neurological Disorders and Stroke: Bells Palsy Fact Sheet

6.  Halperin JJ, Golightly M. Lyme borreliosis in Bell’s palsy. Long Island Neuroborreliosis Collaborative Study Group. Neurology. 1992;42(7):1268-70.

7.  Blackwell D, Clarke TC. QuickStats: Percentage of Adults Who Often Felt Very Tired or Exhausted in the Past 3 Months. MMWR Morb Mortal Wkly Rep. 2013;62(14):275. Published 2013 Apr 12.

8. Blackwell D, Clarke TC. QuickStats: Percentage of Adults Aged ≥18 Years Who Often Had Pain in the Past 3 Months. MMWR Morb Mortal Wkly Rep. 2013;62(17):342. Published 2013 May 3.

9. Canavan C, et al. The epidemiology of irritable bowel syndrome. Clin Epidemiol. 2014;6:71-80.

10. Taylor CA, et al. Subjective Cognitive Decline Among Adults Aged ≥45 Years – United States, 2015-2016. MMWR Morb Mortal Wkly Rep. 2018;67(27):753-757.

11.  Dahlhamer J, et al. Prevalence of Chronic Pain and High-Impact Chronic Pain Among Adults – United States, 2016. MMWR Morb Mortal Wkly Rep. 2018;67(36):1001-1006.

12. Mackey S. The IOM pain report revisited: setting the stage for what’s next in transforming pain care, education and research. Pain Med. 2014;15(6):885-6.

13. Baker PJ. Antibody-Based Diagnostic Tests for Lyme Disease. 2017.

14. Moore A, et al. Current Guidelines, Common Clinical Pitfalls, and Future Directions for Laboratory Diagnosis of Lyme Disease, United States. Emerging Infect Dis. 2016;22(7)

15. Dressler, F, et al. Western blotting in the serodiagnosis of Lyme disease. I. Infect. Dis. 167: 392-400; 1993.

16. Branda JA, et al. Evaluation of Modified 2-Tiered Serodiagnostic Testing Algorithms for Early Lyme Disease. Clin Infect Dis. 2017;64(8):1074-1080.

17. Lyme Policy Wonk: Two-Tiered Lab Testing for Lyme Disease—No Better Than a Coin Toss. Time for change?

18. Klempner MS, et al. Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease. N Engl J Med. 2001;345(2):85-92.

19. Krupp LB, et al. Study and treatment of post Lyme disease (STOP-LD): a randomized double masked clinical trial. Neurology. 2003;60(12):1923-30.

20. Fallon BA, et al. A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy. Neurology. 2008;70(13):992-1003.

21. Berende A, et al. Randomized Trial of Longer-Term Therapy for Symptoms Attributed to Lyme Disease. N Engl J Med. 2016;374(13):1209-20.

22. Baker PJ. What Can One Learn That is Clinically Relevant from the Results of in vitro Studies on Persisters?

23. Abel zur wiesch P, et al. Classic reaction kinetics can explain complex patterns of antibiotic action. Sci Transl Med. 2015;7(287):287ra73.

24. Lantos PM, et al. Unorthodox alternative therapies marketed to treat Lyme disease. Clin Infect Dis. 2015;60(12):1776-82.

25. Baker PJ. Chronic Lyme disease: in defense of the scientific enterprise. FASEB J. 2010;24(11):4175-7.

26. Baker PJ. Straight Talk About Chronic Lyme Disease. Am J Med. 2018;131(6):592-594.

Other recommended references

Zomer TP, et al. Non-specific symptoms in adult patients referred to a Lyme centre. Clin Microbiol Infect. 2018.

Markowicz M, Stanek G. Borrelial serology does not contribute to the diagnostic work-up of patients with nonspecific symptoms. Clin Microbiol Infect. 2018.

LymeScience: Lyme Misdiagnosis Illustrated

LymeScience: How chronic Lyme recruits followers