Study Finds Many Referred Patients Did Not Meet Lyme Disease Criteria
What this Johns Hopkins study found.
Why referral-based studies have important limitations.
How the methodology affects the conclusions.
Referral-based studies are frequently cited in discussions about Lyme disease misdiagnosis. While these studies can provide valuable information, their findings should always be interpreted within the context of the study design.
One important limitation of retrospective chart reviews is that investigators typically do not evaluate the referring physicians’ clinical reasoning. They also do not interview the referring clinicians or assess the clinical context that prompted the referral. As a result, the medical record may not fully capture the diagnostic uncertainty or clinical reasoning that influenced the referring physician’s impression.
Another limitation is that these studies generally focus on whether patients meet predefined diagnostic criteria at the time of review rather than examining the potential consequences of a missed or delayed Lyme disease diagnosis. Both overdiagnosis and underdiagnosis can adversely affect patients, making it important to interpret referral-based studies within the context of their methodology.
Against this background, Kobayashi and colleagues concluded that nearly 3 out of 4 patients referred to the clinic did not meet the investigators’ predefined diagnostic criteria for Lyme disease. They did not interview the referring physicians at Johns Hopkins University School of Medicine. Instead, they conducted a retrospective chart review.
Importantly, patients were only classified as having Lyme disease if their medical records met the investigators’ predefined criteria, which were based largely on the Infectious Diseases Society of America’s (IDSA) clinical guidelines together with the Centers for Disease Control and Prevention (CDC) surveillance case definitions.
The authors found that out of 1,261 patients, all but one were symptomatic when they presented to the clinic, with a median duration of complaints of 558 days, ranging from 1 day to 51 years.
“The 5 most commonly identified symptoms were arthralgia (71.3%), fatigue/malaise (66.8%), headache (42.1%), myalgia (40.8%), and sleep disturbance (34.3%),” writes Kobayashi.
Only a few patients had abnormal physical findings. “The 5 most common abnormal physical findings were rash other than erythema migrans (6.6%), joint swelling (5.9%), tender points (3%), objective sensory abnormality (2.1%), and motor weakness (1.5%),” the authors explain.
The researchers did not report a number of clinical presentations that can occur in Lyme disease, including:
- Lyme encephalopathy [2]
- Lyme neuropathy [2]
- Neuropsychiatric Lyme disease [3]
- Pediatric neuropsychiatric disorders – PANS [4]
- Lyme carditis [5]
- Autonomic dysfunction – POTS [6]
- Post-treatment Lyme fatigue – Post-Lyme disease [7]
- Neuropathic pain [8]
- Persistent symptoms after Lyme disease [9]
- Lyme disease with co-infection, e.g. Babesia [10]
The absence of these clinical presentations from the report does not necessarily mean they were absent among referred patients. Rather, the study did not specifically analyze or discuss these manifestations.
Approximately 1 in 10 patients had a history of co-infections. “Although 139 (11%) co-infections were diagnosed before evaluation at the infectious diseases clinic, none of these infections were confirmed or treated based upon the evaluations performed in this study,” writes Kobayashi.
“Of these 139 putative co-infections, 61 (44%) were said to be caused by Babesia microti or B. duncani, 40 (29%) by Epstein-Barr virus, 30 (22%) by Bartonella, 11 (8%) by Ehrlichia spp., and 32 (23%) were attributed to other infectious agents,” writes Kobayashi.
Frequently Asked Questions
Did the study conclude that three out of four patients never had Lyme disease?
No. The investigators concluded that nearly three out of four referred patients did not meet the study’s predefined diagnostic criteria for Lyme disease based on their retrospective chart review. The study did not determine whether every referred patient had or had not previously been infected with Borrelia burgdorferi. Instead, it determined whether patients met the investigators’ predefined diagnostic criteria using the available medical records.
Did the researchers interview the referring physicians?
No. The investigators reviewed patients’ medical records but did not interview the physicians who referred patients to the Johns Hopkins infectious diseases clinic. Consequently, the study could not evaluate the referring physicians’ clinical reasoning or the factors that influenced their diagnostic impressions.
Did the study evaluate why patients were referred?
No. Because this was a retrospective chart review, the investigators could not fully assess the clinical context that prompted the referral, including evolving symptoms, treatment responses, diagnostic uncertainty, or other considerations that may have influenced the referring clinician’s decision.
What diagnostic criteria were used in the study?
Patients were classified as having Lyme disease only if their medical records met the investigators’ predefined criteria, which were based largely on the Infectious Diseases Society of America’s (IDSA) clinical guidelines together with the Centers for Disease Control and Prevention (CDC) surveillance case definitions.
Did the study examine the consequences of a missed Lyme disease diagnosis?
No. The investigators focused on whether patients met predefined diagnostic criteria at the time of review. The study did not evaluate the potential consequences of missed or delayed Lyme disease diagnoses, including the impact on patient outcomes or the reasons underlying the referring physicians’ clinical concerns.
Clinical Perspective
In my experience, referral-based studies provide useful information, but they represent only one part of the evidence base used to understand Lyme disease diagnosis.. A retrospective chart review cannot evaluate the referring physician’s clinical reasoning, interview the referring clinician, or fully assess the clinical context that prompted the referral.
These studies also typically focus on whether patients meet predefined diagnostic criteria rather than examining the potential consequences of a missed or delayed Lyme disease diagnosis. Both overdiagnosis and underdiagnosis can adversely affect patients, underscoring the importance of combining sound clinical judgment with the best available evidence.
Clinical Takeaway
This referral-based chart review found that many patients sent to a tertiary infectious diseases clinic did not meet the investigators’ predefined diagnostic criteria for Lyme disease. However, the study design has important limitations that should be considered when interpreting its conclusions.
Because the investigators relied on a retrospective review of medical records, they did not evaluate the referring physicians’ clinical reasoning, interview the referring clinicians, or fully assess the clinical context that prompted the referral. Likewise, the study did not examine the potential consequences of a missed or delayed Lyme disease diagnosis. These limitations do not invalidate the findings, but they underscore the importance of interpreting referral-based studies within the context of their methodology.
Accurate Lyme disease diagnosis requires integrating the patient’s history, physical examination, exposure risk, evolving clinical presentation, and appropriate laboratory testing while recognizing both the risks of overdiagnosis and the consequences of missed or delayed diagnosis.
Related Articles
Dismissing chronic Lyme disease for somatic symptom disorder diagnosis
Study finds misdiagnosis and delayed diagnosis common for Lyme disease patients
Getting the diagnosis correct and avoiding anchor bias
References:
- Takaaki Kobayashi, Yvonne Higgins, Roger Samuels, Aurasch Moaven, Abanti Sanyal, Gayane Yenokyan, Paul M Lantos, Michael T Melia, Paul G Auwaerter, Misdiagnosis of Lyme Disease With Unnecessary Antimicrobial Treatment Characterizes Patients Referred to an Academic Infectious Diseases Clinic, Open Forum Infectious Diseases, Volume 6, Issue 7, July 2019.
- Logigian EL, Kaplan RF, Steere AC. Chronic neurologic manifestations of Lyme disease. N Engl J Med. 1990;323(21):1438-1444.
- Fallon BA, Nields JA. Lyme disease: a neuropsychiatric illness. Am J Psychiatry. 1994;151(11):1571-1583.
- Sigra S, Hesselmark E, Bejerot S. Treatment of PANDAS and PANS: a systematic review. Neurosci Biobehav Rev. 2018;86:51-65.
- Muehlenbachs A, Bollweg BC, Schulz TJ, et al. Cardiac Tropism of Borrelia burgdorferi: An Autopsy Study of Sudden Cardiac Death Associated with Lyme Carditis. Am J Pathol. 2016.
- Kanjwal K, Karabin B, Kanjwal Y, Grubb BP. Postural orthostatic tachycardia syndrome following Lyme disease. Cardiology journal. 2011;18(1):63-66.
- Krupp LB, Hyman LG, Grimson R, et al. Study and treatment of post Lyme disease (STOP-LD): a randomized double masked clinical trial. Neurology. 2003;60(12):1923-1930.
- Simons LE. Fear of pain in children and adolescents with neuropathic pain and complex regional pain syndrome. Pain. 2016;157 Suppl 1:S90-97.
- Klempner MS, Hu LT, Evans J, et al. Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease. N Engl JMed. 2001;345(2):85-92.
- Krause PJ, Telford SR, 3rd, Spielman A, et al. Concurrent Lyme disease and babesiosis. Evidence for increased severity and duration of illness. Jama. 1996;275(21):1657-1660.
Dr. Daniel Cameron, MD, MPH
Lyme disease clinician with over 30 years of experience and past president of ILADS.
Symptoms • Testing • Coinfections • Recovery • Pediatric • Prevention
