Lyme Disease and other Tick-Borne Diseases

Number: 0215

Table Of Contents

Policy Applicable CPT / HCPCS / ICD-10 Codes Background References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses Lyme disease and other tick-borne diseases.

1. Medical Necessity

   Aetna considers outpatient intravenous (IV) antibiotic therapy medically necessary in adult and pediatric members with the diagnosis of Lyme disease only when it is based on the clinical presentation of signs and symptoms compatible with the disease and supported by a positive serologic and/or cerebrospinal fluid (CSF) titer by indirect immunofluorescence assay (IFA), Prevue Borrelia burgdorferi antibody detection assay, or enzyme-linked immunosorbent assay (ELISA), which itself is validated by a positive Western Blot Test (see CDC criteria in Footnote1*Note below).Once a definitive diagnosis of Lyme disease is established, Aetna considers an initial 4-week course of outpatient IV antibiotic therapy medically necessary when any of the following conditions is met:

   1. Lyme arthritis that persists after failing to respond to a 4-week course of appropriate oral antibiotic therapy
   2. Moderate-to-severe cardiac involvement as evidenced by any of the following:
      • A first-degree heart block with P-R interval greater than 0.4 seconds
      • Congestive heart failure
      • Myopericarditis
      • Second- or higher degree atrio-ventricular block;

   3. Neurologic involvement of Lyme disease (neuroborreliosis) as evidenced by any of the following:

      • Encephalopathy/encephalomyelitis
      • Meningitis confirmed by CSF analysis showing a lymphocytic pleocytosis with evidence of antibody production against Borrelia burgdorferi in the CSF
      • Sensory/motor radiculoneuropathy or peripheral neuropathy (weakness and/or pain in the extremities or chest);

   4. All cases of Lyme disease in pregnant women who exhibit symptoms and signs of any of the following:

      • Stage II Lyme disease with early dissemination documented by organ-specific manifestations of infection (arthritic, cardiac, or neurologic)
      • Stage III late Lyme disease documented by findings of arthritis and/or neurologic complications, such as encephalomyelitis and subacute encephalitis;

   5. Aetna considers one repeat 4-week course of outpatient IV antibiotic therapy medically necessary when the member meets all of the following criteria:

      1. The member has met the criteria for an initial course of intravenous antibiotic therapy, using lab results obtained within the past 3 months; and
      2. The member has completed an initial course of appropriate intravenous antibiotic therapy; and
      3. The member has objective evidence of either relapse of infection, progression of Lyme disease organ damage, and/or the finding of a new focus or type of organ damage.

   Footnote1* Note: According to the CDC (1995), the recommended method for serologic detection of active disease or previous infection involves a 2-test approach using a sensitive enzyme immunoassay (EIA) or IFA followed by a Western immunoblot. All specimens positive or equivocal by a sensitive EIA or IFA should be tested by a standardized Western immunoblot.

   The CDC (1995) states that when Western immunoblot is used during the first 4 weeks of disease onset (early LD), both immunoglobulin M (IgM) and immunoglobulin G (IgG) procedures should be performed. However, a positive IgM immunoblot alone is not considered sufficient evidence of active disease in a person with Lyme disease of more than 1 month’s duration. Although the presence of IgM antibodies is useful in evaluating early disease, the CDC states that a positive IgM test result alone is not recommended for use in determining active disease in persons with illness greater than 1 month’s duration because the likelihood of a false-positive test result for a current infection is high for these persons. The following criteria for a positive Western Blot are adapted from the CDC (1995):

   IgM immunoblot – 2 of the following bands are present:

   • 21/22/23/24 kDa (OspC)Footnote2**
   • 39 kDa (BmpA)
   • 41 kDa (Fla);

   or

   IgG immunoblot – 5 of the following bands are present:

   • 18 kDa
   • 21/22/23/24 kDa (OspC)Footnote2**
   • 28 kDa
   • 30 kDa
   • 39 kDa (BmpA)
   • 41 kDa (Fla)
   • 45 kDa
   • 58 kDa (not GroEL)
   • 66 kDa
   • 93 kDa.

   A positive serology, on its own, is not considered a medically necessary indication for antibiotic therapy for Lyme disease. According to the CDC, positive antibody tests should be correlated with symptoms to be clinically meaningful. According to the CDC (1995), if an individual with suspected early Lyme disease has a negative serology, serologic evidence of infection is best obtained by testing of paired acute- and convalescent-phase serum samples. Serum samples from persons with disseminated or late-stage Lyme disease almost always have a strong IgG response to Borrelia burgdorferi antigens.

   Footnote2** The apparent molecular mass of outer surface protein C (OspC) is strain-dependent; thus the 21 kDa, 22 kDa, 23 kDa, and 24 kDa proteins referred to above are the same.

2. Experimental, Investigational, or Unproven

   1. Aetna considers initial IV antibiotic therapy experimental, investigational, or unproven for the following indications (not an all-inclusive list), because the benefit of IV antibiotic therapy for these indications has not been established:

      1. Early Lyme disease or new-onset Lyme arthritis
      2. Flu-like syndrome (fatigue, fever, headache, mildly stiff neck, arthralgias, and myalgias)
      3. Non-specific subjective symptoms, such as persistent, chronically debilitating fatigue (chronic fatigue syndrome), difficulty in concentrating, musculoskeletal pain (fibromyalgia), and headache
      4. Prophylaxis in a person who is asymptomatic and the only evidence for Lyme disease is a positive immunologic test (ELISA, IFA, or Western blot)
      5. Mild cardiac involvement of Lyme disease as evidenced by any of the following:
         • first-degree heart block with P-R interval less than 0.4 seconds
         • Left ventricular dysfunction without congestive heart failure
         • Transient ST-T depression, T-wave changes
      6. Isolated manifestations of neurologic involvement of Lyme disease (such as Bell’s facial nerve palsy/paralysis)
      7. Pregnant woman presenting with localized Lyme disease manifested as a single lesion of erythema migrans without any other symptoms suggestive of disseminated disease
      8. Minor neurologic manifestations of Lyme disease (including headache, stiff neck, and irritability).
   2. Aetna considers additional antibiotic therapy in post-treatment, persistently fatigued patients (post-Lyme disease syndrome) experimental, investigational, or unproven because IV antibiotic therapy has not been shown to be effective for this indication.
   3. Aetna considers the following diagnostic tests (not an all-inclusive list) for Lyme disease experimental, investigational, or unproven because there is inadequate scientific evidence to prove their usefulness in clinical practice:
      1. Antigen detection
      2. Biomarkers for antibiotic-refractory Lyme arthritis
      3. Borrelia burgdorferi antibody index testing
      4. Borrelia culture
      5. C6 peptide ELISA assay (using recombinant VlsE1 or peptide antigens of Borrelia burgdorferi)
      6. CD57+ lymphocyte counts
      7. Chemokine CXCL13
      8. Complement split products (e.g., C3a and C4a)
      9. Cyst formation
      10. Cytokine analysis
      11. Immune complexes
      12. iSpot Lyme assay
      13. Lymphocyte markers
      14. Lymphocyte transformation test
      15. Measurement of natural killer (NK) cells
      16. Microscope-based assays
      17. Mycotoxin testing
      18. Neuroadrenal expanded panel (including histamine, serotonin, and hydroxyindoleacetic acid)
      19. Polymerase chain reaction (PCR) for identification or quantification of Lyme disease (B. burgdorferi) spirochetal DNA or RNA
      20. Positron emission tomography (PET) scanning
      21. Provocative testing (testing for B. burgdorferi after antibiotic provocation)
      22. Serum borreliacidal assay
      23. SPECT scanning
      24. T-cell proliferation response assay
      25. Urine antigen assay (e.g., Lyme Borrelia Nanotrap Urine Antigen Test)
      26. Xenodiagnosis (using the natural tick vector, Ixodes scapularis).
   4. Aetna considers scheduled repeated testing for Lyme disease in a member without a change in signs and symptoms not medically necessary.
   5. Concurrent babesiosis or cat-scratch disease is not, in and of itself, considered a medically necessary indication for long-term intravenous antibiotic therapy for Lyme disease. Long-term intravenous antibiotic therapy is generally not medically necessary in immunocompetent persons with Bartonella-associated vasculo-proliferative diseases (bacillary angiomatosis-peliosis and verruga peruana) or Bartonella bacteriemia (other than Bartonella endocarditis). Intravenous antibiotic therapy may be medically necessary in persons with severe Bartonella infection, immunocompromised persons, and systemic Bartonella infection complicated by bony or parenchymal involvement or endocarditis
   6. Aetna considers the following treatments experimental, investigational, or unproven for the treatment of lyme disease because their effectiveness for this indication has not been established:
      1. Alpha lipoic acid or “Healing Detox Drips”
      2. Antibiotic augmented thermo-eradication (AAT)
      3. Anti-sense supportive oligonucleotide therapy
      4. Chelation therapy
      5. Hyperbaric oxygen therapy (see CPB 0172 – Hyperbaric Oxygen Therapy (HBOT))
      6. Intramuscular antibiotics
      7. Intramuscular penicillin
      8. Intravenous ascorbic acid or intravenous magnesium
      9. Platelet-rich plasma infusion
      10. Radiation-based therapies
      11. Reactive oxygen therapy and singlet oxygen therapy.
   7. Aetna considers intravenous antibiotic therapy experimental, investigational, or unproven for the treatment of Q fever because its effectiveness over oral antibiotics for this indication has not been established.
   8. Aetna considers testing ticks for Borrelia burgdorferi and other organisms (e.g., Babesiosis microti, Borrelia miyamotoi, and Ehrlichia chaffeensis) experimental, investigational, or unproven because it has not been proven to be useful for deciding if a person should receive medical treatment following a tick bite.

3. Related Policies

   • CPB 0172 – Hyperbaric Oxygen Therapy (HBOT)
   • CPB 0206 – Parenteral Immunoglobulins
   • CPB 0369 – Chronic Fatigue Syndrome
   • CPB 0650 – Polymerase Chain Reaction Testing: Selected Indications

Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code Code Description

CPT codes covered if selection criteria are met:

0041U Borrelia burgdorferi, antibody detection of 5 recombinant protein groups, by immunoblot, IgM 0042U Borrelia burgdorferi, antibody detection of 12 recombinant protein groups, by immunoblot, IgG 0043U Tick-borne relapsing fever Borrelia group, antibody detection to 4 recombinant protein groups, by immunoblot, IgM 0044U Tick-borne relapsing fever Borrelia group, antibody detection to 4 recombinant protein groups, by immunoblot, IgG 84181 Western Blot, with interpretation and report, blood or other body fluid 84182 Western Blot, with interpretation and report, blood or other body fluid, immunological probe for band identification, each 86617 Borrelia burgdorferi (Lyme disease) confirmatory test (e.g., Western Blot or immunoblot) 86618 Borrelia burgdorferi (Lyme disease) 88346 Immunofluorescence, per specimen; initial single antibody stain procedure 88350 Immunofluorescence, per specimen; each additional single antibody stain procedure (List separately in addition to code for primary procedure) 96365 Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hour + 96366 each additional hour, (List separately in addition to code for primary procedure) + 96367 additional sequential infusion, up to 1 hour (List separately in addition to code for primary procedure) + 96368 concurrent infusion (List separately in addition to code for primary procedure) 96369 Subcutaneous infusion for therapy or prophylaxis (specify substance or drug); initial, up to 1 hour, including pump set-up and establishment of subcutaneous infusion site(s) + 96370 each additional hour (List separately in addition to code for primary procedure) + 96371 additional pump set-up with establishment of new subcutaneous infusion site(s) (List separately in addition to code for primary procedure) 99601 Home infusion/specialty drug administration, per visit (up to 2 hours) + 99602 each additional hour (List separately in addition to code for primary procedure)

CPT codes not covered for indications listed in the CPB:

Alpha lipoic acid or “Healing” Detox Drips, testing for other tick-borne diseases from other organisms, antibiotic augmented thermo-eradication (AAT) therapy – no specific code :

0232T Injection(s), platelet rich plasma, any site, including image guidance, harvesting and preparation when performed 0316U Borrelia burgdorferi (Lyme disease), OspA protein evaluation, urine 77401 – 77417 Radiation treatment delivery 78608 – 78609 Brain imaging, positron emission tomography (PET); metabolic or perfusion evaluation 78811 – 78816 Positron emission tomography (PET) 82136 Amino acids, 2 to 5 amino acids, quantitative, each specimen 82533 Cortisol; total 82626 Dehydroepiandrosterone (DHEA) 83088 Histamine 83497 Hydroxyindolacetic acid, 5-(HIAA) 83520 Immunoassay for analyte other than infectious agent antibody or infectious agent antigen; quantitative, not otherwise specified [chemokine CXCL13] [cytokine analysis] 84260 Serotonin 84681 C-peptide 86160 Complement; antigen, each component [complement split products (e.g., C3a and C4a)] 86161 functional activity, each component [complement split products (e.g., C3a and C4a)] 86162 total hemolytic (ch50) [complement split products (e.g., C3a and C4a)] 86171 Complement fixation tests, each antigen [complement split products (e.g., C3a and C4a)] 86332 Immune complex assay [immune complexes] 86353 Lymphocyte transformation, mitogen (phytomitogen) or antigen induced blastogenesis 86355 B cells, total count [lymphocyte markers] 86357 Natural killer (NK) cells, total count 86359 T cells; total count [lymphocyte markers] 86360 T cells; absolute cd4 and cd8 count including ratio[lymphocyte markers] 87230 Toxin or antitoxin assay, tissue culture [mycotoxin testing for Lyme disease] 87449 Infectious agent antigen detection by immunoassay technique, (eg, enzyme immunoassay [EIA], enzyme-linked immunosorbent assay [ELISA], immunochemiluminometric assay [IMCA]), qualitative or semiquantitative; multiple-step method, not otherwise specified, each organism 87478 Infectious agent detection by nucleic acid (DNA or RNA); Borrelia miyamotoi, amplified probe technique [not covered for testing ticks] 96372 Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular 99183 Physician attendance and supervision of hyperbaric oxygen therapy, per session

Other CPT codes related to the CPB:

96372 Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular

HCPCS codes covered if selection criteria are met:

G0068 Professional services for the administration of anti-infective, pain management, chelation, pulmonary hypertension, and/or inotropic infusion drug(s) for each infusion drug administration calendar day in the individual’s home, each 15 minutes S9494 – S9504 Home infusion therapy, antibiotic, antiviral, or antifungal therapy

HCPCS codes not covered for indications listed in the CPB:

G0219 PET imaging whole body; melanoma for non-covered indications G0277 Hyperbaric oxygen under pressure, full body chamber, per 30 minute interval G0235 PET imaging, any site, not otherwise specified G0252 PET imaging, full and partial-ring PET scanners only, for initial diagnosis of breast cancer and/or surgical planning for breast cancer (e.g. initial staging of axillary lymph nodes) G6003 – G6014 Radiation treatment delivery G6015 – G6016 Modulation treatment delivery J0470 Injection, dimercaprol, per 100 mg J0558 Injection, penicillin G benzathine and penicillin G procaine, 100,000 units J0561 Injection, penicillin G benzathine, 100,000 units J0600 Injection, edetate calcium disodium, up to 1000 mg J0895 Injection, deferoxamine mesylate, 500 mg J1427 Injection, viltolarsen, 10 mg [Anti-sense supportive oligonucleotide therapy] J2510 Injection, penicillin G procaine, aqueous, up to 600,000 units J2540 Injection, penicillin G potassium, up to 600,000 units J3475 Injection, magnesium sulphate, per 500 mg J3520 Edetate disodium, per 150 mg M0300 IV chelation therapy (chemical endarterectomy) P9020 Platelet rich plasma, each unit S9355 Home infusion therapy, chelation therapy; administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drugs and nursing visits coded separately), per diem

ICD-10 codes covered if selection criteria are met:

A69.20 – A69.29 Lyme disease

ICD-10 codes not covered for indications listed in the CPB:

A28.1 Cat-scratch disease A44.0 – A44.9 Bartonellosis A78 Q fever B60.0 Babesiosis G51.0 Bell’s palsy R53.82 Chronic fatigue, unspecified

Testing for the specific tick-borne disease:

CPT codes not covered for indications listed in the CPB:

Testing for other tick-borne diseases from other organisms – no specific code:

86619 Antibody; Borrelia (relapsing fever) 86666 Antibody; Ehrlichia 86668 Antibody; Francisella tularensis 86753 Antibody; protozoa, not elsewhere specified [Babesiosis microti] 86757 Antibody; Rickettsia

ICD-10 codes not covered for indications listed in the CPB:

Z11.2 Encounter for screening for other bacterial diseases [testing ticks for tick-borne diseases] Z11.8 Encounter for screening for other infectious and parasitic diseases [testing ticks for tick-borne diseases]

Background

The use and duration of intravenous antibiotic therapy in Lyme disease (LD) remains controversial. Researchers are currently conducting studies to assess the optimal duration of antibiotic therapy for the various manifestations of LD. In some areas of the country, patients are being treated for months to 1 year or more with daily parenteral or oral antibiotics. In a randomized controlled study, Wormser et al (2003) stated that treatment of patients with early LD has trended toward longer duration despite the absence of supporting clinical trials. These investigators concluded that extending treatment with doxycycline from 10 to 20 days or adding 1 dose of ceftriaxone to the beginning of a 10-day course of doxycycline did not enhance therapeutic efficacy in patients with erythema migrans. Regardless of regimen, objective evidence of treatment failure was extremely rare.

In the largest long-term study of outcomes based on treatment duration in patients with early LD, Kowalski et al (2010) found that patients treated for 10 days with antibiotic therapy for early LD have long-term outcomes similar to those of patients treated with longer courses. The investigators found that treatment failure after appropriately targeted short-course therapy, if it occurs, is exceedingly rare. Kowalski et al (2010) reported on the long-term clinical outcomes of patients with early localized and early disseminated LD based on the duration of antibiotic therapy prescribed. These investigators reported on a retrospective cohort study and follow-up survey of patients diagnosed as having early localized and early disseminated LD from January 1, 2000 through December 31, 2004 was conducted in a LD-hyperendemic area. A total of 607 patients met the study inclusion criteria. Most patients (93 %) were treated with doxycycline for treatment durations of 10 days, 11 to 15 days, or 16 days in 17 %, 33 %, and 47 % of doxycycline-treated patients, respectively. Treatment failure criteria, defined before performing the study, were met in only 6 patients (1 %). Although these 6 patients met a priori treatment failure criteria, 4 of these patients’ clinical details suggested re-infection, 1 was treated with an inappropriate antibiotic, and 1 developed facial palsy early in therapy. Re-infection developed in 4 % of patients. The 2-year treatment failure-free survival rates of patients treated with antibiotics for 10 days, 11 to 15 days, or 16 days were 99.0 %, 98.9 %, and 99.2 %, respectively. Multiple measures of long-term function – including pain, general health, and emotional and physical well-being – were similar among groups. The only statistically significant difference was decreased social functioning in the group of patients with the longest treatment duration.

Randomized controlled studies of treatment of patients who remain unwell after standard courses of antibiotic therapy for LD have shown that repeated or prolonged courses of antibiotic therapy are not effective for such patients. Krupp et al (2003) reported that ceftriaxone therapy in patients with post-Lyme syndrome (PLS) with severe fatigue was associated with an improvement in fatigue but not with cognitive function or an experimental laboratory measure of infection. Because fatigue (a non-specific symptom) was the only outcome that improved and because treatment was associated with adverse events, these authors concluded that their findings did not support the use of additional antibiotic therapy with intravenous ceftriaxone in post-treatment, persistently fatigued patients with PLS. This in agreement with the findings of Kaplan et al (2003) who concluded that patients with post-treatment chronic Lyme disease who have symptoms (e.g., fatigue, depression) but show no evidence of persisting Borrelia infection do not show objective evidence of cognitive impairment. Additional antibiotic therapy was not more beneficial than administering placebo. Added expense and toxicity are the only proven results of such practice. Latrogenic problems, such as gallbladder disease, fungal infections, and other superinfections, and gastrointestinal problems, certainly increase with prolonged use of broad-spectrum antibiotics. This highlights the need for an appropriate diagnosis before subjecting the patient to antibiotic regimens.

In a randomized, controlled clinical trial, a prolonged course of antibiotics produced no sustained benefit in persons with Lyme encephalopathy. Fallon et al (2008) reported on a randomized, placebo-controlled trial assessing the efficacy of a 10-week course of intravenous ceftriaxone in patients with a history of clinical LD, as well as current serologic evidence of Borrelia burgdorferi infection, greater than 3 weeks of previous intravenous ceftriaxone therapy completed greater than 4 months before study entry, and objective evidence of memory impairment (but no history of a condition that could confound neuropsychological assessment). A total of 37 patients with Lyme encephalopathy (out of 3,368 individuals who were screened) were enrolled. Additionally, 20 healthy control subjects were included to correct for practice effects from repeated neurocognitive testing. Neuropsychological testing (assessment of motor function, psychomotor function, attention, memory, working memory, and verbal fluency) was conducted at baseline and at weeks 12 and 24 after study entry. At 12 weeks, ceftriaxone recipients showed better cognitive improvement than did placebo recipients (p = 0.053) or healthy controls (p < 0.01) on an aggregate analysis, although not in any single domain. However, this benefit was not present at 24 weeks. No benefits were noted on concurrent rheumatologic assessments. Adverse events related to the study drug or the catheter were seen in 6 of 23 ceftriaxone recipients (26.1 %) and in 1 of 14 placebo recipients (7.1 %). Commenting on this study, Ellison (2007) said that “[t]he findings that ceftriaxone therapy was not significantly better than placebo, that any benefit was short lived, and that the drug was associated with frequent adverse effects would seem to close the door on any such treatment for Lyme encephalopathy.”

The Infectious Diseases Society of America (Wormser et al, 2006) has concluded that there is no scientific evidence to support the need for multiple or very prolonged courses of antibiotics in LD, and that such treatments may cause serious and even fatal adverse effects.

Pfister and Rupprecht (2006) noted that the diagnostic criteria of active neuroborreliosis include inflammatory changes of the cerebrospinal fluid (CSF) and an elevated specific Borrelia CSF-to-serum antibody index, indicating intrathecal Borrelia antibody production. Patients with neuroborreliosis are usually treated with intravenous ceftriaxone for 2 to 3 weeks. In case of allergy, doxycycline may be used. Treatment efficacy is detected by the improvement of the neurological symptoms and the normalization of the CSF pleocytosis. The measurement of serum and CSF antibodies is not suitable for follow-up, because they frequently persist. Post-Lyme disease (PLD) syndrome is characterized by persistent complaints and symptoms after previous treatment for Lyme borreliosis, e.g., musculoskeletal or radicular pain, dysaesthesia, and neurocognitive symptoms that are often associated with fatigue. There is no formal definition of the PLD syndrome, and its pathogenesis is unclear. Recent controlled studies do not support the use of additional antibiotics in these patients, but recommend primarily symptomatic strategies. Moreover, Feder et al (2006) stated that antibiotic therapy for more than 8 weeks for patients with LD is not indicated. Chronic LD due to antibiotic resistant infection has not been demonstrated.

The diagnosis of LD is valid only in a person with erythema migrans in early LD or for later stages of infection, in a person with a least 1 late manifestation and laboratory confirmation of infection. Laboratory support of the diagnosis of LD requires detection of specific antibodies to this tick-borne spirochete Borrelia burgdorferi in the serum, either by indirect immunofluorescence assay (IFA) or enzyme-linked immunosorbant assay (ELISA), with the latter now preferred because it is more sensitive and specific. A Western blot assay that can detect both IgM and IgG antibodies is used to confirm the diagnosis. Specific IgM antibodies appear first, usually 3 to 4 weeks after the infection begins, while specific IgG antibodies usually appear 6 to 8 weeks after the onset. An elevated IgM is a value greater than 250 mg/dL and an elevated IgG is a value greater than 1,500 mg/dL. After peaking, these antibodies subsequently decline after 4 to 6 months of illness. The critical issue with these antibody tests is that they must be correlated with the timing of the patient’s symptoms. On their own, they are meaningless.

Recent studies have suggested that the C6 ELISA assay, based on a peptide (C6) that reproduces the sequence of invariable region 6 of VlsE, the antigenic variation protein of Borrelia burgdorferi, may improve the sensitivity and standardization of immunoblots for the serologic diagnosis of LD (Marques et al, 2002; Bacon et al, 2003). In this regard, Wilske (2003) stated that it appears promising to use recombinant proteins (DbpA, VlsE, others) or synthetic peptides (the conserved C6 peptide derived from VlsE) as ELISA antigens for the diagnosis of LD. However, a recent randomized controlled study reported that C(6) antibody can not be used to assess treatment outcome or the presence of active infection in patients with PLS (Fleming et al, 2004).

The diagnosis of Lyme neuroborreliosis must be validated with evidence of antibody production against Borrelia burgdorferi in the CSF, shown by a higher titer of antibody in the CSF than in the serum. The most helpful CSF test is intrathecal production of specific antibodies. This test is run on paired CSF and serum samples and distinguishes intrathecal antibody production from a positive CSF titer due to serum leakage. A ratio of CSF to serum antibody of greater than 1.0 suggests local central nervous system antibody production and the presence of neuroborreliosis. With rare exceptions, a positive test documents central nervous system (CNS) invasion by B. burgdorferi. Other CSF findings suggestive of LD include mild mononuclear pleocytosis and protein elevation. Studies that are normal or negative include the CSF glucose level, VDRL, and myelin basic protein. In North American Lyme patients, CSF oligoclonal bands and increased IgG index (very common findings in multiple sclerosis) are unusual. There are a number of experimental CSF tests that look promising (Borrelia-specific immune complexes, polymerase chain reaction [PCR], antigen detection), but they are available only at a few research centers and have not been validated.

According to evidence-based guidelines, PCR of B. burgdorferi DNA or RNA has not been validated for either the diagnosis of LD or monitoring response to therapy. Polymerase chain reaction remains a research technique, in part because PCR can become easily contaminated, producing false-positive results. In addition, no large clinical series have been reported that assess the performance of the test in the non-research setting. American College of Physicians – American Society of Internal Medicine (ACP-ASIM) guidelines on diagnosis of LD (1997) state that PCR of serum or CSF “need[s] further validation” and that “[p]ublished experience with these techniques [PCR] is insufficient to allow development of guidelines for their use.” The Centers for Disease Control and Prevention (2001) states that “PCR has not been standardized for routine diagnosis of Lyme Disease.” The National Institute of Arthritis and Infectious Disease (2001) has explained the reasons why PCR has limited utility in the diagnosis of LD: “To be sure, the polymerase chain reaction (PCR) is an extremely sensitive laboratory test that is capable of detecting very few molecules of bacterial DNA. However, the numbers of Borrelia likely to be present – if at all – in patients suspected of having Lyme disease are too small to generate sufficient amounts of bacterial DNA to be detected by this procedure.”

Guidelines on treatment of LD from the Infectious Diseases Society of America (Wormser et al, 2000) do not state any role for PCR in monitoring the treatment of patients with LD. The American Academy of Pediatrics Committee on Infectious Diseases (2003) stated: “New, more sensitive and more specific diagnostic tests, such as the polymerase chain reaction assay, which may be able to identify the presence of even small quantities of spirochetal DNA, are in development. However, physicians should be cautious when interpreting results of these investigational tests until their clinical usefulness has been proven.” More recently, the American Academy of Pediatrics Committee on Infectious Diseases (2006) stated that PCR has “no role in diagnosis” of LD.

Persistence of B. burgdorferi sero-reactivity long after LD treatment and cure has led to excesses in therapy and attendant drug- and intravenous line-related morbidity, based on the mistaken assumption that persisting sero-positivity equates with persisting infection. Laboratory tests should be employed as an adjunct in the diagnosis of LD, used only when specific symptoms suggest substantial likelihood that the disease is present. Testing as a screening tool should be discouraged.

An incorrect diagnosis of LD is often made, despite negative test results and the absence of findings suggesting LD, because the patient had symptoms compatible with LD. Some clinicians consider LD a diagnosis of exclusion, and associate any illness compatible with LD as LD. Because these patients are rarely, if ever, cured by antibiotics, this practice has contributed to an epidemic of anxiety about the chronicity of LD. The diagnosis is often supposedly confirmed by transient improvement after therapy. Oral therapy has been shown to elicit placebo responses in as many as 35 % of patients undergoing oral antibiotic therapy, and rates for intravenous therapy might even be higher.

According to the American Academy of Pediatrics Committee on Infectious Diseases (2006): “The widespread practice of ordering serologic tests for patients with nonspecific symptoms such as fatigue or arthralgia who have a low probability of having Lyme disease is not recommended. Almost all positive serologic test results in these patients are false-positive results. Patients with acute Lyme disease almost always have objective signs of infection (e.g., erythema migrans, facial nerve palsy, arthritis). Nonspecific symptoms commonly accompany these specific signs but are almost never the only evidence of Lyme disease.”

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An incorrect diagnosis of LD can also be made even in the presence of a positive antibody test. Positive antibody tests are meaningless if not correlated with the duration of the patient’s symptoms. In some instances, patients will be tested repeatedly for Lyme antibodies, until inevitably a false positive result will occur, which is then inappropriately interpreted as evidence of LD and used as justification for prolonged antibiotic therapy. The degree of clinical response associated with parenteral antibiotic treatment or decreasing serum titers do not correlate with antibiotic success and should not be used as a guide or reason for extended antibiotic administration. In general, symptoms that persist beyond a full course of parenteral antibiotic therapy generally are not due to continued infection and may actually indicate that the diagnosis is something other than LD.

An editorial summarizing the controversy surrounding the diagnosis and treatment of LD published in the New England Journal of Medicine by the Ad Hoc International Lyme Disease Group (Feder et al, 2007) systematically refuted the arguments behind the diagnosis and treatment of so-called chronic LD. The Ad Hoc Groupstated that “[c]hronic Lyme disease is the latest in a series of syndromes that have been postulated in an attempt to attribute medically unexplained symptoms to particular infections. Other examples that have now lost credibility are ‘chronic candida syndrome’ and ‘chronic Epstein-Barr virus infection.’ The assumption that chronic, subjective symptoms are caused by persistent infection with B. burgdorferi is not supported by carefully conducted laboratory studies or by controlled treatment trials. Chronic Lyme disease, which is equated with chronic B. burgdorferi infection, is a misnomer, and the use of prolonged, dangerous, and expensive antibiotic treatments for it is not warranted.”

Whereas early LD, late LD, and PLD symptoms/syndrome are recognized conditions, the term “chronic LD” has recently been popularized by a small number of practitioners (Feder et al, 2007; Chang, 2007). Chronic, non-specific symptoms (e.g., fatigue, headache, dizziness) are attributed to persistent or incurable B. burgdorferi infection, and patients are subsequently treated with long-term parenteral antibiotics.

Objective manifestations of LD include erythema migrans (the most common presentation of early Lyme disease), certain neurologic and cardiac manifestations, and pauciarticular arthritis (the most common presentation of late LD) (Chang, 2007; Feder et al, 2007). These symptoms respond well to conventional antibiotic therapy. Symptoms of PLD include fatigue, musculoskeletal pain, and difficulties with concentration or short-term memory following resolution of objective manifestations of infection. These symptoms are usually mild, typically resolve within months, and antibiotic therapy is not indicated; when the difficulties persist longer than 6 months, the condition is termed PLD syndrome. Laboratory testing (usually acute- and convalescent-phase serologies) is a key component of LD diagnosis; in most cases, the testing allows clinicians to confirm evidence of current or past B. burgdorferi infection (Chang, 2007; Feder et al, 2007).

By contrast, chronic LD is the term assigned to patients reporting chronic symptoms without objective clinical, laboratory, or epidemiologic criteria for infection (Chang, 2007; Feder et al, 2007). They receive chronic parenteral antibiotic therapy for periods of many months to years, despite the absence of any scientific evidence to support this practice.

The Ad Hoc International Lyme Disease Group (Feder et al, 2007) states that chronic antibiotic therapy for chronic LD has resulted in life-threatening anaphylaxis, cholecystectomy after biliary complications from ceftriaxone administration, a fatality due to candidemia from intravenous catheter infection, and other serious adverse events related to intravenous catheters.

The American Academy of Neurology (AAN)’s practice parameter on treatment of nervous system LD (Halperin et al, 2007) provided evidence-based recommendations on the treatment of nervous system LD and PLS. Three questions were addressed:

1. which anti-microbial agents are effective?
2. are different regimens preferred for different manifestations of nervous system LD? and
3. what duration of therapy is needed?

These investigators analyzed published studies (1983 to 2003) using a structured review process to classify the evidence related to the questions posed. The panel reviewed 353 abstracts; yielding 112 potentially relevant articles that were reviewed, from which 37 articles were identified that were included in the analysis. The authors concluded that there are sufficient data to conclude that, in both adults and children, this nervous system infection responds well to penicillin, ceftriaxone, cefotaxime, and doxycycline (Level B recommendation). Although most studies have used parenteral regimens for neuroborreliosis, several European studies support use of oral doxycycline in adults with meningitis, cranial neuritis, and radiculitis (Level B), reserving parenteral regimens for patients with parenchymal CNS involvement, other severe neurological symptomatology, or failure to respond to oral regimens. The number of children (greater than or equal to 8 years of age) enrolled in rigorous studies of oral versus parenteral regimens has been smaller, making conclusions less statistically compelling. However, all available data indicate results are comparable to those observed in adults. In contrast, there is no compelling evidence that prolonged treatment with antibiotics has any beneficial effect in post-Lyme syndrome.

Roos (2007) provided the following comment on (AAN)’s practice parameter on treatment of nervous system LD (Halperin et al, 2007): “Misunderstanding of Lyme disease has created a demand by patients with pain, fatigue, and perceived cognitive trouble to seek prolonged parenteral treatment for Lyme disease and “post-Lyme syndrome.” This study provides evidence-based recommendations for appropriate types and duration of antimicrobial therapy for neurologic Lyme disease. It also provides reassurance that the disease can be treated and highlights the lack of evidence that post-Lyme syndrome is due to active B. burgdorferi infection that would require prolonged antibiotic therapy.”

Testing ticks for Borrelia burgdorferi has not been proven to be useful for deciding if a person should receive medical treatment following a tick bite. The Centers for Disease Control and Prevention (CDC, 2005) stated that “In general, the identification and testing of individual ticks is not useful for deciding if a persons should get antibiotics following a tick bite”. The California Department of Health Services does not recommend that ticks be tested to determine if treatment is necessary because:

1. testing methods vary in accuracy,
2. the need for treatment should not be based on these test results, and
3. tick testing results do not necessarily predict if the person bitten will get Lyme disease.

Even if an attached tick tested “negative”, other undetected ticks may have attached to a person and transmitted the bacteria. Additionally, the Rhode Island Department of Health stated that “The testing of ticks for the presence of the bacteria that causes Lyme disease has no role in the clinical diagnosis of Lyme disease”.

Concurrent cat-scratch disease or babesiosis is not, in and of itself, justification for long-term antibiotic therapy for LD. Babesiosis, an infection by a protozoan parasite which in some ways resembling malaria, is most often treated with intravenous or oral clindamycin for 7 days plus oral quinine, or oral atovaquone plus oral azithromycin (Gilbert et al, 2003).

Bartonellosis (infections with Bartonella species) can create symptoms that mimic LD, and in some cases, co-infection can occur. Bartonella can create granulomatous (cat-scratch disease), bacteremic (Bartonella endocarditis, Oroya fever, and trench fever) or vasculoproliferative disease (bacillary angiomatosis-peliosis and verruga peruana). According to available guidelines, the diagnosis of both bacillary angiomatosis and cat-scratch disease rests on tissue examination (Warthin-Starry stains) and serologic tests (immunosorbant or ELISA assay). Bartonella bacteremia is diagnosed with serologic tests and confirmed by blood culture. Oroya fever may be diagnosed by examining a peripheral blood smear. According to available guidelines, most patients with cat-scratch disease do not require more than symptomatic support. A fluctuant or suppurative lymph node may benefit from needle aspiration. Antibiotic therapy should be reserved for immunocompromised individuals or those with evidence of severe or systemic disease. Available guidelines state that severe cat-scratch disease is usually treated with oral doxycycline plus rifampin or ciprofloxacin. Antibiotic therapy for cat-scratch disease should be continued for at least 14 days. The treatment of choice for bacillary angiomatosis-peliosis is either oral erythromycin or oral doxycycline. Oral azithromycin is an alternative. Available guidelines state that patients who are severely ill or unable to absorb oral medications should be treated with intravenous formulations. Rifampin should be added to the regimen for patients in the former category. Because disease relapse is otherwise so common in these immunocompromised hosts, patients should be treated for at least 3 months. Verruga lesions do not respond consistently to anti-microbial agents and sometimes require surgical resection. Bartonella bacteremia also warrants anti-microbial treatment, despite the fact that some immunocompetent hosts with B. quintana bacteremia will clear their infection spontaneously. The same drugs for treatment of bacillary angiomatosis-peliosis are recommended for primary bacteremias. All patients should be evaluated for endocarditis. According to available guidelines, oral therapy is usually sufficient for uncomplicated Bartonella bacteremia. Exceptions may include immunocompromised patients, bony or parenchymal involvement, and endocarditis, for which initial parenteral therapy may be advantageous. Treatment should be administered for at least 6 weeks and for 2 to 4 weeks in patients with and without endocarditis, respectively. Rifampin should be added to the regimen for treatment of endocarditis. Available guidelines state that patients with trench fever usually respond rapidly to oral antibiotic therapy with resolution of fever and other symptoms within 1 to 2 days. Relapses in treated patients have been well described. In patients with Oroya fever, available guidelines state that that penicillin, chloramphenicol, tetracycline, and streptomycin are effective. According to these guidelines, oral chloramphenicol for 7 or more days is the therapy of choice because of the frequent association of Salmonella infection in endemic regions. After the institution of therapy, fever generally disappears within 2 to 3 days, although blood smears may remain positive for some time.

Q fever is caused by Coxiella burnetii (C.b.), an intracellular parasitic gram-negative bacterium. The most common hosts are goats, cattle, sheep, cats, and occasionally dogs. This spore-forming microorganism reaches high concentrations in the placenta of infected animals; with aerosolization occurring during parturition. Human Q fever usually results from inhalation of contaminated aerosol. There are 3 distinct clinical syndromes of the acute form of Q fever:

1. non-specific febrile illness,
2. pneumonia, and
3. hepatitis.

The chronic form of the disease is usually endocarditis, but occasionally it is manifest as hepatitis, osteomyelitis or endovascular infection. The pneumonic form of the disease can range from very mild to severe pneumonia requiring assisted ventilation. Diagnosis of Q fever is based on isolation of the agent in cell culture, its direct detection, namely by PCR, and serology. Detection of high phase II antibodies titers 1 to 3 weeks after the onset of symptoms and identification of IgM antibodies are indicative to acute infection. High phase I IgG antibody titers of greater than or equal to 1:800 as revealed by micro-immunofluorescence offer evidence of chronic C.b. infection. For acute Q fever, a 2-week treatment with doxycycline is recommended as the first-line therapy. In the case of Q fever endocarditis a long-term combined antibiotic therapy (e.g., doxycycline plus quinolones, or doxycycline plus hydroxychloroquine) is necessary to prevent relapses (Maurin and Raoult, 1999; Kovacova and Kazar, 2002; Marrie, 2003). There is a lack of evidence regarding the use of intravenous antibiotic therapy for patients with Q fever. A recent review (Parker et al, 2006) did not address the use of intravenous antibiotic therapy for the treatment of Q fever.

Ljostad et al (2007) examined the diagnostic sensitivity and temporal course of intra-thecal Borrelia burgdorferi (Bb) antibody production in acute Lyme neuroborreliosis (LNB). These researchers recruited consecutive adult patients with LNB diagnosis based on strict selection criteria. Serum and CSF were obtained, and clinical examination was performed pre-treatment, and 13 days and 4 months post-treatment. Pre-treatment positive Bb antibody index (AI) was detected in 34 of 43 (79 %). All 9 pre-treatment Bb AI negative patients, and 26 of 34 pre-treatment Bb AI positive patients reported symptom duration less than 6 weeks. Eight patients, all Bb AI positive, reported symptom duration of 6 weeks or longer. Consequently, pre-treatment diagnostic sensitivity of Bb AI was 74 % when symptom duration was less than 6 weeks, and 100 % when 6 weeks or longer. Three patients converted from negative to positive Bb AI status post-treatment. The 6 patients who were persistently Bb AI negative had lower CSF cell count and protein at presentation, when compared with the patients with positive Bb AI. The authors concluded that the diagnostic sensitivity of Bb AI is suboptimal in acute early LNB. Repeated post-treatment Bb AI testing, to confirm or reject LNB diagnosis, is unreliable, as the majority of initial Bb AI negative patients remained negative at follow-up.

Blanc et al (2007) stated that the AI has a very good specificity but only moderate sensitivity in diagnosing LNB. These investigators noted that given the lack of consensual criteria for neuroborreliosis and the absence of a “gold standard” diagnostic test, they proposed pragmatic diagnostic criteria for neuroborreliosis, namely the presence of 4 of the following 5 items:

1. no past history of neuroborreliosis,
2. positive CSF ELISA serology,
3. positive anti-Borrelia AI,
4. favorable outcome after specific antibiotic treatment, and
5. no differential diagnosis.

They stated that these new criteria will need to be tested in a larger, prospective cohort.

Orel (1997) described the physico-chemical concept of the singlet oxygen therapy application using photochemically sensibilized air or drinking a water, already barbaturized by an activated singlet oxygen of air. This technology has been applied in the treatment of several clinical conditions including LD. However, there is a lack of evidence regarding its effectiveness.

Shoemaker et al (2008) stated that current laboratory markers do not readily detect acute LD. These researchers assessed the utility of complement and its split products as markers of LD in patients shortly after a tick bite. A total of 31 consecutive acute LD patients, 14 with and 17 without erythema migrans (EM) skin rash, seen by a physician within 96 hrs of a tick bite were matched with 24 consecutive tick bite patients without LD symptoms and 46 healthy control subjects. Complement and split products measured included factor B, Bb, C4, C3c, C3a(des Arg), C4a(des Arg), C1q- and C3d-containing immune complexes, and C2. C2, C4, C3 and factor B levels were within normal ranges in all groups. C3a and C4a levels were significantly higher in acute LD patients than in tick bite and healthy control groups (both p < 0.001). All acute LD patients, regardless of EM, had elevated levels of C3a or C4a. Few tick bite controls had elevated levels of C3a (2/20) or C4a (5/24) and only 1 of the healthy control subjects had elevated C3a (0/46) or C4a (1/32). The authors concluded that these findings suggested that C3a and C4a may be useful markers of LD in patients seen shortly after tick bite, even in those without EM. They noted that the findings of this small study need to be confirmed in a larger study with clinical follow-up. Furthermore, additional studies are needed to evaluate the effects of B. garinii and B. afzelii (which are more common in Europe) infection on the complement system in patients with LD.

Single photon emission computed tomographic (SPECT) scans are often abnormal in patients with LD, but no pattern is specific for LD and these scans are often abnormal in patients without LD (Kalina et al, 2005; Halperin, 2008). Halperin (2010) stated that SPECT brain scans have been used with increasing frequency. In one study, quantitative SPECT, applied in a highly selected group of patients with well-characterized nervous system LD, showed patchy brain hypo-metabolism. However, qualitative brain SPECT, the technique used in clinical laboratories, is highly variable even in normal patients, and has no positive or negative predictive value in nervous system LD.

The European Federation of Neurological Societies’ guidelines on the diagnosis and management of European Lyme neuroborreliosis (Mygland et al, 2010) stated that the following 3 criteria should be fulfilled for definite LNB, and 2 of them for possible LNB:

1. neurological symptoms;
2. CSF pleocytosis; and
3. Bb-specific antibodies produced intra-thecally.

Moreover, PCR and CSF culture may be corroborative if symptom duration is less than 6 weeks, when Bb antibodies may be absent. Otherwise, PCR is not recommended. Furthermore, there is insufficient evidence to recommend the following tests for diagnostic purposes: antigen detection, chemokine CXCL13, cyst formation, immune complexes, lymphocyte markers, lymphocyte transformation test, and microscope-based assays. Adult patients with definite or possible acute LNB (symptom duration less than 6 months) should be offered a single 14-day course of antibiotic treatment. Oral doxycycline (200 mg daily) and intravenous ceftriaxone (2 g daily) are equally effective in patients with symptoms confined to the peripheral nervous system, including meningitis. Patients with CNS manifestations should be treated with intravenous ceftriaxone (2 g daily) for 14 days and late LNB (symptom duration greater than 6 months) for 3 weeks. Children should be treated as adults, except that doxycycline is contraindicated under 8 years of age (9 in some countries). If symptoms persist for more than 6 months after standard treatment, the condition is often termed PLDS. Antibiotic therapy has no impact on PLDS.

Marques et al (2009) noted that it has been reported that patients with chronic LD have a decreased number of natural killer (NK) cells, as defined by the CD57 marker. These researchers performed immunophenotyping in 9 individuals with PLDS, 12 who recovered from LD, and 9 healthy volunteers. The number of NK cells was not significantly different between the groups. A review on Lyme borreliosis (Stanek et al, 2012) states that “measurement of the number of CD57 natural killer cells and use of live microscopy on blood to search for spirochaetes, have not been shown to be reliable and are not recommended for clinical use”. Also, an UpToDate review on “Diagnosis of Lyme disease” (Hu, 2012) does not mention measurement of NK cells as a diagnostic tool.

The practice guidelines by the Infectious Diseases Society of America on the “Clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis” (Wormser et al, 2006) did not mention the use of SPECT. Also, the AAN’s practice parameter on “Diagnosis of Patients with Nervous System Lyme Borreliosis” (1996) includes no role for SPECT scans. A review article by Halperin (2008), who also was the first author of an AAN assessment on this issue, stated that “brain SPECT imaging is notoriously unreliable and is rarely helpful”.

An UpToDate review on “Nervous system Lyme disease” (Halperin, 2011) states that “[s]ince Lyme encephalomyelitis is so rare, MRI of the brain and spine is only rarely abnormal in Lyme disease. When present, encephalomyelitis is evident on MRI as areas of increased signal on T2 and FLAIR sequences. When these areas are large and active, positron emission tomography (PET) demonstrates them to be hypermetabolic. Single photon emission computed tomographic (SPECT) brain scans have been used with increasing frequency. In one study, quantitative SPECT, applied in a highly selected group of patients with well-characterized nervous system Lyme disease, demonstrated patchy brain hypometabolism. However qualitative brain SPECT, the technique used in clinical laboratories, is highly variable even in normal patients, and has no positive or negative predictive value in nervous system Lyme disease”. Furthermore, an UpToDate review on “Diagnosis of Lyme disease” (Hu, 2012) does not mention the use of SPECT.

Schmidt et al (2011) examined chemokine CXCL13 as a potential biomarker for LNB. From March 2008 to August 2009, CSF and serum samples from all patients in whom a B burgdorferi-specific AI was requested (n = 692) and CSF analysis revealed CSF pleocytosis (n = 192) were included in the study. Because of the low number of patients with untreated LNB, 13 additional retrospectively selected samples of patients with untreated LNB were added. CXCL13 concentrations were measured by ELISA and receiver operating characteristic curves were generated. CSF CXCL13 was highly elevated in all patients with untreated acute LNB (mean = 15,149 pg/ml) compared with that in the patients without LNB (mean = 247 pg/ml). At a cut-off of 1,229 pg/ml, the sensitivity of CXCL13 was 94.1 %, which is higher than the AI (85.7 %). Only 7 patients (5 with a CNS lymphoma and 2 with bacterial meningitis) had a CXCL13 level above the cut-off, resulting in a specificity equal to the AI of 96.1 %. The authors concluded that CXCL13 shows high sensitivity and specificity for acute, untreated LNB. They stated that this novel marker has a high potential for use as a complimentary diagnostic tool for LNB.

In an editorial that accompanied the afore-mentioned study, Tumani and Cadavid (2011) stated that there are several limitations to the current study:

1. although patients with suspected LNB were prospectively recruited, the number of patients who fulfilled the diagnostic criteria for definite LNB was small (n = 14), so the conclusions were based on data from a similar number of retrospective cases (n = 13, with CSF samples stored for up to 9 years),
2. Follow-up of patients with LNB was not performed, and
3. a commercially available ELISA assay was used, which was calibrated in buffer rather than in CSF, so measurements may not be absolutely accurate or comparable to other assay conditions.

The editorialists noted that “[s]everal important issues remained to be answered with regard to the use of CSF levels of CXCL13 in patients with LNB …. Further studies are also needed to evaluate the usefulness of CSF levels of CXCL13 to determine the optimal duration of antibiotic treatment. This is of importance especially in cases with suspected “post-Lyme disease”, which may represent a major challenge in routine clinical practice and may prompt physicians to use prolonged unjustified antibiotic treatment”.

Klempner et al (2013) stated that the authors of 4 National Institutes of Health-sponsored antibiotic treatment trials of patients with persistent unexplained symptoms despite previous antibiotic treatment of Lyme disease determined that re-treatment provided little if any benefit and carries significant risk. Two groups recently provided an independent re-assessment of these trials and concluded that prolonged courses of antibiotics are likely to be helpful. These investigators have carefully considered the points raised by these groups, along with their own critical review of the treatment trials. On the basis of this analysis, the authors concluded that there is a meaningful clinical benefit to be gained from re-treatment of such patients with parenteral antibiotic therapy cannot be justified.

Lantos and colleagues (2014) stated that much of the controversy that surrounds Lyme disease pertains to whether it produces prolonged, treatment-refractory infection, usually referred to as chronic Lyme disease. Some have proposed that round morphologic variants of B. burgdorferi, known variably as “cyst forms” and “L-forms,” are responsible for the pathogenesis of chronic Lyme disease. These investigators undertook a systematic review of the literature to determine if there is a documented role of these variants in Lyme disease pathogenesis or in syndromes compatible with chronic Lyme disease. Two systematic literature searches were performed to identify studies in which round morphologic variants of B. burgdorferi have been described in-situ in human specimens. The primary literature search identified 6 studies that reported round morphologic variants of B. burgdorferi in specimens obtained from 32 total patients. No study described these forms in patients who had purely subjective symptom complexes (e.g., fatigue or pain). No study investigated a causal relationship between morphologic variants and clinical disease or evaluated treatment of morphologic variants in-vivo. Of 29 additional studies that described the morphology of B. burgdorferi from patients with Lyme disease, the organism was invariably described as having spirochetal morphology. The authors concluded that in the context of the broader medical literature, it is not currently possible to ascribe a pathogenic role to morphologic variants of B. burgdorferi in either typical manifestations of Lyme disease or in other chronic disease states that are often labeled chronic Lyme disease. They stated that there is no clinical literature to justify specific treatment of B. burgdorferi morphologic variants.

Newberg et al (2002) stated that there were no positron emission tomography (PET) studies reported in the literature with regards to brain metabolism and function in patients with Lyme disease. These patients frequently present with various neurological symptoms, including memory problems. These researchers used [(18)F]fluorodeoxyglucose (FDG) PET to determine the metabolic landscape in 23 patients with Lyme disease. Images were evaluated for cortical and subcortical abnormalities by 2 experienced reviewers blinded to the clinical information. The most striking finding was hypo-metabolism in the temporal lobes in 17/23 (74 %) patients. Of these, 12 had bilateral temporal lobe hypo-metabolism, 2 had left temporal lobe, and 3 had right temporal lobe hypo-metabolism. Seven of the patients with temporal lobe hypo-metabolism had diffuse cortical hypo-metabolism that included the frontal and parietal lobes. Lyme disease appears to have 2 primary patterns of brain involvement on FDG PET scans, specific temporal lobe hypo-metabolism or a diffuse cortical hypo-metabolism. The involvement of the temporal lobes in both patterns is likely associated with the memory disturbances described in many of these patients. The authors concluded that although there was no clear diagnostic pattern, and many of the defects were mild, FDG PET imaging may provide important information regarding the areas of the brain affected in patients with neurological symptoms associated with Lyme disease.

Kalina et al (2005) noted that Lyme disease is a multi-system infectious disease caused by the tick-borne spirochete, B. burgdorferi. Central nervous system (CNS) involvement typically causes local inflammation, most commonly meningitis, but rarely parenchymal brain involvement. These investigators described a patient who presented with clinical findings suggesting a brainstem process. Magnetic resonance imaging (MRI) and PET suggested a brainstem neoplasm. Prior to biopsy, laboratory evaluation led to the diagnosis of Lyme disease. Clinical and imaging abnormalities improved markedly following anti-microbial therapy. The authors described Lyme disease involvement of the cerebellar peduncles with hyper-metabolism on PET. They stated that although MRI is the primary imaging modality for most suspected CNS pathology, the practical applications of PET continue to expand.

An UpToDate review on “Diagnosis of Lyme disease” (Hu, 2013a) does not mention the use of PET as a management tool. Furthermore, the review does not mention testing for neuroadrenal expanded panel (including histamine, serotonin, and hydroxyindoleacetic acid (HIAA)).

An UpToDate review on “Treatment of Lyme disease” (Hu, 2013b) does not mention the use of intramuscular antibiotics of intravenous ascorbic acid as therapeutic options.

The iSpot Lyme assay measures cytokine production in-vitro, specifically interferon gamma, from T-cells in response to activation from Lyme antigen. The interferon-gamma ELISPOT (immunospot) has been used in Lyme disease research since the mid-1990s. A few scientific papers have investigated its use as a diagnostic test for Lyme disease; however, there is no consensus on its use.

Norberg et al (2012) examined the diagnostic performance of Borrelia (Bb)-induced interferon (IFN)-gamma secretion detected by ELISPOT modified to be feasible for clinical laboratories as a supplementary test to the laboratory diagnosis of Lyme neuroborreliosis (LNB) in an endemic setting. Between 2002 and 2004, patients with symptoms of suspected clinical LNB were included in a study conducted on the Aland islands in the Finnish archipelago, which is a hyper-endemic area for Lyme borreliosis (LB). A total of 14 patients with confirmed LNB and 103 patients with non-LNB were included, and the numbers of spontaneous and Bb-induced IFN-gamma-secreting cells were assayed by the ELISPOT test. The ELISPOT assay showed a weak diagnostic performance with a sensitivity of 36 % and a specificity of 82 %. The authors concluded that the findings in this study showed that this ELISPOT-assay modified to be feasible in clinical routine laboratories is not useful as a supplementary diagnostic tool in the laboratory diagnosis of patients with clinically suspected LNB.

Jin et al (2013) noted that Lyme Borreliosis is an infectious disease caused by the spirochete B. burgdorferi that is transmitted through the bite of infected ticks. Both B cell-mediated humoral immunity and T cell immunity develop during natural Borrelia infection. However, compared with humoral immunity, the T cell response to Borrelia infection has not been well-elucidated. In this study, a novel T cell-based assay was developed and validated for the sensitive detection of antigen-specific T cell response to B. burgdorferi. Using IFN-gamma as a biomarker, these researchers developed a new enzyme-linked immunospot method (iSpot Lyme™) to detect Borrelia antigen-specific effector/memory T cells that were activated in-vivo by exposing them to recombinant Borrelia antigens ex-vivo. To test this new method as a potential laboratory diagnostic tool, these investigators performed a clinical study with a cohort of Borrelia-positive patients and healthy controls. They demonstrated that the iSpot Lyme assay has a significantly higher specificity and sensitivity compared with the Western Blot assay that is currently used as a diagnostic measure. These preliminary findings need to be validated by well-designed studies.

An UpToDate review on “Diagnosis of Lyme disease” (Hu, 2014) does not mention the use of iSpot/cytokine/interferon as a diagnostic tool/biomarker.

Marques noted that animal studies suggested that B. burgdorferi may persist after antibiotic therapy and can be detected by various means including xenodiagnosis using the natural tick vector (Ixodes scapularis). No convincing evidence exists for the persistence of viable spirochetes after recommended courses of antibiotic therapy in humans. These researchers determined the safety of using I. scapularis larvae for the xenodiagnosis of B. burgdorferi infection in humans. Laboratory-reared larval I. scapularis ticks were placed on 36 subjects and allowed to feed to repletion. Ticks were tested for B. burgdorferi by PCR, culture, and/or isothermal amplification followed by PCR and electrospray ionization mass spectroscopy. In addition, attempts were made to infect immunodeficient mice by tick bite or inoculation of tick contents. Xenodiagnosis was repeated in 7 individuals. Xenodiagnosis was well-tolerated with no severe adverse events. The most common adverse event was mild itching at the tick attachment site. Xenodiagnosis was negative in 16 patients with post-treatment Lyme disease syndrome (PTLDS) and/or high C6 antibody levels and in 5 patients after completing antibiotic therapy for erythema migrans. Xenodiagnosis was positive for B. burgdorferi DNA in 1 patient with erythema migrans early during therapy and in a patient with PTLDS. There is insufficient evidence, however, to conclude that viable spirochetes were present in either patient. The authors concluded that xenodiagnosis using Ixodes scapularis larvae was safe and well-tolerated. They stated that further studies are needed to determine the sensitivity of xenodiagnosis in patients with Lyme disease and the significance of a positive result.

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An UpToDate review on “Diagnosis of Lyme disease” (Hu, 2014) states that “Xenodiagnosis for Lyme disease involves the use of a tick vector to detect the presence B. burgdorferi. Although not clinically available, xenodiagnosis has been used to detect B. burgdorferi in animal and human studies. In one study, I. scapularis larvae were allowed to feed on 36 human participants (23 with a history of Lyme disease) until the larvae were engorged. The ticks were then tested for B. burgdorferi by polymerase chain reaction (PCR), culture, and/or isothermal amplification followed by PCR and electrospray ionization mass spectroscopy. Xenodiagnosis was well tolerated; the most common adverse event was mild itching at the tick attachment site. Of the 23 patients with a history of Lyme disease, 19 tested negative for B. burgdorferi, two had indeterminate results and two tested positive by PCR, but not by culture. Of the two who tested positive, one had erythema migrans and was receiving antibiotics, and one had post-treatment Lyme disease. Further studies are needed to determine the sensitivity of xenodiagnosis in patients with Lyme disease, as well as the significance of a positive result”.

Sanchez and colleagues (2016) provided an update on diagnosis, treatment, and prevention of tick-borne infections. These investigators performed a search of PubMed and Scopus for articles on diagnosis, treatment, and prevention of tick-borne infections published in English from January 2005 through December 2015. The search yielded 3,550 articles for diagnosis and treatment and 752 articles for prevention. Of these articles, 361 were reviewed in depth. Evidence supports the use of Food and Drug Administration (FDA)-approved serologic tests, such as an EIA, followed by Western blot testing, to diagnose extra-cutaneous manifestations of Lyme disease. Microscopy and PCR assay of blood specimens are used to diagnose active human granulocytic anaplasmosis (HGA) and babesiosis. The effectiveness of oral doxycycline, amoxicillin, and cefuroxime axetil for treating Lyme disease has been established in multiple trials. Ceftriaxone is recommended when parenteral antibiotic therapy is recommended. Multiple trials have shown effectiveness for a 10-day course of oral doxycycline for treatment of erythema migrans and for a 14-day course for treatment of early neurologic Lyme disease in ambulatory patients. Evidence indicates that a 10-day course of oral doxycycline is effective for HGA and that a 7- to 10-day course of azithromycin plus atovaquone is effective for mild babesiosis. Based on multiple case reports, a 7- to 10-day course of clindamycin plus quinine is often used to treat severe babesiosis. A recent study supports a minimum of 6 weeks of antibiotics for highly immunocompromised patients with babesiosis, with no parasites detected on blood smear for at least the final 2 weeks of treatment. The authors concluded that evidence is evolving regarding the diagnosis, treatment, and prevention of Lyme disease, HGA, and babesiosis. Recent evidence supports treating patients with erythema migrans for no longer than 10 days when doxycycline is used and prescription of a 14-day course of oral doxycycline for early neurologic Lyme disease in ambulatory patients. The duration of anti-microbial therapy for babesiosis in severely immunocompromised patients should be extended to 6 weeks or longer.

In a randomized, double-blind, placebo-controlled trial, Berende and associates (2016) examined if longer-term antibiotic treatment of persistent symptoms attributed to Lyme disease leads to better outcomes than does shorter-term treatment. These researchers assigned patients with persistent symptoms attributed to Lyme disease – either related temporally to proven Lyme disease or accompanied by a positive IgG or IgM immunoblot assay for Borrelia burgdorferi – to receive a 12-week oral course of doxycycline, clarithromycin plus hydroxychloroquine, or placebo. All study groups received open-label intravenous ceftriaxone for 2 weeks before initiating the randomized regimen. The primary outcome measure was health-related quality of life, as assessed by the physical-component summary score of the RAND-36 Health Status Inventory (RAND SF-36) (range of 15 to 61, with higher scores indicating better quality of life), at the end of the treatment period at week 14, after the 2-week course of ceftriaxone and the 12-week course of the randomized study drug or placebo had been completed. Of the 281 patients who underwent randomization, 280 were included in the modified intention-to-treat analysis (86 patients in the doxycycline group, 96 in the clarithromycin-hydroxychloroquine group, and 98 in the placebo group). The SF-36 physical-component summary score did not differ significantly among the 3 study groups at the end of the treatment period, with mean scores of 35.0 (95 % confidence interval [CI]: 33.5 to 36.5) in the doxycycline group, 35.6 (95 % CI: 34.2 to 37.1) in the clarithromycin-hydroxychloroquine group, and 34.8 (95 % CI: 33.4 to 36.2) in the placebo group (p = 0.69; a difference of 0.2 [95 % CI: -2.4 to 2.8] in the doxycycline group versus the placebo group and a difference of 0.9 [95 % CI: -1.6 to 3.3] in the clarithromycin-hydroxychloroquine group versus the placebo group); the score also did not differ significantly among the groups at subsequent study visits (p = 0.35). In all study groups, the SF-36 physical-component summary score increased significantly from baseline to the end of the treatment period (p < 0.001). The rates of adverse events (AEs) were similar among the study groups; 4 serious AEs thought to be related to drug use occurred during the 2-week open-label ceftriaxone phase, and no serious drug-related AE occurred during the 12-week randomized phase. The authors concluded that in patients with persistent symptoms attributed to Lyme disease, longer-term antibiotic treatment did not have additional beneficial effects on health-related quality of life beyond those with shorter-term treatment.

Alpha Lipoic Acid or “Healing Detox Drips” for the Treatment of Lyme Disease

Puri et al (2015) noted that while pharmacotherapy with intravenous ceftriaxone, a third-generation cephalosporin, is a potential treatment of Lyme neuroborreliosis, there is concern that it can cause the formation of biliary sludge, leading to hepatobiliary complications such as biliary colic, jaundice and cholelithiasis, which are reflected in changes in serum levels of bilirubin and markers of cholestatic liver injury (alkaline phosphatase and gamma-glutamyltranspeptidase). It has been suggested that the naturally occurring substances alpha-lipoic acid and glutathione may be helpful in preventing hepatic disease. Alpha-lipoic acid exhibits anti-oxidant, anti-inflammatory and anti-apoptotic activities in the liver, while glutathione serves as a sulfhydryl buffer. These researchers examined if co-administration of alpha-lipoic acid and glutathione is associated with significant changes in serum levels of bilirubin, alkaline phosphatase and gamma-glutamyltranspeptidase during the treatment of Lyme neuroborreliosis with long-term intravenous ceftriaxone. Serum levels of bilirubin, alkaline phosphatase and gamma-glutamyltranspeptidase were measured in 42 serologically positive Lyme neuroborreliosis patients before and after long-term treatment with intravenous ceftriaxone (2 to 4 g daily) with co-administration of oral/intravenous alpha-lipoic acid (600 mg daily) and glutathione (100 mg orally or 0.6 to 2.4 g intravenously daily). None of the patients developed biliary colic and there were no significant changes in serum bilirubin, alkaline phosphatase or gamma-glutamyltranspeptidase levels over the course of the intravenous ceftriaxone treatment (mean length 75.0 days). The authors concluded that co-administration of alpha-lipoic acid and glutathione is associated with no significant changes in serum bilirubin, alkaline phosphatase or gamma-glutamyltranspeptidase levels during the treatment of neuroborreliosis with intravenous ceftriaxone.

Antibiotic Augmented Thermo-Eradication (AAT) Therapy

Douwes (2018) noted that antibiotic augmented thermo-eradication (AAT) therapy is a combination of antibiotics with extreme whole-body hyperthermia (WBH) at 41.6 degrees C (106.9 degrees F) for the treatment of chronic LD. This procedure is carried out in a special unit; and patients are under sedation and intensive monitoring. Heat is provided via infrared radiation (850 to 1,300 nm); and the body temperature is raised to 41.6 degrees C and is maintained for 2 hours. In chronic borreliosis, only 2 WBH sessions in combination with antibiotics are needed to eradicate the Borrelia completely. Of the 809 evaluable patients 6 to 12 months after AAT therapy, 601 (74.3 %) reported good-to-very good results, 130 (16 %) reported satisfactory results, and 78 (9.6 %) had no benefits. The author stated that AAT therapy is a promising alternative for the treatment of chronic LD. However, there is insufficient evidence to support the use of AAT therapy for the treatment of chronic LD.

An UpToDate review on “Treatment of Lyme disease” (Hu and Shapiro, 2021) does not mention antibiotic augmented thermo-eradication as a management / therapeutic option.

Biologic Markers of Antibiotic-Refractory Lyme Arthritis

Jarosz and Badawi (2019) Lyme disease or Lyme borreliosis (LB) noted that Lyme disease is the most common vector-borne disease in North America and Europe. It is an inflammatory disease caused by the bacterium Borrelia burgdorferi. The role of the inflammatory processes mediated by prostaglandins (PGs), thromboxanes and leukotrienes (LTs) in LB severity and symptoms resolution is yet to be elucidated. These investigators examined the role of PGs and related lipid mediators in the induction and resolution of inflammation in LB. They conducted a comprehensive search in PubMed, Ovid Medline, Embase and Embase Classic to identify cell-culture, animal and human studies reporting the changes in PGs and related lipid mediators of inflammation during the course of LB. These researchers identified 18 studies to be included into this systematic review. The selected reports consisted of 7 cell-culture studies, 7 animal studies, and 4 human studies (from 3 patient populations). Results from cell-culture and animal studies suggested that PGs and other lipid mediators of inflammation were elevated in LB and may contribute to disease development. The limited number of human studies showed that subjects with Lyme meningitis, Lyme arthritis (LA) and antibiotic-refractory LA (A-RLA) had increased levels of an array of PGs and lipid mediators (e.g., LTB4, 8-isoPGF2α, and phospholipases A2 activity). Levels of these biomarkers were significantly reduced following the treatment with antibiotics or non-steroidal anti-inflammatory drugs (NSAIDs). The authors concluded that dysregulation of PGs and related lipid mediators may play a role in the etiology of LB and persistence of inflammation that may lead to long-term complications. Moreover, they stated that further investigation into the precise levels of a wide range of PGs and related factors is critical as it may propose novel biomarkers that can be used for early diagnosis.

Badawi and colleagues (2019) noted that Lyme disease may result in substantial morbidity, primarily from persistent LA that could develop into A-RLA. These researchers evaluated a range of biomarkers for their potential predictive value in the development of A-RLA. They conducted a systematic review of studies examining biomarkers among patients with A-RLA from Medline via Ovid, Embase and Web of Science databases and identified a total of 26 studies for qualitative analysis. All studies were of patient populations from the USA, with the exception of 1 from Europe. These investigators identified an array of biomarkers that are commonly modulated in the A-RLA compared with subjects with antibiotic-responsive LA. These included a range of inflammatory markers (IL-6, IL-8, IL-10, IL-1β, IL-23, IL-17F, TNFα, IFNγ, CXCL9, CXCL10, CCL2, CCL3 and CCL4, CRP), factors along the innate and adaptive immune response pathways (e.g., CD4+ T cells, GITR receptors, OX40 receptors, IL-4+CD4+Th2 cells, IL-17+CD4+ T cells) and an array of miRNA species (e.g., miR-142, miR-17, miR-20a, let-7c and miR-30fam). The authors concluded that the evidence base of biologic markers for A-RLA is limited. However, in the small set of studies conducted to-date, a range of promising biomarkers have been identified. Cytokines and chemokines related to Th17 pathway together with a number of miRNAs species (miR-146a, miR-155 and let-7a) may be promising candidates in the prediction of A-RLA. These investigators stated that within well-powered and properly designed studies, a panel of multiple biomarkers may yield clinically relevant prediction of the possible resistance at the time of LA first diagnosis.

Combined Antibiotics

On behalf of the Pharmacotherapy Commission of the German Society for Rheumatology, Gaubitz and colleagues (2014) summarized the current evidence for diagnosis and treatment of Lyme arthritis and the most frequent skin manifestations of Borrelia burgdorferi infections. Lyme arthritis is a monoarticular or oligoarticular form of arthritis that typically involves the knee. A positive ELISA for IgG antibodies should be followed by an IgG immunoblot. A positive PCR test from synovial fluid adds increased diagnostic certainty. Serum positivity for antibodies to Borrelia burgdorferi without typical symptoms does not justify antibiotic treatment. Oral antibiotic treatment for erythema migrans is recommended using doxycycline, 200 mg once-daily for 10 to 21 days, alternative choices are amoxicillin, cefuroxime and azithromycin. For children below 8 years of age, amoxicillin is recommended. Lyme arthritis can usually be successfully treated with orally administered anti-microbial agents. Doxycycline, 1 × 200 or 2 × 100 mg for 30 days is the antibiotic agent of choice. Amoxicillin (3 × 500 to 1,000 mg) can be alternatively chosen. Patients who have persistent or recurrent joint swelling after a recommended course of oral antibiotic therapy should be treated intravenously. In this situation, ceftriaxone at 2 g per day for 14 to 21 days is recommended. There is no evidence to recommend long-term and combined treatments.

Furthermore, an UpToDate review on “Treatment of Lyme disease” (Hu, 2019) does not mention combined antibiotics as a therapeutic option.

Evaluation of Peripheral Neuropathy

Wormser and colleagues (2017) noted that in older studies, a chronic distal symmetric sensory neuropathy was reported as a relatively common manifestation of late Lyme disease in the United States. However, the original papers describing this entity had notable inconsistencies and certain inexplicable findings, such as reports that this condition developed in patients despite prior antibiotic treatment known to be highly effective for other manifestations of Lyme disease. More recent literature suggested that this entity is seen rarely, if at all. The authors concluded that a chronic distal symmetric sensory neuropathy as a manifestation of late Lyme disease in North America should be regarded as controversial, and in need of rigorous validation studies before acceptance as a documented clinical entity.

Intramuscular Antibiotic Therapy

The ISDA guidelines (Wormser, et al., 2006) cite a study (citing Steere, et al. 1985) that suggests that IM administration may be less effective than intravenous administration based upon response rates, although the two modes of administration were not directly compared.

In a double-blind, placebo-controlled trial carried out from 1980 to 1982 (Steere et al, 1985), a total of 20 patients with established Lyme arthritis were assigned treatment with 2.4 million U of intramuscular benzathine penicillin weekly for 3 weeks (total, 7.2 million U) and 20 patients received saline; 7 of the 20 penicillin-treated patients (35 %) had complete resolution of arthritis soon after the injections and have remained well during a mean follow-up period of 33 months. In contrast, all 20 patients given placebo continued to have attacks of arthritis (p < 0.02). In 1983, of 20 patients treated with intravenous penicillin G, 20 million U a day for 10 days, 11 (55 %) had complete resolution of arthritis and have remained well since. As compared with non-responders, penicillin-responsive patients in both studies were more likely to have previously received antibiotics for erythema chronicum migrans (p < 0.02) and less likely to have been given intra-articular corticosteroids during or at the conclusion of parenteral therapy (p < 0.1). The Lyme spirochete was not cultured from synovium or joint fluid. The authors concluded that established Lyme arthritis can often be treated successfully with parenteral penicillin. Moreover, they stated that neither of the regimens tested was uniformly effective, and further investigation is needed to determine the optimal course of therapy.

Steere and associates (1987) compared phenoxymethyl penicillin, erythromycin, and tetracycline, in each instance 250-mg 4 times a day for 10 days, for the treatment of early Lyme disease (stage 1). None of 39 patients given tetracycline developed major late complications compared with 3 of 40 penicillin-treated patients and 4 of 29 given erythromycin (p = 0.07). However, with all 3 antibiotic agents, nearly 50 % of patients had minor late symptoms. For neurologic abnormalities (stage 2), 12 patients were treated with high-dose IV penicillin, 20 million U a day for 10 days. Pain usually subsided during therapy, but a mean of 7 to 8 weeks was needed for complete recovery of motor deficits. For the treatment of established arthritis (stage 3), 20 patients were assigned treatment with IM benzathine penicillin (7.2 million U) and 20 patients received saline; 7 of the 20 penicillin-treated patients (35 %) were apparently cured, but all 20 patients given placebo continued to have attacks of arthritis (p < 0.02). Of 20 arthritis patients treated with IV penicillin G, 20 million U a day for 10 days, 11 (55 %) were apparently cured. Thus, all 3 stages of Lyme disease can be treated with antibiotic therapy, but some patients with late disease may not respond. This study presented the same data that were reported in the authors’ 1985 study.

Cimmino and co-workers (1996) examined the effectiveness of various therapeutic regimens for Lyme arthritis. The first treatment was IM benzathine penicillin 2.4 million units weekly for 3 weeks, and had a success rate of 35 %. Another study employed IV penicillin G at a dosage of 20 million units daily for 10 days, which cured 55 % of patients; and IV ceftriaxone has been shown to be superior to penicillin with a response rate of 94 %. However, these results have been challenged in recent reports. Oral doxycycline or amoxicillin in association with probenecid appeared to work equally well although neuroborreliosis was more frequent following treatment with amoxicillin. An anecdotal report indicated the clinical value of long-term benzathine penicillin for chronic Lyme arthritis. Long-term antibiotic therapy, which is recommended also for Reiter’s syndrome, may be useful for eradicating the sanctuaries of Borrelia burgdorferi. Disease-modifying drugs such as hydroxychloroquine or sulphasalazine, a drug which is commonly used in reactive arthritis following enteric infections, may be of value in Lyme arthritis resistant to antibiotics, but have not been tested to-date. The role of intraarticular injections of steroids or synovectomy is still controversial. The authors concluded that antibiotic treatment is the cornerstone of Lyme arthritis treatment; additional interventions should be studied for patients with Lyme arthritis resistant to antibiotics.

Fingerle and Wilske (2006) noted that every manifestation of Lyme borreliosis needs to be treated with antibiotics. The type of antibiotic applied and duration of treatment will depend on the stage and severity of the disease. Erythema migrans, Borrelia lymphocytoma, Lyme arthritis and acrodermatitis chronica atrophicans are primarily treated orally. If neurological symptoms, severe Lyme carditis or eye manifestations are present, IV treatment is initially recommended. For oral therapy, doxycycline, amoxicillin, cefuroxime and, if intolerance is shown, azithromycin, are available. For IV treatment ceftriaxone, cefotaxime or penicillin G is employed. The overall prognosis for treated Lyme borreliosis is good. However, in particular when manifestations with substantial organic injury have persisted, incomplete healing must be expected. With the exception of erythema migrans, every manifestation should be subjected to a careful diagnostic work-up prior to the start of treatment, because premature antibiotic administration is not only associated with an elevated risk for the patient, but can also mask important diagnostic signs. This review on stage-oriented treatment of Lyme borreliosis did not mention IM penicillin as a therapeutic option.

The CDC’s guideline on Lyme disease (2016) did not mention IM penicillin as a therapeutic option. In addition, the CDC (Marzec et al, 2017) stated that “The number of persons who undergo treatments for chronic Lyme disease is unknown, as is the number of complications that result from such treatments. Systematic investigations would be useful to understand the scope and consequences of adverse effects resulting from treatment of persons with a diagnosis of chronic Lyme disease. Data sources to consider include clinician surveys, administrative claims databases, or implementation of state or local reporting systems for adverse outcomes related to these treatments”.

Furthermore, an UpToDate review on “Treatment of Lyme disease” (Hu, 2017) does not mention intramuscular antibiotic as a therapeutic option.

Intramuscular Penicillin

In a double-blind, placebo-controlled study, Steere and colleagues (1985) examined the effects of parenteral penicillin therapy in the treatment of Lyme arthritis. This trial was carried out from 1980 to 1982; a total of 20 patients with established Lyme arthritis were assigned treatment with 2.4 million U of intra-muscular (IM) benzathine penicillin weekly for 3 weeks (total of 7.2 million U) and 20 patients received saline; 7 of the 20 penicillin-treated patients (35 %) had complete resolution of arthritis soon after the injections and have remained well during a mean follow-up period of 33 months. In contrast, all 20 patients given placebo continued to have attacks of arthritis (p < 0.02). In 1983, of 20 patients treated with intravenous (IV) penicillin G, 20 million U a day for 10 days, 11 (55 %) had complete resolution of arthritis and have remained well since. As compared with non-responders, penicillin-responsive patients in both studies were more likely to have previously received antibiotics for erythema chronicum migrans (p < 0.02) and less likely to have been given intra-articular corticosteroids during or at the conclusion of parenteral therapy (p < 0.1). The Lyme spirochete was not cultured from synovium or joint fluid. The authors concluded that established Lyme arthritis can often be treated successfully with parenteral penicillin. However, neither of the regimens that these investigators tested was uniformly effective, and they stated that further experience is needed to determine the optimal course of therapy.

Steere and associates (1987) compared phenoxymethyl penicillin, erythromycin, and tetracycline, in each instance 250-mg 4 times a day for 10 days, for the treatment of early Lyme disease (stage 1). None of 39 patients given tetracycline developed major late complications compared with 3 of 40 penicillin-treated patients and 4 of 29 given erythromycin (p = 0.07). However, with all 3 antibiotic agents, nearly 50 % of patients had minor late symptoms. For neurologic abnormalities (stage 2), 12 patients were treated with high-dose IV penicillin, 20 million U a day for 10 days. Pain usually subsided during therapy, but a mean of 7 to 8 weeks was needed for complete recovery of motor deficits. For the treatment of established arthritis (stage 3), 20 patients were assigned treatment with IM benzathine penicillin (7.2 million U) and 20 patients received saline; 7 of the 20 penicillin-treated patients (35 %) were apparently cured, but all 20 patients given placebo continued to have attacks of arthritis (p < 0.02). Of 20 arthritis patients treated with IV penicillin G, 20 million U a day for 10 days, 11 (55 %) were apparently cured. Thus, all 3 stages of Lyme disease can be treated with antibiotic therapy, but some patients with late disease may not respond. This study presented the same data that were reported in the authors’ 1985 study.

Cimmino and co-workers (1996) examined the effectiveness of various therapeutic regimens for Lyme arthritis. The first treatment was IM benzathine penicillin 2.4 million units weekly for 3 weeks, and had a success rate of 35 %. Another study employed IV penicillin G at a dosage of 20 million units daily for 10 days, which cured 55 % of patients; and IV ceftriaxone has been shown to be superior to penicillin with a response rate of 94 %. However, these results have been challenged in recent reports. Oral doxycycline or amoxicillin in association with probenecid appeared to work equally well although neuroborreliosis was more frequent following treatment with amoxicillin. An anecdotal report indicated the clinical value of long-term benzathine penicillin for chronic Lyme arthritis. Long-term antibiotic therapy, which is recommended also for Reiter’s syndrome, may be useful for eradicating the sanctuaries of Borrelia burgdorferi. Disease-modifying drugs such as hydroxychloroquine or sulphasalazine, a drug which is commonly used in reactive arthritis following enteric infections, may be of value in Lyme arthritis resistant to antibiotics, but have not been tested to-date. The role of intraarticular injections of steroids or synovectomy is still controversial. The authors concluded that antibiotic treatment is the cornerstone of Lyme arthritis treatment; additional interventions should be studied for patients with Lyme arthritis resistant to antibiotics.

Fingerle and Wilske (2006) noted that every manifestation of Lyme borreliosis needs to be treated with antibiotics. The type of antibiotic applied and duration of treatment will depend on the stage and severity of the disease. Erythema migrans, Borrelia lymphocytoma, Lyme arthritis and acrodermatitis chronica atrophicans are primarily treated orally. If neurological symptoms, severe Lyme carditis or eye manifestations are present, IV treatment is initially recommended. For oral therapy, doxycycline, amoxicillin, cefuroxime and, if intolerance is shown, azithromycin, are available. For IV treatment ceftriaxone, cefotaxime or penicillin G is employed. The overall prognosis for treated Lyme borreliosis is good. However, in particular when manifestations with substantial organic injury have persisted, incomplete healing must be expected. With the exception of erythema migrans, every manifestation should be subjected to a careful diagnostic work-up prior to the start of treatment, because premature antibiotic administration is not only associated with an elevated risk for the patient, but can also mask important diagnostic signs. This review on stage-oriented treatment of Lyme borreliosis did not mention IM penicillin as a therapeutic option.

The CDC’s guideline on Lyme disease (2016) did not mention IM penicillin as a therapeutic option. In addition, the CDC (Marzec et al, 2017) stated that “The number of persons who undergo treatments for chronic Lyme disease is unknown, as is the number of complications that result from such treatments. Systematic investigations would be useful to understand the scope and consequences of adverse effects resulting from treatment of persons with a diagnosis of chronic Lyme disease. Data sources to consider include clinician surveys, administrative claims databases, or implementation of state or local reporting systems for adverse outcomes related to these treatments”.

Furthermore, an UpToDate review on “Treatment of Lyme disease” (Hu, 2019) does not mention IM penicillin as a therapeutic option.

Mycotoxin Testing for Lyme Disease

UpToDate reviews on “Clinical manifestations of Lyme disease in adults” (Hu, 2018a), “Lyme disease: Clinical manifestations in children” (Shapiro, 2018) “Diagnosis of Lyme disease” (Hu, 2018b) do not mention mycotoxin testing.

Prolonged Intravenous (IV) Antibiotics for the Treatment of Lyme Disease

Klempner and colleagues (2001) noted that it is controversial whether prolonged antibiotic treatment is effective for patients in whom symptoms persist after the recommended antibiotic treatment for acute Lyme disease. These researchers conducted 2 randomized trials: one in 78 patients who were sero-positive for IgG antibodies to Borrelia burgdorferi at the time of enrollment and the other in 51 patients who were sero-negative. The patients received either intravenous (IV) ceftriaxone, 2 g daily for 30 days, followed by oral doxycycline, 200 mg daily for 60 days, or matching IV and oral placebos. Each patient had well-documented, previously treated Lyme disease but had persistent musculoskeletal pain, neurocognitive symptoms, or dysesthesia, often associated with fatigue. The primary outcome measures were improvement on the physical- and mental-health-component summary scales of the Medical Outcomes Study 36-item Short-Form General Health Survey (SF-36) – a scale measuring the health-related quality of life – on day 180 of the study. After a planned interim analysis, the data and safety monitoring board recommended that the studies be discontinued because data from the first 107 patients indicated that it was highly unlikely that a significant difference in treatment efficacy between the groups would be observed with the planned full enrollment of 260 patients. Base-line assessments documented severe impairment in the patients’ health-related quality of life. In intention-to-treat (ITT) analyses, there were no significant differences in the outcomes with prolonged antibiotic treatment as compared with placebo. Among the sero-positive patients who were treated with antibiotics, there was improvement in the score on the physical-component summary scale of the SF-36, the mental-component summary scale, or both in 37 %, no change in 29 %, and worsening in 34 % among sero-positive patients receiving placebo, there was improvement in 40 %, no change in 26 %, and worsening in 34 % (p = 0.96 for the comparison between treatment groups). The results were similar for the sero-negative patients. The authors concluded that there was considerable impairment of health-related quality of life among patients with persistent symptoms despite previous antibiotic treatment for acute Lyme disease. However, in these 2 trials, treatment with IV and oral antibiotics for 90 days did not improve symptoms more than placebo.

Lantos (2011) stated that the diagnosis of chronic Lyme disease has been embroiled in controversy for many years. This is exacerbated by the lack of a clinical or microbiologic definition, and the commonality of chronic symptoms in the general population. An accumulating body of evidence suggested that Lyme disease is the appropriate diagnosis for only a minority of patients in whom it is suspected. In prospective studies of Lyme disease, very few patients go on to have a chronic syndrome dominated by subjective complaints. There is no systematic evidence that Borrelia burgdorferi, the etiology of Lyme disease, can be identified in patients with chronic symptoms following treated Lyme disease. Multiple prospective trials have revealed that prolonged courses of antibiotics neither prevent nor alleviate such post-Lyme syndromes. The author concluded that extended courses of IV antibiotics have resulted in severe adverse events (AEs), which in light of their lack of efficacy, make them contraindicated.

Delong and associates (2012) stated that that Lyme disease (Lyme borreliosis) is caused by the tick-borne spirochete Borrelia burgdorferi. Long-term persistent illness following antibiotic treatment is not uncommon, particularly when treatment is delayed. Current treatment guidelines for persistent disease primarily rely on findings from 4 randomized, controlled trials (RCTs), strongly advising against re-treatment. These researchers performed a biostatistical review of all published RCTs evaluating antibiotic re-treatment, focusing on trial design, analysis and conclusions. A total of 4 RCTs met the inclusion criteria; all examined the efficacy of IV ceftriaxone versus placebo at approximately 3 or 6 months. Design assumptions for the primary outcomes in the 2 Klempner trials and 2 outcomes in the Krupp trial were unrealistic and the trials were likely under-powered to detect clinically meaningful treatment effects. The Klempner trials were analyzed using inefficient statistical methods. The Krupp RCT was well-designed and analyzed for fatigue, finding statistically significant and clinically meaningful improvement. Fallon corroborated this finding. Fallon also found improvement in cognitive functioning, a primary outcome, at 12 weeks which was not sustained at 24 weeks; improvements in physical functioning and pain were demonstrated at week 24 as an interaction effect between treatment and baseline symptom severity with the drug effect increasing with higher baseline impairment. The authors concluded that this biostatistical review revealed that re-treatment could be beneficial. Primary outcomes originally reported as statistically insignificant were likely under-powered. These researchers stated that the positive treatment effects of ceftriaxone were encouraging and consistent with continued infection, a hypothesis deserving additional study. They stated that additional studies of persistent infection and antibiotic treatment are needed.

On behalf of the Pharmacotherapy Commission of the German Society for Rheumatology, Gaubitz and colleagues (2014) summarized the current evidence for diagnosis and treatment of Lyme arthritis and the most frequent skin manifestations of Borrelia burgdorferi infections. These investigators stated that patients who have persistent or recurrent joint swelling after a recommended course of oral antibiotic therapy should be treated intravenously. In this situation, ceftriaxone at 2 g per day for 14 to 21 days is recommended; moreover, there is no evidence to recommend long-term and combined treatments.

An UpToDate review on “Treatment of Lyme disease” (Hu, 2019) states “No comparative trials have been performed to identify the optimal antibiotic regimen for Lyme carditis or to confirm that outcomes are improved with initial treatment with intravenous antibiotics compared with oral antibiotics. Supportive data come from case reports and small case series. Intravenous (IV) therapy – As discussed above, patients who are symptomatic (e.g., syncope, dyspnea, or chest pain), have second or third degree atrioventricular (AV) block, or have first degree AV block with a markedly prolonged PR interval (≥ 300 milliseconds) should be hospitalized, monitored with cardiac telemetry, and treated with intravenous antibiotics. When IV therapy is required, the drug of choice is ceftriaxone (2 g IV once daily in adults; 50 to 75 mg/kg IV once daily in children), but appropriate alternatives include IV cefotaxime or penicillin G. Desensitization to ceftriaxone, cefotaxime, or penicillin should be considered in patients who require IV therapy but have a history of an IgE-mediated (anaphylactic) reaction to these agents. IV antibiotics should be continued until high-grade AV block has resolved and the PR interval has become less than 300 milliseconds. The patient may then be switched to oral therapy to complete a 21 to 28 day course. Appropriate oral antibiotics include doxycycline, amoxicillin, and cefuroxime axetil”.

Furthermore, a draft clinical practice guidelines by the Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR) on “The prevention, diagnosis and treatment of Lyme disease” (Lantos et al, 2019) states that “Under most circumstances, oral therapy is effective and preferred over intravenous therapy due to equivalent efficacies, tolerability, and cost. However, indications for intravenous therapy, such as treatment in the hospitalized patient, are discussed in this guideline”.

Urine OspA Protein Evaluation

Magni et al (2015) state that there is a clinical need to improve the diagnostic specificity of early stage Lyme assays in the period prior to the mounting of a robust serology response. The authors evaluated urinary Borrelia outer surface protein A (OspA) C-terminus peptide in early stage Lyme borreliosis (LB) before and after treatment, and in patients suspected of late stage disseminated LB. The authors employed Nanotrap particles to concentrate urinary OspA and used a highly specific anti-OspA monoclonal antibody (mAb) as a detector of the C-terminus peptides. They mapped the mAb epitope to a narrow specific OspA C-terminal domain OspA236-239 conserved across infectious Borrelia species but with no homology to human proteins and no cross-reactivity with relevant viral and non-Borrelia bacterial proteins. 268 urine samples from patients being evaluated for all categories of LB were collected in a LB endemic area. The urinary OspA assay, blinded to outcome, utilized Nanotrap particle pre-processing, western blotting to evaluate the OspA molecular size, and OspA peptide competition for confirmation. The authors report OspA test characteristics: sensitivity 1.7 pg/mL (lowest limit of detection), % coefficient of variation (CV) = 8 %, dynamic range 1.7-30 pg/mL. Pre-treatment, 24/24 newly diagnosed patients with an erythema migrans (EM) rash were positive for urinary OspA while false positives for asymptomatic patients were 0/117 (Chi squared p < 10−6). For 10 patients who exhibited persistence of the EM rash during the course of antibiotic therapy, 10/10 were positive for urinary OspA. Urinary OspA of 8/8 patients switched from detectable to undetectable following symptom resolution post-treatment. Specificity of the urinary OspA test for the clinical symptoms was 40/40. Specificity of the urinary OspA antigen test for later serology outcome was 87.5 % (21 urinary OspA positive/24 serology positive, Chi squared p = 4.072e−15). 41 of 100 patients under surveillance for persistent LB in an endemic area were positive for urinary OspA protein. The authors concluded that OspA urinary shedding was strongly linked to concurrent active symptoms (e.g. EM rash and arthritis), while resolution of these symptoms after therapy correlated with urinary conversion to OspA negative.

The authors do note that PCR analysis of urinary Borrelia, or urinary Borrelia culture was not done, because of the very low sensitivity of these tests in human urine. Consequently, a weakness of this study is that a true positive diagnosis of LB could only be based on the CDC clinical criteria (e.g. EM rash and other objective symptoms), and the development of a later positive serology in patients who underwent therapy at the time of the clinical diagnosis of LB. Despite this weakness, the strong correlation of urinary OspA with treatment response may offer a new class of information to assist the treating physician to determine whether a first round of therapy is successful in primary cutaneous early stage LB. In a population of patients being under surveillance for persistent or recurrent LB, the percentage of positive urinary OspA patients is in keeping with previous studies on patients estimated to actually have LB in endemic areas. It is impossible to know if urinary OspA, assuming that is indicative of Borrelia burgdorferi infection, is caused by a recurrent or new infection. Thus, urinary OspA measurements may provide additional information to assist the clinical workup of patients under investigation of disseminated later stages of LB.

Lyme Borrelia Nanotrap Antigen Test (Galaxy Diagnostics, Inc.) is a urine-based test developed for the direct detection of outer surface protein A (OspA) antigen to confirm Borrelia burgdorferi infection at all stages of Lyme disease. Serology tests are indirect, detecting the presence of antibodies to Borrelia burgdorferi, only confirming prior exposure. Galaxy Diagnostics report unpublished validation data that shows the test is able to detect active infection in patients with negative Two-Tiered Testing (TTT) (ELISA with reflex to Western blot) results. They note that further research is needed to confirm clinical utility for other presentations of Lyme borreliosis, including Lyme arthritis, Lyme carditis, and neuroborreliosis (Galaxy, 2022).

The CDC currently does not recommend capture assays for antigens in urine (CDC, 2018). CDC recommends a two-step testing process (ELISA with reflex to Western blot) for Lyme disease. Both steps are required and can be done using the same blood sample. If this first step is negative, no further testing is recommended. If the first step is positive or indeterminate (sometimes called “equivocal”), the second step should be performed. The overall result is positive only when the first test is positive (or equivocal) and the second test is positive (or for some tests equivocal) (CDC, 2021).

The Infectious Diseases Society of America (IDSA) published “Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR): 2020 Guidelines for the Prevention, Diagnosis and Treatment of Lyme Disease state that “some commercially available laboratory testing methods, including nonstandard serology interpretation, urine antigen, DNA testing, the use of a lymphocyte transformation test, or quantitative CD57 lymphocyte assay should be avoided for clinical use due to lack of systematic, independent, reproducible validation studies”.

Anti-Sense Supportive Oligonucleotide Therapy

Apostolou e al (2022) noted that anti-sense therapy is widely used as an alternative therapeutic option for various diseases. RNA interference might be effective in infections via the degradation of messenger RNA and, thus, translation process. Therefore, proteins essential for microorganisms and viruses’ proliferation and metabolism are inhibited, leading to their elimination. These researchers examined the use of oligonucleotide in patients infected by Epstein-Barr (EBV) or herpes simplex viruses (HSV) 1/2 or with Lyme disease caused by Borrelia burgdorferi. Blood samples were collected from 115 patients and the different species were characterized using molecular biology techniques. Then, SOT molecules (supportive oligonucleotide therapy), which are specific small interfering RNA (siRNA), were designed, produced, and evaluated, for each specific strain. Oligonucleotides were administered intravenously to patients and then a quantitative PCR test was used to examine the effectiveness of SOT. This study showed that for Lyme disease, 1 or 2 SOT administrations could result in a statistically significant decrease in DNA copies, while for viruses, 2 or 3 administrations were needed to achieve a statistically significant reduction in the genetic material. The authors concluded that these preliminary findings indicated that ant-i-sense SOT therapy can be considered a potential treatment for viral as well as Lyme diseases. These investigators stated that more samples need to be tested to implement SOT in the clinical routine; however, the preliminary inferential statistical data were encouraging for these infections.

Platelet Rich Plasma Infusion

An UpToDate review on “Treatment of Lyme disease” (Hu and Shapiro, 2022) does not mention platelet rich plasma as a management / therapeutic option.

Radiation-Based Therapies / Reactive Oxygen Therapy

An UpToDate review on “Treatment of Lyme disease” (Hu and Shapiro, 2022) states that “Certain nonpharmacologic interventions (e.g., cognitive behavioral therapy, tai chi, yoga, acupuncture) may have a role in the management of symptoms associated with post-treatment Lyme disease syndrome; however, clinicians must evaluate the potential risks and benefits of these treatments. One study reported on the use of alternative therapies that were offered to patients who felt they had ongoing infection with B. burgdorferi (e.g., oxygen and reactive oxygen therapy; energy- and radiation-based therapies; nutritional therapy; chelation and heavy metal therapy; and biologic and pharmacologic therapies); these therapies did not show benefit and, in some settings, were harmful”.

Long-Term Effectiveness of Tick-Borne Encephalitis Vaccines

Miazga et al (2023) stated that despite the availability of vaccination, tick-borne encephalitis (TBE) remains a global public health problem. In a systematic review, these investigators examined the long-term effectiveness of vaccinations against TBE using vaccines available on the European market. The analysis was carried out on the results of a systematic review performed in accordance with the Cochrane Handbook for Systematic Reviews of Interventions. The search was conducted in 3 databases, namely Medline (via PubMed), Embase (via Ovid), and the Cochrane Library database. The authors followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, and the selection of the articles was performed by 2 independent researchers. From a total of 199 citations, 9 studies were included in this review. According to the primary studies identified in the search, the effectiveness of available anti-TBE vaccines ranges from 90.1 % to 98.9 %; however, in individuals above the age of 60 years, the protection waned as early as 1 year after vaccination. Administration of a booster dose 3 years after completion of the basic vaccination schedule significantly extended the period of protection against TBE. The authors concluded that anti-TBE vaccines available in Europe exhibited a high level of effectiveness; however, the level of protection against TBE decreased following vaccination. Thus, in addition to the conventional schedule, booster vaccines should be administered every 5 years in individuals before the age of 60 years, and more frequently, e.g., every 3 years, in individuals aged 60 years and beyond.

Post-Treatment Lyme Disease Syndrome (PTLDS)

Prats et al (2023) noted that about 10 % of patients experience prolonged symptoms after LD. Post-treatment LD syndrome (PTLDS) is a controversial topic. It has been described as a source of over-diagnosis and off-label treatment. These investigators discussed the diagnostic errors and AEs associated with the diagnosis and treatment of PTLDS. They carried out a systematic review of the literature in the Medline and Cochrane Library databases, according to PRISMA criteria, including RCTs, observational studies, and case reports addressing diagnostic errors and AEs published between January 2010 and November 2020 in English or French. Selection used a quadruple reading process on the basis of the titles and abstracts of the different articles, followed by a full reading. A total of 17 studies were included: 1 RCT, 6 observational studies, and 10 case reports. In the 6 observational studies, over-diagnosis rates were very high, ranging from 80 % to 100 %. The new diagnoses were often psychiatric, rheumatological and neurological. Disorders with somatic symptoms were often cited. Diagnostic delays were identified for cancers and fronto-parietal dementia. In the RCTs and observational studies, prolonged anti-infective treatments were also responsible for AEs, with emergency room (ER) visits and/or hospitalization. The most common AEs were diarrhea, sometimes with Clostridium difficile colitis, electrolyte abnormalities, sepsis, bacterial and fungal infections, and anaphylactic reactions. The authors concluded that this review highlighted the risks of prolonged anti-infective treatments that have not been proven to be beneficial in PTLDS. It emphasized the ethical imperative of the “primum non nocere” principle, which underscores the importance of not causing harm to patients. Physicians should exercise caution in diagnosing PTLDS and consider the potential risks associated with off-label treatments.

References

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