Seminal Papers in Lyme disease

Definition

Lyme disease is an infection caused by Borrelia species of spirochaetes carried by ticks of the Ixodes genus.

Prevalence / Incidence

Most common tick borne disease.
In USA 17730 cases reported to CDC in 2000, 23763 cases reported in 2002.
CDC acknowledges ‘considerable under reporting’

The bacterium

Mainly B burgdorferi, B garinii and B afzelii but numerous other species
Borrelia burgdorferi strain B31 (culture MI) has been fully sequenced.
910 kbp linear chromosome.
12 linear and 9 circular plasmids total 610 kbp.
More than 3x no. of plasmids of any other bacterium.

Facts

1) Lyme disease can be present without physical signs or raised inflammatory markers.
2) Serological tests are unreliable in the diagnosis of Lyme disease. How unreliable is not known.
3) The optimum treatment for Lyme disease is not known.
4) The prevalence of chronic Lyme disease is not known.

From: Bakken et al – Performance of 45 Laboratories participating in a Proficiency Testing program for Lyme disease serology

Used six samples from known Lyme patients known to contain anti- Bb antibody. Over one half failed to identify samples which should have been identified. Also same labs came up with different results for the same sample.

“Until a national commitment is made serological testing will be of questionable value for the diagnosis of Lyme disease.”

From Coyle et al “Detection of Bb specific antigen in antibody negative CSF in neurologic Lyme disease”

Identified Osp A (a specific Bb antigen) in 43% of those patients who were negative for Bb antibodies by Elisa. CSF frequently normal to conventional tests even in neurologic Lyme disease.

“B. Burgdorferi antigen can be detected in CSF without positive CSF antibody. Since CSF antigen implies intrathecal seeding of the infection the diagnosis of infection by B burgdorferi should not be excluded solely on the basis of normal routine CSF or negative CSF antibody analyses.”

From: Luger and Krause in Serologic tests for Lyme disease

Sent samples to different labs and same sample to same lab at a different time. Large variability on results even from same lab and same sample at different times. Only used nine patients all with known +ve serology. Some labs picked up less than half.

“It is recommended that the results of serologic testing should not be relied on as the sole criteria in making the diagnosis of Lyme disease.”

“Lyme disease is a clinical diagnosis that may be supported by serological evidence.”

Diagnosis of Lyme disease

Diagnosing LD in practice

So if we don’t like to rely on serological tests how do we diagnose LD? Need to talk about diagnosis

Tick bite.

Definite – When?
Possible history of tick bite:
Risk factors for tick bites.

Erythema migrans

EM rash
“Definite” EM /Possible EM /previous EM
EM absent in over 50% of cases

Variable morphology.
May be chronic or transient.
May have central clearing. (“Bull’s eye rash”)
Histology only useful to exclude other diagnoses.
Common on legs especially groins but may occur anywhere on the body.

 

Symptoms of Lyme disease

Fatigue, flushes/chills, night sweats, sore throat, swollen glands, stiff neck, migrating arthralgias, joint stiffness, arthritis, myalgias, chest pain, palpitations, abdominal pains, nausea, diarrhoea, sleep disturbance, poor concentration, memory loss, depression, back pain, blurred vision and eye pain, jaw pain, testicular or pelvic pain, tinnitus, vertigo, parasthesiae, peripheral or cranial nerve disturbance, headaches, dizziness.

From "ilads guidelines"

Diagnosing LD in practice

“Protean manifestations” - CDC
Symptom evolution:
Polysymptomatic / multisystem.
Increase in symptoms over time
Periodicity to symptoms
Suspect in some cases of CFS,ME, Fibromyalgia

Possible reasons for diversity of symptoms in LD

Host factors
Presence of co-infections
Presence of co-existing infections
Variable virulence of Borrelia

Laboratory tests for Lyme disease.

No lab test can exclude Lyme disease which is a clinical diagnosis.

Types of test: serological, DNA based
False negatives,
False positives.

Response to appropriate antimicrobial therapy:

Early or recurrent - Herxheimers.
Late – Clinical improvement.

From Liegner: Lyme disease the sensible pursuit of answers

“In patients for which a state of antigen excess exists free antibodies may escape detection and may be revealed only after use of methods to dissociate such immune complexes. Thus the very patients who are unable to generate detectable levels of free antibodies, who are least apt to contain the infection, and who may present with the most serious illness among those with Lyme disease are least likely to be offered treatment.”

Lyme disease may exist in an asymptomatic or latent form with symptoms becoming apparent years after exposure to Borrelia.

From Pfister et al: Latent Lyme neuroborreliosis: Presence of B. burgdorferi in the CSF without concurrent inflammatory signs

Case report. Patient had received multiple tick bites. Essentially asymptomatic patient (tinnitus). Normal CSF but Borrelia isolated from it.

“We consider this clinical setting to be consistent with a latent Lyme neuroborreliosis”

Borrelia can be recovered from patients even after prolonged courses of antibiotics.

From Haupl et al: Persistence of Borrelia Burgdorferi in ligamentous tissue from a patient with Chronic Lyme Borreliosis

Case involved patient with culture confirmed relapsing CLD. Poor correlation with humoral response noted. Bb was cultured after repeat courses of antibiotics and shown by em on surgically removed tissue.

Hauple: “The humoral immune response correlated with neither the cellular reactivity in vitro nor the clinical activity of the disease manifestations.

Repeated antibiotic treatment was necessary to stop the progression of the disease but obviously did not completely eliminate B burgdorferi from all sites of infection. This was confirmed by the culture of viable B burgdorferi from a ligament sample obtained surgically.”

From Oksi et al in Borrelia Burgdorferi detected by culture and PCR in clinical relapse of disseminated Lyme borreliosis

Study of 165 patients. Demonstrated that Borrelia present proven by culture and /or PCR despite 3 months of antibiotics in a significant proportion of patients.

“We conclude that the treatment of Lyme borreliosis with appropriate antibiotics for even more than 3 months may not always eradicate the spirochaete.”

From: Battafarano et al: Chronic septic arthritis caused by Borrelia burgdorferi

“…this case documents persistent spirochaetal infection despite multiple antibiotic courses.”

“…synovial histology and culture should be pursued to rule out persistent Borrelia infection. Synovial fluid PCR anaysis may be further used to support the diagnosis.”

From: Priem et al in Detection of Borrelia burgdorferi by PCR in synovial membrane but not in synovial fluid from patients with persisting Lyme borreliosis after antibiotic therapy

Four cases of Lyme arthritis where synovial fluid was negative by PCR but synovial membrane was positive. All had received prior antibiotic therapy

Borrelia found in knee synovectomy sample of a patient treated with 3 courses of IV ceftriaxone, IM penicillin, 2 courses of IV penicillin, and a years course of oral doxycycline

“These data suggest that in patients with treatment resistant Lyme arthritis negative PCR results in SF after antibiotic therapy do not rule out the intra-articular persistence of B burgdorferi DNA”

From: Borrelia burgdorferi detecetd by culture and PCR in clinical relapse of disseminated Lyme borreliosis

“We conclude that the treatment of Lyme borreliosis with appropriate antibiotics even for more than three months may not always eradicate the spirochaete”

From: Hudson et al in Culture positive Lyme borreliosis

Case report of 42 year old knee joint arthralgias, skin rash, myalgias, fatigue, memory impairment, fullness in the head, unable to work. Definite tick bite. Recurrent EM despite multiple courses af antibiotics. Elisa neg. Culture positive.

Showed that antibiotic therapy for three months failed to eradicate Borrelia in a significant proportion of cases as shown by persistent +ve PCRs and or culture

“Despite receiving appropriate antibiotic therapy our patient remained unwell. Lyme borreliosis can become a chronic illness often refractory to repeated antibiotic treatment and associated with persistent culture positivity.”

From: Donta S : Tetracycline therapy for Chronic Lyme disease

272 patients treated with tetracycline 500mg tds. For a mean of 4 months. Good results claimed with 90% improved or cured ( 20% asymptomatic at 12months) Improvement did not correlate with serological status

“ our results demonstrate that patients with similar clinical symptoms who are seronegative have responses to antibiotic treatment that are not distinguishable from those of seropositive patients”.

“ The optimum treatment for chronic Lyme disease remains to be delineated.”

“Controlled trials need to be conducted to validate these observations”

Difficulties arise in designing suitable clinical trials in CLD

Patient selection: – Difficult to produce matched controls. Differing presentations of CLD. Differing durations of illness. Coinfections. Which symptoms to follow.

Long time scale may be needed; eg. no use comparing 3 weeks with 6 weeks of treatment.

From Krause et al in Concurrent Lyme disease and Babesiosis

Synergism found between Borrelia and Babesia; each seems to exaggerate the effect of the other.

“Circulating spirochaetal DNA was detected more than 3 times as often in co-infected patients as in those with Lyme disease alone.” (p = .06)

Synergism between two conditions implies that treatment of one will help to treat the other and vice versa.

Fallon et al: Lyme disease a Neuropsychiatric illness

“A broad range of psychiatric reactions have been associated with Lyme disease including paranoia, dementia, schizophrenia, bipolar disorder, panic attacks, major depression, anorexia nervosa and OCD. Depressive states among patients with late Lyme disease are fairly common ranging across studies from 26% to 66%.”