▸ Conduct a noninferiority, double-blind, randomized, controlled trial to determine whether oral doxycycline is as good as IV ceftriaxone (as has been demonstrated in Europe) for acute neurologic Lyme disease.
▸ Test nonantimicrobial therapies to help patients who have chronic symptoms despite taking antibiotics.
This five-step approach will lead to better diagnostic tests, will help elucidate the prevalence and pathophysiology of chronic persistent symptoms, and will lead to more rational and effective treatment selection.
To determine whether unsuspected coinfections or uncommon strains of Borrelia burgdorferi are the culprits for persistent symptoms, many powerful techniques are now available to address such issues. Whole-genome sequencing has enabled the mapping of 13 additional U.S. strains of B. burgdorferi that should help to clarify whether distinct B. burgdorferi variants lead to different clinical manifestations and treatment responses. The combination of multiplex polymerase chain reaction with mass spectrometry (called MassTag PCR) can screen for multiple tick-borne pathogens using a single sample. This technology has revealed that 30% of ticks in New York state have a polymicrobial infection and that 2% carry the Powassan virus (Vector Borne Zoonotic Dis. 2010;10:217-21). Another technology, such as the Ibis T5000, uses broad-range PCR followed by electrospray ionization mass spectrometry to probe specimens for potential microbes in a nonbiased manner. It produces results within hours. Furthermore, “deep sequencing” technology can probe the entire microbial population in a single sample.
Advances in neuroimaging can help clarify the pathophysiology of chronic symptoms. Recent progress in the identification of radioligands that target the peripheral benzodiazepine receptor will allow PET scanning to determine whether patients with posttreatment Lyme disease syndrome (PLDS) have CNS microglial activation. Patients with PLDS often complain of multifocal pain, and many report diffuse hyperalgesia and/or allodynia. Could this result from central mechanisms that augment pain or attenuate activity in descending antinociceptive pathways, as has been demonstrated in fibromyalgia? The demonstration of abnormally activated central pain neural circuits in PLDS would suggest new directions in treatment. Such research could include peripheral tests of pain thresholds (pressure, heat, auditory), functional MRI studies of central sensory augmentation, and probing neurotransmitter activity via CSF and MR spectroscopy.
Recent animal and human studies also provide new directions. Could persistent symptoms among PLDS patients reflect the immune response to a small reservoir of persistent infection, as has been suggested by the finding of persistent B. burgdorferi in mouse and canine models after antibiotic treatment in U.S. and European studies? (These studies have led to a xenodiagnosis study in humans that is funded by the National Institute of Allergy and Infectious Diseases. It will test whether an uninfected tick feeding on a PLDS patient can attract B. burgdorferi even if B. burgdorferi was nondetectable in that human host by culture or PCR.) Do persistent symptoms reflect a persistently activated immune response with a persistent sickness syndrome, as has been suggested for many postinfectious illnesses? Recent studies demonstrate that approximately 50% of patients with PLDS have elevated antineuronal antibodies, with total antibody reactivity comparable to that seen among patients with systemic lupus erythematosus but far higher than among recovered controls (Brain Behav. Immun. 2010;24:1018-24). The pathophysiology underlying this immune abnormality and its relationship to clinical symptomatology deserve further study as it may suggest future immunologically based therapies.