Objective laboratory tests that improve the diagnosis and treatment of this subset of patients appear to be on the horizon, thanks in part to investments in the creation of carefully constructed cohorts and biodeposits of well-defined PTLD patients (see Biodeposits and Research Cohorts). In 2020, for example, the first PTLD biomarker was published in one cohort, which was then confirmed in a second independent cohort of PTLD patients in the United States. This metabolomic signature distinguishes patients with LD clinically cured without PTLD from LD patients with PTLD (59). The change in gene expression has been shown to persist after treatment of early LD in a small sample of patients observed longitudinally for 6 months. Although no transcriptome signature has been identified that could distinguish between patients who recover after treatment and those who do not, the signature may lead to further objective testing for early LD (67). Recently, a signature of the gut microbiome has also been identified that could distinguish PTLD patients from healthy controls and ICU patients, suggesting that PTLD is a clear and definable disease, although the underlying etiology remains uncertain (58). Other biomarkers related to LD and PTLD are discussed below (pathogenesis section). Taken together, these findings suggest that new diagnoses and treatments for PTLD are now within reach. 112.
Maccallini P, Bonin S, Trevisan G. Autoimmunity to a glycolytic enzyme as a possible cause of persistent symptoms in Lyme disease. Hypotheses Med. (2018) 110:1–8. doi: 10.1016/j.mehy.2017.10.024 Bb has one of the most complex genomes of any bacteria characterized to date (reviewed in (143)). Bb contains a single linear chromosome of ~900 k base pairs (bp) with between 7 and 21 different plasmids, the size of which of 5 to 84 kbp has been verified from genomic sequences for 27 Bb isolates determined since the elucidation of the Bb B31 genome sequence in 1997 (144). The single chromosome appears to be very constant in terms of genetic content and organization across these B isolates. In total, dozens of Borreliella isolates were sequenced (144–147). These include subgenomes of 64 recently identified isolates in collections across Canada, an emerging field for ML (148). To date, chromosomal arrangements have been reported from these isolates, but no equivalent plasmid content analysis has been performed.
In the B genome, the conserved linear chromosome encodes most household genes, while the variable set of linear and circular plasmids encodes most outer membrane lipoproteins (149-151). Three plasmids, cp26, lp17 and lp54, have so far been preserved from sequenced Bb isolates (discussed in (143)). However, the content and number of plasmids appear to be much more variable, with these being lost once Bb is cultured in vitro over a longer period of time. It should be noted that while extrachromosomal DNA is often referred to as plasmids – non-essential DNA that carries pathogenic material and/or implies selective advantage in a particular situation – some Bb „plasmids“ carry essential genes and look more like mini-chromosomes. Knowledge about plasmids is currently limited, in part due to the limitations imposed by next-generation sequencing technologies with short readings and the resulting assembly challenges. Long-read sequencing technology is poised to improve our understanding of plasmid content and its dynamics between species and strains (150, 152). 14. Johnson L, Aylward A, Stricker RB. Access to health care and burden of care for patients with Lyme disease: a major survey in the United States. Health policy. (2011) 102:64–71. doi: 10.1016/j.healthpol.2011.05.007 Washington, DC was also a high-incidence area with 8.9 cases per 100,000 population.
Note that Massachusetts uses a surveillance method that relies primarily on laboratory reports, and information on most cases of Lyme disease that occur in that state is not sent to the CDC.  LD, also known as Lyme disease, is a growing health problem in the United States. LD is caused by pathogenic species of the genus Borreliella (for a relationship with the genus Borrelia, see Genomic Insights From Borreliaceae Lineages). These spirochetal bacteria are transmitted from vertebrate reservoirs to human hosts through the bites of infected Ixodes spp. ticks. Borreliella burgdorferi (B. burgdorferi, hereafter Bb) is the most common causative agent of LD in the United States (1). The CDC recently estimated ~476,000 diagnosed cases of LD per year in the United States based on insurance data from 2010 to 2018 (2), a significant increase from its previous estimate of ~329,000 annual cases using similar methods to generate data from 2005 to 2010 (3). If left untreated, Bb infection can lead to health problems that affect the skin, joints, nervous system or, more rarely, the heart (4).
While most people recover after antibiotic treatment for LD, others suffer from chronic health conditions that can last for months or years. A well-defined clinical subset of LD patients with persistent symptoms after treatment is post-treatment Lyme disease (PTLD) (see section 2.3.2 PTLD). Medical costs associated with LD and LTP are estimated to be between $712 billion and $1.3 billion per year in the United States (5). The causes of PTLD are not yet well understood, but are an active area of research because of their critical importance for advancing therapeutic development and effective treatment of this patient population.