Lyme Disease in Humans

Abstract

Lyme disease (Lyme borreliosis) is a tick-borne, zoonosis of adults and children caused by genospecies of the Borrelia burgdorferi sensu lato complex. The ailment, widespread throughout the Northern Hemisphere, continues to increase globally due to multiple environmental factors, coupled with increased incursion of humans into habitats that harbor the spirochete. B. burgdorferi sensu lato is transmitted by ticks from the Ixodes ricinus complex. In North America, B. burgdorferi causes nearly all infections; in Europe, B. afzelii and B. garinii are most associated with human disease. The spirochete's unusual fragmented genome encodes a plethora of differentially expressed outer surface lipoproteins that play a seminal role in the bacterium's ability to sustain itself within its enzootic cycle and cause disease when transmitted to its incidental human host. Tissue damage and symptomatology (i.e., clinical manifestations) result from the inflammatory response elicited by the bacterium and its constituents. The deposition of spirochetes into human dermal tissue generates a local inflammatory response that manifests as erythema migrans (EM), the hallmark skin lesion. If treated appropriately and early, the prognosis is excellent. However, in untreated patients, the disease may present with a wide range of clinical manifestations, most commonly involving the central nervous system, joints, or heart. A small percentage (~10%) of patients may go on to develop a poorly defined fibromyalgia-like illness, post-treatment Lyme disease (PTLD) unresponsive to prolonged antimicrobial therapy. Below we integrate current knowledge regarding the ecologic, epidemiologic, microbiologic, and immunologic facets of Lyme disease into a conceptual framework that sheds light on the disorder that healthcare providers encounter.

Figure 1.

Number of confirmed and probable Lyme disease cases in the United States, 1992–2015. Arrows indicate notable changes in case definitions. The case definition was revised in 1996 to recommend a two-step testing method and in 2008 to increase specificity of laboratory evidence of infection and to include provision for report of probable cases (reproduced from Schwartz et al., 2017).

Figure 2.

Average annual number of confirmed Lyme disease cases by county of residence in the United States, 2008–2015. Each dot represents one confirmed case (reproduced from Schwartz et al., 2017).

Figure 3.

Ixodes scapularis stages.

Figure 4.. The enzootic cycle of Borrelia burgdorferi.

Ixodes ticks undergo a three-stage life cycle (larva, nymph and adult, with one blood meal per stage). Larval ticks acquire spirochetes by feeding on an infected reservoir animal, and the bacterium is retained during the subsequent stages. Transmission of spirochetes to a competent reservoir host by a feeding nymph perpetuates the enzootic cycle for the next generation of larval ticks. Adult ticks are not important for maintenance of B. burgdorferi in the wild; however, deer are important for maintenance of the tick population because adult ticks mate on them. Nymphs are responsible for the vast majority of spirochete transmission to humans, generally considered dead-end hosts, as are dogs. (Reprinted with permission from Radolf et al. 2012.)

Figure 5.. The borrelial cell envelope.

The outer membrane contains outer-surface lipoproteins (Osps) in high density and β-barrel outer-membrane-spanning proteins such as BamA in low density. The inner membrane is rich in integral membrane proteins, many of which are transporters. BbCRASP, complement regulator-acquiring surface protein; OppA1, oligopeptide permease A1; PTS, phosphotransferase system. Reprinted with permission from Radolf et al. 2012.

Figure 6.. B. burgdorferi gene regulatory programs throughout the enzootic cycle.

The second messengers (p)ppGpp and cyclic di-GMP regulate gene expression during the tick phases of the cycle. RpoS transcribes genes required for transmission (nymphal blood meal) and infection of the vertebrate reservoir. RpoS is OFF in unfed ticks and feeding larvae. (Figure courtesy of Dr. Ashley Groshong).

Figure 7.

Silver stained biopsy from an erythema migrans lesion showing a spirochete that has penetrated a dermal venule. (Reproduced with permission from Duray, 1989b).

Figure 8.. Erythema migrans (EM) lesions:

(A) Diffuse EM expanding centripetally over the right quadriceps. (B) EM lesion on the right torso forming a classic “bulls-eye” pattern; note the central eschar (the tick bite site). (C) Ulcerated necrotic and EM lesion. Black lines demarcate area of receding erythema following antibiotic therapy. (D) Multiple EM lesions of disseminated early Lyme disease over the posterior trunk and lower back.

Figure 9.

Biopsy taken from the center of an EM lesion showing a superficial and deep perivascular and interstitial infiltrate of lymphocytes and histiocytes. H&E, × 100 (Reprinted with permission from de Koning et al.)

Figure 10.. Borrelial lymphocytoma.

Image shows a firm, indolent swelling of the left nipple of an eight-year-old boy with prior history of a tick bite and serological evidence of Lyme disease. Photograph courtesy of Ulrich Heininger, University Children’s Hospital, Basel, Switzerland.

Figure 11.

Localization of spirochetes (left panel, immunohistochemistry, arrowhead) with collagen (middle panel, blue, trichrome, arrowhead) and decorin (right panel, red, immunohistochemistry) in the myocardium of a patient with fatal myocarditis. (Reproduced with permission from Muehlenbachs et al., 2016).

Figure 12.

Lyme arthritis manifested as left knee swelling in a young adult. Clinically there was no redness, few constitutional symptoms, and little pain. The patient recovered after a 4-week course of oral antibiotics. Photgraph courtesy of Dr. Jeffrey Thompson, Connecticut Children’s Medical Center.