View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by PubMed Central YALE JOURNAL OF BIOLOGY AND MEDICINE 84 (2011), pp.103-108. Copyright © 2011. FOCUS: YALE SCHOOL OF MEDICINE BICENTENNIAL close to home: A history of yale and Lyme Disease Shana Elbaum-Garfinkle Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, Connecticut Yale scientists played a pivotal role in the discovery of Lyme disease and are credited as the first to recognize, name, characterize, and treat the affliction. Today, Lyme disease is the most commonly reported vector-borne illness in the United States, affecting approximately 20,000 people each year, with the incidence having doubled in the past 10 years [1]. Lyme disease is the result of a bacterial infection transmitted to humans through the bite of an in - fected deer tick, which typically results in a skin rash at the site of attack. While most cases, when caught early, are easily treated by antibiotic therapy, delayed treatment can lead to se - rious systemic side effects involving the joints, heart, and central nervous system. Here we review Yale’s role in the discovery and initial characterization of Lyme disease and how those early discoveries are crucial to our current understanding of the disease. Recognition — Lyme ARthRitis Yale School of Medicine, sparking an in - The Yale Team vestigation that would culminate in the characterization of what is now widely In the early fall of 1975, two mothers known as Lyme disease [2]. from Old Lyme, Connecticut, desperately The initial studies carried out in Lyme, sought medical help regarding the mysteri - Connecticut, and two surrounding towns on ous outbreak of arthritis and juvenile arthri - the eastern bank of the Connecticut River tis in their families and town. In the face of in New London County were led by Allan unexplainable symptoms and unsatisfying C. Steere, MD, and Stephen E. Malawista, diagnoses, they reached out to the Con - MD, from the Rheumatology section of the necticut State Department of Health and the Yale School of Medicine, in conjunction To whom all correspondence should be addressed: Shana Elbaum-Garfinkle, 226 Whitney Bass 228, New Haven, CT; Tele: 203-432-5647; Fax: 203-432-5175; E-mail: [email protected]. †Abbreviations: ECM, erythema chronicum migrans ; EM, erythema migrans ; Osps, outer surface proteins; TROSPA, tick receptor protein. Keywords: Lyme disease; Lyme arthritis 103 104 Elbaum-Garfinkle: Yale’s role in the discovery of Lyme disease with David R. Snydman, MD, and Francis onset occurring from June through Septem - M. Steele, PhD, from the Connecticut State ber. Rheumatoid arthritis, a known autoim - Department of Health, among others. Dr. mune disease leading to inflammation of the Steere, the first author of the study, was a joints, had never before been, nor would it first-year fellow in rheumatology at the have been, expected to cluster geographi - time. Dr. Malawista, then Head of the cally or temporally in this way. Rheumatology Section at Yale, continues to The Skin Lesion-EM pioneer Lyme disease research at Yale. The term erythema migrans (EM) was The Investigation first mentioned in a presentation at the 1909 In December 1975, Steere and Malaw - meeting of the Swedish Dermatological So - ista led a surveillance study [3] to investigate ciety in Stockholm by Arvid Afzelius [2]. the cause of a sudden outbreak of rheuma - EM, also reported as erythema chronic mi - toid arthritis in and around Lyme. The study grans (ECM), was sometimes associated focused on the three contiguous towns of Old with a tick bite and was accompanied by Lyme, Lyme, and East Haddam, where 51 nerve pain, paralysis, or meningitis. In Eu - residents were diagnosed with juvenile rope, doctors believed that EM might be arthritis or arthritis of unknown cause (39 caused by a bacterium, and penicillin and children and 12 adults) out of a total popula - other antibiotics were moderately effective tion of 12,000. The investigation consisted at treating it. This connection between ticks of thorough physical examinations and blood and EM led Steere and Malawista to hypoth - work of each patient on site at Yale. Addi - esize that Lyme disease might be transmitted tionally, detailed patient histories were col - by the bite of an arthropod such as a tick. lected through interviews with each patient’s However, in the United States, there was local physician and family members. little experience with EM, and in the Euro - While the early physical examinations pean cases, EM never presented with arthritis. and laboratory tests revealed nothing out of Intrigued by the EM lesion described by pa - the ordinary, the interview aspect was sur - tients in their first study, Steere and Malaw - prisingly informative. Approximately 25 ista eagerly awaited the next “high season.” percent of the patients in the study reported Indeed, during the summer of 1976, 30 new a skin lesion with an expanding bull’s-eye patients were identified, a survey of which pattern four or more weeks preceding the strengthened the connection between the ini - onset of arthritic symptoms. The authors tial presentation of EM and the later devel - found this to be particularly intriguing, as opment of arthritis [5]. The Yale team thus the lesion matched the description of ery - officially declared EM as the initial mark of thema chronicum migrans (ECM), or ery - infection and as the diagnostic hallmark of thema migrans (EM), a lesion previously “Lyme arthritis,” the initial name given for reported in Europe that was thought to be a the disease by Yale investigators [6]. result of an infectious agent but had never The Tick before been associated with arthritis [4]. The mysterious arthritis also emerged While Steere and Malawista suggested in interesting patterns geographically and the tick as the vector of Lyme arthritis as temporally. Most of the patients lived in early as 1976 [3,5,6], in 1978 they showed close proximity within the towns ― several epidemiological evidence for a tick vector children lived on a particular road, and the by expanding their surveillance of the Lyme arthritis afflicted several members from the area across the Connecticut River [7]. They same family. The patients also exclusively found that the incidence of Lyme arthritis lived in the rural wooded areas of town, with was 30 times greater on the east side of the no cases present in the town centers. No - river, where Lyme is located, than it was on tably, there was also a unique temporal clus - the west side, similar to the difference in tering to the symptoms, with the majority of deer and deer tick distribution in the area [8]. Elbaum-Garfinkle: Yale’s role in the discovery of Lyme disease 105 Scientists later confirmed that ticks in - ally only a small piece of a larger puzzle. deed are the transmission vector of the in - Now that the EM skin lesion was confirmed fectious agent in Lyme disease. In the United as the initial mark of infection, the Yale team States, Lyme disease is transmitted by the made a major effort to inform and educate deer tick, or Ixodes scapularis , member of the area near Lyme. The Yale team also the Ixodes family. Other related Ixodes ticks asked local healthcare providers to refer pa - have been found in Europe and Asia. The tients to them soon after infection, enabling Ixodes tick can become infected at any point them to further characterize the disease and of its 2-year lifespan, which consists of three onset. As the result of these further studies, distinct stages — larvae, nymph, and adult the team reports that Lyme disease can man - [9,10]. The tick’s survival depends on a feed - ifest in a variety of systemic ways, includ - ing or “blood meal” at each stage of its life. ing those involving the nervous system [13], The larvae hatched in late summer feed on the heart [14], and the joints [15-19]. small animals such as the white-footed In 1984, the Yale School of Medicine mouse that can be infected but remain brought together Lyme disease researchers asymptomatic, serving as a continuous re - from all over the world at the First Interna - source for infection. The larvae then molt tional Conference on Lyme Disease in New into nymphs who feed again the following Haven [10,20]. For the first time, profession - spring to early summer. Transmission to hu - als from a range of disciplines, including mans typically occurs by ticks in this stage, rheumatology, immunology, dermatology, as increases in outdoor activity coincides and neurology, as well as public health offi - with the nymph feeding cycle. The small size cials and practicing physicians were gathered of the nymph, about the size of a poppy seed, in recognition of this new complex and sys - allows them to go unnoticed. Furthermore, it temic disease. In 1985, Steere and Malawista has been shown that a tick must feed for 48 were awarded the Ciba-Geigy International or more hours to transmit infection. In the League Against Rheumatism Prize, an honor fall, nymphs molt into adult ticks, which then given once every 4 years, for the discovery feed on large animals, deer in particular. and elucidation of Lyme disease. A group of Adult ticks, which may actually mate on the Yale scientists continue to lead research ef - deer itself, are transmitted by deer to the sur - forts in various aspects of Lyme disease, in - roundings, usually leafy areas, where new cluding disease epidiomology (Durland Fish, larvae are hatched the following summer. PhD, and Eugene D. Shapiro, MD, from the Deer thus play an important role in the Yale School of Public Health); the life cycle tick life cycle by supplying a blood meal and of the bacterium (Erol Fikrig, MD, Infectious potentially serving as a mating ground for Diseases, Yale School of Medicine); and in - adult ticks.