The Worldwide Saga of Lyme Borreliosis 1 Jorge L. Benach and Juan Carlos García-Moncó Abstract neighbourhood in their town had developed what The clinical–epidemiological studies of a cluster they had been told was juvenile rheumatoid ar- of arthritis in Lyme, Connecticut, intersected thritis. Soon thereafter, a joint investigation by the with ongoing studies on tick-borne diseases in Connecticut State Health Department and the Long Island, New York, to set the stage for the Yale University School of Medicine was begun discovery of the spirochaete agent of Lyme dis- to investigate the reports made by both mothers. ease. Studies on the microbiology of spirochaetes This fortuitous occurrence developed into a most in other parts of the country were instrumental dramatic epidemiological study that resulted in for the cultivation of the newly discovered the identification of a world-wide infection. organism. The multinational clinical studies in The possibility of a focal episode of juvenile Europe throughout the twentieth century on the rheumatoid arthritis in Lyme kindled the inter- dermatological and neurological manifestations est of Dr Allen Steere, who had just joined the characterized and enlarged the syndrome that we Division of Rheumatology at Yale, which in now know as Lyme borreliosis. For reasons that turn was headed by Dr Stephen Malawista, a are discussed in this chapter, controversies have noted rheumatologist with a long track record arisen among advocate patient groups and the on inflammatory rheumatic diseases. Dr Steere, clinicians and scientists that are at the forefront joined by Dr David Snydman of the State Health of research in Lyme borreliosis. Polarized opin- Department, put together an active surveillance ions on what constitutes this disease and how to system in the affected towns of Lyme, Old Lyme treat it have resulted in unprecedented litigation and East Haddam (Connecticut) to identify cases involving medical societies and advocate patient of the disorder reported by the two mothers. groups with no obvious end in sight. The active community surveillance disclosed 39 children (Steere et al., 1977b) with recurrent 1.1 The epidemic of attacks of swelling and pain in large joints, notably oligoarticular arthritis in in the knees, and some for substantial periods Connecticut and the north-east of time. In addition, there were twelve adults, The story of Lyme disease in Connecticut has who were related to or lived near the arthritic been told on numerous occasions and has often children, with similar signs and symptoms. The been cited as an example of a very positive surveillance showed an epidemic of oligoarticular interplay among the lay community, academic arthritis in a focal geographic area. The focality medicine, and public health workers. In October of Lyme disease has remained a constant feature 1975, two mothers, Polly Murray and Judith of this disease. In fact, even within these affected Mensch, from Lyme, Connecticut, contacted the towns, clustering of cases was actually the norm in Connecticut State Health Department to report that many of the patients lived in several adjoining that a number of children who lived in the same streets. Furthermore, there was also clustering UNCORRECTED PROOFS – NOT FOR REDISTRIBUTION 2 | Benach and García-Moncó within families, with six having more than one (Steere et al., 1978). Two studies provided indi- affected member, although the manifestations of rect evidence for a role of Ixodes scapularis in the the disease may have had onsets in different years. development of the erythema migrans. One study In the first study, the prevalence of the disease showed that the incidence of Lyme disease was was 4.3 per 1000 residents but was three times 2.8 cases per 1,000 residents in the three com- higher among children. The overrepresentation munities of Lyme, Old Lyme, and East Haddam, of children in Lyme disease has also remained a on the east side of the Connecticut river. This was constant feature of this disease. This investigation in marked contrast to the almost 30-fold lower essentially excluded juvenile rheumatoid arthri- incidence of 0.1 cases per 1000 in several com- tis as the cause of the epidemic given that the munities on the west side of the river (Steere and prevalence of arthritis in these Connecticut com- Malawista, 1979). The other study by Wallis et al . munities was 100 times greater than that expected (1978) showed that I. scapularis were much more prevalence for juvenile rheumatoid arthritis. Thus, abundant on the east side (with a high incidence with a high degree of certainty that the articular of erythema migrans and Lyme arthritis) of the manifestations being reported in the three towns Connecticut River than on the west where the in Connecticut were not juvenile rheumatoid incidence of the disease was significantly less. arthritis, the disease was named Lyme arthritis. On the east side of the river, subadult I. scapularis With the enlarging clinical spectrum, this name were also more abundant on white-footed field was changed to Lyme disease. mice, Peromyscus leucopus, while the adults were The enlarging investigation revealed that more abundant on white-tailed deer. Importantly, approximately one-quarter of the patients had attempts to recover a possible aetiological agent developed an erythematous cutaneous lesion that from the ticks collected in the affected areas were in some cases appeared to expand into reddish, unsuccessful. Nonetheless, the epidemiological often annular, concentric rings. Interestingly, the evidence strongly implicated these ixodid ticks in skin lesion appeared weeks before the onset of the natural history of Lyme disease. the articular manifestations. This lesion had been One final important step was taken that led to previously described in Sweden in 1909 by Arvid successful therapy of Lyme disease with antibiot- Afzelius (see below) who named it ‘erythema ics. European erythema migrans had long been migrans’ because of its propensity to enlarge. known to be responsive to antibiotic therapy, Sometime later, the lesion became known as while studies demonstrating the efficacy of antibi- ‘erythema chronicum migrans’ to emphasize its otic therapy for this skin lesion had also appeared protracted duration. Afzelius associated the lesion in the USA (Scrimenti, 1970). Therefore, Steere with the bite of Ixodes ricinus ticks. During the and collaborators gave antibiotics to patients with summer of 1976, the Yale investigators followed erythema migrans and compared the outcomes prospectively the patients with the cutaneous le- with those in untreated patients from their in- sions (Steere et al., 1977a). Many of these patients vestigations. The results showed that penicillin, developed arthritis, while some also developed given early in the illness, shortened the duration neurological or cardiac abnormalities (Steere of erythema migrans and appeared to prevent or et al., 1980a). The neurological manifestations lessen subsequent arthritis (Steere et al., 1980b). among the prospective study group subsequently Prior to the Connecticut epidemic, erythema were defined by Reik and coworkers in 1979 migrans in North America was first described in (Reik et al., 1979). The addition of neurological 1969 in a case report of a hunter from Wisconsin. and cardiac involvement to the already known The attending physician treated this patient skin and articular manifestations underscored successfully with penicillin (Scrimenti, 1970). the complex, multi-organ system disease that was A cluster of four cases of erythema migrans that being characterized in Connecticut. occurred in the summer of 1975 in south-eastern The established association of erythema Connecticut was also reported before the Yale migrans with the bite of Ixodes ricinus ticks in University studies (Mast and Burrows, 1976a,b). Europe led to investigations showing that a local Although determining when erythema migrans Ixodes species was associated with Lyme disease first appeared in the USA is difficult, the lack of UNCORRECTED PROOFS – NOT FOR REDISTRIBUTION History of Lyme Borreliosis | 3 any reports prior to 1960 indicate that Lyme populations as non-target organisms and may disease became epidemic in the 1970s coincident have helped keep these populations in check; with the reports from Connecticut, Long Island, banning of this pesticide may have allowed for a New York and Massachusetts. In retrospect, the gradual increase in the tick populations in large Wisconsin case was a harbinger of the subsequent geographic areas of the country. Another environ- emergence of Lyme disease in the upper Midwest. mental change reflects the increased suburbaniza- Moreover, it is likely that cases of Lyme disease tion of rural land leading to a closer relationship in these endemic areas were not diagnosed as of wildlife with new human residents. While this such before it gained widespread recognition. demographic trend is certainly well-documented For example, in eastern Long Island, which is a and can explain the increase in the number of major area endemic for Lyme disease, there are cases of tick-borne diseases, it does not explain persistent anecdotes of a condition known as the large increases in the tick populations. To the ‘Montauk knee’ that sounds suspiciously like explain the latter, increases in the populations of the monoarticular arthritis of Lyme. This entity reservoirs have been implicated as the sources evidently has been around for decades, and it is of large numbers of vectors. This is particularly tempting to speculate that the Montauk knee may true in the case of deer and the Ixodes scapularis actually have been the late stage of Lyme disease. ticks. As mentioned earlier, the increases in cases of RMSF and its vector, D. variabilis, were not an 1.2 The role of other tick-borne isolated event. In fact, another, possibly larger and diseases in the discovery of the of higher public health impact, increase in the agent of Lyme disease numbers of human-biting I. scapularis led to the epidemic of Lyme disease in the northeast and 1.2.1 The tick revolution of the 1970s upper Midwest.