Our Year in Review series highlights the major medical news stories of 2012. One story that has continued to evolve this year has been the natural history of Lyme disease and how ecological influences can predict its incidence and spread. Here is the original article, published on June 18. In a companion article, you'll find out what has happened since.
The summer of 2012 may turn out to be the worst year ever for Lyme disease in the northeastern U.S. because of recent shifts in the acorn and white-footed mouse populations, even as researchers are making advances in the understanding and treatment of refractory cases.
Lyme disease results from the bite of a tick infected with the spirochete Borrelia burgdorferi. It typically manifests at first with the expanding rash known as erythema migrans. Many patients then develop a severe flu-like illness, with muscle aches, fever, chills, and lethargy.
Some infected individuals go on to develop intermittent arthritis, usually of the large joints, that can require extensive antibiotic treatment. And in an unfortunate few, even after 3 months of oral and intravenous antibiotics, the arthritis can persist for years.
It's a complex ecological, molecular, and immunological story.
Of Mice and Acorns
In the autumn of 2010, oak trees in the northeast had the most abundant crop of acorns seen in more than 20 years.
"Acorns are a highly nutritious food source for rodents, especially the white-footed mouse," said Richard S. Ostfeld, PhD, of the Cary Institute of Ecosystem Studies in Millbrook, N.Y.
In abundant acorn years, mice survive well through the winter on stored supplies and do not need to roam for food where they would be vulnerable to predators. The mice also breed early and often in those years, increasing their numbers significantly.
After the boom 2010 acorn autumn, the summer of 2011 had the highest population of white-footed mice seen in the Northeast in more than 20 years, Ostfeld explained. Those hordes of mice served as a favored food source when tick larvae hatched in August.
"That was a great thing for the ticks and a terrible thing for us," Ostfeld told MedPage Today.
Tick survival is much higher when their food source is mice than if they feed on raccoons, opossums, squirrels, or birds, which are able to remove ticks during grooming.
After a dormant winter, I. Scapularis larvae emerge between May and July, "and we're right in the middle of the highest risk season for tick bites right now, and there's a very high number of infected ticks," Ostfeld said.
An Unusual Arthritis
In 1975, a group of 39 children in the small town of Lyme, Conn., were diagnosed with what was then called juvenile rheumatoid arthritis, Allen C. Steere, MD, who led the team that identified the outbreak, recalled at the recent European Congress of Rheumatology meeting in Berlin.
The children had symptoms typical of the oligoarticular form of the disease, which is now termed juvenile idiopathic arthritis, with one or more swollen joints, most commonly the knee, said Steere, of Massachusetts General Hospital in Boston. In addition, the synovial tissue was typical of what is seen in inflammatory arthritis.
The frequency was 10 to 100 times what would be expected for juvenile arthritis, and the clustering was particularly marked -- among children living on four roads, 1 in 10 developed the arthritis.
"That was the clue from which everything about Lyme disease descends," Steere said during his presentation.
Analyses of the pattern of infection suggested an arthropod-transmitted disease, and in one-quarter of affected children, the parents recalled an unusual skin lesion some weeks before the onset of arthritis.
So Steere, then a young researcher at Yale, began looking for cases of the erythematous rash, following the patients prospectively.
Many of the cases had no further disease manifestations, but about 1 in 5 developed joint pains, and half of these children went on to have intermittent periods of arthritis over several years.
In the decades since Steere's group first identified the tick-borne infection, it has spread throughout the northeast and mid-Atlantic states, and today some 20,000 cases are reported each year.
It has become apparent that there are marked variations in strains of B. burgdorferi, which can be typed according to ribosomal RNA intergenic spacer type (RST) or variations in the outer surface protein C (OspC).
About 30% of infections are caused by an RST1/OspC1 type A or B strain, a genotype that appears to be a relatively recently evolved clonal lineage that has greater inflammatory potential compared with other B. burgdorferi strains.
A series of experiments determined that when macrophages and peripheral blood mononuclear cells were stimulated with RST1 strains of the pathogen, there was a significantly higher level of expression of factors associated with innate immune responses, including interleukin (IL)-6 and 8, tumor necrosis factor (TNF) alpha, and IL-1-beta.
Similar findings were seen in serum samples of patients with the erythema migrans rash who had been infected by the RST1 strains, with particularly high levels of the interferon-gamma inducible chemokines CCL2 and CXCL9 and 10, which are potent chemokines that draw T-effector CD4+ and CD8+ cells into the joint.
It also turned out that patients with antibiotic-refractory arthritis were more commonly infected with the RST1 strains than were patients with antibiotic-responsive arthritis.
These observations suggest that RST1/OspC strains of B. burgdorferi are associated with "greater inflammation and more severe disease, establishing a link between spirochetal virulence and host inflammation," Steere and colleagues wrote in a 2011 report in the American Journal of Pathology.
A Potent Polymorphism
His group then looked for host factors that also might contribute to susceptibility to the refractory arthritis and identified a candidate polymorphism in toll-like receptor 1. Toll-like receptor polymorphisms have previously been shown to influence immune function, and this TLR1-1805GG polymorphism was seen with a high frequency in patients with antibiotic-refractory Lyme arthritis.
In fact, he and his colleagues reported in the May Arthritis & Rheumatism, the odds ratios for this polymorphism were 1.7 in patients with treatment-resistant arthritis compared with those having only the rash and 1.9 compared with patients who had arthritis that cleared with antibiotics.
When they then examined samples of joint fluid from these patients, they found that the levels of CXCL9 and CXCL10 were about twice as high in the refractory patients as in treatment-responsive patients, and 15 times higher than in serum of patients who had only the rash.
This TLR1 polymorphism is found in about half of Caucasian individuals of European origin, but in only 7% of blacks and in no Asians tested thus far.
"Something happened in Europe that selected for this polymorphism. In fact, it was the difference between life and death. I would even postulate that plague -- another vector-borne disease -- could be a possible explanation," Steere said.
Immunity Gone Awry
The normal response to infection with B. burgdorferi involves suppression of the proliferative response in the joint, with the production of small amounts of interferon and TNF alpha, along with large amounts of IL-10.
This response, in conjunction with treatment with antibiotics, is sufficient in the majority of patients to eliminate the spirochete, and the arthritis resolves.
However, with immune dysregulation, the balance of CD4+ T-effector cells and T-regulatory cells is disrupted, and the T-regulatory cells are less able to suppress the effector cells, leading to overproduction of interferon gamma and TNF-alpha.
This aberrant T cell response then may contribute to the development of site-specific autoimmunity, possibly by stimulating autoantibody production by B cells.
Further supporting the hypothesis that refractory Lyme arthritis results from autoimmunity is the observation that autoantigens are present.
"We think we have now identified the first meaningful autoantigen in Lyme arthritis, by looking at proliferative responses of peripheral blood mononuclear cells to epitopes of endothelial cell growth factor," Steere said.
Laboratory tests have shown that when peripheral blood cells from healthy controls are exposed to these ECGF epitopes, there is no response. However, significant T-cell responses are seen to multiple epitopes of ECGF in patients with both antibiotic-responsive and refractory Lyme arthritis, and even in patients who had only the rash.
Nonetheless, the presence of these ECGF autoantibodies does not completely account for the development of autoimmunity, Steere said.
"It reminds me of what one sees in rheumatoid arthritis, where autoantibodies may appear before the disease develops, but are not always associated with disease. A trigger is needed," he said.
"We postulate that it's the excessive inflammation, autoantigen accumulation in the joint, and site-specific immune dysregulation that causes the pathologic response," he said.
Novel Treatments and Beyond
Much conflict has arisen among patients with refractory Lyme arthritis, with various advocacy groups demanding access to long-term and even indefinite antibiotic treatment, and medical societies arguing that no benefit would result from such an approach.
At Steere's referral center in Boston, patients with refractory arthritis today are being treated as having autoimmune disease rather than persistent infection, using disease-modifying anti-rheumatic drugs, such as methotrexate and TNF-alpha inhibitors, if no response has been seen after 3 months of antibiotics.
This approach is promising, he said, and successfully clears the arthritis in some, though not all patients, similar to what is seen in rheumatoid arthritis.
So while progress has been made, treatment remains imperfect.
Because of this, cautioned ecologic scientist Ostfeld, the main line of defense against Lyme disease remains tick avoidance.
"Use repellents on shoes, socks, and pant legs, and do full-body tick checks anytime you've been in the woods or fields," he said.
"In addition, be very aware of the flu-like symptoms. There's very little actual influenza in the summer months, so be sure to seek medical attention for symptoms such as fever and lethargy," he advised.
Steere reported no conflicts of interest.
European Congress of RheumatologySource Reference: Steere A "Lyme disease: old and new insights" EULAR 2012; Abstract SP0177.