1.1 Lyme disease, general

The disease is named after the town of Lyme in Connecticut, USA, where in 1975 a large number of children developed a disease that resembled juvenile rheumatoid arthritis. The infection occurs in America, Europe, Australia and Asia (China, Japan and Korea). It is not known to have spread to other parts of the world (insufficient data) and there are no confirmed cases from the southern hemisphere. In Europe and North America it is the most common human disease that is transmitted by ticks. The disease is caused by Borrelia burgdorferi. The bacterium was identified in 1982. There are at least 11 different genomic species. The current taxonomic classification recognises B. burgdorferi sensu stricto, B. gariniii, B. afzelii, B. valaisiana, B. lusitaniae (Portugal, Tunisia), B. bissetti (?), B. andersoni, B. sinica (China). B. turdii, B. tanuki and B. japonica exist in Japan. B. garinii and B. afzelii do not occur in the USA, but they do exist in Europe. The strains in Europe are very heterogeneous, unlike those in the USA. This makes serological diagnosis difficult. There are differences in terms of virulence and organotropism. For example B. afzelii, with its main reservoir in pheasants, is more frequent in people with skin disorders (e.g. acrodermatitis), while B. garinii, with a rodent reservoir, is more often associated with neuroborreliosis. B. burgdorferi s.s. is found more frequently in people with articular symptoms. In 1999 it was established that many people in one particular area of the USA develop a typical erythema chronicum migrans after a tick bite, but routinely test negative for Lyme. It could be that other -still undiscovered- bacteria are involved. Ticks can simultaneously be infected with more than one species of Borrelia.

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Borrelia are thin, spiral-shaped motile bacteria. There are 7 to 11 flagellae in the periplasmic space. They are wrapped around the cell and attached to the poles. This arrangement allows the bacteria to stay motile in a viscous medium in which other bacteria would be quickly immobilised (see Reynold’s number).

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Although many bacteria have a circular chromosome and may contain a number of plasmids, the genetic structure of Borrelia burgdorferi is quite unusual. The genome of these bacteria consists of a 950 Kbp linear chromosome and an additional 500,000 bp (base pairs) spread over 9 small linear and 12 circular plasmids. The entire genome has been mapped. The genes that code for the main outer wall proteins (outer surface proteins, namely OspA, OspB, OspC and OspD) are found on plasmids. These proteins are genetically variable and play a part in the pathogenesis. Borrelia that are found in the tick’s stomach carry OspA on their membrane. When the tick takes blood the bacteria are activated and migrate to the salivary glands. It is then that the production and expression of OspA is reduced and that of OspC is increased. This may be important for vaccination (see below). Similarities between a specific part of OspA and LFA-1 (lymphocyte function-associated antigen), a protein present on some human cells, might explain the origin of autoimmune problems in chronic Lyme disease.

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Borrelia species and geographical distribution

B. afzelli	Europe and parts of Asia
B. garinii	Europe and parts of Asia
B. burgdorferi ss	Europe and North America
B. bissettii	Slovenia and North America
B. andersoni	North America
B. valaisiana	Central Europe, UK, Ireland
B. lusitaniae	Portugal, Tunesia
B japonica	Japan
B. turdii	Japan
B. tanuki	Japan
B. sinica	China

 

 

1.2 Lyme disease, transmission

The bacteria are transmitted by so-called hard ticks. A tick has to be present for a fairly long period (several hours) before bacteria are introduced in the bite. In Europe the disease is transmitted by Ixodes ricinus, in Asia by Ixodes persulcatus. [These ticks are also a vector of FSSE / RSSE tick encephalitis]. In the eastern part of North America they are transmitted by Ixodes scapularis (includes the former I. dammini) and in the western part of North America by Ixodes pacificus. [Ixodes scapularis is also a vector for babesiosis and for human granulocytic ehrlichiosis]. It is possible that the seabird tick Ixodes uriae might carry borrelia across the world.

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European ticks successfully inoculate the host much more quickly and more often than their American counterparts. In Europe transmission is thought to take place in 50% of cases if the tick has been present for 16 hours. This rises to 100% after 48 hours, but not every transmission results in disease. Certain bird ticks can also be carriers of Borrelia burgdorferi and play a part in spreading it over large geographical distances. It is quite possible that other vectors will be identified in future. With the known tick vectors there is transstadial transmission (from egg to larva to nymph to adult). Transovarial transmission has been described but seems to be very inefficient (most infected eggs die early). This means that bites by tick larvae are do not lead to infection with Borrelia. [However, larvae of Ixodes ricinus can transmit European Spring-Summer encephalitis virus.] The bacteria have also been found in warble flies, horseflies and mosquitoes, but these insects do not appear to play a significant role in transmission. Contact transmission has been described in mice (through the urine). *(MY QUESTION HERE, WHY NOT HUMANS?)

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The enzootic cycle is complex. The tick larvae that are responsible for transmission prefer to feed near the ground, on rodents such as mice, while nymphs and adult ticks usually wait for a larger host on higher vegetation at a height of 40-70 cm. While they are waiting they spread their front legs (“questing”). In the north-east and central northern parts of the USA there is efficient transmission between tick larvae and tick nymphs and white-footed mice (Peromyscus leucopus). In the Southeast of the USA the nymphs prefer to suck the blood of lizards. The adults prefer to feed off deer (white-tailed deer, Odocoileus virginianus). The increase in the deer population in the late 20th century accelerated the Lyme epidemic in these areas. The bacteria can also infect dogs, birds, squirrels, hedgehogs and rabbits, and some of these animals can also play a part in the transmission chain. In northern California and Oregon the vector ecology is rather different. The spirochaete is maintained in nature by rats (“dusky-footed wood rat”) and Ixodes neotomae ticks. These ticks do not bite people. Although nymphs of Ixodes pacificus bite people, they prefer to feed off lizards, which cannot be infected by the bacteria. Transmission to people can only occur if I. pacificus nymphs have fed by chance on infected rats and then bite a person. Rodent populations can fluctuate a great deal from year to year. One of the factors involved here is the food supply for these small animals, such as acorns and seeds. These in turn are affected by the weather and the rainfall in any given season. Some enzootic cycles include ticks that rarely or never suck people’s blood. These quiet foci have no direct implications for people but demonstrate the complexity of the ecological niche occupied by these bacteria. Birds such as blackbirds, robins and pheasants can be infected and these play a part in the complex cycle. If the temperature falls below –10°C or rises above 30°C, the mortality rate of the ticks increases. Although ticks like high humidity (80-100%), they avoid open water. The low, dense vegetation in woods and along footpaths reduces to some extent marked fluctuations in humidity (buffer effect).

 

1.3 Lyme disease, clinical

A “complete, classic” presentation of the disease is very unusual in day-to-day clinical practise. The disease has dermatological, neurological, cardiological and rheumatological components. It is characterised at first by skin rash (erythema migrans) where the tick has bitten. This painless non-itching rash, spreading slowly in a circle, occurs in about 75% of patients, usually after a little more than a week (range 3 to 31 days). In Lyme disease, there is a typical time interval between the tick bite and the appearance of the rash. If a skin reaction develops immediately or during the first 24 hours after a tick bite, it is usually the result of an allergic or toxic reaction, not a borrelial infection. The rash is sometimes confused with urticaria, a reaction to an insect bite, tinea corporis or streptococcal cellulitis. Routine laboratory tests do not show signs of inflammation at this stage. Regional lymphadenopathy occurs in slightly less than half of patients. Even without treatment the rash disappears after 3 to 4 weeks. Later, similar but usually smaller annular lesions can occur elsewhere on the skin. This indicates that the bacteria have disseminated. After a variable interval, intermittent joint pains and arthritis (usually in large joints such as the knee), neurological complications and invasion of the heart occur. Invasion of the myocardium can lead to conduction abnormalities. Cardiac symptoms and electrocardiogram abnormalities usually disappear within 3-6 weeks, but complete heart block can be fatal. Luckily this is very rare. Localised borrelial lymphocytoma (previously called lymphadenosis benigna cutis) is a solitary bluish-red swelling, measuring up to a few centimeters in diameter. It tend to appear on earlobes and nipples. There is a dense infiltration with lymphocytes (esp. B-lymphocytes). Acrodermatitis chronica atrophicans is a rather frequent chronic skin manifestation of Lyme borreliosis. It tends not to resolve spontaneously. It is most often located on the extensor sites of the hands and feet. Initially the lesion is usually unilateral; later on it may become symmetrical. The lesion(s) enlarge(s) slowly over months to years. There is an important lymphocyte and plasma-cell infiltration of the dermis. Clinically, it is sometimes confused with vascular insufficiency. Neuroborreliosis can result in many different symptoms, but pain due to radiculoneuritis is common. Meningoradiculioneuritis is also known as Bannwarth’s syndrome (syn. Garin-Bujadoux-Bannwarth syndrome). Isolated peripheral neuritis also occurs. Cranial nerves can be affected, especially the facial nerve (paralysis on one or both sides). Borrelial lymphocytic meningitis can lead to mild to very severe headache. There will be lymphocytic pleiocytosis in the liquor, with a normal or slightly raised protein level. There can be features of disseminated encephalomyelitis which might resemble multiple sclerosis.

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Other symptoms such as eye damage (conjunctivitis, keratitis, choroiditis, optic neuritis), parotitis and myositis can also occur but are rare. Intermittent occurrence of joint disorders separated by periods in which the patient is free of symptoms can occur in a number of patients. Borrelia burgdorferi can be transmitted through the placenta to the foetus, with serious consequences. If antibodies are produced after the infection, they provide substantial protection against re-infection.

 

1.4 Lyme disease, diagnosis

Diagnosis is based on the patient’s previous medical history and a clinical examination, backed up with serology, Western Blot or PCR. Production of IgM is at its greatest ± 3-6 weeks after infection and IgG is produced a little later. Serodiagnosis is therefore not sensitive in the early phase after the bite. These antibodies  remain present for years with a titre that falls only very slowly. In the acute phase, serology can therefore still be negative. If possible, an uncertain or positive serology should be followed by a Western Blot (higher specificity). Culturing of the bacteria is possible and very specific, but is difficult and not very sensitive (e.g. Barbour-Stoenner-Kelly medium, with a generation time of 12 hours). The bacteria can be detected in biopsies using silver stains and immunofluorescence. The sensitivity and specificity of the laboratory tests need to be improved further. The Lyme urine antigen test is not reliable.

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Antigen mixtures can be used for serological diagnosis, but some test kits are based on monospecific antigens (e.g. 41-kD flagellin). In view of the differences in antigen composition in the B. burgdorferi complex, this latter test is less reliable in Europe than in the USA. In addition to antigenic variation, various cross-reactions with antigens of other, more or less related bacteria, make the serological interpretation difficult. Antibody production is inhibited if antibiotics are administered shortly after infection (before the 4th week).

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A number of studies indicate that overdiagnosis and overtreatment of Lyme disease is common. This can result in various problems, including mental fixation on the disease. On the other hand, underdiagnosis should be avoided, but at present there is no ready solution to this dilemma. *(GRRRRRRRRRRRRRRR)

 

1.5 Lyme disease, treatment

Treatment of the early stages consists of 2 to 4 weeks vibramycine, amoxycillin or cefuroxime axetil (Zinnat®). Macrolides are only the fourth choice. Vibramycine is preferred since it is also active against erhlichia, bacteria which can be co-transmitted during a tick bite and which are not sensitive to beta-lactam antibiotics. Ceftriaxone (Rocephine®) 2 gram per day IV for 2 to 4 weeks is the treatment of choice in the later stages, but is much more expensive. Pregnant women and immunodeficient patients with early symptoms such as erythema migrans might also benefit from parenteral treatment, although at present there are not sufficient data.  Cefotaxime (Claforan®) or penicillin G in high doses are alternatives. There are a number of patients (up to 10%) who do not respond to the therapy. In this situation, an association with HLA-DR4 and HLA-DR2 has been described. Here the symptoms will drag on due to an auto-immune mechanism and sometimes also due to the persistence of B. burgdorferi in the lesions. The molecule OspA is very similar to a human protein (LFA-1), which could give rise to auto-immunity in people who have the variant HLA-DRB1*0401. Patients who display persistent pain and tiredness after adequate treatment of Lyme disease do not improve more often after prolonged treatment with antibiotics than a placebo group.  *(ANOTHER GRRRRRRR)

 

1.6 Lyme disease, prevention

Avoid tick bites by keeping clear of grass and bushes, wear clothes that cover the body, use agents that repel ticks (repellents with permethrin or DEET), examine your skin after walking in the country and remove ticks quickly. A tick is best removed by carefully grasping it around the base near the mouth, and pulling it out gently without squeezing it flat. It is probable that by squeezing it flat a large quantity of bacteria will penetrate into the skin.

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There are data suggesting that after a single dose of 200 mg of vibramycin within 72 hours of the tick bite, the risk of infection is reduced by almost 90%. However, more study on this strategy is required.

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There is a whole cell vaccine for dogs. Vaccines based on recombinant OspA (a bacterial protein present in tick saliva) have been evaluated in the USA for use in people (Imulyme® and LYMErix®). Because just about every strain of B. burgdorferi contains a variant OspC, a vaccine based on OspC would certainly have to be multivalent *(GRRRRRRRR). On the other hand, OspA is only expressed in the tick’s gastrointestinal system. OspA has virtually no antigenic variation. A vaccine based on OspA acts by immobilising or killing the spirochaetes in the tick, even before OspA is replaced by OspC. The purpose is to prevent the disease. It is unlikely that the administration of the vaccine itself can trigger Lyme-like symptoms, but this needs to be investigated further. Preliminary results of randomised, placebo-controlled studies were promising. After three injections, 90-100% of the young people displayed a protective immune response. In older people (>65 years) this was clearly less efficacious. The antigens that occur in Europe are different from those found in America and a different vaccine composition will be needed. Since the time that the vaccine has become licenced (1998) and available in the USA, there has been little interest of the general public, leading to the withdrawal of the vaccine from the market for commercial reasons in early 2002. *(GRRRRRRRR)

 

It is not clear whether this bacterium is itself a pathogen or whether it is present as a saprophyte in necrotic material. The bacteria can, unlike the other Borrelia, be cultured in an anaerobic environment. In combination with certain anaerobic bacteria (fusobacteria = anaerobic Gram-negative “fusiform bacteria”) this bacterium is suspected of causing ulcerative damage in the:

§         throat: Plaut-Vincent’s angina. This results in a major throat infection with localised necrosis. DD diphtheria of the throat, local anthrax or plague.

§         gums: Trench mouth or Vincent’s stomatitis, a necrotising and ulcerative gingivitis of the cheek. This occurs in malnourished children and sometimes after herpes simplex.

§         Cheeks / lips: Cancrum oris (noma) is characterised by pain and very important tissue destruction. Treatment consists of penicillin, correct nutrition and treatment of any underlying disorder (e.g. kala-azar, etc). Plastic surgery will be needed.

§         scrotum: Gangrene of the scrotum (Fournier’s gangrene).

§         skin: Painful (in the acute stage), purulent, foul-smelling ulcers, mainly on the legs or feet (phagedenic or tropical ulcer). Ulcers such as this can drag on for years or sometimes heal spontaneously. In some patients a spinocellular carcinoma develops which is invasive locally and can metastasise to the local lymph nodes. Treatment consists of penicillin and metronidazole. Local wound cleaning, antiseptics and non-adhesive dressings are important. Dry dressings should be avoided because they prevent the forming of new epithelium (when the dressing is removed the new cells are pulled off).

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Note on Spirochaetes

Spirochaetes are very thin, spiral shaped organisms. There are a number of species. The bacteria take their name from various sources: Borrelia (after the French bacteriologist Amédée Borrel), leptospires (meaning “fine coils”), treponemes (“turning, drilling”). Spirilla are usually classified separately. As yet there is no definitive nomenclature for the various subspecies.

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Summary of Spirochaetes:

Borrelia: 6 to 10 mm in length. 5 to 10 very irregular coils. The various species are morphologically identical.

·         B. recurrentis: louse-borne borreliosis

·         B. duttonii, B. hispanica, B. persica and others: tick-borne borreliosis

·         B. burgdorferi: Lyme disease

·         B. vincenti: Tropical ulcer, Plaut-Vincent’s angina, Cancrum oris, Fournier’s scrotal gangrene, Trench mouth (necrotising ulcerative gingivitis)

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Leptospira: 6 to 20 mm in length. Very fine coils and two terminal hooks.

·         L. interrogans     : among others, Weil’s disease

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Treponema: 5 to 24 mm in length. Corkscrew-shaped, 8 to 20 coils.

·         T. pallidum:        syphilis, bejel (non-venereal syphilis)

·         T. pertenue:       framboesia

·         T. carateum:       pinta

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Sometimes confused with spirochaetes:

·         Spirillum: short (2 to 4 mm), thick and regular

·         Spirillum minus: Sodoku or rat bite fever

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Insufficient data as yet:

·         Brachyspira sp. and Serpulina sp.: bacteria thought to be responsible for so-called intestinal spirochaetosis.