Chapter 37: Spirochetes

Spirochetes are bacteria with a spiral morphology ranging from loose coils to a rigid corkscrew shape. The three medically important genera include the cause of syphilis, the ancient scourge of sexual indiscretion, and Lyme disease, a more recently discovered consequence of an innocent walk in the woods.

BACTERIOLOGY

MORPHOLOGY AND STRUCTURE

The spiral morphology of spirochetes (Figure 37–1) is produced by a flexible, peptidoglycan cell wall around which several axial fibrils are wound. The cell wall and axial fibrils are completely covered by an outer bilayered membrane similar to the outer membrane of other gram-negative bacteria. In some species, a hyaluronic acid slime layer forms around the exterior of the organism and may contribute to its virulence. Spirochetes are motile, exhibiting rotation and flexion; this motility is believed to result from movement of the axial filaments, although the mechanism is not clear.

Many spirochetes are difficult to see by routine microscopy. Although they are gram negative, many either take stains poorly or are too thin (0.15 μm or less) to fall within the resolving power of the light microscope. Only darkfield microscopy (Figure 37–2), immunofluorescence, or special staining techniques can demonstrate these spirochetes. Other spirochetes such as Borrelia are wider and readily visible in stained preparations, even routine blood smears.

GROWTH AND CLASSIFICATION

Parasitic spirochetes grow more slowly in vitro than most other disease-causing bacteria. Some species, including the causative agent of syphilis, have not been grown beyond a few generations in cell culture. Some are strict anaerobes, others require low concentrations of oxygen, and still others are aerobic. Compared with other bacterial groups, the taxonomy of the spirochetes is underdeveloped. Because spirochetes are difficult to grow and study; thus, there are relatively few phenotypic properties on which to base a classification. The medically important genera Treponema, Leptospira, and Borrelia have been distinguished primarily by morphologic characters such as the nature of their spiral shape and the arrangement of flagella. Modern DNA homology and ribosomal RNA analyses have supported these groupings.

SPIROCHETAL DISEASES

Some spirochetes are free living; some are members of the microbiota of humans and animals. The oral cavity, particularly the dental crevice, harbors a number of nonpathogenic species of Treponema and Borrelia as part of its flora. Under unusual conditions, these spirochetes, together with anaerobes in the flora, can cause necrotizing, ulcerative infection of the gums, oral cavity, or pharynx (Vincent infection, trench mouth). The pathogenesis of these opportunistic infections is not understood, but they are correlated with immunocompromise, severe malnutrition, and neglect of basic hygiene (Table 37–1). The term “trench mouth” refers to the occurrence of these infections in troops under the appalling conditions that existed in the trenches during World War I.

The major spirochetal diseases are caused by selected species of three genera that are not found in the microbiota, Treponema (T pallidum), Leptospira (L interrogans), and Borrelia (B recurrentis, B hermsii, and B burgdorferi). Most Borrelia and Leptospira infections are zoonoses transmitted from wild and domestic animals. Treponema pallidum is a strict human pathogen transmitted by sexual contact. Some rare nonvenereal treponemal diseases are summarized in Appendix 37–1.

Treponema pallidum is the causative agent of syphilis, a venereal disease first recognized in the 16th century as the “great pox,” which rapidly spread through Europe in association with urbanization and military campaigns. Some argue that it was brought back from the New World by the sailors with Christopher Columbus. Its extended course and the protean, often dramatic nature of its findings (genital ulcer, ataxia, dementia, ruptured aorta) are due to a state of balanced parasitism that spans decades. The cause of syphilis is actually a subspecies (T pallidum subsp. pallidum) closely related to other agents that cause rare nonvenereal treponematoses. Treponema pallidum is used here to indicate the pallidum subspecies.

BACTERIOLOGY

Treponema pallidum is a slim spirochete 5 to 15 μm long with regular spirals whose wavelength and amplitude resemble a corkscrew (Figure 37–2). The organism is readily seen only by immunofluorescence, darkfield microscopy, or silver impregnation histologic techniques. Live cells show characteristic rotating motility with sudden 90-degree angle flexions, which suggest a gentleman quickly bowing at the waist. Treponema pallidum is extremely susceptible to any deviation from physiologic conditions. It dies rapidly on drying and is readily killed by a wide range of detergents and disinfectants. The lethal effect of even modest elevations of temperature (41-42°C) was the basis for the technique of fever therapy for syphilis introduced in Vienna a century ago. To induce the fever patients were infected with malaria parasites!

Beyond these observations, the study of the biology and pathogenesis of T pallidum is severely impeded by our inability to grow the organism in culture. It multiplies for only a few generations in cell cultures and is difficult to subculture. Sustained growth is achieved only in animals (rabbit testes), which are the sole source of bacteria for diagnostic reagents and scientific study. The T pallidum genome is amenable to study, and much of what follows is based on extrapolations comparing genomic sequences found there with those in other pathogenic bacteria. The T pallidum genome, however, is among the smallest known. In order to survive it is dependent on its host supplying the most basic nutrients and metabolites. The picture of the syphilis spirochete is that of a minimalist pathogen, growing very slowly and producing few definitive structures or products.

The sluggish growth (mean generation time more than 30 hours) of T pallidum is felt to be due to lack of enzymes that detoxify reactive oxygen species (catalase, oxidase) and the absence of efficient energy (ATP)-producing pathways such as the tricarboxylic acid cycle and electron transport chain. Treponema pallidum shares the gram-negative structural style of other spirochetes, but its outer membrane lacks LPS and contains few proteins. The genome is on a single circular chromosome. It is small for bacteria and there are no plasmids or systems for uptake of exogenous DNA.

SYPHILIS

EPIDEMIOLOGY

Treponema pallidum is an exclusively human pathogen under natural conditions. In most cases, infection is acquired from direct sexual contact with a person who has an active primary or secondary syphilitic lesion (Figure 37–3). Partner notification studies suggest transmission occurs in over 50% of sexual contacts in which a lesion is present. Less commonly, the disease may be spread by nongenital contact with a lesion (eg, of the lip), sharing of needles by intravenous drug users, or transplacental transmission to the fetus within the first 3 years of the maternal infection. Late disease is not infectious. Modern screening procedures have essentially eliminated blood transfusion as a source of the disease. The incidence of new cases of primary and secondary syphilis in developed countries declined to an all time low at the end of the 20th century, but since then has risen more than 10%. Worldwide, syphilis remains a major public health problem, with an estimated 12 million new cases annually. There is evidence that syphilitic lesions are a portal for HIV transmission.

PATHOGENESIS

The spirochete reaches the subepithelial tissues through unapparent breaks in the skin or possibly by passage between the epithelial cells of mucous membranes aided by at least one adhesin that binds to fibronectin and elements of the extracellular matrix. Beyond a few candidate adherence or digestive proteins there is little to explain the organism’s invasiveness beyond the propulsive motility generated from its corkscrew structure. In the submucosa, it multiplies slowly stimulating little initial tissue reaction. This is probably due to the relative paucity of antigens in the T pallidum outer membrane that could be exposed to the immune system. In experimental infections, the organisms spread from the primary site to the bloodstream within minutes and are established in distant tissues within hours. As lesions develop, the basic pathologic finding is an endarteritis. The small arterioles show swelling and proliferation of their endothelial cells. This reduces or obstructs local blood supply, probably accounting for the necrotic ulceration of the primary lesion and subsequent destruction at other sites (Figure 37–4A–C). Dense, granulomatous cuffs of lymphocytes, monocytes, and plasma cells surround the vessels. There is no evidence that this injury is due to any toxins or other classic virulence factors produced by T pallidum. Although the primary lesion heals spontaneously, the bacteria have already disseminated to other organs by way of local lymph nodes and the bloodstream.

The disease is clinically silent until the disseminated secondary stage develops and then is silent again with entry into latency. Although evasion of host defenses is clearly taking place, the mechanisms involved are unknown. Treponema pallidum strains found in secondary lesions have not been demonstrated to differ antigenically from those in the primary chancre. It may be that the combination of the low antigen content of its outer membrane combined with the extremely slow multiplication rate allows the organism to stay below whatever critical antigenic mass is required to trigger an effective immune response.

IMMUNITY

Clinical observations suggest an immune response in syphilis that is slow and imperfect. Immunity to reinfection does not appear until early latency, and for at least one-third of those infected the subsequent host response is successful in clearing most but not all of the treponemes.

The immune mechanisms involved are far from clear, but appear to involve both humoral and cell-mediated responses. Resistance to reinfection is correlated with appearance of antitreponemal antibody, which is able to immobilize and kill the organism. Exposed treponemal outer membrane proteins (OMPs) are the most probable target of these antibodies. Cell-mediated responses appear to be dominant in syphilitic lesions with T lymphocytes (CD4+ and CD8+) and macrophages, the primary cell types, present. Activated macrophages play a major role in the clearance of T pallidum from early syphilitic lesions. The relapsing course of primary and secondary syphilis may reflect shifts in the balance between developing cellular immunity and suppression of T lymphocytes. Syphilis in immunocompromised patients such as those with acquired immunodeficiency syndrome (AIDS) may present with unusually aggressive or atypical manifestations.

SYPHILIS: CLINICAL ASPECTS

MANIFESTATIONS

Primary Syphilis

The primary syphilitic lesion is a papule that evolves to an ulcer at the site of infection. This is usually the external genitalia or cervix, but could be in the anal or oral area depending on the nature of sexual contact. The lesion becomes indurated and ulcerates but remains painless, though slightly sensitive to touch. The fully developed ulcer with a firm base and raised margins is called the chancre (Figure 37–4A). Firm, nonsuppurative, painless enlargement of the regional lymph nodes usually develops within 1 week of the primary lesion and may persist for months. The median incubation period from contact until appearance of the primary lesion is about 3 weeks (range 3-90 days). It heals spontaneously after 4 to 6 weeks.

Secondary Syphilis

Secondary or disseminated syphilis develops 2 to 8 weeks after the appearance of the chancre in about a third of primary patients. The primary lesion has usually healed but may still be present. This most florid form of syphilis is characterized by a symmetric mucocutaneous maculopapular rash and generalized nontender lymph node enlargement with fever, malaise, and other manifestations of systemic infection. Skin lesions are distributed on the trunk and extremities, often including the palms (Figure 37–4B), soles, and face, and can mimic a variety of infectious and noninfectious skin eruptions. Some patients develop painless mucosal warty erosions called condylomata lata. These erosions usually develop in warm, moist sites such as the genitals and perineum. All the lesions of secondary syphilis are teeming with spirochetes and are highly infectious. They resolve spontaneously after a few days to many weeks, but the infection itself has resolved in only one-third of patients. In the remaining two-thirds, the illness enters the latent state.

Latent Syphilis

Latent syphilis is by definition a stage in which no clinical manifestations are present, but continuing infection is evidenced by serologic tests. In the first few years, latency may be interrupted by progressively less severe relapses of secondary syphilis. In late latent syphilis (>4 years), relapses cease, and patients become resistant to reinfection. Transmission to others is possible from relapsing secondary lesions and by transfusion or other contact with blood products. Mothers may transmit T pallidum to their fetus throughout latency. About one-third of untreated cases do not have any manifestation of disease beyond this stage.

Tertiary Syphilis

Another one-third of patients with untreated secondary syphilis develop tertiary syphilis. The manifestations may appear as early as 5 years after infection but characteristically occur after 15 to 20 years. The manifestations depend on the body sites involved, the most important of which are the nervous and cardiovascular systems.

Neurosyphilis is due to the damage produced by a mixture of meningovasculitis and degenerative parenchymal changes in virtually any part of the nervous system. The most common entity is a chronic meningitis with fever, headache, focal neurologic findings, and increased cells and protein in the cerebrospinal fluid (CSF). Cortical degeneration of the brain causes mental changes ranging from decreased memory to hallucinations or frank psychosis. In the spinal cord, demyelination of the posterior columns, dorsal roots, and dorsal root ganglia produces a syndrome called tabes dorsalis (Figure 37–5), which includes ataxia, wide-based gait, foot slap, and loss of the sensation. The most advanced central nervous system (CNS) findings include a combination of neurologic deficits and behavioral disturbances called paresis, which is also a mnemonic (personality, affect, reflexes, eyes, sensorium, intellect, speech) for the myriad of changes seen.

Cardiovascular syphilis is due to arteritis involving the vasa vasorum of the aorta and causing a medial necrosis and loss of elastic fibers. The usual result is dilatation of the aorta and aortic valve ring. This in turn leads to aneurysms of the ascending and transverse segments of the aorta and/or aortic valve incompetence. The expanding aneurysm can produce pressure necrosis of adjacent structures or even rupture. A localized, granulomatous reaction to T pallidum infection called a gumma (Figure 37–4C) may be found in skin, bones, joints, or other organ. Any clinical manifestations are related to the local destruction as with other mass-producing lesions, such as tumors.

Congenital Syphilis

Fetuses are susceptible to syphilis only after the fourth month of gestation and adequate treatment of infected mothers before that time prevents fetal damage. Because active syphilitic infection is devastating to infants, routine serologic testing is performed in early pregnancy and should be repeated in the last trimester in women at high risk for acquiring syphilis. Untreated maternal infection may result in fetal loss or congenital syphilis, which is analogous to secondary syphilis in the adult. Although there may be no physical findings, the most common are rhinitis and a maculopapular rash. Bone involvement produces characteristic changes in the architecture of the entire skeletal system (saddle nose, saber shins). Anemia, thrombocytopenia, and liver failure are terminal events.

DIAGNOSIS

Microscopy

Treponema pallidum can be seen by darkfield microscopy in primary and secondary lesions, but the execution of this procedure requires experience and attention to detail. The suspect lesion must be cleaned and abraded to produce a serous transudate from below the surface of the ulcer base. This material can be captured in a capillary tube or placed directly on a microscope slide if a darkfield setup is close at hand. The microscopist must observe the corkscrew morphology and characteristic motility to make a diagnosis (Figure 37–2). A negative result from examination does not exclude syphilis; to be readily seen, the fluid must contain thousands of treponemes per milliliter. Darkfield microscopy of oral and anal lesions is not recommended because of the risk of misinterpretation of other spirochetes present in the resident flora.

Direct fluorescent antibody methods have been developed but are available only in certain centers.

Serologic Tests

Most cases of syphilis are diagnosed serologically using serologic tests that detect antibodies directed at either lipid or specific treponemal antigens. The former are called nontreponemal tests, and the latter are referred to as treponemal tests. Their use in screening, diagnosis, and therapeutic evaluation of syphilis has been refined over many decades (Figure 37–6).

Nontreponemal Tests

Nontreponemal tests measure antibody directed against cardiolipin, a lipid complex so called because one component was originally extracted from beef heart. Anticardiolipin antibody is called reagin, and the tests that detect it depend on immune flocculation of cardiolipin in the presence of other lipids. The most common nontreponemal tests are the rapid plasma reagin (RPR) and the Venereal Disease Research Laboratory (VDRL). The results become positive in the early stages of the primary lesion and, with the possible exception of some patients with advanced HIV infection, are uniformly positive during the secondary stage. They slowly wane in the later stages of the disease. In neurosyphilis, VDRL test results on CSF may be positive when the serum VDRL has reverted to negative. Nontreponemal tests are nonspecific; they may be falsely positive in a variety of autoimmune diseases or in diseases involving substantial tissue or liver destruction, such as lupus erythematosus, viral hepatitis, infectious mononucleosis, and malaria. False-positive results can also occur occasionally in pregnancy and in patients with HIV infection.

Sensitivity and low cost make nontreponemal tests preferred for screening, but positive results must be confirmed by one of the more specific treponemal tests described in the following text. The tests are also valuable for monitoring treatment because the height of the antibody titer is directly related to activity of disease. With successful antibiotic therapy, positive nontreponemal serologies slowly revert to negative.

Treponemal Tests

Treponemal tests detect antibody specific to T pallidum. The microhemagglutination test for T pallidum (MHA-TP), uses antigens attached to the surface of erythrocytes, which then agglutinate in the presence of specific antibody. A variety of enzyme immunoassay (EIA) procedures also detect specific antibody.

Treponemal tests are considerably more specific than the cardiolipin-based nontreponemal tests. Their primary role in diagnosis is to confirm positive RPR and VDRL results obtained in the evaluation of a patient suspected of having syphilis or in screening programs. These tests are not useful for screening or after therapy because, once positive, they usually remain so for life except for the immunocompromised. The basic approach is a two-step process. Initial screening is done with a nontreponemal test, and if positive, the result is confirmed with a treponemal test. Advances in the speed and economy of automated and point-of-care treponemal EIA tests have led some to advocate a “reverse algorithm” in which the treponemal test is done first. The time course of serologic tests in the various stages of syphilis is illustrated in Figure 37–6.

The use of serologic tests in the diagnosis of congenital syphilis is complicated by the presence of IgG antibodies in infants, who acquire it transplacentally from their mothers. If available, treponemal IgM tests are useful in establishing the presence of an acute infection in infants.

TREATMENT AND PREVENTION

Treponema pallidum remains exquisitely sensitive to penicillin, which is the preferred treatment in all stages. In primary, secondary, or latent syphilis, persons hypersensitive to penicillin may be treated with doxycycline or tetracycline. The efficacy of agents other than penicillin has not been established in tertiary or congenital syphilis. It is recommended that penicillin-hypersensitive patients with neurosyphilis or congenital syphilis be desensitized rather than use an alternate antimicrobial. Safe sex practices are as effective for prevention of syphilis as they are for other sexually transmitted diseases. The development of a vaccine awaits greater understanding of pathogenesis and immunity.

BACTERIOLOGY

Leptospira interrogans is the member of the genus Leptospira that is pathogenic to humans and animals. There are other free-living species of Leptospira. This species is a slim spirochete 5 to 15 μm long, with a single axial filament; fine, closely wound spirals; and hooked ends (Figure 37–7). It is not visualized with the usual staining procedures, and detection is best accomplished using darkfield microscopy. It can be grown in aerobic culture using certain special enriched semisolid media. The outer membrane contains LPS and OMPs with adhesive or factor H-binding properties.

Leptospira interrogans has over 200 serotypes, many of which were previously accorded species status (eg, L icterohaemorrhagiae, L canicola, L pomona) based on geographic occurrence, differences in host species, and associated clinical syndromes. The distinction among serotypes is of epidemiologic and epizoologic importance but has no clinical significance. Leptospira interrogans can survive days or weeks in some waters in the environment at a pH above 7.0. Acidic conditions, such as those that may be found in urine, rapidly kill the organism. It is highly sensitive to drying and to a wide range of disinfectants.

LEPTOSPIROSIS

EPIDEMIOLOGY

Leptospirosis is a worldwide disease of a variety of wild and domestic animals, particularly rodents, cattle, and dogs. It is usually transmitted to humans through water contaminated with animal urine. Secondary human-to-human transmission occurs rarely. Individuals who are exposed to animals (eg, farmers, veterinarians, slaughterhouse employees) are at increased risk, although most clinical cases are now associated with recreational exposure to contaminated water (eg, irrigation ditches or other bodies of water receiving farmland drainage). In tropical areas, leptospirosis may account for up to 10% of hospital admissions, particularly after rains or floods.

PATHOGENESIS AND IMMUNITY

The organism gains entrance to the tissues through small skin breaks, the conjunctiva, or, most commonly, ingestion through the upper alimentary tract mucosa. The active motility of the hooked ends driven by periplasmic flagella may allow the organism to burrow into tissues. A few OMPs mediate adherence in much the way seen with invasive members of the Enterobacteriaceae and one with serum factor H-binding properties interferes with complement-mediated killing. The organisms spread widely through the bloodstream to all parts of the body including the CSF. In animals, they colonize the proximal renal tubule, from which they are shed into the urine, facilitating transmission to new hosts. The kidney is also a target organ in human disease, causing tubular infection and interstitial nephritis.

Clearing of the bacteremia is associated with the appearance of circulating antibody but little else is known of immune mechanisms. Antibody is also rising during the second phase of the disease, which suggests an immunologic component to its pathogenesis. This is supported by the absence of response to antimicrobials when given at this stage and the typical failure to recover the organism from the CSF in cases of leptospiral meningitis.

LEPTOSPIROSIS: CLINICAL ASPECTS

MANIFESTATIONS

Most infections are subclinical and detectable only serologically. After an incubation period of 7 to 13 days, an influenza-like febrile illness with fever, chills, headache, conjunctival suffusion, and muscle pain develops in persons who become ill. This disease phase is associated with bacteremia. Leptospires are also found in the CSF at this stage, but without clinical or cytologic evidence of meningitis. The fever often subsides after about a week coincident with the disappearance of the organisms from the blood, but it may recur with a variety of clinical manifestations depending partly on the serogroup involved. This second phase of the disease usually lasts 3 or more weeks and may manifest as an aseptic meningitis resembling viral meningitis or as a more generalized illness with muscle aches, headache, rash, pretibial erythematous lesions, biochemical evidence of hepatic and renal involvement, or all of these. In its most severe form (Weil disease), there is extensive vasculitis, jaundice, renal damage, and sometimes a hemorrhagic rash. The mortality rate in such cases may be as high as 10%.

DIAGNOSIS

The diagnosis of leptospirosis is primarily serologic. Although the spirochetes can theoretically be detected, darkfield examination of body fluids is not recommended. The yield is very low and the chance for confusion with fibrin and debris is significant. Likewise, leptospires can be isolated from the blood, CSF, or urine, but culture is rarely attempted because the organisms take weeks to grow in a special medium that few laboratories bother to stock. The standard serologic test (microagglutination) is limited to reference laboratories. There are two FDA-approved serologic test kits that may be available in locales where the disease is common.

TREATMENT AND PREVENTION

Penicillin is the primary treatment for all forms of leptospirosis. Doxycycline and ceftriaxone are alternatives. Doxycycline is recommended as chemoprophylaxis for individuals engaging in high-risk activities, such as swimming in jungle rivers or kayaking in developing countries. Other measures include rodent control, drainage of waters known to be contaminated, and care on the part of those subject to occupational exposure to avoid ingestion or contamination with L interrogans. Vaccines are used in cattle and household pets to prevent the disease, and this has reduced its occurrence in humans.

More than 15 species of Borrelia have been associated with human disease, and other species are responsible for similar diseases in animals. Borrelia burgdorferi is the cause of Lyme disease. Other members of the genus cause relapsing fever, an illness with intermittent fevers and little else. The relapsing fevers differ in their specific vector and geographic distribution. The human body louse is the vector for B recurrentis, but the remainder of the relapsing fevers are linked to several ticks and species of Borrelia; these are discussed together here as B hermsii, the most common cause of relapsing fever in North America.

Borrelia are long (10-30 μm), slender, spirochetes containing multiple (7-20) axial flagella. In contrast to Treponema and Leptospira, its spirals form loose, irregular waves. The basic organizational structure of the cell and its motility conform to that of the other gram-negative spirochetes, but unlike the others, Borrelia are readily demonstrated by common staining methods such as the Giemsa or Wright stains. Borrelia are microaerophilic and have been successfully grown in specially supplemented (N-acetylglucosamine, fatty acids) liquid or semisolid media. The organisms are generally deficient in genes for synthesis of many essential nutrients (amino acids, fatty acids, nucleic acids) and thus must obtain them from external sources. A distinct feature of Borrelia is the partitioning of the genome between the chromosome and multiple circular and linear plasmids. In some species, a large proportion (>40%) of the genome is in the plasmids, including genes important in animal and human disease.

BACTERIOLOGY

The outer membrane of all Borrelia species contains abundant OMPs and lipoproteins. In some species, these surface proteins have been observed to vary antigenically too abundantly to be explained by simple mutation. Experiments with B hermsii have demonstrated up to 40 antigenically distinct variants of the same protein arising from a single cell. The genetic mechanism for this antigenic variation involves recombination between genes located in the distinctive linear plasmids. Multiple copies of the genes for these proteins are present. Some genes express the protein, whereas others are “silent” because they lack crucial promoter sequences. When structural sequences from a silent gene are transferred by recombination to an expressing gene on another plasmid, the protein expressed is altered, which may make it antigenically different. This recombination mechanism resembles that described for antigenic variation of gonococcal pili (see Chapter 30, Figures 22–5, 30–7).

RELAPSING FEVER

EPIDEMIOLOGY

Relapsing fever occurs in two forms linked to the mode of transmission and the Borrelia species involved. The louse-borne form usually appears in epidemics, because of circumstances connected with body lice, whereas the tick-borne form does not. For this reason, the two forms are sometimes called epidemic (louse-borne) and endemic (tick-borne) relapsing fever. Here they are identified simply by the insect involved.

The occurrence and distribution of tick-borne relapsing fever are determined by the biology of multiple species of a single tick genus (Ornithodoros) and their relation to the primary Borrelia reservoir in rodents and other small animals (rabbits, birds, lizards). Borrelia hermsii is one of at least 15 Borrelia species associated with this cycle. Ticks may remain infectious for several years even without feeding, and transovarial passage to their progeny extends the infectious chain even further. Humans are infected when they accidentally enter this cycle and are bitten by an infected tick. The bite is painless and the feeding period is brief (less than 20 minutes). Because the ticks usually feed at night, cases of relapsing fever are most often associated with overnight recreational forays into wild, wooded areas. A large outbreak in the United States involved National Park employees and tourists who slept in tick- and rodent-infested cabins on the Northern Rim of the Grand Canyon.

The epidemiologic conditions associated with louse-borne relapsing fever are much more exacting. The human body louse has no other host, infected lice live no more than 2 months, and there is no transovarial passage to progeny. Borrelia recurrentis is the only species involved. Lice are infected from human blood, but the spirochetes multiply in their hemolymph, not any of the feeding parts or excrement. This means they can infect another human only if the louse is crushed by scratching and the Borrelia reach a superficial wound or mucosal surface. Infected lice must be passed human to human for the disease to persist. These conditions are met by circumstances that combine overcrowding with extremely low levels of general hygiene. War, other kinds of social breakdown, and dire poverty are the prime associates. Currently, this variety of relapsing fever appears to be limited to East and Central Africa and the Peruvian Andes.

PATHOGENESIS

The disease manifestations develop at times when thousands of spirochetes are circulating per milliliter of blood. The febrile illness has endotoxin-like features, but the exact mechanisms of disease are unknown. Between episodes, the organisms disappear from the blood and are sequestered in internal organs only to reappear during relapses. The OMPs are antigenically different with each relapse. The relapsing cycles correlate with antibody production to the new protein followed by clearing emergence of a new antigenic type.

IMMUNITY

Immunity to relapsing fever is largely humoral and appears to involve lysis of the organism in the presence of complement. The disease is controlled when variants from the antigenic repertoire are no longer able to escape the immune response.

RELAPSING FEVER: CLINICAL ASPECTS

MANIFESTATIONS

After a mean incubation period of 7 days, massive spirochetemia develops, with high fever, rigors, severe headache, muscle pains, and weakness. The febrile period lasts about 1 week and terminates abruptly with the development of an adequate immune response. The disease relapses 2 to 4 days later, usually with less severity, but following the same general course. Tick-borne relapsing fever is usually limited to one or two relapses, but with louse-borne disease three or four may occur.

Louse-borne relapsing fever is more severe than tick-borne disease, possibly because of predisposing social conditions. Fatalities are rare in tick-borne disease but may be as high as 40% in untreated louse-borne fever. Fatal outcomes are due to myocarditis, cerebral hemorrhage, and hepatic failure.

DIAGNOSIS

Diagnosis of relapsing fever is readily made during the febrile period by Giemsa or Wright staining of blood smears. The appearance of the spirochete among the red cells is characteristic. Culture and serologic tests are available only in reference laboratories.

TREATMENT

Patients with relapsing fever respond well to doxycycline or tetracycline (louse-borne) therapy, with erythromycin and ceftriaxone as alternatives. If the level of spirochetes is high at the time treatment is initiated, a systemic febrile reaction (Jarisch-Herxheimer) resembling gram-negative sepsis may ensue. This is felt to be due to rapid lysis of the organisms with release of outer membrane LPS. It is more common in louse-borne than tick-borne relapsing fever.

PREVENTION

Prevention of tick-borne relapsing fever involves attention to deticking, insecticide treatment, and rodent control around habitations such as mountain cabins, which are known to be associated with infection. Control of louse-borne relapsing fever involves delousing, particularly dusting of clothing with appropriate insecticides. Ultimately, improved hygiene stops outbreaks and prevents further occurrences.

BACTERIOLOGY

Borrelia burgdorferi consists of at least 18 subspecies (eg, B burgdorferi sensu stricto, B afzelii, B garini, and others), which differ in geographic distribution and some clinical manifestations. Five of these are known to cause Lyme disease. All these are referred to here as B burgdorferi. As with other species of Borrelia, there are multiple classes of OMPs, many of which undergo antigenic variation. Recent studies have focused on a class called outer surface proteins (Osps), which have been linked to aspects of pathogenesis and immunity. In response to environmental signals (temperature, pH) two of these proteins, OspA and OspC, are differentially expressed, depending on the stage of tick or mammalian infection. Other Osps have been shown to bind to fibronectin and serum factor H.

LYME DISEASE

EPIDEMIOLOGY

Borrelia burgdorferi exists in a complex cycle involving ticks, mice, and deer (Figure 37–8). Lyme disease occurs when the ticks feed on humans who enter their wooded habitat. The disease is endemic in several regions of the United States, Canada, and temperate Europe and Asia. Approximately 90% of the more than 30 000 cases reported each year in the United States occur in areas along the northeastern and mid-Atlantic seaboard, including Old Lyme, Connecticut, where the disease was first recognized. Most cases probably go unreported, particularly outside the primary endemic regions.

The primary reservoir of B burgdorferi is rodents, particularly white-footed mice. Infection is transmitted by Ixodes ticks (Figure 37–9), whose complete life cycle involves rodents for the early stages and deer for adult maturation. In the spring, fertile female ticks, engorged from their blood meals, fall from their deer hosts to the ground and deposit their eggs. During the summer, the tick larvae seek out and obtain a blood meal from mice and the B burgdorferi ingested by the larvae are maintained through the subsequent development stages of the tick. The following spring or summer, the small (1-2 mm) nymphs feed again on vertebrate hosts to obtain the blood required for maturation to adulthood. The engorged, satiated nymphs fall off their hosts and mature into adults by parasitizing available deer, thus completing a life cycle that has occupied a full 2 years. Vertebrates other than deer can be infected by both the adult and nymph stages of the tick, but human Lyme disease is acquired primarily from nymphs, because they are active at the time of year when humans are most likely to invade their ecosystem. The infecting dose is very low (<20 organisms), making even a single tick bite a risk for disease. Deer are essential to the mating and survival of the tick, and thus the disease does not occur in areas in which deer are not abundant.

PATHOGENESIS

Because Lyme disease is a recently discovered disease with a complex biology, it is not surprising that the pathogenic mechanisms in humans remain to be established clearly. Studies in ticks have shown changes in the antigenic makeup of B burgdorferi as it migrates from the midgut and salivary glands and again after it reaches mammalian tissue. OspA is the major outer surface protein expressed when B burgdorferi resides in ticks, where it mediates binding to midgut cells. OspA expression diminishes during tick feeding and engorgement, whereas OspC increases, so that by the time of transmission to animal hosts, OspC predominates. OspC has been shown to protect the spirochetes from macrophage ingestion and antibody against it is protective in animals.

After infection, the B burgdorferi surface proteins that mediate adhesion to fibronectin or elements of the extracellular matrix could be important in the early stages of disease. By analogy with other bacterial proteins that bind serum factor H, similar Osps of B burgdorferi are likely to facilitate persistence by interference with effective complement deposition. The spirochete is not known to produce digestive enzymes, but tissue spread and dissemination may be facilitated by the utilization of host proteases. As the organism spreads, inflammation is stimulated by the cell wall peptidoglycan and possibly by elements of the outer membrane, although B burgdorferi lacks classic LPS. When deposited in joint tissues, these elements may contribute to the arthritis of Lyme disease.

Clinical investigations in patients with Lyme disease have noted modulation of immune responses, including inhibition of mononuclear and natural killer cell function, lymphocyte proliferation, and cytokine production. The ability of B burgdorferi to downregulate deleterious immune responses could serve as a survival strategy or play a role in chronic disease. Chronic disease, particularly Lyme arthritis, has aspects of autoimmunity and its relapsing characteristics may be related to antigenic variation of surface lipoproteins. A subcategory of arthritis patients refractory to antimicrobial therapy have been shown to have heightened and persistent humoral immune responses to OspA.

IMMUNITY

The immune response to B burgdorferi infection develops slowly, with IgM followed by IgG antibody over weeks to months. Although immune-mediated killing by the classical complement pathway has been demonstrated, the molecular target is unknown. Host neutrophils and macrophages can phagocytose opsonized spirochetes and induce a metabolic burst leading to spirochetal death. OspC elicits protective immunity in rodents, but this protection is short-lived and ineffective against challenge with heterologous B burgdorferi isolates. Antigens capable of eliciting broadly protective immune responses have not been identified.

LYME DISEASE: CLINICAL ASPECTS

MANIFESTATIONS

Lyme borreliosis is a highly variable disease involving many body systems. It occurs in overlapping patterns that come and go at different times. The skin lesion spreading from the site of the tick bite is its most distinctive feature. Relapsing arthritis is the most persistent finding and the one most likely to become chronic. Lyme disease is rarely fatal, but if untreated, it is often a source of chronic ill health.

The primary lesion begins sometime in the first month after a tick bite, which is often unnoticed. A macule or papule appears at the site of the bite and expands to become an annular lesion with a raised, red border and central clearing forming a bull’s-eye pattern. As the bull’s-eye ring expands and evolves, it forms the lesion known as erythema migrans (Figure 37–10). Along with the skin lesions, fever, fatigue, myalgia, headache, joint pains, and mild neck stiffness are often present. Approximately 50% of untreated patients develop secondary skin lesions that closely resemble the primary one, but are not at the site of the tick bite. In untreated patients, the skin lesions usually disappear over a period of weeks, but constitutional symptoms may persist for months.

Days to months after the onset of the primary lesion, a second stage may develop in which involvement of the nervous or cardiovascular system is superimposed. Neurologic abnormalities include a fluctuating meningitis, cranial nerve palsies, and peripheral neuropathy. Cardiac disease is usually limited to conduction abnormalities (atrioventricular block), but in some cases acute myocarditis can lead to cardiac enlargement. Both neurologic and cardiac abnormalities fluctuate in intensity, but generally resolve completely in a matter of weeks.

Weeks to years after the onset of infection, arthritis marks the continuing state of the disease. It develops in almost two-thirds of untreated patients. Typically, it too follows a fluctuating or intermittent course, generally involving the large joints, particularly the knees. The arthritis may become chronic with erosion of the bone and cartilage, although the spirochetes are rarely demonstrable in the lesions. Less common chronic neurologic dysfunctions include subtle encephalitis affecting memory, mood, or sleep, and peripheral neuropathies.

DIAGNOSIS

Presently, the diagnosis of early Lyme disease is based on exposure and typical clinical findings. Although B burgdorferi can be cultured from erythema migrans skin lesions, blood, joint fluid, and CSF, few laboratories have the skill to accomplish this or even stock the special medium required. The spirochetes are seldom detected on any kind of direct microscopic examination. Nucleic acid amplification procedures able to detect B burgdorferi-specific DNA sequences in body fluids (joint, CSF) have been developed.

With culture generally unavailable, the diagnosis in later stages of disease usually rests on the demonstration of circulating antibodies to B burgdorferi. The current recommendation is to first perform a sensitive screening test (enzyme immunoassay) followed by a confirmatory immunoblot (Western blot), which detects specific antigens of the organism. For persons who lack a typical clinical or epidemiologic history, great caution should be exercised before making a diagnosis of Lyme disease based only on positive serologic tests.

TREATMENT

Doxycycline, amoxicillin, and cefuroxime are the first-line antimicrobials for the treatment of early Lyme disease and arthritis. Azithromycin and clarithromycin are alternatives. The response to treatment is typically slow, requiring the continuation of antimicrobials for 30 to 60 days. Chronic Lyme disease is most probably an autoimmune state, and thus antimicrobial agents would not be effective.

PREVENTION

The most useful preventive measures in endemic areas are the use of clothes that reduce the likelihood of the infected nymph reaching the legs or arms, careful search for nymphs after potential exposure, and removal of the tick by its head with tweezers. Duration of tick attachment to humans is also a factor in transmission; the risk is greatest when the tick has been feeding for at least 48 to 72 hours. Some insect repellents may provide added protection. Prophylactic doxycycline may be used following a tick bite, but only in a highly endemic region.