Chapter 24: Spirochetes

Three genera of spirochetes cause human infection: (1) Treponema, which causes syphilis and the nonvenereal treponematoses; (2) Borrelia, which causes Lyme disease and relapsing fever; and (3) Leptospira, which causes leptospirosis (Table 24–1).

Spirochetes are thin-walled, flexible, spiral rods (Figure 24–1). They are motile through the undulation of axial filaments that lie under the outer sheath. Treponemes and leptospirae are so thin that they are seen only by dark-field microscopy, silver impregnation, or immunofluorescence. Borreliae are larger, accept Giemsa and other blood stains, and can be seen in the standard light microscope.

Additional information regarding the clinical aspects of infections caused by the organisms in this chapter is provided in Part IX entitled Infectious Diseases beginning on Introduction.

1. Treponema pallidum

Disease

Treponema pallidum causes syphilis.

Important Properties

Treponema pallidum has not been grown on bacteriologic media or in cell culture. Nonpathogenic treponemes, which are part of the normal flora of human mucous membranes, can be cultured.

Treponema pallidum grows very slowly. The medical importance of that fact is that antibiotics must be present at an effective level for several weeks to kill the organisms and cure the disease (see “Treatment” section later). For example, benzathine penicillin is the form of penicillin used to treat primary and secondary syphilis because the penicillin is released very slowly from this depot preparation, and bactericidal concentrations are present for weeks after administration of the antibiotic.

The antigens of T. pallidum induce specific antibodies, which can be detected by immunofluorescence or hemagglutination tests in the clinical laboratory. They also induce nonspecific antibodies (reagin),¹ which can be detected by the flocculation of lipids (cardiolipin) extracted from normal mammalian tissues (e.g., beef heart).

Both specific antitreponemal antibody and nonspecific reagin are used in the serologic diagnosis of syphilis.

Transmission & Epidemiology

Treponema pallidum is transmitted from spirochete-containing lesions of skin or mucous membranes (e.g., genitalia, mouth, and anus) of an infected person to other persons by intimate contact. It can also be transmitted from pregnant women to their fetuses. Rarely, blood for transfusions collected during early syphilis is also infectious. Treponema pallidum is a human organism only. There is no animal reservoir.

Syphilis occurs worldwide, and its incidence is increasing. It is one of the leading notifiable diseases in the United States. Many cases are believed to go unreported, which limits public health efforts. There has been a marked increase in the incidence of syphilis in men who have sex with men in recent years.

Pathogenesis & Clinical Findings

Treponema pallidum produces no important toxins or enzymes. The organism often infects the endothelium of small blood vessels, causing endarteritis. This occurs during all stages of syphilis but is particularly important in the pathogenesis of the brain and cardiovascular lesions seen in tertiary syphilis.

In primary syphilis, the spirochetes multiply at the site of inoculation, and a local, nontender ulcer (chancre) usually forms in 2 to 10 weeks (Figure 24–2). The ulcer heals spontaneously, but spirochetes spread widely via the bloodstream (bacteremia) to many organs.

One to 3 months later, the lesions of secondary syphilis may occur. These often appear as a maculopapular rash, notably on the palms and soles (Figure 24–3), or as moist papules on skin and mucous membranes (mucous patches). Moist lesions on the genitals are called condylomata lata (Figure 24–4). These lesions are rich in spirochetes and are highly infectious, but they also heal spontaneously. Patchy alopecia also occurs. Constitutional symptoms of secondary syphilis include low-grade fever, malaise, anorexia, weight loss, headache, myalgias, and generalized lymphadenopathy. Pharyngitis, meningitis, nephritis, and hepatitis may also occur. In some individuals, the symptoms of the primary and secondary stages may not occur, and yet the disease may progress.

About one-third of these early (primary and secondary) syphilis cases will “cure” themselves, without treatment. Another third remain latent (i.e., no lesions appear, but positive serologic tests indicate continuing infection). The latent period can be divided into early and late stages. In the early latent period, which can last for 1 or 2 years after the secondary stage, the symptoms of secondary syphilis can reappear and patients can infect others. In the late latent period, which can last for many years, no symptoms occur and patients are not infectious. In the remaining one-third of people, the disease progresses to the tertiary stage. Tertiary syphilis may show granulomas (gummas), especially of skin and bones; central nervous system involvement, also known as neurosyphilis (e.g., tabes, paresis); or cardiovascular lesions (e.g., aortitis, aneurysm of the ascending aorta). In tertiary lesions, treponemes are rarely seen.

Treponema pallidum also causes congenital syphilis. The organism is transmitted across the placenta, typically after the third month of pregnancy, and fetal infection can occur. In the infected neonates, skin and bone lesions, such as Hutchinson’s teeth, mulberry molars, saber shins, saddle nose, rhagades, snuffles, and frontal bossing, are common. Other findings, such as hepatosplenomegaly, interstitial keratitis, and eighth nerve deafness, also occur. Fetal infection can also result in stillbirth.

Immunity to syphilis is incomplete. Antibodies to the organism are produced but do not stop the progression of the disease. Patients with early syphilis who have been treated can contract syphilis again. Patients with late syphilis are relatively resistant to reinfection.

Laboratory Diagnosis

There are three important approaches.

Microscopy

Spirochetes are demonstrated in the lesions of primary or secondary syphilis, such as chancres or condylomata lata, by dark-field microscopy or by direct fluorescent antibody (DFA) test. They are not seen on a Gram-stained smear. In biopsy specimens, such as those obtained from the gummas seen in tertiary syphilis, histologic stains such as silver stain or fluorescent antibody can be used.

Nonspecific Serologic Tests

These tests involve the use of nontreponemal antigens. Extracts of normal mammalian tissues (e.g., cardiolipin from beef heart) react with antibodies in serum samples from patients with syphilis. These antibodies, which are a mixture of IgG and IgM, are called “reagin” antibodies (see earlier). Flocculation tests (e.g., Venereal Disease Research Laboratory [VDRL] and rapid plasma reagin [RPR] tests) detect the presence of these antibodies. These tests are positive in most cases of primary syphilis and are almost always positive in secondary syphilis. The titer of these nonspecific antibodies decreases with effective treatment, in contrast to the specific antibodies, which are positive for life (see later).

False-positive reactions occur in infections such as leprosy, hepatitis B, and infectious mononucleosis and in various autoimmune diseases. Therefore, positive results have to be confirmed by specific tests (see later). Results of nonspecific tests usually become negative after treatment and should be used to determine the response to treatment. These tests can also be falsely negative as a result of the prozone phenomenon. In the prozone phenomenon, the titer of antibody is too high (antibody excess), and no flocculation will occur. On dilution of the serum, however, the test result becomes positive (see Chapter 64). These tests are inexpensive and easy to perform and therefore are used as a method of screening the population for infection. The nonspecific tests and the specific tests (see later) are described in more detail in Chapter 9.

The laboratory diagnosis of congenital syphilis is based on the finding that the infant has a higher titer of antibody in the VDRL test than the mother. Furthermore, if a positive VDRL test result in the infant is a false-positive one because maternal antibody has crossed the placenta, the titer will decline with time. If the infant is truly infected, the titer will remain high. However, irrespective of the VDRL test results, any infant whose mother has syphilis should be treated.

Specific Serologic Tests

These tests involve the use of treponemal antigens and therefore are more specific than those described earlier. In these tests, T. pallidum reacts in immunofluorescence (FTA-ABS)² or hemagglutination (TPHA, MHA-TP)³ assays with specific treponemal antibodies in the patient’s serum.

These antibodies arise within 2 to 3 weeks of infection; therefore, the test results are positive in most patients with primary syphilis. These tests remain positive for life after effective treatment and cannot be used to determine the response to treatment or reinfection. They are more expensive and more difficult to perform than the nonspecific tests and therefore are not used as screening procedures.

Treatment

Penicillin G is effective in the treatment of all stages of syphilis. A single injection of benzathine penicillin G (2.4 million units) can eradicate T. pallidum and cure early (primary and secondary) syphilis. Note that benzathine penicillin is used because the penicillin is released very slowly from this depot preparation. Treponema pallidum grows very slowly, which requires that the penicillin be present in bactericidal concentration for weeks. If the patient is allergic to penicillin, doxycycline can be used but must be given for prolonged periods to effect a cure.

Tertiary syphilis manifesting with gummas or with cardiovascular findings can also be treated with benzathine penicillin G, but three doses are recommended, However, in neurosyphilis, high doses of aqueous penicillin G are administered because benzathine penicillin penetrates poorly into the central nervous system. No resistance to penicillin has been observed in T. pallidum. However, strains resistant to azithromycin have emerged.

Pregnant women with syphilis should be treated promptly with the type of penicillin used for the stage of their disease. Neonates with a positive serologic test should also be treated. Although it is possible that the positive test is caused by maternal antibody rather than infection of the neonate, it is prudent to treat without waiting several months to determine whether the titer of antibody declines.

More than half of patients with secondary syphilis who are treated with penicillin experience fever, chills, myalgias, and other influenzalike symptoms a few hours after receiving the antibiotic. This response, called the Jarisch-Herxheimer reaction, is attributed to the lysis of the treponemes and the release of endotoxin-like substances. Patients should be alerted to this possibility, advised that it may last for up to 24 hours, and told that symptomatic relief can be obtained with aspirin. The Jarisch-Herxheimer reaction also occurs after treatment of other spirochetal diseases such as Lyme disease, leptospirosis, and relapsing fever. Tumor necrosis factor (TNF) is an important mediator of this reaction because passive immunization with antibody against TNF can prevent its symptoms.

Prevention

Prevention depends on early diagnosis and adequate treatment, use of condoms, administration of antibiotic after suspected exposure, and serologic follow-up of infected individuals and their contacts. To prevent congenital syphilis, all pregnant women should be screened by using a treponemal test such as FTA-ABS.

The presence of any sexually transmitted disease makes testing for syphilis mandatory, because several different infections are often transmitted simultaneously. There is no vaccine against syphilis.

2. Nonvenereal Treponematoses

These are infections caused by spirochetes that are virtually indistinguishable from those caused by T. pallidum. They are endemic in populations and are transmitted by direct contact. All these infections result in positive (nontreponemal and treponemal) results on serologic tests for syphilis. None of these spirochetes have been grown on bacteriologic media. The diseases include bejel in Africa, yaws (caused by T. pallidum subspecies pertenue) in many humid tropical countries, and pinta (caused by Treponema carateum) in Central and South America. All can be cured by penicillin.

Borrelia species are irregular, loosely coiled spirochetes that stain readily with Giemsa and other stains. They can be cultured in bacteriologic media containing serum or tissue extracts. They are transmitted by arthropods. They cause two major diseases, Lyme disease and relapsing fever.

1. Borrelia burgdorferi

Disease

Borrelia burgdorferi causes Lyme disease (named after a town in Connecticut). Lyme disease is also known as Lyme borreliosis. Lyme disease is the most common tick-borne disease in the United States. It is also the most common vector-borne disease in the United States. Approximately 20,000 cases each year are reported to the Centers for Disease Control and Prevention, and that number is thought to be significantly less than the actual number.

Important Properties

Borrelia burgdorferi is a flexible, motile spirochete that can be visualized by dark-field microscopy and by Giemsa and silver stains. It can be grown in certain bacteriologic media, but routine cultures obtained from patients (e.g., blood, spinal fluid) are typically negative. In contrast, culture of the organism from the tick vector is usually positive.

Transmission & Epidemiology

Borrelia burgdorferi is transmitted by tick bite (Figures 24–5, 24–6, 24–7). The tick Ixodes scapularis is the vector on the East Coast and in the Midwest; Ixodes pacificus is involved on the West Coast. The organism is found in a much higher percentage of I. scapularis (35%–50%) than I. pacificus (approximately 2%) ticks. This explains the lower incidence of disease on the West Coast. The main reservoir of the organism consists of small mammals, especially the white-footed mouse, upon which the nymphs feed.⁴

Large mammals, especially deer, are an obligatory host in the tick’s life cycle but are not an important reservoir of the organism.

The nymphal stage of the tick transmits the disease more often than the adult and larval stages do. Nymphs feed primarily in the summer, which accounts for the high incidence of disease during the months of May to September.

The tick must feed for 24 to 48 hours to transmit an infectious dose. This implies that inspecting the skin after being exposed can prevent the disease. However, the nymphs are quite small and can easily be missed. There is no human-to-human spread.

The disease occurs worldwide. In the United States, three regions are primarily affected: the states along the North Atlantic seaboard, the northern midwestern states (e.g., Wisconsin), and the West Coast, especially California. Approximately 80% of the reported cases occurred in four states: New York, Connecticut, Pennsylvania, and New Jersey.

Lyme disease is the most common vector-borne disease in the United States. The major bacterial diseases transmitted by ticks in the United States are Lyme disease, Rocky Mountain spotted fever, ehrlichiosis, anaplasmosis, relapsing fever, and tularemia. Ixodes scapularis ticks transmit three diseases: two bacterial diseases, Lyme disease and human granulocytic ehrlichiosis, and the protozoan disease, babesiosis. Coinfection with B. burgdorferi and Babesia occurs, especially in endemic areas such as Massachusetts and other northeastern states.

Pathogenesis

Pathogenesis is associated with spread of the organism from the bite site through the surrounding skin followed by dissemination via the blood (bacteremia) to various organs, especially the heart, joints, and central nervous system. No exotoxins, enzymes, or other important virulence factors have been identified.

Note that the organism must adapt to two markedly different hosts, the tick and the mammal (either mice or humans). It does so by changing its outer surface protein (OSP). These OSPs vary antigenically within humans.

Multiple episodes of Lyme disease are due to reinfection, rather than relapse caused by reactivation of the organism. There is no evidence for a latent stage of B. burgdorferi.

Clinical Findings

The clinical findings have been divided into three stages; however, this is a progressive disease, and the stages are not discrete. In stage 1 (early localized stage), the most common finding is erythema chronicum migrans (also called erythema migrans), an expanding, erythematous, macular rash that often has a “target” or “bull’s eye” appearance (Figure 24–8).

The rash appears between 3 and 30 days after the tick bite. Both the tick bite and the rash are painless and nonpruritic. The rash expands over the course of days to weeks and resolves spontaneously in a few weeks.

The rash may be accompanied by nonspecific “flulike” symptoms such as fever, chills, fatigue, myalgia, and headache. Secondary skin lesions frequently occur. Arthralgias, but not arthritis, are another common finding in this early stage. In approximately 25% of cases of Lyme disease, no rash is seen, either because the rash did not occur or because it occurred in an area of the body that is not easily visualized.

In stage 2 (early disseminated stage), which occurs weeks to months later, cardiac and neurologic involvement predominates. Myocarditis, accompanied by various forms of heart block, occurs. Acute (aseptic) meningitis and cranial neuropathies, such as facial nerve palsy (Bell’s palsy), are prominent during this stage. Bilateral facial nerve palsy is highly suggestive of Lyme disease. Peripheral neuropathies also occur.

A latent phase lasting weeks to months typically ensues. In stage 3 (late disseminated stage), arthritis, usually of the large joints (e.g., knees), is a characteristic finding. Lyme arthritis is thought to be autoimmune in origin. Encephalopathy also occurs in stage 3.

Some patients treated for Lyme infection continue to have prolonged subjective symptoms of fatigue, joint pains, or mental status changes after objective findings have disappeared. This is called “chronic Lyme disease” by some, but there is controversy about whether this exists. No confirmed microbiologic evidence for B. burgdorferi infection has been detected in those patients, and prolonged antibiotic therapy does not relieve the symptoms.

Laboratory Diagnosis

Although the organism can be grown in the laboratory, cultures are rarely positive and hence are usually not performed. The diagnosis is typically made serologically by detecting either IgM antibody or a rising titer of IgG antibody with an enzyme-linked immunosorbent assay (ELISA) or an indirect immunofluorescence test. IgM is typically detectable 2 weeks after infection and peaks at 3 to 6 weeks. Serologic tests done before 2 weeks are likely to yield negative results. Thirty days after infection, tests for IgG are more reliable.

Unfortunately, there are problems with the specificity and sensitivity of these tests because of the presence of cross-reacting antibodies against spirochetes in the normal flora. A positive test result should be confirmed with a Western blot (immunoblot) analysis. In addition, patients treated early in the disease may not develop detectable antibodies. A polymerase chain reaction (PCR) test that detects the organism’s DNA is also available.

Treatment & Prevention

The treatment of choice for stage 1 disease or other mild manifestations is either doxycycline or amoxicillin. Amoxicillin should be used in pregnant women and young children, as doxycycline is contraindicated. For more severe forms or late-stage disease, ceftriaxone is recommended. There is no significant antibiotic resistance.

Prevention involves wearing protective clothing and using insect repellents. Examining the skin carefully for ticks is also very important, because the tick must feed for 24 to 48 hours to transmit an infective dose.

Should prophylactic antibiotics be given to people who have been bitten by a tick? The decision depends on two main factors: the percentage of infected ticks in the area and the length of time the tick has fed on the person. If the percentage of infected ticks is high and the length of time is more than 48 hours, it may be cost-effective to prescribe doxycycline prophylactically. Any person bitten by a tick should be advised to watch carefully for a rash or flulike symptoms for the next 3 weeks.

A vaccine containing a recombinant outer surface protein (OspA) of B. burgdorferi as the immunogen was available but has been withdrawn.

2. Borrelia recurrentis & Borrelia hermsii

Borrelia recurrentis, Borrelia hermsii, and several other borreliae cause relapsing fever. During infection, the antigens of these organisms undergo variation. As antibodies develop against one antigen, variants emerge and produce relapses of the illness. This can be repeated 3 to 10 times.

Borrelia recurrentis is transmitted from person to person by the human body louse. Humans are the only hosts. Borrelia hermsii and many other Borrelia species are transmitted to humans by soft ticks (Ornithodoros). Rodents and other small animals are the main reservoirs. These species of Borrelia are passed transovarially in the ticks, a phenomenon that plays an important role in maintaining the organism in nature.

During infection, the arthropod bite introduces spirochetes, which then multiply in many tissues, producing fever, chills, headaches, and multiple-organ dysfunction. Each attack is terminated as antibodies arise.

Diagnosis is usually made by seeing the large spirochetes in stained smears of peripheral blood. They can be cultured in special media. Serologic tests are rarely useful. Tetracycline may be beneficial early in the illness and may prevent relapses. Avoidance of arthropod vectors is the best means of prevention.

3. Borrelia miyamotoi

Borrelia miyamotoi causes a relapsing feverlike syndrome. It was discovered in 1995 in Japan but causes disease worldwide, including the United States. It is transmitted by Ixodes ticks. Clinically, the disease begins with an influenzalike syndrome (fever, headache, and myalgia) accompanied by hepatitis and thrombocytopenia. Relapsing episodes occur. The manifestations can resemble anaplasmosis (see Chapter 26) that is also transmitted by Ixodes ticks. There is no rash, unlike Lyme disease.

The diagnosis is typically made serologically by detecting IgM antibody or by PCR assay testing for the gene encoding the Glp Q protein that is specific for B. miyamotoi. Doxycycline and ceftriaxone are effective treatment choices. There is no vaccine. Wearing clothing impregnated with Permethrin can reduce the risk of tick bites.

Leptospiras are tightly coiled spirochetes with hooked ends. They stain poorly with dyes and so are not seen by light microscopy, but they are seen by dark-field microscopy. They grow in bacteriologic media containing serum.

Leptospira interrogans is the cause of leptospirosis. Leptospirosis is common in tropical countries, especially in the rainy season, but is rare in the United States. Leptospira interrogans is divided into serogroups that occur in different animals and geographic locations. Each serogroup is subdivided into serovars by the response to agglutination tests.

Leptospiras infect various animals, including rats and other rodents, domestic livestock, and household pets. In the United States, dogs are the most important reservoir. Animals excrete leptospiras in urine, which contaminates water and soil.

Swimming in contaminated water or consuming contaminated food or drink can result in human infection. Outbreaks have occurred among participants in triathlons and adventure tours involving swimming in contaminated waters. Miners, farmers, and people who work in sewers are at high risk. In the United States, the urban poor have a high rate of infection as determined by the presence of antibodies. Person-to-person transmission is rare.

Human infection results when leptospiras are ingested or pass through mucous membranes or skin. They circulate in the blood and multiply in various organs, producing fever and dysfunction of the liver (jaundice), kidneys (uremia), lungs (hemorrhage), and central nervous system (aseptic meningitis). The illness is typically biphasic, with fever, chills, intense headache, and conjunctival suffusion (diffuse reddening of the conjunctivae) appearing early in the disease, followed by a short period of resolution of these symptoms as the organisms are cleared from the blood. The second, “immune,” phase is most often characterized by the findings of aseptic meningitis and, in severe cases, liver damage (jaundice) and impaired kidney function. Serovar-specific immunity develops with infection.

Diagnosis is based on history of possible exposure, suggestive clinical signs, and a marked rise in IgM antibody titers. Occasionally, leptospiras are isolated from blood and urine cultures.

The treatment of choice is penicillin G. There is no significant antibiotic resistance. Prevention primarily involves avoiding contact with the contaminated environment. Doxycycline is effective in preventing the disease in exposed persons.

Anaerobic saprophytic spirochetes are prominent in the normal flora of the human mouth. These spirochetes participate in mixed anaerobic infections, such as infected human bites and stasis ulcers.