Spirochete Infections - Clinical Tree

Key Points

Human disease caused by spirochetes typically follows a clinical course that reflects three sequential phenomena: (1) early, local proliferation of the organisms at the site of introduction, (2) spirochetemia with systemic dissemination, and (3) persistence of small numbers of microbes at various, often immune, “privileged” sites.
Direct detection of pathogenic spirochetes is sometimes possible by microbiologic culture, microscopy, or genomic amplification, but diagnosis more often relies upon the demonstration of a patient’s serologic response to the offending agent.
Venereal syphilis is a historic sexually transmitted disease caused by Treponema pallidum subsp. pallidum and its incidence is rising, including neonatal syphilis.
In the early stages of disease, venereal syphilis may be diagnosed using direct microscopic visualization although today it is rarely performed.
Serologic detection of syphilis, by far the most common mode of diagnosis, comprises methods that semiquantitatively measure antibody to various lipoproteins, as well as methods that detect antibody to treponeme-specific antigens. Serologic testing algorithms may begin with a nontreponemal assay, or with a treponeme-specific assay (referred to as the reverse algorithm ).
Yaws, endemic syphilis (bejel), and pinta are not sexually transmitted, are endemic to various tropical and Middle Eastern regions, and are caused by T. pallidum subsp. pertenue, T. pallidum subsp. endemicum, and T. carateum , respectively.
Presumptive diagnosis of the endemic treponematoses can sometimes be made on the basis of clinical and epidemiologic data; however, as with venereal syphilis, serologic and direct microscopic techniques may prove useful.
The most common tickborne disease in North America and Europe, Lyme disease is caused chiefly by Borrelia burgdorferi sensu stricto, Borrelia garinii, and Borrelia afzelii.
Typical clinical manifestations of Lyme disease include erythema migrans (early localized disease), neuroborreliosis (early disseminated or late-stage disease), and/or Lyme arthritis (late-stage disease).
Because no single laboratory test performs sufficiently in all clinical scenarios, a diagnosis of Lyme disease must be based on a combination of (1) clinicoepidemiologic characteristics, (2) host serologic response (as measured by enzyme-linked immunosorbent assay/immunofluorescence assay and immunoblot), (3) molecular evidence, and/or (4) culture results.
Epidemic, louseborne relapsing fever has a worldwide distribution and is caused by Borrelia recurrentis.
Endemic, tickborne relapsing fever has a limited geographic distribution and is caused by several Borrelia spp., including Borrelia hermsi and Borrelia turicata.
Acute onset of high fever and constitutional symptoms followed by cycles of evanescence and recrudescence is frequently recognized in both forms of relapsing fever.
Diagnosis of relapsing fever is most often established through the demonstration of spirochetes in peripheral blood smears stained by a Giemsa technique.
One of the most common zoonotic diseases throughout the world, leptospirosis is caused by various serovars of different species within the genus Leptospira.
Although leptospirosis is usually subclinical or mild and flulike, a small proportion of patients develop severe symptoms related to gastrointestinal/hepatic disease, meningitis, renal failure, and/or myocarditis (also referred to as Weil disease).
Although Leptospira spp. can be cultivated in vitro, diagnosis is usually made by demonstrating seroconversion.
Brachyspira aalborgi and Brachyspira pilosicoli have been demonstrated in and isolated from the colon of humans with diarrheal disease, but their pathogenicity has not been firmly established.
Demonstration of spirochetes along the colonic epithelial cell borders using routine, immunohistochemical, or in situ hybridization microscopy from biopsy material is more commonly performed than cultivation or genomic amplification assays.

Acknowledgments

I gratefully acknowledge the contribution of P. Rocco LaSala, Michael Loeffelholz, Mike Smith, Gail Woods, and others who authored this chapter in previous editions.

I also acknowledge Bobbi Pritt, Elitza Theel, Blake Buchan, and Anne Paxon for permission to use the acute tickborne disease testing algorithm that they published in CAP Today ( ).

Spirochetes ( spiro, “coiled”; chaete, “hair”) are slender, spiral-shaped bacteria containing one or more complete rotations that form a helix. They are gram negative but can be visualized only by darkfield or phase microscopy, silver impregnation, and immunohistochemical stains in tissue sections. Flagella-like organelles called periplasmic fibrils or axial filaments are attached near the poles of the bacteria and permit a corkscrew-like motility. Many commensal and nonpathogenic species of spirochetes exist, and human disease is limited primarily to infection by members of three genera: Treponema, Borrelia, and Leptospira . Widely diverse from an epidemiologic standpoint, spirochetes within these genera demonstrate a number of pathogenic, and hence clinical, similarities upon acquisition by humans. Although Brachyspira spp. have been associated with gastrointestinal syndromes, definitive causation of disease by these bacteria has not been universally accepted.

Treponema

The genus Treponema contains two species responsible for disease in humans. Treponema pallidum is divided into three subspecies, each of which is the etiologic agent of a distinct clinical entity: subspecies pallidum, pertenue, and endemicum are the etiologic agents of venereal syphilis, yaws, and endemic syphilis (bejel), respectively. Pinta is caused by the second closely related species, Treponema carateum . Controversy exists even to this day concerning the origins of the sexually transmitted form of infection. Previously, the debate focused largely on deducing geographic regions of disease occurrence (e.g., Old World vs New World) based on morphologic skeletal abnormalities of excavated remains that were presumably a result of T. pallidum subsp. pallidum infection. Work utilizing phylogenetic molecular methods seems to support the “Columbian” theory (i.e., that a form of venereal infection was acquired during exploration of the New World and was subsequently introduced into Europe) ( ).

Classic Treponemal Disease

Syphilis

Description

T. pallidum subsp. pallidum, the etiologic agent of venereal syphilis, is a thin (0.2 μm) spirochete, 6 to 20 μm in length with 10 to 13 coils ( Fig. 61.1, A ). The disease appears to have spread rapidly throughout Europe during the 16th century, and its absence in the medical literature prior to this period suggests that the organism was brought from the New World.

Fig. 61.1, Electron photomicrographs of pathogenic spirochetes. A Two spiral-shaped Treponema pallidum bacteria (36,000×). B Leptospira interrogans strain RGA bound to a 0.2-μm filter.

Epidemiology

Man is the only natural reservoir for T. pallidum subsp. pallidum. Transmission occurs by direct contact with active lesions, largely through sexual contact. Vertical transmission across the placenta, the second most common mode of infection, may result when a latently infected female becomes pregnant or when a pregnant woman becomes infected ( ; ). Infection may also rarely be transmitted by nonsexual contact with an active lesion, by transfusion of fresh blood products from an infected person (although organisms do not survive >48 hours under typical blood bank storage conditions), by accidental needlestick, or when infectious specimens are handled in the laboratory.

The incidence of venereal syphilis in the United States declined dramatically with the advent of penicillin following World War II and remained stable until the mid-1980s, when the incidence began to increase once again, presumably as the result of increased intravenous drug use and sexual promiscuity. A continuous decline in infection rates was observed among women of childbearing age throughout the 1990s and was paralleled by a comparable decrease in the incidence of congenital syphilis. Following a nadir in disease incidence in 2000 that marked the lowest rate of syphilis in the United States during recorded history, the rate of primary and secondary syphilis has increased almost every year since 2013. In 2017, 30,644 cases of primary and secondary syphilis were reported, representing an increase of 76% compared to the number of cases in 2013, and yielding a rate of 9.5 cases/100,000 population compared to a rate of 5.3 cases /100,000 population in 2013 ( ). Similarly, after a steady decline from 2008 to 2012, since 2013 the national rate of congenital syphilis has increased each year from 9.2 cases/100,000 live births to 23.3 cases/100,000 live births, representing a 153% increase during 2013 to 2017 (more than doubled) ( Fig. 61.2 ). In 2017, 918 cases of congenital syphilis were reported, including 64 syphilitic stillbirths and 13 infant deaths. The increase in congenital syphilis rate reflects the increase in primary and secondary syphilis among all women, including reproductive-age women during 2013 to 2017 (increase in rates were 155.6% and 142.8%, respectively) ( ).

Fig. 61.2, Congenital syphilis. Reported cases by year of birth and rates of reported cases of primary and secondary syphilis among women aged 15–44 years, United States, 2008–2017. CS, Congenital syphilis; P, primary syphilis; S, secondary syphilis.

Pathogenesis and Pathology

T. pallidum subsp. pallidum penetrates an intact mucous membrane or gains access to tissue through abraded skin, multiplies at the inoculation site, and then enters the lymphatic and circulatory system and spreads throughout the body. For the intradermal inoculation in humans, the 50% infectious dose has been calculated to be 57 organisms ( ). Clinical lesions appear when a critical mass of organisms is reached locally (≈10 ⁷ spirochetes); therefore the incubation period is directly related to the size of the initial inoculum with the mean incubation period in humans of ∼21 days, it rarely exceeds 6 weeks ( ).

The host immunologic response to T. pallidum subsp. pallidum is influenced by the structure of the bacterium. The outer membrane is a phospholipid bilayer that lacks lipopolysaccharide and has few demonstrable protein antigens. The lack of exposed outer membrane proteins as well as the presence of antigenetically unique organisms within T. pallidum subsp. pallidum populations are key factors in the organism’s ability to evade opsonization and clearance by macrophages ( ).

This delayed and attenuated immune response allows T. pallidum subsp. pallidum to disseminate and to produce a chronic infection. The course of syphilis can be divided into predictable stages. Its primary stage, the development of a chancre, occurs at a median of 3 weeks postinoculation, although a primary lesion may not develop in all patients. Additionally, because of its painless nature, the lesion may go unnoticed in a proportion of cases. Upon healing within 2 to 8 weeks, the chancre gives rise to the secondary stage. Typically manifesting about 6 weeks after inoculation (range, 2–12 weeks), this stage is characterized by widespread dissemination of spirochetes via the bloodstream and the development of mucocutaneous and organ involvement with the presence of constitutional symptoms. Upon resolution of the secondary stage, the infection enters a period of latency, during which time the patient exhibits minimal manifestations of infection. The first year of this stage, termed the early latent period, may be characterized by occasional relapses, whereas relapse is not common during the late latent period. Following a period of 10 to 25 years, approximately one-third of untreated patients develop tertiary syphilis, the most serious manifestations of which involve the cardiovascular system or the central nervous system (CNS).

Whatever organ is involved or whatever stage of the disease is reached, the histologic hallmark of syphilis is obliterative endarteritis, demonstrating concentric endothelial and fibroblastic proliferations with an associated mononuclear cell infiltrate rich in plasma cells ( Fig. 61.3, A ). Endarteritis results from the binding of spirochetes to endothelial cells via fibronectin molecules that have attached to the surface of the bacteria ( ). Treponemes may be demonstrable in tissues with silver impregnation (see Fig. 61.3, B ) and immunohistochemical stains, particularly during the first and second stages of disease ( ). With progression, both the plasma cell infiltrate and the concentration of treponemes lessen in intensity. Although commonplace in the pretreatment era, syphilitic gummas, or large visceral necrotizing granulomas, develop as tertiary-stage manifestations but are now rarely seen ( ).

Fig. 61.3, Histologic photomicrographs of a secondary syphilis case. A Superficial dermis showing a dense, perivascular lymphomononuclear infiltrate containing many plasma cells (arrows) (hematoxylin & eosin [H&E], ≈400×), which was confirmed in B to contain numerous argyrophilic spirochetes (arrows) (Steiner silver impregnation technique, 400×). Patient was subsequently shown to have a high rapid plasma reagin (RPR) titer.

Elucidation of the complete genomic sequence of T. pallidum subsp. pallidum has provided insight into the pathogenesis and molecular epidemiology of this organism. Molecular typing tools have identified geographically specific strains ( ). The 12-member T. pallidum repeat (Tpr) gene family displays similarities to variable outer membrane antigens of other spirochetes. One member, TprK , contains a discrete variable region that could undergo an antigenic variation resulting in avoiding the immune surveillance of the host ( ).

Clinical Manifestations

Syphilis is a chronic infection with a multiplicity of expressions, primarily related to the stage at which it manifests. The primary chancre is characteristically ulcerated with raised, firm edges and a smooth base and is notable for absence of an exudate or pain ( Fig. 61.4, A ). Although these are typically solitary, multiple chancres can occur in up to one-third of patients. Patients with previous infection can present with atypical lesions, such as a small papule, or may not develop a lesion at all. Regional lymphadenopathy, with moderately enlarged, rubbery, nonsuppurative lymph nodes, is seen in some patients.

Dissemination marks the secondary stage, and patients present with signs and symptoms of a systemic illness. More than 90% develop a rash that begins on the trunk and extremities (although any body surface can be involved) as small macules that progress to papules, and in some patients to pustules, over a period of weeks. The appearance of the rash on the palms and soles is characteristic (see Fig. 61.4, B ), and enlargement and coalescence of papules produce the pale plaques of condyloma lata (see Fig. 61.4, C ). Approximately 90% of patients also exhibit generalized lymphadenopathy, and as many as three-fourths may suffer fever, malaise, anorexia, arthralgia, pharyngitis, and weight loss. Mucous patches are seen in up to one-third of cases. About 40% of persons develop CNS symptoms during this stage, particularly among those coinfected with human immunodeficiency virus (HIV), although only 1% to 2% present with acute meningitis ( ; ). The remainder may experience headache and meningismus, uveitis, sensorineural hearing loss, and cranial nerve involvement.

The tissue destruction of tertiary syphilis usually becomes evident decades after the primary infection. Cardiovascular syphilis occurs as a result of weakening of the tunica media and results in an aneurysm of the ascending aorta with aortic valve insufficiency and narrowing of the coronary artery ostia. Syphilitic gummas may involve the skin, brain, skeletal system, or mucocutaneous tissues, although any organ can be affected. Both cardiovascular syphilis and syphilitic gummas became much less frequent after the advent of antibiotic treatment. Meningovascular syphilis occurs 5 to 10 years after initial infection and clinically presents as seizures, stroke, and aphasia. Multiple small infarcts due to endarteritis in the CNS are the cause of this form. Parenchymatous neurosyphilis, which presents 15 to 30 years after initial infection, is a degenerative process with loss of neurons and myelinated tracts resulting in a complex of neurologic and psychiatric manifestations, including general paresis, tabes dorsalis, and pupillary abnormalities. Some patients lack clinical signs or symptoms altogether but demonstrate cerebrospinal fluid (CSF) abnormalities such as pleocytosis, increased protein, a reactive Venereal Disease Research Laboratory (VDRL) test, or antibody against T. pallidum indicating CNS infection.

Congenital syphilis occurs clinically as two forms: an early or infantile form (<2 years of age) and a late form following a period of latency (few years to several decades). Although transplacental passage of spirochetes can occur during any trimester, congenital acquisition during early gestational age results in stillbirth more often than does acquisition during late gestation or parturition ( ). As may be expected, congenital transmission is more frequent during the primary, secondary, and early latent periods of maternal infection ( ). Necrotizing funisitis, or inflammation of the umbilical cord, is characteristic of congenital syphilis, although it is typically present in only the most severe cases. In the infantile form, a diffuse rash with sloughing of the skin, osteochondritis, and periostitis are characteristic; however, affected newborns may be asymptomatic ( ). Diffuse fibrosis of the liver (hepar lobatum) and lung (pneumonia alba) is also seen. After a latent period, the late form presents in childhood or adulthood with a wide variety of signs and symptoms; however, the triad of interstitial keratitis, Hutchinson teeth, and eighth nerve deafness is classic. Periostitis, saber shins, and saddle deformity of the nose are also seen frequently.

Syphilis and HIV infection are increasingly seen as coinfections because these diseases share common risk factors and may even potentiate one another. Through several mechanisms, syphilis increases the risk for acquisition and transmission of HIV. The disrupted mucosal barrier at the chancre can facilitate HIV infection and transmission. The inflow of host immune cells to the site of syphilis infection increases the number of targets available for HIV infection. In addition, recruited monocytes express increased amounts of the HIV coreceptor CCR5 ( ). While the clinical presentation of syphilis in HIV-infected persons is usually similar to that in individuals without HIV, cases of more severe primary and secondary lesions, as well as unusual presentations, have been reported ( ). Patients with AIDS have a high incidence of eye involvement, with anterior uveitis being the most common manifestation of T. pallidum infection in this setting ( ). HIV infection status may affect laboratory tests for syphilis, and vice versa. Early syphilis infection is associated with an increase in plasma HIV viral load and a decrease in the CD4 cell count ( ). A multicenter prospective study showed that CSF nontreponemal tests were more likely to remain positive (“serofast”) following syphilis therapy in HIV-infected individuals than in HIV-uninfected patients ( ). It remains to be seen, however, if such laboratory evidence of treatment failure is a true reflection of potential clinical relapse. What does seem clear, as evidenced by multiple studies, is that anti-HIV therapy itself improves the likelihood of serologic response following syphilis treatment in HIV-positive patients ( ; ).

Yaws

Yaws (also called frambesia tropica, pian, parangi, paru, buba, or bouba ) is a chronic disease caused by T. pallidum subsp. pertenue and is the most prevalent of the nonvenereal treponematoses. This disease, which has afflicted residents of the tropics since antiquity, is common in rural areas of tropical countries with heavy rainfall. After a decline in the 1950s due to large campaigns to control the treponematoses, the incidence of yaws has increased in some areas. Following a massive azithromycin campaign during the past several years, there is an apparent lack of recent publications about yaws. However, it is not clear whether yaws transmission was actually interrupted; therefore more information is needed ( ).

Yaws is contracted chiefly during childhood by direct contact, with breaks in the skin allowing entry of treponemes. Early lesions generally appear about 3 weeks later but may not develop for months. One or several papules appear, most frequently on the lower extremities, and then ulcerate or progress to papillomatous lesions. Numerous treponemes are found in these lesions. Spontaneous resolution is usual; however, relapses preceded by malaise, fever, and generalized lymphadenopathy followed by disseminated skin lesions are common. Most patients enter a period of latency during which no clinical signs or symptoms are evident. For most, the disease shows no additional manifestations; however, the destructive lesions of tertiary yaws were previously reported to occur in up to 10% of untreated patients and they involve irreversible, destructive lesions of bone, cartilage, soft tissue, and the skin, which is the most commonly affected. However, the destructive lesions of tertiary yaws are now rarely seen ( ). Cardiovascular and CNS lesions similar to those seen in syphilis, although rare, have been reported to occur ( ; ).

Endemic Syphilis

Endemic syphilis (bejel) is a nonvenereal chronic infection caused by infection with T. pallidum subsp. endemicum. The disease is ancient and, although no longer as widespread as it once was, still occurs in the Middle East and Africa in hot, dry climates. Because no recent data are available for the endemic syphilis (the most recent World Health Organization [WHO] global estimate was in 1995), the prevalence of the disease is unknown ( ). Endemic syphilis is transmitted by direct contact with active lesions, contaminated fingers, and eating or drinking utensils. Crowded living conditions and poor hygiene are common associated factors. Children 2 to 15 years of age are primarily infected, although the disease can be found in adults in the same family, and those adults who did not suffer from the disease in childhood can be infected by their children. The inoculum is small, and the primary lesions of early endemic syphilis, most frequent on the oropharyngeal mucosa, often are not apparent. Initial clinical manifestations of the disease are usually seen in a secondary stage, with mucous patches, condyloma lata, angular stomatitis, generalized lymphadenopathy, and painful osteoperiostitis. This is followed by a latent period of variable length. The late stage is characterized by tissue destruction of the skin, bones, and cartilage, with a predilection for the nose and palate (so-called gangosa ), and sometimes laryngeal involvement.

Pinta

Pinta (carate, mal de pinto, azul) is caused by infection with T. carateum . The disease is endemic in rural tropical Central America and northern South America, where it is found rarely and only in remote villages ( ). Since no recent data are available, the prevalence of the disease is unknown ( ). Children younger than 5 years of age are primarily infected. Inoculation is thought to occur via nonvenereal skin or mucous membrane contact. Characterization of the pathogenesis of the disease is difficult because, unlike other treponematoses that are pathogenic in humans, an animal model is unavailable and the treponeme cannot be cultured continuously. A primary papule or plaque develops at the site of inoculation after weeks to months, with or without localized lymphadenopathy. The primary lesion resolves, and several months to years later, disseminated secondary lesions, or pintids, which resemble scaly psoriasiform plaques, appear and remain for long periods or resolve and recur. In late pinta, lesions demonstrate hypopigmentation and skin atrophy or hyperkeratosis, which can persist for life. The skin appears to be the only organ affected in this disease ( ).

Laboratory Diagnosis of Treponematoses

Because the etiologic agents of the human treponematoses cannot be isolated easily by routine culture methods, testing for disease generally is completed directly by visualization of the organisms in material from lesions or indirectly by immunologic methods. Consequently, different stages of the treponematoses often require a particular testing modality. In the early stages when lesions are present, highly specific microscopic techniques are used. Upon resolution of lesions, a variety of serologic tests are employed for diagnosis. It is important to remember that none of these laboratory tests is capable of distinguishing between the closely related species and subspecies of pathogenic treponemes, so differentiating between them requires clinical, epidemiologic, and, when possible, genomic information ( ).

Darkfield Microscopy

When direct sampling of lesions is possible, such as in primary, secondary, or early congenital syphilis (chancres, mucous patches, or condyloma lata), the lesion should be cleansed with sterile water (no soap or antiseptic) and gently abraded. Pressure is applied, causing serous exudate to collect in the lesion. A drop of the fluid is placed on a slide, and a coverslip is placed over the fluid. The specimen must be examined within ∼20 minutes, as visualization of motility is necessary for definitive identification. Because of their narrow width, treponemes cannot be visualized by conventional light microscopy. Instead, darkfield microscopy is necessary. This technique makes use of a patch stop, which creates the microscopist’s “dark field,” and a condenser lens that targets the spirochetes with light waves at an oblique angle, some of which are scattered into the objective, giving the appearance of bright organisms in a dark background ( Fig. 61.5, A ). The darkfield examination can be positive several weeks before a positive serologic test and has a sensitivity of 80% in diagnosing syphilis ( ). Highly skilled microscopists are required to avoid false positives. Because of possible confusion with commensal treponemes in the mouth, however, it is not recommended that this technique be utilized for oral lesions. Additionally, three Treponema spp. that are normal inhabitants of the genital region ( T. phagedenis, T. refringens, and T. minutum ) could potentially be confused with T. pallidum on darkfield examination. Careful cleaning of the area is important in reducing the likelihood of this occurrence. The characteristic motility of T. pallidum is an important feature that distinguishes it from saprophytic spirochetes.

Immunohistochemical Microscopy

Monoclonal and polyclonal antibodies with specificities for spirochetes, treponemes, or T. pallidum have been used by pathologists for detection in paraffin-embedded tissues ( ). With this technique, antitreponemal antibodies bound to spirochetes in tissue sections are detected after a series of immunologic reactions typically consisting of a primary, biotinylated antibody conjugate with organism specificity followed by an enzyme-conjugated streptavidin complex. After development of the enzyme with an appropriate chromogenic substrate, organisms are highlighted against a pale counterstained background. This allows for easy detection of rare bacteria and affords the capability for histologic localization. The procedure reportedly offers improvement in sensitivity and specificity over silver impregnation stains for the detection of treponemes, but this is largely dependent upon the source of primary antibody.

Nontreponemal Serologic Tests

The nontreponemal assays detect antibodies to lipoprotein material and cardiolipin released from cells damaged by treponemes. As a consequence, they are not specific for Treponema . These tests have been used traditionally to screen for syphilis and to monitor the course of the disease after treatment. Standard tests include the VDRL, manual rapid plasma reagin (RPR), unheated serum reagin (USR), and toluidine red unheated serum (TRUST). All these tests use a phospholipid antigen, some fortified with lecithin and cholesterol. Flocculation is the endpoint for the manual standard tests, whereas absorbance values are calculated spectrophotometrically in the enzyme-linked immunosorbent assay (ELISA). Serum is the preferred specimen for each. Heating of the serum to eliminate nonspecific reactions is required in the VDRL, whereas the addition of choline chloride to the RPR and USR eliminates the need for heating, making these popular choices among diagnostic laboratories. Antibody-antigen reactions in the VDRL and USR are assessed using a microscope at 100×, and the addition of charcoal to the RPR and dye to the TRUST makes the reactions macroscopically visible ( Fig. 61.6 ).

Fig. 61.6, Rapid plasmin reagin test card showing nonreactive, weakly reactive, and strongly reactive serum samples (wells 1 to 3) with their respective agglutination patterns.

In April 2019, the US Food and Drug Administration (FDA) cleared another fully automated system, the AIX1000 (Gold Standard Diagnostics, Davis, CA), for nontreponemal RPR testing. The AIX1000 automates the processing, analysis, result interpretation, and archiving of RPR screens and semiquantitative titers. This methodology reduces variation associated with manual testing and interpretation, and the images of each RPR result are stored digitally and are retrievable for review ( ).

Antibodies detected by the nontreponemal tests generally develop 1 to 4 weeks after the appearance of the primary chancre. The time at which the specimen is taken during the primary stage therefore will affect assay sensitivity. The titer rises, remains high during the first year of infection, and then gradually declines. The tests will ultimately revert to negative in most patients in the absence of therapy, particularly during the late latent stage. Thus these tests are general markers of disease activity. False-negative nontreponemal tests may also be associated with very high titers of antibody (prozone phenomenon), which are seen most commonly in secondary syphilis. This condition is easily resolved by diluting the specimen prior to testing. False-positive results may occur with acute illnesses such as hepatitis, other viral infections, pregnancy; or chronically with the connective tissue diseases ( ; ).

Standard nontreponemal tests afford the capability of semiquantitative reporting by testing serial twofold specimen dilutions (i.e., titers). Follow-up titers are used to determine the efficacy of treatment, with a fourfold decrease in titer considered an adequate response ( ). Follow-up testing by the same method is necessary because titers between different nontreponemal tests cannot be directly compared. Patients treated in early syphilis are more likely to revert to negative than those treated in late syphilis ( ). In a small minority of patients, nontreponemal tests will remain positive despite adequate therapy—a situation known as the serofast response .

Reports have documented various aberrant nontreponemal test results with patients coinfected with HIV and syphilis, including delayed seroconversion; however, seronegative syphilis does not appear to be prevalent in AIDS patients ( ). The false-positive rate is reportedly increased in AIDS patients (4% vs 1% in non-AIDS); however, the increased rate of positivity may be associated with intravenous drug abuse rather than HIV infection itself ( ; ; ). False-negative results also occur in AIDS patients with syphilis because of an exaggerated nontreponemal antibody response that occurs in some patients, with the resultant prozone effect ( ). Furthermore, as mentioned previously, a small number of AIDS patients may experience minimal to no decline in nontreponemal antibody titers despite presumably adequate therapy, although this may be related to the stage at which treatment was initiated rather than HIV coinfection ( ). The sensitivity of nontreponemal tests varies based on the disease stage. During primary, secondary, latent, and late syphilis, sensitivity is approximately 75% to 88%, 100%, 88% to 100%, and 71% to 73%, respectively. Specificity varies based on population but is usually greater than 96% ( Table 61.1 ).

TABLE 61.1

Sensitivities of Serologic Tests for Syphilis in Different Stages of Disease

Data from: Larsen SA, Steiner BM, Rudolph AH: Laboratory diagnosis and interpretation of tests for syphilis, Clin Microbiol Rev 8:1, 1995; Sena AC, White BL, Sparling PF: Novel Treponema pallidum serologic tests: a paradigm shift in syphilis screening for the 21st century, Clin Infect Dis 51:700, 2010; Park IU, Fakile YF, Chow JM, et al: Performance of treponemal tests for the diagnosis of syphilis, Clin Infect Dis 68(6):913, 2019.

Test	STATE OF SYPHILIS, % SENSITIVITY (RANGE)					% Specificity (Range)
Test	Primary		Secondary	Latent	Late	% Specificity (Range)
Nontreponemal
VDRL		78 (74-87)	100	95 (88-100)	71 (37-94)	98 (96-99)
RPR		86 (77-100)	100	98 (95-100)	73	98 (93-99)
Treponemal
FTA-ABS		84 (70-100)	100	100	96	97 (94-100)
MHA-TP		76 (69-90)	100	97 (97-100)	94	99 (98-100)
TPPA		88 (86-100)	100	100	NA	96 (95-100)
IgG ELISA		100	100	100	NA	100
CLIA		98	100	100	100	99
Centaur CIA		94.5	100	100	94.1	95.5 (93.0-97.3)
Trep-Sure EIA		94.5	100	100	98.5	82.6 (78.4-86.1)
LIAISON CIA		96.4	100	97.6	92.6	94.5 (91.8-96.5)
Bioplex MBIA		96.4	100	95.1	94.1	96.7 (94.4-98.2)
INNO-LIA		96.4	100	100	91.1	98.5 (96.8-99.5)

CLIA, Chemiluminescent immunoassay; EIA, enzyme immunoassay; ELISA, enzyme-linked immunosorbent assay; FTA-ABS, fluorescent treponemal antibody absorption; MBIA, microbead immunoassay; MHA-TP, microhemagglutination assay for antibodies to Treponema pallidum ; NA, not available; RPR, rapid plasma reagin; TPPA, T. pallidum particle agglutination; VDRL, Venereal Disease Research Laboratory.

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