LECTURE 5
ETIOLOGY, PATHOGENESIS, GENERAL MOTION OF SYPHILIS. IMMUNITY. PRIMARY SYPHILIS. SECONDARY SYPHILIS. TREATMENT OF SYPHILIS.
SYPHILIS – a chronic infectious disease that occurs when the pale treponema infection. Infection occurs primarily through sex, but can be transmitted transplacentally (congenital syphilis) by household contacts (household syphilis), and transfusion of blood (blood transfusion path).
Etiology.
The causative agent of syphilis is a pale treponema (Treponema pallidum), belonging to the order Spirochaetales, family Spirochaetaceae, genus Treponema. Morphologically pale treponema (treponema pallidum) differs from Spirochetae buccalis, Sp. refringens, Sp. balanitidis, Sp.pseudopallida. Under the microscope pale treponema is a spiral organism that resembles a corkscrew. It has an average of 8-14 uniform curls of equal value. The total length of treponemes ranging from 7 to 14 mm, thickness – 0,2-0,5 mm. For the pale treponema marked mobility is typical. She characterized by progressive, rocking, pendulum, and the contractile An underground (its axis) motion. Electron microscopy revealed a complex structure of the morphological structure of the pale treponema. It turned out that the treponema covered with a thick covering of three-layer membrane, cell wall and Muko-poly-saccharide capsule-shaped substance. Under the cytoplasmic membrane are fibrils – thin filaments, which have a complex structure and conditional diverse movement. Fibrils are attached to the terminal coils and the individual sections of the cytoplasmic cylinder with blefaroplastis. The cytoplasm is finely granular, in it are nuclear vacuole, nucleolus and mesosoma. Found that the influence of various exogenous and endogenous factors (in particular, the previously used arsenic preparations, and now – antibiotics) had an impact on the pale treponema, changing some of its biological properties. Thus, it appears that pale treponema can turn into cysts, spores, L-shape, grain, which while reducing the activity of immune reserves patient can reverse the spiral of virulent species and cause akgivnye manifestations of the disease. Antigenic mosaic of pale treponemes proved the presence in serum of patients with syphilis of multiple antibodies: protein, complement-, polysaccharide, reagin, agglutinins, lipid, etc.
Using an electron microscope revealed that pale treponema in the lesions most often located in the intercellular clefts, peri-endothelial space of blood vessels, nerve fibers, especially in early forms of syphilis. Being pale treponemes in peri-epineurium is not yet evidence of nervous system disease. Most such an abundance of treponemes occurs with symptoms of septicemia. In the process of phagocytosis is often a condition of endotsitobiosis, where treponemes in leukocytes are in a poly-membrane phagosome. The conclusion of treponemes in polimembrane phagosome – a phenomenon very unfavorable, as in a state of endotsitobiosis, pale treponema long remain protected from the effects of antibodies and antibiotics. At the same time the cell, which formed a phagosome, as if to protect the body against infection and disease progression. This delicate balance can be maintained for a long time, describing the latent (hidden) during syphilitic infection.
Upon infection, syphilis, can be asymptomatic (with the patient in the L-forms pale treponemes) and “accidental” discovery of infection in the stage of latent syphilis (lues latens seropositiva, lues ignorata), ie, during the presence of treponemes in the body, probably in the form of cyst-forms, which have antigenic properties and, consequently, lead to the production of antibodies, and this is confirmed by positive serology reactions for syphilis in blood of patients with no visible clinical signs of disease. In addition, some patients show a stage of neuro-and viscero-syphilis, ie, the disease develops as a “bypass” the active form.
To get culture of pale treponemes required complex conditions (special medium under anaerobic conditions, etc.). However, the culture treponema quickly lose morphological and pathogenic properties. In addition to these forms of treponemes, it was assumed the existence of granular and filterable forms of invisible pale treponemes.
Outside of the organism pale treponema is very sensitive to external influences, chemicals, drying, heating, and the effect of sunlight. At the household goods stores pale treponema its virulence to dry. Temperature 40-42 ° C increases the activity of treponemes first, and then leads to their death; heating to 60 ° C kills them within 15 min., And up to 100 ° C, – immediately. Low temperatures do not have a harmful effect on the pale treponemu, and is now deposited treponemes in the absence of oxygen at temperatures from -20 to -70 ° C or dried from the frozen state is a common method to keep the pathogenic strains.
Conditions and ways of infected syphilis.
The causative agent of syphilis – pale treponema – enters into the body through broken skin or mucous membranes. The entrance gates, through which enters the agent of syphilis, may be so insignificant that the interviewers go unnoticed. A patient with syphilis is contagious to others, especially during the presence of his active manifestations of infection on the surface of which is pale treponema “washed out” with the serum from the depth of tissue due to friction (walking), frictions (during intercourse), irritation (mechanical or chemical) as well as food (in case a syphilitic papules in the mouth).
Currently, the main route of infection with syphilis should be acknowledged sexual contact with a healthy patient, cases of domestic infection (when using common utensils, cigarettes, pipes, etc.) are rare. The non-sexual infection can occur if the patient in the mouth are erosionary syphilitic elements. Much less frequently observed in cases where the treponema found in the discharge of syphilitic elements fall on the household items that become an intermediary in the transmission of infection (treponemes in a wet environment for a long time can survive outside the body). Doctors and other medical personnel can become infected when viewed from a patient with syphilis or during medical procedures. Such cases were observed among midwives, doctors, surgeons, obstetricians and gynecologists, dentists, Venereologists, laboratory staff who conducted the study on the pale treponema. To avoid such exposure is necessary to work with the patient in the gloves to monitor the integrity of the skin brush, and after examination of the patient (especially with contagious stage of syphilis), hand disinfectants wipe solution and wash them with soap and water.
Very rare cases of syphilis in the direct transfusion (transfusion) of blood from a patient with syphilis donor. It is believed that the saliva of the patient is contagious because of the presence in her pale treponemes only if the patient in the oral cavity are syphilitic elements. It is supposed infectiousness of milk lactating women, patients with syphilis, even in the nipple is not visible syphilitic changes.
Just treat the question of the infectiousness of semen, despite the absence of symptoms of the disease on the genitals of patients with active syphilis. At the same time believe that the urine and sweat of patients with syphilis is not contagious. One of the possible ways of transmission of syphilis infection is a placenta from a sick mother to fetus through the placenta. As a result, may develop congenital syphilis.
It was established experimentally that the development of syphilitic infection plays a role of the agent introduced into the organism of experimental animals. We can assume that in humans it has a certain value (which is why the persons who are repeatedly in sexual contact with the patient the active form of syphilis, the possibility of infection is greatly increased compared with those who had a one-time and short-term sexual relationship). However, the lack of criteria infection causes Venereologists conduct preventive treatment for all persons who had sexual contact with a sick form of infectious syphilis, as well as to those persons (particularly children) who were in close household contact.
PRIMARY SYPHILIS
The mouth, perhaps surprisingly, is rarely the site of primary syphilis, and because of its transient nature, the oral ulceration of primary syphilis often goes unnoticed by the patient or by any unsuspicious clinician. In addition, albeit rarely, the lesions of primary disease may be confused with other pre-existing mucocutaneous disease. A chancre develops within 1 to 3 weeks of acquisition. Primary syphilis is usually the consequence of orogenital or oroanal contact with an infectious lesion. Kissing may, very rarely, cause transmission; indeed, it has been suggested that intrafamilial oral acquisition of syphilis in a child may have occurred via this route, although more usually oral syphilis in a child is indicative of sexual abuse.
Primary syphilis of the mouth manifests as a solitary ulcer usually of the lip or, more rarely, the tongue. The upper lip is more commonly affected than the lower in males, while the opposite occurs in females—probably reflecting the anatomy involved with fellatio and cunninlingus. The pharynx or tonsils may rarely be affected. The ulceration is usually deep, with a red, purple, or brown base and an irregular raised border. There is usually an accompanying cervical lymphadenopathy. The ulceration of primary syphilis may be confused with other solitary ulcerative disorders, most notably traumatic ulceration, squamous cell carcinoma, and non-Hodgkin’s lymphoma.
The diagnosis of primary syphilis may be aided by detailed analysis of the sexual and/or social lifestyles of the patient and of any of the available sexual partner; however, often the diagnosis of early disease can be difficult. Affected patients often do not have a positive nonspecific reaginic test, eg, Rapid Plasma Reagin (RPR) or Venereal Disease Reference Laboratory (VDRL) tests. The specific tests for IgG antibodies to T. pallidum become positive before the reaginic tests, and thus should be carried out when the nonspecific tests prove negative but a diagnosis of primary disease is still likely.
Treponemes are present in primary lesions and can be detected by dark field microscopy; however, this test is fraught with the risk of nosocomial transmission and is thus no longer considered suitable. In addition, there can be confusion between the spirochetes of T. pallidum with the normal commensals of the mouth.
Histopathology is not always helpful, as there are no specific histopathological features, and the detection of T. pallidum with Warthin-Starry stain or silver nitrate stain may not be possible. Monoclonal anthodyl immunoperoxidase staining techniques can detect T. pallidum and is a relatively routine clinical investigation of biopsy material. However, molecular methods such as in situ and tissue PCR still remain nonroutine investigations for all types of syphilis. The tests used to detect IgM antibodies to T. pallidum may detect early infection.
SECONDARY SYPHILIS
The features of secondary syphilis reflect the hematogenous spread of T. pallidum, and similarly to its other mucocutaneous features, the oral manifestations of secondary syphilis can be more extensive and/or variable than those of the primary disease. Oral lesions arise in at least 30% of patients with secondary syphilis, although very rarely oral ulceration may be the only manifestation of infection. The 2 principal oral features of secondary syphilis are mucous patches and maculopapular lesions, although nodular lesions may rarely arise.
MACULOPAPULAR LESIONS
· Macular syphilides: Macular lesions tend to arise on the hard palate and manifest as flat-to-slightly raised, firm, red lesions.16
· Papular syphilides: These are rare. They manifest as red, raised, firm round nodules with a grey center that may ulcerate. The papules usually arise on the buccal mucosa or commissures.17
· Mucous patches: A variety of descriptions of mucous patches have been reported, but in general these manifest as oval-to-crescenteric erosions or shallow ulcers of about 1 cm diameter, covered by a grey mucoid exudate and with an erythematous border.16 The patches usually arise bilaterally on the mobile surfaces of the mouth,18 although the pharynx, gingivae, tonsils, and very rarely the hard palate can be affected.19 At the commissures, the mucous patches may appear as split papules, while on the distal and lateral aspects of the tongue, they tend to ulcerate or manifest as irregular fissures. The mucous patches may coalesce to give rise to, or arise de novo as, serpiginous lesions, sometimes termed snail track ulcers.19-22
ULCERONODULAR DISEASE (LUES MALIGNA)
Ulceronodular disease is an explosive generalized form of secondary syphilis characterized by fever, headache, and myalgia, followed by a papulopustular eruption that rapidly transforms into necrotic, sharply demarcated ulcers with hemorrhagic brown crusts, organized in rupioid layers commonly on the face and scalp. The mucosa is involved in about one third of affected patients. Lues maligna gives rise to crateriform or shallow ulcers on the gingivae, palate or buccal mucosa, with multiple erosions on the hard and soft palates, tongue and lower lip.
NODULAR DISEASE
Rarely, secondary syphilis can manifest as nodules alone. This nodular eruption of syphilis has a predilection for the face, mucous membranes, palms of the hands and soles of the feet. Lesions may occur on the vermillion, mimicking squamous cell carcinoma or keratoacanthoma.
DETECTION OF INFECTION IN SECONDARY DISEASE
Treponema pallidum can usually be detected on the surface of erosions or ulcers by darkfield microscopy, although as noted above, this test should be avoided. The patient will have positive serological tests.
The histopathological features of secondary syphilis are variable. Often the changes are nonspecific, although they may include perivascular infiltrates with a preponderance of plasma cells and epidermal psoriasiform hyperplasia. Warthin-Starry strains will only detect spirochetes in about a third of instances, although newer methods may increase the in situ detection of the causative agent.
OUTCOMES OF THERAPY
The lesions of secondary syphilis will resolve spontaneously within 3 to 12 weeks, regardless of therapy, and about 25% of untreated patients will have recurrence of secondary disease.
LATENT SYPHILIS
In early latent syphilis, usually the first 12 months after secondary disease, affected patients are infectious. In late latent syphilis the infectivity falls.
TERTIARY SYPHILIS
Clinical disease arises in about one third of patients with untreated secondary syphilis. The oral complications of tertiary syphilis center upon gumma formation, and much more rarely, syphilitic leukoplakia (and risk of oral squamous cell carcinoma) and neurosyphilis.
GUMMA FORMATION
Gummas tend to arise on the hard palate and tongue, although very rarely they may occur on the soft palate, lower alveolus, and parotid gland. A gumma manifests initially as 1 or more painless swelling. When multiple, they tend to coalesce, giving rise to serpigninous lesions. The swellings eventually develop into areas of ulceration, with areas of breakdown and healing. There may be eventual bone destruction, palatal perforation, and oro-nasal fistula formation. Rarely, a gumma may erode into blood vessels—eg, the inferior alveolar artery. Gumma manifests radiologically as ill-defined radiolucencies that may resemble malignancy. The areas of ulceration eventually heal, although the resultant scarring can, at least on the tongue, cause fissuring.
SYPHILITIC LEUKOPLAKIA AND RISK OF SQUAMOUS CELL CARCINOMA
Syphilitic leukoplakia would appear to be a homogenous white patch affecting large areas of the dorsum of the tongue. There are few good descriptions of syphilitic leukoplakia, and it is unclear whether this lesion truly reflects syphilis, or more likely a tobacco smoking habit—indeed this was observed by Hutchinson in the 19th century.
An association between tertiary syphilis and oral squamous cell carcinoma—particularly of the tongue—has been suggested for many years. Both clinically- and serologically-based studies have suggested an increased prevalence of syphilis in patient groups with squamous cell carcinoma of the tongue (up to 60% in one study), the association being stronger in males than females. A relatively recent study of 16,420 people with syphilis resident in the US found a significantly raised frequency of cancer of the tongue (and Kaposi’s sarcoma) in males.A noncontrolled study found that 5 of 63 UK patients with squamous cell carcinoma of the tongue had serological evidence of past syphilis as detected by both specific and nonspecific tests. However, it remains unclear whether any risk of oral squamous cell carcinoma in syphilis is a direct consequence of infection (which seems unlikely) or is the effect of recognized causative factors for oral malignancy, ie, tobacco, alcohol, and malnourishment.
NEUROSYPHILIS
Aside from the well-recognized Argyll Robertson pupil, tertiary syphilis can give rise to both unilateral and bilateral trigeminal neuropathy and facial nerve palsy. Potentially, syphilitic osteomyelitis may give rise to trigeminal neuropathy.
DETECTION OF INFECTION IN TERTIARY DISEASE
Gummas are characterized histopathologically by endarteritis obliterans, necrosis with epithelioid and giant cells and a plasma cell infiltrate. Spirochetes are difficult to detect. In tertiary disease, the nonspecific tests may not be positive; the most reliable test is FTA, although this may remain positive even after successful therapy.
INTERACTIONS BETWEEN HIV AND SYPHILIS
According to WHO, Brazil had about 660,000 people living with human immunodeficiency virus (HIV) at the end of 2003, and 15,000 people had died of AIDS during that year. Heterosexual transmission, sex between men, and injecting drug users (IDU) continue to be almost equally responsible for the burden of HIV infection. However, the HIV epidemic in Brazil has changed over the last decade, with IDU being responsible for almost 30% of all HIV cases.
Strong evidence supports several biologic mechanisms through which sexually transmitted diseases (STDs) facilitate HIV transmission by increasing both HIV infectiousness and HIV susceptibility. Thus, the detection of STDs and the establishment of effective treatment is an important strategy of HIV control.
INFLUENCE OF HIV DISEASE UPON SYPHILIS
It was initially suggested that concurrent HIV infection and syphilis is not uncommon, particularly in young adults, men having sex with men, and traders of commercial sex. HIV disease might significantly influence the clinical source of syphilis, as it does for some STDs and other conditions related to HIV-associated immune deficiency, and the associated infection is often more aggressive than the mono-infection.6 A Nigerian study of 31 people with concurrent HIV infection and syphilis found that 64.2% of the patients had developed unusual lesions affecting more than 50% of the body. Also, the chancres seen at the sites of inoculation had an atypical appearance.
However, a recent detailed study suggests that other than an increased number and frequency of genital ulcers in secondary disease, HIV disease does not greatly impact the clinical care of syphilis. Nevertheless, there have been reports of prolonged primary disease and secondary disease; additionally, neurosyphilis38 may present more quickly and ulceronodular disease is more likely in patients infected with HIV than in those not infected.
INFLUENCE OF ORAL SYPHILIS UPON HIV DISEASE
Patients with concurrent HIV infection and syphilis usually have a history of sexually transmitted infection, and it is common that these patients have more than 1 condition (eg, genital ulcers, injected drug addition, etc) that are potential sources of exposure.37 The genital ulceration of syphilis increases the risk of HIV transmission.41 Nonulcerative STD, however, also have the capacity of increasing the likelihood of HIV transmission,42 and the detection and treatment of syphilis can probably help to reduce HIV transmission.43 While there are no data to support the notion, it is likely that oral syphilis principally influences HIV disease by increasing the likelihood of HIV transmission (and other related viruses) by oral sexual routes. A recent study found no association between early syphilis and changes in blood or semen viral load or CD4 count in HIV-positive individuals. According to the study, increased HIV-1 infectivity associated with early syphilis is unlikely to be associated with increased levels of HIV-1 RNA in blood or semen. There is now compelling evidence, based upon case and epidemiological studies, that HIV can be transmitted via orogenital contact. In addition, as persons in high-risk groups for HIV move away from high-risk sexual activities, there is likely to be an increased frequency of orogenital contact, and hence oral sex will contribute to a greater frequency of new infections than previously. Oral ulcerative disease, such as that of all the stages of syphilis, will increase the HIV load in the mouth, and hence the potential for HIV transmission via oral sex.44 In addition, this increased risk of HIV transmission will be further worsened by ulcerative disease secondary to the use of the recreational drugs, crack cocaine45 and cocaine powder. Finally the oral ulcerative disease of syphilis is likely to increase the nonsexual spread of human herpes virus 8 (HHV-8).46
Tests used to screen for syphilis include:
Venereal disease research laboratory (VDRL) test. The VDRL test checks for an antibody that can be produced in people who have syphilis. This antibody is not produced as a reaction to the syphilis bacteria specifically, so this test is sometimes not accurate. The VDRL test may be done on a sample of blood or spinal fluid. The VDRL test is not very useful for detecting syphilis in very early or advanced stages.
Rapid plasma reagin (RPR) test. The RPR test also detects syphilis antibodies.
Enzyme immunoassay (EIA) test. This is a newer blood test that checks for antibodies to the bacteria that cause syphilis. A positive EIA test should be confirmed with either the VDRL or RPR tests.
Tests used to diagnose syphilis include:
Fluorescent treponemal antibody absorption (FTA-ABS) test. The FTA-ABS test checks for antibodies to the bacteria that cause syphilis and can be used to detect syphilis except during the first 3 to 4 weeks after exposure to syphilis bacteria. The test can be done on a sample of blood or spinal fluid.
Treponema pallidum particle agglutination assay (TPPA). The TPPA test is used to confirm a syphilis infection after another method tests positive for the syphilis bacteria. This test detects antibodies to the bacteria that cause syphilis. This test is not done on spinal fluid.
Darkfield microscopy. This test uses a special microscope to examine a sample of fluid or tissue from an open sore (chancre) for the syphilis bacteria. This test is used mainly to diagnose syphilis in an early stage.
Microhemagglutination assay (MHA-TP). The MHA-TP is used to confirm a syphilis infection after another method tests positive for the syphilis bacteria.
Approach Considerations
T pallidum cannot be cultivated in vitro and is too small to be seen under the light microscope. Serologic testing is considered the standard method of detection for all stages of syphilis. (Note, however, that serologic tests cannot be used to differentiate the different species of the treponeme family—for example, yaws.)
In suspected acquired syphilis, first perform nontreponemal serology screening using the Venereal Disease Research Laboratory (VDRL), rapid plasma reagin (RPR), or the recently developed ICE Syphilis recombinant antigen test.
Sensitivity of the VDRL and RPR tests are estimated to be 78-86% for detecting primary syphilis, 100% for detecting secondary syphilis, and 95-98% for detecting tertiary syphilis. Specificity ranges from 85-99% and may be reduced in individuals who have coexisting conditions (ie, collagen vascular disease, pregnancy, intravenous drug use, advanced malignancy, tuberculosis, malaria, viral and rickettsial diseases).
VDRL test results turn positive 1-2 weeks after chancre formation. Nontreponemal tests usually become nonreactive with time after treatment. However, in some patients, nontreponemal antibodies can persist, sometimes for the life of the patient.
Because of the possibility of false-positive results, confirmation for any positive or equivocal nontreponemal test result should follow with a treponemal test, such as the fluorescent treponemal antibody-absorption (FTA-ABS), quantitative VDRL/RPR, microhemagglutination assay T pallidum (MHA-TP), T pallidum hemagglutination (TPHA), and T pallidum particle agglutination (TPPA) tests.Treponemal enzyme immunoassay (EIA) for immunoglobulin G (IgG) and immunoglobulin M (IgM) may be performed.
FTA-ABS is commonly used as a confirmatory test following positive VDRL or RPR test findings. FTA-ABS has a sensitivity of 84% for detecting primary syphilis infection and almost 100% sensitivity for detecting syphilis infection in other stages. Its specificity is 96%.
Some labs have adopted reverse sequence screening in order to reduce time, labor, and costs. Reverse screening test sera first by automatable treponemal enzyme and chemiluminescence immunoassays (EIA/CIA), followed by testing of reactive sera with a nontreponemal test. Results of the first direct comparison of traditional and reverse screening suggest reverse screening may not be as inferior to traditional testing as previously thought. Six out of 1000 patients tested were falsely reactive by reverse screening, compared to none by traditional testing. However, reverse screening identified 2 patients with possible latent syphilis that were not detected by RPR. The CDC recommends traditional testing, but if reverse screening is used all sera that produce reactive EIA/CIA results should be reflexively tested with a quantitative nontreponemal test. Sera with discordant results should be reflexively tested with a confirmatory TPPA test.
Testing must be performed more than once in patients diagnosed with latent syphilis in order to exclude laboratory error.
Dark-field microscopy is essential in evaluating moist cutaneous lesions, such as the chancre of primary syphilis or the condyloma lata of secondary syphilis (see the image below).
When dark-field microscopy is not available, direct immunofluorescence staining of fixed smears (direct fluorescent antibody T pallidum [DFA-TP]) is an option. Both procedures detect the causative organism at a rate of approximately 85-92%.
Slit-lamp examination and ophthalmic assessment can be used to differentiate between acquired and congenital syphilis (presence of interstitial keratitis) in patients with latent infection of uncertain duration.
Diagnosis of neurosyphilis can be challenging. The VDRL test for cerebrospinal fluid (VDRL-CSF) is highly specific but has low sensitivity. Therefore, the diagnosis of neurosyphilis usually depends on a combination of reactive serologic test results, CSF cell count, CSF protein, and clinical manifestations with or without a reactive VDRL-CSF. Some specialists recommend performing an FTA-ABS test on CSF. The CSF FTA-ABS is less specific for neurosyphilis than the VDRL-CSF, but it is highly sensitive.
Infants with suspected congenital syphilis and positive VDRL or FTA-ABS test results can undergo 19S IgM FTA-ABS serologic testing (maternal IgM is not passed to the fetus in utero). However, the false-negative rate is 35%, and the false-positive rate is 10%. The Captia Syphilis-M enzyme-linked immunosorbent assay is an option.
The United States Preventive Services Task Force (USPSTF) has reaffirmed its recommendation for screening all pregnant women for syphilis infection at the first prenatal visit. High-risk women (eg, uninsured women, women living in poverty, sex workers, illicit drug users, those with other sexually transmitted diseases, those living in communities with high syphilis morbidity) should also be tested in the third trimester and at delivery.
If the test results are positive for syphilis, the treatment of choice is parenteral benzathine penicillin G. Dosage and the length of treatment depend on the stage and clinical manifestations of the disease.
Patients with confirmed syphilis infections should be tested for other sexually transmitted diseases, including HIV.
According to the 2010 CDC STD guidelines, there is insufficient evidence to establish whether infants who have congenital syphilis and whose mothers are coinfected with HIV need different evaluation, treatment, or follow-up for syphilis than is recommended for all infants.
Imaging Studies
Imaging studies should be performed depending on the organ system involved. For example, granulomatous disease can be seen on computed tomography (CT).
Obtain chest radiography in patients with tertiary syphilis to screen for aortic dilatation. Linear calcification of the ascending aorta on chest films suggests asymptomatic syphilitic aortitis. Radiologic abnormal findings commonly seen with advanced gummas of bone include periostitis, destructive osteitis, or sclerosing osteitis.
Angiography may be useful to distinguish between abdominal aneurysms of syphilitic versus arteriosclerotic origin. About 10% of syphilitic aneurysms occur superior to the renal arteries, while arteriosclerotic abdominal aneurysms usually are found inferior to the renal arteries.
CT scanning and magnetic resonance imaging (MRI) of the head and body may be used to document the complications of tertiary syphilis.
Lumbar Puncture
Invasion of the central nervous system (CNS) by treponemes occurs in 30-40% of patients with primary or secondary syphilis; however, no studies show this to be a predictor of poor neurologic outcome. According to the 2010 CDC STD treatment guidelines, CSF laboratory abnormalities are common in persons with early syphilis, even when clinical neurological findings are absent. If clinical evidence of neurological involvement is found, a CSF examination should be performed.
Current guidelines in clinical infectious diseases state that physicians should evaluate CSF in individuals with latent syphilis of unknown duration or with late latent syphilis if (1) treatment fails, (2) neurologic or ocular symptoms are present; or (3) the patient has underlying HIV infection. LP is only relatively indicated in patients with high titers on serological tests (≥1:32). It is also indicated if there are other changes indicative of active syphilis (eg, gumma, aortitis).
LP should be performed on patients suspected of having neurosyphilis with no contraindication. CSF examination is the only means by which the occurrence of asymptomatic neurosyphilis in latent syphilis can be excluded.
Examination of the CSF should include the VDRL test, cell count, and protein level. Abnormalities of any of these measurements combined with a suggestive history and examination strongly indicate the presence of neurosyphilis. Derangements of these values are consistently found in neurosyphilis. A positive VDRL test result indicates active syphilis. A positive polymerase chain reaction (PCR) test finding is sensitive in detecting past invasion of the CNS but does establish whether the T pallidum organisms are still alive.
Histologic Findings
The primary lesion of syphilis is a chancre. Histologically, skin and mucosal lesions show a perivascular and perijunctional infiltrate of lymphocytes, plasma cells, and macrophages. At times, capillary endothelial proliferation and subsequent obliteration of small blood vessels may be appreciable. Focal erosion or ulceration is common.
The inflammatory reaction of secondary syphilis is histologically similar to that of the primary chancre but is less intense. Skin lesions are typified by a “lichenoid-psoriasiform” configuration with a perijunctional infiltrate of lymphocytes, histiocytes, and plasmacytes (see the image below). Often the histiocytic component of the infiltrate is prominent, and thus the biopsy may assume a “lichenoid-granulomatous” configuration.
Lues hematoxylin and eosin stain. Histopathological examination shows a lichenoid infiltrate that is stereotypical of the secondary stage of syphilis. Note that vacuolar alteration of the superjacent epithelium can be seen much like a noninfectious form of lichenoid dermatitis. The subjunctional infiltrate is rich in histiocytes and plasmacytes. At times, an overtly granulomatous lichenoid infiltrate can be seen.
Approach Considerations
Penicillin is the treatment of choice for treating syphilis. According to the Centers for Disease Control and Prevention (CDC) (see current CDC recommendations), patients with known penicillin allergies should undergo penicillin allergy skin testing and penicillin desensitization, if necessary.The 2010 CDC STD treatment guidelines recommend desensitization in penicillin-allergic pregnant women, followed by treatment with penicillin.
Clinical and serologic conversions are the endpoints of medical treatment for syphilis. Follow-up Venereal Disease Research Laboratory (VDRL) test levels should be obtained to document treatment efficacy.
Antibiotic Therapy
Penicillin
Penicillin was established as an effective treatment for syphilis before the widespread use of randomized clinical trials. The treatment guidelines published by the CDC (see current CDC recommendations) are based largely on uncontrolled trials and expert opinion. Guidelines are based on staging, with later stages requiring longer courses of treatment due to the slower rate of bacterial replication.
Penicillin remains the mainstay of treatment and the standard by which other modes of therapy are judged. The 2010 CDC STD treatment guidelines support the use of penicillin as the preferred drug for treating all stages of syphilis.Penicillin is the only therapy used widely for neurosyphilis, congenital syphilis, or syphilis during pregnancy. Rarely, T pallidum has been found to persist following adequate penicillin therapy; however, there is no indication that the organism has acquired resistance to penicillin.
The following regimens are recommended for penicillin treatment:
· Primary or secondary syphilis – Benzathine penicillin G 2.4 million units intramuscularly (IM) in a single dose
· Early latent syphilis – Benzathine penicillin G 2.4 million units IM in a single dose
· Late latent syphilis or latent syphilis of unknown duration – Benzathine penicillin G 7.2 million units total, administered as 3 doses of 2.4 million units IM each at 1-week intervals
· Pregnancy – Treatment appropriate to the stage of syphilis is recommended.
In patients with a history of penicillin allergy, skin testing is recommended. Patients who are skin test negative can receive conventional treatment with penicillin; skin test positive patients should be desensitized in the hospital. Make every effort to document penicillin allergy before choosing an alternative treatment, because the efficacy of alternative regimens is questionable in all stages of syphilis. Many treatment failures have been reported.
According to the 2010 CDC STD guidelines, no treatment regimens for syphilis have been shown to be more effective in preventing neurosyphilis in patients who are HIV positive than the syphilis regimens recommended for patients who are HIV negative. Careful monitoring after therapy is required
Alternatives to penicillin
As stated in the 2010 CDC guidelines, several therapies exist that might be effective in nonpregnant, penicillin-allergic patients with primary or secondary syphilis.
Tetracycline, erythromycin, and ceftriaxone have shown antitreponemal activity in clinical trials; however, they currently are recommended only as alternative treatment regimens in patients allergic to penicillin. The 2010 CDC guidelines suggest that a 10- to 14-day trial of ceftriaxone is effective for treating early syphilis, although the optimal dose and duration have not been established. Doxycycline and tetracycline have been used for many years.
Azithromycin has also been studied. A meta-analysis of randomized clinical trials comparing azithromycin to benzathine penicillin G for early syphilis was published in 2008 showing favorable results for azithromycin. The CDC 2010 STD treatment guidelines cite the effectiveness of azithromycin in treating early syphilis. However, there are documented cases of treatment failure due to azithromycin-resistant mutations in T pallidum in several areas of the United States. Therefore, azithromycin should be used only when the use of penicillin or doxycycline is not feasible. Its use in men who have sex with men (MSM) or pregnant women is contraindicated. A 2010 study by Hook et al showed a single dose of azithromycin (2 g PO) to be equivalent to the treatment of choice, benzathine penicillin G (2.4 million units IM) in patients with early syphilis without HIV. Serological cure after 6 months of follow-up was not significant between the 2 treatments, although azithromycin recipients had a higherincidence of adverse effects (mostly self-limited gastrointestinal symptoms).
A larger, multicenter trial is needed to confirm these results before this treatment can be recommended. Azithromycin treatment failures have been reported by the CDC.
Jarisch-Herxheimer reaction
Following the initiation of treatment, the dying treponemes release inflammatory molecules that trigger a cytokine cascade possibly leading to a response known as the Jarisch-Herxheimer reaction. Symptoms include myalgias, fever, headache, and tachycardia, sometimes with exacerbation of whatever current syphilitic lesions are manifested (eg, rash or chancre).
The reaction is common, develops within several hours after beginning antibiotic treatment, and usually clears within 24 hours after onset. Its exact etiology is unclear, although it may be due to an immunological reaction to the rupture of spirochetes.
Management of this reaction often involves symptomatic treatment (eg, with antipyretics and analgesics) and observation. In pregnant women, treatment may induce early labor or cause fetal distress. Patients should be informed of the possibility of this reaction before undergoing antibiotic therapy. As stated in the CDC 2010 STD treatment guidelines, although the Jarisch-Herxheimer reaction might induce obstetric complications such as early labor or fetal distress, this risk should not preclude or delay therapy for syphilis.Women are advised to seek obstetric care after treatment if they notice any fever, uterine contractions, or a decrease in fetal movement.
Prevention of Syphilis
The primary goal of prevention is to limit the spread of syphilis. This entails counseling patients to use safe sex practices and advising patients who abuse intravenous (IV) drugs to never share needles and to use cleaeedles. Notification and treatment of sexual partners and exposed drug partners are paramount. Prevention also entails educating health care workers to use universal precautions when treating all patients.
Studies of primary screening for syphilis in clinics and emergency departments are favorable for screening of high-risk, inner-city populations. Routine screening is advocated for all at-risk mothers.
Two reports from 2009 indicate that circumcision does not help prevent the transmission of syphilis, although circumcision may help prevent the transmission of viral sexually transmitted diseases.
Long-Term Monitoring
Inpatient care is generally reserved for complications of late syphilis.
Monitor patients with syphilis to ensure adequacy of treatment. The Clinical Effectiveness Group notes that follow-up visits in patients with syphilis should be performed at 3-, 6-, and 12-month intervals. Patients with HIV infection or patients treated with a nonpenicillin regimen should be monitored for life.
Generally speaking, therapy is considered a failure if the signs and symptoms of syphilis return. This occurs when the titer of the nontreponemal test increases 4-fold or a 4-fold decrease from the initial VDRL titer does not occur within 1 year.
However, clearly defined criteria regarding treatment failure are lacking. In their literature review, Augenbraun and Rolfs found that 15-25% of patients treated for syphilis do not have a 4-fold decrease in titers over a 3-month period, and some do not have a decrease for 6 months or longer.Information is lacking on whether these patients are at higher risk for progression. Currently accepted guidelines are as follows:
· Any reappearance of symptoms is defined as a relapse.
· More than a double-dilution increase (ie, a 4-fold titer increase) in serologic tests is a relapse.
· Patients with latent syphilis who have initially high titers (≥1:32) and fail to have a double-dilution decrease (4-fold titer decline) 12-24 months after therapy should be reevaluated for neurosyphilis and possible retreatment.
· Some treponemal test results may remain positive for life despite effective treatment. Individuals in this circumstance require proper documentation to avoid unnecessary retreatment.
· Supervise retreatment to ensure compliance.
Recommendations for specific patient subsets are as follows.
Patients with treated primary or secondary syphilis
Patients treated for primary and secondary syphilis should have follow-up VDRL testing at 3, 6, and 12 months after treatment. Patients with HIV should be monitored closely, as they are known to have more rapid progression of disease. Most patients with primary syphilis who are treated adequately have a nonreactive VDRL within 1 year, and almost all patients treated for secondary syphilis have a negative VDRL result within 2 years. A small minority of patients remain seropositive in spite of successful treatment.
According to the 2010 CDC STD guidelines, HIV-infected individuals should be assessed clinically and serologically for treatment failure at 3, 4, 9, 12, and 24 months post therapy.
If the VDRL titer of 1:8 or more fails to fall at least 4 fold within 12 months or if the titer starts to rise, consider more intensive retreatment, and examine the cerebrospinal fluid (CSF). If all clinical and serologic examinations remain satisfactory for 2 years following treatment, the patient can be reassured that cure is complete, and no further follow-up care is needed.
Patients with latent syphilis
Perform quantitative reagin testing for up to 2 years. Schedule annual follow-up visits for an indefinite period of time for patients with persistently positive serologic tests.
The 2010 CDC STD treatment guidelines state that HIV-infected individuals with latent syphilis should receive the same stage-specific treatment as recommended for HIV-negative individuals.
Patients with benign tertiary or cardiovascular syphilis
Patients should be observed by the physician for the rest of their lives to monitor for complications.
Patients with neurosyphilis
Patients with neurosyphilis should have follow-up at 6-month intervals for at least 3 years with physical examinations, CSF evaluation (eg, cell count, protein, reagin titer), and serologic testing.
Medication Summary
The goal of pharmacotherapy is to eradicate the causative organism of syphilis, T pallidum. Penicillin is the mainstay of treatment, the standard by which other modes of therapy are judged, and the only therapy that has been used widely for neurosyphilis, congenital syphilis, or syphilis during pregnancy.
Penicillin
The drug of choice is parenteral penicillin G for all stages of syphilis. According to the 2010 CDC STD treatment guidelines, penicillin G is the only therapy that is clinically documented to be effective against syphilis during pregnancy. Since the dividing time of T pallidum is slow (days), penicillin G benzathine is the only penicillin effective for single-dose therapy because it is in depo form and levels remain therapeutic in the blood for up to 30 days. Avoiding Bicillin C-R (combination procaine and benzathine), which remains in blood for only 7 days, is essential.
On rare occasions, T pallidum has been found to persist after adequate penicillin therapy; however, no indication exists that T pallidum has acquired resistance to the drug.
According to the Centers for Disease Control and Prevention (CDC; see current CDC recommendations), patients with known penicillin allergies should undergo penicillin allergy skin testing and penicillin desensitization, if necessary.[25]
Alternatives to penicillin
Since T pallidum resistance to penicillin has not emerged, the primary need for alternative drugs in treating syphilis is reserved for penicillin-allergic patients.
Researchers are studying the efficacy of ceftriaxone and azithromycin in treating syphilis. Central nervous system (CNS) penetration and its similarity to penicillin support the use of ceftriaxone in the treatment of syphilis. Studies are presently inconclusive, and CDC guidelines neither support nor refute its use. Given the limited data available to support its efficacy, prudence dictates a 5- to 7-day course of treatment for early syphilis.
The long half-life of azithromycin and its clinical efficacy in vitro against syphilis support its use in treating early syphilis. At present, however, clinical data remain insufficient to recommend its use.
No good evidence indicates that the non–beta-lactam antibiotics, which are used as alternatives to penicillin, are clinically effective in syphilis. Erythromycin has been associated with high failure rates. Doxycycline may be an option for patients who refuse parenteral therapy.
ntibiotics
Class Summary
Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.
Penicillin G benzathine (Bicillin L-A)
Benzathine penicillin G is the first-line agent for primary and secondary syphilis infection. It is a spirocheticide with in vivo activity against T pallidum. It interferes with cell wall mucopeptide synthesis during replication.
Penicillin G procaine
Penicillin G procaine is the first-line agent for treating late latent syphilis.
Doxycycline (Doryx, Vibramycin)
Doxycycline is used as alternative therapy for syphilis infection. It inhibits bacterial growth by binding to the 30S ribosomal unit, preventing protein synthesis.
Tetracycline (Sumycin)
Tetracycline is used as alternative therapy for syphilis infection. It inhibits bacterial growth by binding to the 30S ribosomal unit, preventing protein synthesis.
Erythromycin (E.E.S., E-Mycin)
Erythromycin inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. It is used for treatment of staphylococcal and streptococcal infections. In children, age, weight, and severity of infection determine proper dosage. When twice-daily dosing is desired, half of the total daily dose may be taken q12h. For more severe infections, double the dose.
Ceftriaxone (Rocephin)
Ceftriaxone is an alternative agent for penicillin-allergic patients. It is a third-generation cephalosporin with broad-spectrum, gram-negative activity; it has lower efficacy against gram-positive organisms and higher efficacy against resistant organisms. It arrests bacterial growth by binding to one or more penicillin binding proteins.
Azithromycin (Zithromax)
Azithromycin acts by binding to the 50S ribosomal subunit of susceptible microorganisms and blocks dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Nucleic acid synthesis is not affected.
Azithromycin concentrates in phagocytes and fibroblasts as demonstrated by in vitro incubation techniques. In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues. This drug is used to treat mild-to-moderate microbial infections.
