Syphilis
Salient
features
·
A
disease caused by the spirochete Treponema pallidum subspecies pallidum that
is almost exclusively sexually transmitted.
·
Syphilis
disproportionately affects men who have sex with men.
·
The
most common and recognizable manifestations are usually cutaneous.
·
Syphilis
passes through 4 distinct clinical phases:
o
Primary
stage, characterized by a chancre.
o
Secondary
stage, characterized typically by skin eruption(s) with or without
lymphadenopathy and organ disease.
o
A
latent period of varied duration, characterized by the absence of signs or
symptoms of disease, with only reactive serologic tests as evidence of
infection.
o
Tertiary
stage, with cutaneous, neurologic, or cardiovascular manifestations.
·
Neurosyphilis
and ophthalmic syphilis can occur at any stage.
·
The
recommended treatment for most types of syphilis is benzathine penicillin G,
with dose and administration schedule determined by disease stage.
·
Any
patient diagnosed with syphilis should be tested for other sexually transmitted
infections, including HIV.
Introduction
Syphilis is a chronic systemic infectious disease caused
by the spirochaetal bacterium Treponema pallidum subsp. pallidum. The disease
is usually transmitted by direct sexual contact with a lesion during the
primary or secondary stage, in utero by the trans-placental route or during
delivery as the baby passes through an infected canal. Sixty percent of those
in contact with persons having primary and secondary syphilis become infected. Like
the gonococcus, this bacterium is fragile and dies when removed from the human
environment. Unlike the gonococcus, T. pallidum may infect any organ,
causing an infinite number of clinical presentations; thus the old adage, “he
who knows syphilis knows medicine.”
Epidemiology
Incidence and
prevalence
Syphilis is distributed worldwide and most infections
occur in developing countries where it is a leading cause of genital ulcer
disease. Worldwide, the rates of primary and secondary syphilis decreased
dramatically with the introduction of penicillin treatment after the Second
World War.
Age
Syphilis occurs in sexually active individuals of all
ages and is commoner in young adults.
Sex
There is marked preponderance of cases in males. It is
generally considered that male to female transmission is more efficient.
Associated diseases
Acquired syphilis commonly coexists with other STIs;
hence comprehensive screening is advised when syphilis is detected.
Histopathology
The fundamental pathological changes in syphilis are the
same in early and late disease. They occur in and around the blood vessels in
the form of a perivascular infiltration of lymphocytes and plasma cells,
accompanied by intimal proliferation in both the arteries and veins
(endarteritis obliterans).
In primary syphilis, there is ulceration and a diffuse
dermal infiltrate of plasma cells, lymphocytes, and histiocytes. Endarteritis
obliterans is also present. Spirochetes may be
detected with Warthin–Starry or immunohistochemical staining.
In secondary syphilis,
there is great variability in the histopathological pattern, reflecting the
variable clinical appearance of the disease. The epidermis may be normal,
psoriasiform, necrotic or ulcerated. Dermal infiltrates of plasma cells,
lymphocytes and histiocytes can be perivascular, lichenoid, nodular, or
diffuse. Older lesions of secondary syphilis may be granulomatous and can
resemble sarcoidosis or other granulomatous dermatoses, except for the presence
of plasma cells. Endarteritis obliterans can also be seen in secondary syphilis. Immunohistochemistry
for treponema shows numerous microorganisms, which in secondary syphilis tend
to be more prominent within the epidermis. Lues maligna
is characterized by vasculitis.
In tertiary syphilis, the
characteristic lesion of mucocutaneous surfaces is the syphilitic gumma. Tuberculoid granulomas (with or without caseation) are
present together with plasma cells. Endarteritis obliterans and necrotic
areas are pronounced. Gummata most often originate in subcutaneous tissues and
spread in all directions. Spirochaetes are not readily demonstrable in these
lesions.
Heubner arteritis occurs in cardiovascular and
meningovascular syphilis. It is characterized by lymphocytic and plasma cell
infiltration of the vasa vasorum and adventitia of large and medium‐sized
vessels. Occlusion of the vasa vasorum results in medial necrosis and
fibroblast proliferation. There is associated subintimal proliferation, which
leads to luminal occlusion and thrombosis.
Morphology
In daily practice, T. pallidum is demonstrated by dark‐field
microscopy. It appears as a pale, white, fine, corkscrew organism with close
and very regular coils. There are between eight and 20 coils. It contains a
periplasmic flagellum and is actively motile. The movements of T. pallidum are
pathognomonic. It rotates around its long axis and thus appears to quiver and
screw slowly backwards and forwards; it shows a highly typical angling
movement, forming both acute and obtuse angles. Treponemes can also be
demonstrated by the direct fluorescent‐antibody method and
by rapid immunofluorescent staining (RIS) of smears from lesions.
|
CHARACTERISTICS OF TREPONEMA PALLIDUM |
|
· 6–20
microns in length, 0.1–0.18 microns in diameter · Regular
tight spirals · Inability
to survive outside an animal host · Cannot
be cultured in vitro for an extended time period · Limited
capacity for DNA repair · Outer
membrane: -lipid-rich -contains
uniform sized transmembrane rare outer membrane proteins
(TROMP) -lacks
lipopolysaccharide · Periplasmic
flagella |
Microbiology
The organism is microaerophilic and a highly invasive and persistent pathogen
and unable to survive outside the mammalian host. T. pallidum initiates
an inflammatory response at the site of inoculation and is disseminated during
the primary infection. The organism has a surface‐associated
hyaluronidase enzyme, which may play a role in this process. Phagocytosis by
cytokine‐activated
macrophages, as part of a predominant T‐helper 1 (Th1) type
early response, aids bacterial clearance and resolution of the primary lesion.
Pathogenesis of
Untreated Syphilis
Syphilis is a chronic systemic infection that
progresses through active and latent stages. Inoculation and penetration occurs
via mucosal surfaces and abraded skin, followed by attachment to host cells and
multiplication of the microorganism. Within a few hours, treponemes enter lymphatics and blood and produce
systemic infection and metastatic foci before development of a primary lesion. The
organism can cross many barriers in the body, such as the blood–brain barrier
and the placental barrier, to infect many tissues and organs. That
dissemination leads ultimately to manifestations of syphilis distant from the
site of the initial chancre(s) in an infected person and in a developing fetus.
Spirochetes divide locally, with host inflammatory response and chancre
formation, either a single lesion or less commonly, multiple lesions. Cellular immunity
is of major importance in healing of early lesions and control of infection (Th
1 type).
Infection at all stages leads to infiltration by
lymphocytes, macrophages, and plasma cells. CD4+ T cells predominate in
chancres, and CD8+ T cells predominate in lesions of secondary syphilis.
Infection leads also to elaboration of Th1 cytokines, including IL-2 and
IFN-γ, although down regulation of the Th1 response during secondary syphilis,
coincident with the peaking of antibody titers, might contribute to the
organism's ability to evade the host immune response.
The humoral immune response begins with production of IgM
antibodies approximately 2 weeks after exposure, followed 2 weeks thereafter by
IgG antibodies. IgM in addition to IgG continues to be produced during
infection and can lead to immune-complex formation. Antibody titers peak during
bacterial dissemination, in secondary syphilis. Some antibodies cross-react
with other treponemal species and some are specific for T. pallidum subspecies
pallidum.
The immune response is sufficient to prevent syphilis
reinfection in persons who have untreated syphilis. In other words, in what is
called Colles’ law or “chancre immunity,” persons with untreated syphilis will
not experience another episode of primary syphilis as long they remain
untreated. However, the immune response is insufficient to eradicate T.
pallidum from the host. In addition to suppressing the Th1 response, the
organism is thought to evade those host defenses by taking harbor in
immune-privileged tissues (e.g., central nervous system, eye, and placenta),
failing to be present in sufficient quantities (e.g., during latent infection)
to trigger a host response. The immune response is also not adequate to prevent
reinfection after a person is cured of syphilis, although it might modify the
course of reinfection. Compared with persons with syphilis for the first time,
for example, reinfected persons are less likely to have manifestations of
primary or secondary syphilis and more likely to be diagnosed with latent
syphilis.
The immune response is also likely responsible for the
tissue damage caused in syphilis. Damage to axons located near the site of a
chancre might explain why that lesion, although ulcerative, is typically
painless.
|
Contact (⅓ become infected) ↓ average 3 weeks Primary (chancre)-resolves in 3-8 weeks ↓ (3–12 weeks) Secondary (mucocutaneous lesions, organ involvement) ↓ resolves in 4–12 weeks Early latent → Relapsing (1/4) (2 years from contact) ↓ |
|
|
Late latent (more than 2 years) |
|
|
Clinical remission (⅔) Cured 33% ((⅓) Serofast 33% (⅓) |
Tertiary (⅓)-33% Late benign (17%) Cardiovascular (8%) Neurosyphilis (8%) |
Primary stage
The primary
lesion develops 10–90 days after infection (median of 3 weeks) as an indolent
papule, followed by surface necrosis and the typical well-circumscribed
ulceration that is firm to palpation (chancre). It is
accompanied by enlarged regional lymph nodes. Histopathologically, the
microorganism is observed among cells typical of a Th1-predominant cellular
response; the latter leads to macrophage activation and destruction of a large
number of treponemes.
Secondary stage
The
secondary stage is characterized by dissemination and multiplication of the microorganism
in different tissues either simultaneously with or up
to 6 months after healing of the primary local lesion. This stage
follows primary syphilis in almost every patient in the absence of appropriate
treatment. Circulating immune complexes (which
contain treponemal outer membrane proteins), human anti-fibronectin antibodies,
and complement are present during this stage of the disease and play a role in
the pathogenesis of the different types of lesions. Chancre may still
present when secondary lesions appear (15% of cases). It is possible to pass
into secondary syphilis without suffering from primary chancre, when the
disease is transmitted by other means like transfusion of infected blood.
Secondary
syphilis is characterized by a broad spectrum of clinical manifestations
involving the skin as well as systemic signs such as malaise, fever and
generalized enlargement of the lymph nodes. Secondary lesions subside within
2-6 weeks, infection entering latent stage. Pregnant women can infect a fetus
via transplacental passage of the microorganism.
Latency
Latency is
the period between healing of the clinical lesions and appearance of late
manifestations, and it can last for many years. About 70% of untreated
individuals will remain in this stage for the rest of their lives and are
immune to new primary infection. Latent syphilis is divided into early (1 year
or less) and late (more than 1 year) subsets, and it is characterized by
positive serologic tests for specific antibodies without clinical signs or
symptoms. Non treponemal serologic titers are usually are higher during early
latent syphilis than late latent syphilis. Infectivity may occur intermittently
due to the presence of treponemes in the bloodstream, and pregnant women with
latent syphilis may infect the fetus in utero.
Tertiary stage
The tertiary
stage is also called late syphilis and is characterized by the presence of a
small number of organisms and a high cellular immune reactivity against the
organism. Signs of late syphilis can be recognized in approximately one-third
of untreated individuals several months to years after being infected with
treponemes. The microorganisms may invade the central nervous and
cardiovascular systems as well as the skin (and other organs), leading to
damage related to host delayed-type hypersensitivity responses, which produce
local inflammation and gummas in affected tissues.
Course
Even without
treatment, chancre heals completely in 4 to 6 weeks. The infection either
becomes latent or clinical manifestations of secondary syphilis appear.
Secondary syphilis usually manifests as macular exanthem initially; after
weeks, lesions resolve spontaneously and recur as maculopapular or papular
eruptions. In 20% of untreated cases, up to three to four such recurrences
followed by periods of clinical remission may occur over a period of 1 year.
Infection then enters a latent stage, in which there are no clinical signs or
symptoms of the disease. After untreated syphilis has persisted for >4 years,
it is rarely communicable, except in the case of pregnant women, who, if
untreated may transmit syphilis to their fetuses, regardless of the duration of
their disease. One-third of patients with untreated latent syphilis developed
clinically apparent tertiary disease. Gummas hardly ever heal spontaneously.
Noduloulcerative syphilides undergo spontaneous partial healing, but new
lesions appear at the periphery.
Syphilis and HIV
Syphilis and
other STIs that produce genital ulcers further increase the risk of acquiring
HIV. Reasons for the increased risk of HIV transmission include:
1.
lack
of an epithelial barrier due to ulceration of the skin or mucous membranes
2.
large
numbers of macrophages and T cells with receptors for HIV
3.
Production
of cytokines by macrophages stimulated by treponemal lipoproteins.
In addition, syphilitic manifestations are altered in
HIV-positive patients, with a higher likelihood of neurologic findings and (in those
with secondary syphilis) ulcerative lesions.
CLINICAL FEATURES
Stages
Syphilis is an intermittent disease and if untreated, may
pass through four stages: primary, secondary, latent and late. Latent stage is divided
into early and late latent that precedes the onset of tertiary syphilis. The
definitions of early and late syphilis by the CDC and World Health Organization
(WHO) differ slightly. Early syphilis includes the primary and secondary
stages as well as early latency (CDC: acquired <1 year previously; WHO:
acquired <2 years previously). Late syphilis extends from late
latency (CDC: acquired >1 year previously; WHO: acquired >2 years
previously) through the tertiary stage.
Risk of transmission
The greatest
risk of transmission occurs during the primary, secondary, and early latent
stages of disease. Patients with secondary syphilis are the most contagious
because of the large number of lesions. One third of persons with a single
exposure to early syphilis will become infected.
Syphilis is
most commonly acquired sexually, when a person comes in contact with infectious
lesions of syphilis on another person. Infectious lesions of syphilis in
adults, which include chancres, condylomalata, and mucous patches, can be
present anywhere on the body but are typically located in or around the
genital, anal, or oral area. Direct contact with infectious lesions during
oral, vaginal, or anal sex, or during other sexual activities, can result in
inoculation and infection. Lesions on keratinized skin (e.g., palmoplantar
lesions and maculopapular rash on the trunk) typically do not contain
sufficient treponemes to be infectious.
Syphilis can
also be acquired through nonsexual contact, blood transfusion, accidental
inoculation in an occupational setting (e.g., laboratory or healthcare worker)
or nonoccupational setting (e.g., tattooing), or through exposure in utero.
Incubation period
Persons recently exposed to and infected with syphilis
who have yet to manifest signs or symptoms of the disease are said to have
incubating syphilis. The incubation period of syphilis is generally given as
9–90 days, and varies inversely with the size of the spirochaete inoculum.
Typically, most genital primary sores appear 3 weeks after exposure. Enlarged
glands appear in one groin after a further week and can be detected in both
groins 5 weeks after infection. Reactive reaginic serological tests are
detectable at 5.5–6 weeks, the macular rash at 8 weeks, papular lesions at 3
months and condylomata at 6 months.
Clinical manifestations of syphilis
L, lues; LI, primary syphilis; LII, secondary syphilis;
LIII, tertiary syphilis.
Presentation
PRIMARY SYPHILIS
As defined by CDC surveillance case definitions, primary
syphilis is a stage of syphilis characterized by one or more chancres, in the
presence of laboratory evidence from tissues or sera consistent with syphilis.
The primary chancre appears at the site of initial treponemal
invasion of the dermis and usually presents as a single, indolent, round or
oval, indurated ulcer that is associated with regional adenopathy. It may occur
on any skin or mucous membrane surface and is usually situated on the external
genitalia.
The chancre starts as a dusky red macule that evolves
into a papule and then a round-to-oval ulcer. The typical chancre, also called
a Hunterian chancre or “ulcus durum” (hard ulcer), measuring up to 1 cm in
diameter and is sharply demarcated with regular, raised border that is
indurated, hard and button‐like consistency, giving the
lesion a cartilaginous feel. The base is usually clean, and the chancre is
classically not painful unless secondarily infected. The ulcer is often
surrounded by a narrow, red border, 1–2 mm wide. This marks the limits of the inflammatory reaction and is
most productive of T.
pallidum. The lesion may be crusted due to drying of
serous exudate. The induration of the ulcer is probably the best known characteristic.
‘Kissing’ ulcers, sometimes hourglass in shape, are not uncommon. About 50% of
lesions are atypical and lack the classic features. If the infection is
inoculated into pre‐existing lesions such as anal fissures,
genital herpes or balanitis, the chancre may assume the shape of these
conditions. In most cases, there is only a single chancre. Multiple chancres
may appear simultaneously or within a few days of each other. The absence of
any of the typical features of a chancre does not rule out syphilis, however.
Variations in clinical presentation can result from the number of spirochetes
inoculated, the patient's immune status, concurrent antibiotic therapy, and
impetiginization. Patients might not be aware of chancres, especially if
painless and located in areas that are not visible, such as the anus, vagina,
cervix, or oral cavity; in these cases, syphilis is
more frequently diagnosed during the secondary stage.
Common genital locations for a chancre in men include the
glans, near the frenulum, the coronal sulcus, or on the underside of the
prepuce. Retraction of the foreskin when a chancre is present on the underside
causes the foreskin to flip suddenly, a sign known as the dory flop, after the
movement of a dory, a small wooden fishing boat, which flips suddenly when
overturned. The dory flop sign can help distinguish chancres from other
nonindurated causes of genital ulcer disease, such as herpes simplex virus
infection and chancroid that present without the induration that leads to the
sudden flip of the foreskin. Uncommon presentations include giant necrotic
chancre, phagedenic chancre (a deep, bright-red, necrotic ulcer with a soft
base and exudate, resulting from secondary bacterial infection associated with
immunosuppression), phimosis resulting from adherence of a chancre on the
foreskin to the glans, and balanitis. Less commonly, the primary lesion appears
on the shaft of the penis. Less common sites are the pubic region or the
external urinary meatus where it may be mistaken for meatitis associated with urethritis
with scanty serous discharge. Lesions are often surrounded by edema.
In MSM, the anus and rectum may be sites of primary
infection. Anal lesions may present as an indurated fissure. Pain, itching and
bleeding may occur, especially after defecation. Like genital primary lesions, extra
genital sores are accompanied by regional adenitis.
In women, most cases of early syphilis have reached the
secondary stage when diagnosed because the painless primary lesion may be in the
cervix. The most common sites for a vulvar chancre are the labia minora or
majora, around the urethral orifice, on the clitoris or, quite commonly, on the
posterior commissure where it may masquerade as an indurated fissure. Chancres
in women can be more edematous than indurated. A chancre very rarely occurs on
the vaginal wall.
Extra genital chancres in many areas of the body have
been reported. Oral sex is identified as the likely mode of syphilis
acquisition. Chancres may be found on the lips as a result of kissing,
cunnilingus or fellatio. The indurated ulcer may be surrounded by edema.
Chancres of the tongue and tonsil and primary lesions of the fingers also occur
in sexual foreplay. Other extra genital chancres may follow from nibbling or
biting the nipple, ear, neck or arm.
The chancre heals spontaneously in 3–8 weeks without
treatment and 1–2 weeks with treatment. Scarring typically does not occur,
although in about one‐third of cases, it leaves a regularly
edged, slightly depressed, thin, depigmented, atrophic scar.
Relapses of primary syphilis, called monorecidive
syphilis or chancre redux, arise in the setting of untreated or inadequately
treated syphilis and are rare.
The appearance of the
genital and perianal chancre is followed by painless swelling of the inguinal
lymph nodes, initially unilateral. Maxillary and submental lymph nodes enlarge
when infection is in or around the oral cavity. Wherever they appear, the
enlarged glands are discrete, rubbery and freely movable.
SECONDARY SYPHILIS
As defined by CDC surveillance case definitions,
secondary syphilis is a stage of syphilis characterized by localized or diffuse
mucocutaneous lesions, often with generalized lymphadenopathy, in the presence
of laboratory evidence from tissues or sera consistent with syphilis. The
chancre may still be present.
|
Clinical features of
secondary syphilis |
|
1.
Prodromal symptoms and signs: 1.
Weight loss 2.
Low-grade fever 3.
Malaise 4.
Headache (meningeal irritation) 5.
Sore throat 6.
Conjunctivitis (iridocyclitis) 7.
Arthralgia (periostitis) 8.
Myalgias 9.
Hepatosplenomegaly (mild hepatitis) 2.
Generalized lymphadenopathy with indolent enlargement
of lymph nodes (50–85%) 3.
Skin manifestations: 1.
Early (10%): generalized eruption; non-pruritic,
roseola-like, discrete macules, initially distributed on the flanks and
shoulders 2.
Late (70%): generalized maculopapular and
papulosquamous eruptions; more infiltrated lesions, often copper-colored;
annular plaques on the face; corymbose arrangement (satellite papules around
a larger central lesion); occurs in successive waves and is polymorphic 3.
Localized syphilids (specific infiltrations of
treponemes; positive darkfield examination): 1.
palms and soles: symmetric papules and plaques with a
collarette of scale (collarette of Biett) 2.
anogenital area: condylomata lata 3.
seborrheic area: “corona veneris” along the hairline 4.
Hypo pigmented macules, mainly on the neck (post
inflammatory; “necklace of Venus”) 4.
Manifestations involving mucous membranes (30%): 1.
Syphilitic perlèche, split papules 2.
Mucous patches: “plaques muqueuses” in the oropharynx
(equivalent to condylomata lata in the genital area) 3.
Syphilitic sore throat: inflammation of the whole
pharynx 5.
Patchy alopecia (7%): “moth-eaten” localized areas of
hair loss; toxic telogen effluvium |
Lesions of secondary syphilis, classically called
“syphilids” or, when affecting the skin, “syphiloderms,” typically erupt 3–12
weeks after the chancre appears (up to 6 months after exposure). It is characterized by recurrent disease activity, with
mucocutaneous as well as systemic manifestations. Prodromal symptoms include
low-grade fever, malaise, sore throat, adenopathy, weight loss, muscle aches,
and sometimes a headache from meningeal irritation. In up to 25% of
cases lesions of the secondary syphilis develop while the chancre is still
present, with overlap more common among HIV-infected persons. Rash is present
in nearly all cases of secondary syphilis, although the specific type of rash
varies.
Rashes in secondary syphilis have three common features:
The rashes do not itch.
The rashes are coppery red.
The lesions are symmetrically distributed.
The manifestations of generalized treponemal
dissemination first appear as macular at around 8 weeks and become papular by 3
months. The diverse features of secondary syphilis are discussed in the list
below.
Macular syphilide (roseolar rash)
This is the earliest generalized syphilide. It appears as
symmetrical, coppery red, round and oval spots of no substance. On the back,
the lesions clearly follow the lines of cleavage of the skin. When a roseola is
fading, it sometimes leaves a pattern of depigmented spots on a hyper pigmented
background. Such a leukoderma syphiliticum is most commonly located on the back
or sides of the neck and was formerly known as the ‘necklace of Venus’.
Papular syphilide
During the second stage of syphilis, the most commonly
observed clinical presentation (80%) is a generalized, papulosquamous eruption.
The papule is the basic lesion of secondary syphilis. Individual papules seldom
exceed 0.5 cm in diameter. More usually, early papular rashes are in fact
maculopapular, however, a purely papular rash, widely and symmetrically
distributed, may also be seen.
Early papules are shiny, but gradually a thin layer of
scale forms. This is the typical papulosquamous syphilide. A white scaly ring
on the surface of papulosquamous lesions, called Biette's collarette, is
characteristic but not pathognomonic for syphilis. Older lesions tend to be
more pigmented. In the late phases of a popular syphilide, papules and plaques covered
by massive layers of scales may closely resemble psoriasis. Palmoplantar
lesions is present in nearly 75% of cases, may be macular or papular, discrete
or diffuse, and non scaling, slightly scaly, or hyperkeratotic (“syphilitic
corn”). Plantar lesions can also extend to the lateral and posterior aspects of
the foot.
Also highly infectious are condylomalata, which present
as moist, flat, well-demarcated papules or plaques in intertriginous areas, commonly
in the labial folds in females or in the perianal region in all patients. In
men, it frequently occupies the entire surface of the glans penis, the coronal
sulcus and the inner aspect of the prepuce. They may become hypertrophic and,
instead of infiltrating deeply, protrude above the surface, forming a soft,
red, often mushroom-like mass 1–3 cm in diameter, usually with a smooth, moist,
weeping, gray surface. However, any moist intertriginous area of the body can
harbor condylomalata, including the axillae, penoscrotal junction, web spaces
between toes, and the folds under breasts or an abdominal panniculus.
Sometimes, the papules form a line along the hair margin,
the corona veneris. A corymbose syphilide is one with a large central papule
surrounded by small satellite papules.
Annular papules and plaques can be present around the
mouth and nose, in a presentation colloquially referred to as “nickels and
dimes”. Papules and plaques, sometimes annular and occasionally papulosquamous,
can also be present on the penis and scrotum.
Malignant lues is a rare manifestation that presents as sharply
marginated, necrotic ulcers covered by thick, dirty crusts (like oyster shells)
and are more common with coexisting HIV infection.
Syphilitic alopecia
Non-scarring patchy hair loss is characteristic of
syphilis. The hair falls out leaving small, scattered, irregularly thinned,
‘moth‐eaten’
patches of semi‐baldness. Loss of lateral third of the
eyebrows can occur. Syphilitic alopecia may be accompanied by a more
generalized, diffuse alopecia associated with generalized infection and anemia.
Lesions of the mucous membranes
Mucous membrane lesions are present in one-third of
patients with secondary syphilis; they may be the only manifestation of the
infection. Mucous patches are the most characteristic mucous membrane lesions
of secondary syphilis. On the mucous
membranes, the basic papular eruptions are less distinctive, but they tend to
be symmetrically distributed. As the surface epithelium dies, it turns grey and
forms round or oval erosions called mucous patches on the palate or inner
aspects of the lips and cheeks. These mucous patches may coalesce to form
‘snail‐track’
ulcers.
Confluence of mucous patches on the tongue has been termed plaques fauches en
prairie. Mucous patches also present on the genitalia, chiefly in women and are
most common on the labia minora, vaginal mucosa, and cervix. At the corners of
the mouth, they appear as “split papules” with an erosion traversing the
center. Mucous patches are teeming with spirochetes and, hence, highly
infectious. Mucous patches and condylomalata have been reported in 8% and 17%
of patients with secondary syphilis, respectively.
Less common presentations of secondary syphilis include
lichenoid, nodular, follicular, pustular, framboesiform, and palmoplantar keratodermas.
With the exception of mucous patches and condylomalata,
cutaneous manifestations of secondary syphilis do not contain a substantial
number of treponemes and, therefore, are not typically infectious.
Generalized lymphadenopathy
This occurs in 50% of secondary syphilis cases. The lymph
nodes most frequently affected are the inguinal, posterior cervical,
postauricular, and epitrochlear. As in the localized lymphadenopathy of primary
infection, the nodes are painless, discrete, mobile and rubbery.
Neurological involvement
During the secondary stage the central nervous system may
be invaded. Abnormalities in the cerebrospinal fluid (CSF), such as raised cell
count and increased protein, can be found in at least 15% of cases. Less often,
serological tests are positive in the CSF. The patient may complain of headache
only.
In addition, patients with secondary syphilis can
experience systemic symptoms that include (in roughly descending order of
prevalence) sore throat, malaise, headache, weight loss, fever, musculoskeletal
aches, visual disturbances, and hoarseness. Pharyngitis and tonsillitis,
laryngitis, uveitis, gastritis, hepatitis, renal disease (membranous
glomerulopathy), and periostitis have all been reported in secondary syphilis,
as have hematologic abnormalities including lymphopenia, anemia, and elevated
erythrocyte sedimentation rate.
LATENT SYPHILIS
Untreated secondary syphilis typically resolves spontaneously
over a period of 3–12 weeks and the patient enters the latency stage within the
first year of infection when there
are no clinical stigmata of active disease. Diagnosis is based on a
positive syphilis serology test result in the setting of no clinical evidence
of treponemal infection. Latent syphilis therefore is a diagnosis of exclusion,
after signs of syphilis, including those that can be present on accessible
mucosal surfaces (e.g., oral cavity, perineum, perianal area, underneath the
foreskin, labia, vaginal walls, and cervix), have been excluded. Latency may
remain indefinitely, be interrupted by a relapse of secondary syphilis, or
progress to the tertiary stage.
To establish a diagnosis of latent syphilis, strict
criteria are called for. Clinical evidence of active, early, late or congenital
syphilis must be absent; the CSF must be normal and a chest X‐ray
(preferably posteroanterior and left oblique, to view the aorta at a right
angle) must also be normal. Positive (reactive) serological tests for syphilis
(STS) must be confirmed by examination of a second specimen.
For disease surveillance purposes, CDC divides latent
syphilis into three subcategories, early latent, late latent and latent
syphilis of unknown duration. Clinical management of patients with late latent
syphilis and latent syphilis of unknown duration is identical and differs from
clinical management of patients with early latent syphilis.
Early latent
stage: within 1 year of the onset of latency (CDC definition), with the
possibility of recurrence of the disease. Approximately 25% of untreated
patients in the secondary stage may experience a relapse, most of them
(approximately 90%) during the first year, often with mucosal or mucocutaneous
manifestations in the anogenital area. The patient who experiences a relapse
with secondary syphilis is infectious. During this stage vertical transmission
of infection may still occur, but sexual transmission is less likely in the
absence of mucocutaneous lesions.
Early latent syphilis can be diagnosed if, within the
year preceding discovery of the reactive serologic test, a person had one of
the following:
1. Documented
seroconversion or fourfold or greater increase in titer of a nontreponemal
test;
2. Unequivocal
symptoms of primary or secondary syphilis;
3. A
sex partner documented to have primary, secondary, or early latent syphilis; or
4. Reactive
nontreponemal and treponemal tests from a person whose only possible exposure
occurred within the previous 12 months.
Latent syphilis of unknown duration is a subcategory of
latent syphilis that is diagnosed in patients aged 13–35 years who have a
nontreponemal titer ≥32 and in whom early latent syphilis cannot be diagnosed
according to the criteria previously mentioned.
Differentiating persons with latent syphilis of unknown
duration from those with late latent syphilis is important for two reasons.
First, sex partners of those with latent syphilis of unknown duration are
managed like partners of those with primary, secondary, or early latent
syphilis, while partners of those with late latent syphilis are managed less
aggressively, as discussed later. Second, persons with syphilis who do not meet
criteria for early latent syphilis but who, on the basis of their relatively young
age and high titer, are thought to have acquired syphilis—and, possibly, have
transmitted it to sex partners—more recently than persons with late latent
syphilis. Identification and follow up with partners of persons with latent
syphilis of unknown duration compared with late latent syphilis, is more likely
to contribute to syphilis prevention and control efforts.
The
final subcategory of latent syphilis is late latent
stage: after 1 year from the onset of the disease (CDC definition); is
diagnosed in a patient with latent syphilis who cannot be diagnosed with the
above subcategories. Relapses after 1 year are very infrequent. This disease
state may last for many months or years.
The
outcome of late latent syphilis in the absence of treatment: About one-third of infected individuals have
a non-reactive RPR test, no sign of reactivation during the remainder of their
lives, and only the specific antibody assays (e.g. MHA-TP, FTA-ABS) remain
positive. Another one-third of patients remain clinically asymptomatic for the
rest of their lives, but antibodies against cardiolipin (e.g. RPR, VDRL)
persist together with a positive MHA-TP or FTA-ABS assay. In the remaining
one-third, clinical symptoms of tertiary syphilis occur.
The specific antibody assays (e.g. MHA-TP) usually remain
positive.
TERTIARY SYPHILIS
Classic tertiary syphilis, as a consequence of untreated
syphilis, is nowadays rare. After a period of latency of up to 20 years,
manifestations of late syphilis can occur. However, screening for syphilis in
blood donors and pregnant women has contributed greatly to the prevention of
late syphilis. In addition, since the commencement of the antibiotic era, many
people with latent and asymptomatic late syphilis have happened to receive
penicillin or other treponemicidal antibiotics in circumstances unconnected
with syphilis (‘happenstance antibiotic therapy’). Such inadvertent therapy has
also contributed to the decline of late syphilis.
Tertiary syphilis has a
variable range of manifestations that appear months to years after initial
infection. In particular, these include involvement of the skin, bones, CNS,
heart, and great vessels. Approximately one-half of patients with
tertiary syphilis have “benign” late syphilis with the development of gummas,
about one-quarter develops cardiovascular manifestations, and one-quarter
develop neurologic symptoms (with additional overlap of different
manifestations).
In tertiary syphilis, non-treponemal serologic tests are
usually positive with high titers. Patients with tertiary syphilis (or any
symptoms related to late syphilis) should undergo lumbar puncture and CSF
examination to determine if neurosyphilis is present before therapy is
initiated.
“Benign”
late syphilis
Late benign
syphilis refers to signs and symptoms of syphilis that occur after secondary
syphilis that do not involve the cardiovascular or nervous systems. Lesions of
late benign syphilis are caused by delayed type hypersensitivity responses to
the small number of treponemes present in the involved tissue or organ. The
hallmark of late benign syphilis is the gumma, a granulomatous nodular lesion
with variable central necrosis, which most commonly affect the skin, bones,
liver and other organs like tongue and oral cavity, upper respiratory tract,
myocardium, and digestive as well as nervous systems.
Cardiovascular
syphilis
Cardiovascular syphilis has a late onset, with a latent
period of 15–30 years, and it occurs in about 8% of individuals with untreated
infection and was thought to be responsible for most deaths caused by syphilis.
Syphilis typically causes syphilitic aortitis affecting the ascending aorta,
leading to aortic regurgitation, and can also cause coronary ostial stenosis
and saccular aneurysm. T. pallidum DNA has been detected in an aortic aneurysm,
demonstrating that infection of the aorta leads to direct damage to the tissue.
Neurosyphilis
Neurosyphilis—literally, infection of the central nervous
system (CNS) by T. pallidum—is commonly considered to be a manifestation of
“tertiary syphilis,” although neurosypyhilis can in fact occur during any stage
of infection. CDC case definitions for neurosypyhilis are divided into
confirmed (any stage of infection and a reactive CSF-VDRL), and probable (any
stage of infection, a nonreactive CSF-VDRL, elevated protein or white blood
count without other known causes of those abnormalities, and clinical symptoms
or signs of neurosyphilis without other known causes for those symptoms or signs).
“Neuroinvasion,” in which T. pallidum disseminates to
cerebrospinal fluid and meninges, occurs very early in syphilis. Neuroinvasion
can be transient, with the body clearing the infection, or more sustained, in
which case it is called asymptomatic neurosyphilis, defined by CSF
abnormalities but the absence of any neurologic symptoms and signs.
Asymptomatic neurosyphilis, if discovered, is usually treated to prevent
progression to symptomatic neurosyphilis. While in some individuals the CSF
abnormalities may resolve spontaneously or can progress to late symptomatic
neurosyphilis.
Early symptomatic neurosyphilis typically manifests as
meningitis, resulting in meningismus, fever, or cranial nerve abnormalities
(especially cranial nerves II, III, IV, VI, VII, and VIII), or
meningovasculitis, resulting in meningitis with stroke, usually affecting the
portion of the brain supplied by the middle cerebral artery. Uveitis is the
most common ophthalmic manifestation of early neurosyphilis, presenting as eye
pain, redness, and photophobia, and sensorineural hearing loss is the most
common manifestation of otologic syphilis. Ophthalmic and otologic
manifestations of early neurosyphilis are managed in the same way as neurologic
manifestations.
The
two syndromes commonly associated with late neurosyphilis (parenchymatous) are general paresis of
the insane, also known as dementia paralytica, and tabes dorsalis.
Clinicians
diagnosing a person with syphilis should perform a neurologic review of systems
and perform a neurologic examination. According to CDC recommendations,
indications for CSF examination in persons with syphilis include the following:
·
Neurological, ophthalmic
or auditory symptoms and signs.
·
Other clinical evidence
of active infection – aortitis, gumma or iritis.
·
Treatment failure.
·
HIV infection.
·
A non‐treponemal serum titer
of more than 32 if the duration of syphilis is over 1 year.
·
A non‐penicillin‐based treatment regimen
is planned.
Laboratory
diagnosis of neurosyphilis
In addition to the clinical findings, the diagnosis of
neurosyphilis (including acute syphilitic meningitis, meningovascular syphilis
and parenchymatous neurosyphilis) is based upon reactive blood and CSF
serologies, which are almost always positive. CSF abnormalities include
elevation of pressure, protein concentration and immunoglobulin level as well
as a mononuclear pleocytosis. The presence of specific antitreponemal
antibodies in the CSF is mandatory, but it is not proof of the diagnosis of
neurosyphilis, since IgG antibodies can diffuse into the CSF or result from
contamination of the CSF by blood. Establishment of local antibody synthesis is
possible by using the CSF-IgG index, obtained by dividing the CSF to serum IgG
ratio by the CSF to serum albumin ratio. A result >0.7 is indicative of IgG
synthesis in the brain due to local inflammation. The intrathecal T. pallidum
antibody index is calculated by dividing the TPHA titer in the CSF by the CSF
to serum albumin ratio multiplied by a factor of 103, and an index
>100 is indicative of the synthesis of treponemal-specific antibodies within
the CNS. The presence of nonspecific antibodies, e.g. a positive VDRL test or
RPR assay in CSF, is observed in most, but not all, cases, and a negative test
does not exclude the presence of neurosyphilis.
The typical CSF
findings of neurosyphilis consist of:
· Moderate
mononuclear pleiocytosis (10–400 cells/mL)
· Elevated
total protein (0.46–2.0 g/L)
|
MOTHER-TO-CHILD TRANSMISSION OF UNTREATED SYPHILIS AND ITS
CONSEQUENCES |
|
Risk |
|
·
Infection
of the mother from conception to 7th month of pregnancy: risk of transmission
is nearly 100% (often fetal demise or severe congenital syphilis) ·
Infection
at least 2 years before pregnancy: reduced risk of transmission to 50% ·
Infection
during 7th, 8th, or early 9th month: reduced risk of transmission ·
Infection
3–6 weeks before labor: no placental transmission; risk of perinatal
transmission |
|
Consequences of infection |
|
· Spontaneous abortion (second or third
trimester) (10%) ·
Stillbirth
(10%) ·
Infant
death (20%) ·
Congenital
syphilis (20%) ·
Healthy
child (40%) |
Prognosis
The cure rates with initial treatment of early syphilis
are better than 95%. The long‐term outcome of adequately
treated cases is excellent. In late syphilis, infection can usually be arrested
although some treponemes may persist in less accessible sites (e.g. the eye and
nervous system). As long as immune function is normal, this rarely has clinical
sequelae. The outlook for HIV‐positive and other
immunocompromised patients appears to be less assured; however, long‐term
studies in these patients are needed.
Laboratory Diagnosis
of Syphilis
Diagnosis of syphilis depends on clinical suspicion
combined with laboratory testing to directly or indirectly detect infection
with T. pallidum. Of note, in cases where clinical suspicion for syphilis is
high, clinicians should not wait for the results of laboratory testing before
administering appropriate treatment.
The
diagnosis of syphilis is based on the direct detection of treponemes or
treponemal DNA by microscopy or molecular biologic techniques as well as
various serologic tests that assess antibody responses to either cardiolipin
(non-treponemal tests) or treponemal antigens (treponemal tests). Serological testing remains the bedrock of
screening in most settings but the choice of tests will vary; enzyme
immunoassay (EIA) tests are now the most commonly used screening tests. All
patients who have syphilis should also be tested for HIV infection.
Direct Detection of T. pallidum
Dark field Microscopy
Dark field microscopic examination is the diagnostic test
of choice in chancres of primary syphilis and moist lesions of secondary
syphilis (condylomata lata and mucous patches). In primary syphilis, dark field
examination will often be positive before serologic tests become reactive. In
secondary syphilis, it provides immediate confirmation of a clinical diagnosis.
Because nonpathogenic treponemes are normally present in the oral cavity and
can be mistaken for T. pallidum, dark field microscopy cannot be used to test
oral lesions. The number of T. pallidum organisms in secondary syphilis lesions
except for mucous patches and condylomalata is generally not sufficient to
allow dark field diagnosis.
Universal precautions must be used when collecting and
handling dark field specimens, since lesions of syphilis suitable for dark field
examination is very infectious. Dark field specimens are prepared by removing
crusts from the surface of the lesion, cleaning the surface of the lesion with
a sterile saline-soaked gauze, squeezing the base of the lesion with two gloved
fingers to induce the presence of a serous exudate free of red blood cells on
the surface, and collecting the exudate with a glass slide, cover slip, or
bacteriological loop. The slide is examined within 5–20 minutes by a trained
microscopist, using a dark field microscope, for the presence of organisms with
the characteristic morphology and motility of T. pallidum. Sensitivity is
approximately 74%–79%, but declines as minutes elapse, as dead treponemes
cannot exhibit the motility required for diagnosis. Of note, prior application
of a topical antibiotic to a lesion can yield a false-negative dark field
specimen. Repeat testing on two or more consecutive days is advised.
In all highly suspect genital and/or oral lesions where
it proves impossible to demonstrate T. pallidum, lymph node puncture material,
mixed with injected sterile saline (0.5 mL), should be examined. Any treponeme found will always be T. pallidum.
Direct Fluorescence Antibody Test
The lesional exudate is smeared on a glass slide and
stained with fluorescein-labeled
anti-T. pallidum antibodies. In contrast to dark field microscopic examination,
the smear can be held for later evaluation and oral or anal lesions can be
examined because only T. pallidum is stained. The sensitivity of the test is
73%–100%.
Molecular amplification tests
PCR-based
assays for detection of T. pallidum DNA from lesions are commercially
available and may be useful in special circumstances, e.g. neurosyphilis and extragenital primary syphilis for detecting the low
numbers of treponemal products.
Histopathologic Examination
Histopathologic examination is not essential for a
diagnosis of syphilis, which can in many cases be made on the basis of clinical
findings, serologic testing, and, for appropriate lesions and if available,
dark field microscopy. In unusual or questionable cases, however,
histopathologic examination can be useful.
Serological tests
Serologic tests for syphilis include
nontreponemal tests, which detect IgG and IgM antibodies to lipoidal material
released from damaged host cells and possibly from T. pallidum; and treponemal
tests, which detect antibodies to T. pallidum itself. Accurate serologic
diagnosis of syphilis requires both types of test.
Nontreponemal Serologic Tests
The most widely used nontreponemal tests are the rapid
plasma reagin (RPR) and venereal disease research laboratory (VDRL) tests. These
nontreponemal tests are the standard tests, and Reactivity to these tests does not develop until 1–4 weeks
after the chancre appears in primary syphilis. Titers are highest
throughout the secondary phase. The titer
slowly declines after the secondary stage, and it may spontaneously become
negative in some cases of late latent syphilis and neurosyphilis. Cases
of seronegative secondary syphilis in HIV-infected persons have been reported.
Results can be qualitative (reactive/nonreactive) or quantitative. Qualitative non-treponemal
tests are suitable for screening purposes, and reactive results have to be
confirmed by antibody titer. Quantitative results are reported as titer,
which refers to serial dilutions of serum by a factor of 2 (1:2, 1:4, 1:8, and
so on). Titers of these antibodies correlate with
disease activity and are useful in screening and monitoring treatment. The
reported titer represents the most dilute sample that gives a reactive result.
Because of the importance of using nontreponemal titers to assess response to
treatment, a titer for each person diagnosed with syphilis must be obtained on
the day-of-treatment. Without a day-of-treatment titer, it is very difficult to
interpret subsequent titers to determine whether the person has responded to
treatment appropriately.
The performance of a quantitative non-treponemal test is generally
requested even with a positive dark field examination, in order to provide a
baseline for longitudinal evaluation after antibiotic therapy. A fourfold
decrease in the antibody titer indicates successful treatment, while a fourfold
increase indicates relapse or reinfection. In most persons, following appropriate
treatment, nontreponemal titers will revert to nonreactive. In persons treated
for primary syphilis, nontreponemal tests become nonreactive in 60% by 4 months
and in nearly all patients by 12 months. In persons treated for secondary
syphilis, the tests usually become nonreactive 12–24 months after treatment. If
therapy is administered in the early latent stage, nontreponemal tests may
remain reactive in low titers for up to 5 years or longer. Persons with late
latent syphilis may have nonreactive nontreponemal test results, even without a
history of treatment. In some persons nontreponemal antibodies can persist at a
low titer for long periods, and sometimes for life, in what is called a
serofast reaction which, might be more common in HIV-infected persons.
False-negative results occur during very early infection
or in latent and late syphilis. In a small percent of secondary syphilis cases,
very high antibody titers inhibit test reactivity, producing a false-negative
result, called the prozone phenomenon. To exclude the prozone phenomenon the
test must be repeated with diluted serum. Many laboratories do not routinely
check for the prozone phenomeon, so clinicians must request rule out of the
prozone phenomenon in the appropriate setting (e.g., a patient with a
suspicious rash and a negative nontreponemal test result).
Biologic false-positive results
constitute approximately 1% of reactive nontreponemal tests and usually have
low titers (<1:8).
Treponemal Serologic Tests
Specific treponemal serologic tests
include the T. pallidum particle agglutination (TPPA) test, the
microhemagglutination assay for T. pallidum (MHA-TP), the fluorescent
treponemal antibody absorption assay (FTA-ABS), the T. pallidum haemagglutination
test (TPHA), and treponemal enzyme immunoassays (EIAs). These tests, which use
whole or fragments of T. pallidum as antigen, directly detect infection with T.
pallidum. They are used to confirm syphilis, since a reactive treponemal test
result essentially rules out the possibility of a biologic false positive
reaction on a nontreponemal test. A reactive nontreponemal test result followed
by a reactive treponemal test result, hence, confirms a diagnosis of syphilis.
The specificity is very high and biologic false-positive reactions seldom
occur. The sensitivity varies with the stage of syphilis: between 70% and 100%
in primary syphilis, 100% in secondary and latent syphilis, and about 95% in
late syphilis. These specific treponemal tests are also positive earlier than
the nontreponemal tests and may be used to confirm the diagnosis of primary
syphilis in a patient with a negative RPR/VDRL.
EIA tests are available that detect
both IgG- and IgM specific antibodies against T. pallidum. The IgM
becomes detectable 3 weeks after infection (around the time of the appearance
of the chancre). The IgG test becomes positive at 4–5 weeks, so the IgM test is
much more useful in diagnosing primary syphilis.
The IgM EIA test, however, becomes
negative following treatment in early syphilis, so that at 1 year, 92% of
treated early syphilis patients are negative on the IgM EIA.
Persons who have had syphilis usually
will have reactive treponemal test results for life, even after successful
treatment, making a reactive treponemal test in a person with a history of
syphilis generally not useful clinically. However, 15%–25% of treponemal tests
become nonreactive between 2 and 3 years after treatment of primary syphilis.
False-positive results in treponemal
tests are also rare but have been associated with infections, autoimmune or
connective tissue disease, or narcotic addiction. All positive results are
confirmed by another treponemal test.
A new algorithm is followed for
laboratory diagnosis of syphilis. In this newer algorithm, a treponemal EIA is
performed first rather than nontreponemal tests as the first step. If and only
if that EIA result reactive, a nontreponemal test is performed. Reactive
results on both tests confirm a diagnosis of syphilis. In some cases, a
reactive treponemal EIA result is followed by a nonreactive nontreponemal test
result. In those cases, a tie-breaker test, usually consisting of an alternate
treponemal test, can be performed, with data combined with clinical suspicion
to determine diagnosis and treatment. A nontreponemal RPR/VDRL is also
performed on all positives to determine the titer and monitor treatment
success.
New algorithm for syphilis serology testing
|
LIMITATIONS OF NON-TREPONEMAL
AND TREPONEMAL TESTS |
|
Non-treponemal tests |
|
1.
Lack of reactivity in early dark field-positive primary
syphilis 2.
Usually become negative with effective therapy (~15% of
patients with early syphilis do not achieve a fourfold decline in titers 1
year after appropriate treatment, which is considered to represent a
therapeutic failure) 3.
False-negative results 1.
Prozone phenomenon: inhibition of flocculation in the
setting of high titers of antibodies; requires serum dilution 2.
Temporary negative result: secondary syphilis in the
setting of HIV infection; reactive on subsequent testing 4.
Biologic false-positive results due to tissue damage 1.
Pregnancy 2.
Autoimmune diseases (e.g. lupus erythematosus) 3.
Drug abuse 4.
Lymphomas 5.
Infectious diseases (e.g. malaria) 6.
Vaccinations 7.
Hepatic cirrhosis 8.
Antiphospholipid syndrome 9.
Idiopathic, familial 5.
False-positive: endemic treponematoses and borreliosis |
|
Treponemal tests |
|
1.
Lack of reactivity in early dark field-positive primary
syphilis 2.
Remain positive indefinitely, so not useful for
monitoring response to treatment 3.
Biologic false-positive: autoimmune diseases, HIV
infection, hypergammaglobulinemia 4.
False-positive: endemic treponematoses and borreliosis |
Overview of the diagnosis tests in syphilis
Most
specific test: DG microscopy
Most
specific blood test: TPHA/TPPA
Most
sensitive blood test: IgM-FTA-Abs/EIA
Test
for monitoring Rx: VDRL
Time
taken for seropositivity in primary syphilis
EIA (IgM)/IgM-FTA-Abs =3 weeks
TPHA/TPPA= 4-6 weeks
VDRL/PRP = 5 weeks
Management overview
Parenteral penicillin G is the preferred drug at all
stages of syphilis, with the preparation, dose, and length of treatment
dependent on the clinical manifestations, stage of disease, and age of the
patient Penicillin remains not only the most effective treponemicide, but it is
easy to administer, has few side effects and is relatively inexpensive.
A treponemicidal level of the antimicrobial should be
achieved in the serum and (for patients with neurosyphilis) in the CSF. Results
continue to be excellent for all forms and stages of treponemal disease, and
there are no signs that T. pallidum has developed resistance to this
antibiotic. Injectable penicillins are generally preferred to oral preparations
because of problems of patient compliance and uncertain absorption from the
gastro‐intestinal
tract. Benzathine
penicillin G, the recommended preparation of penicillin
for most stages of syphilis, has a long half-life, which is critical therapeutically
because of the slow dividing time of T. pallidum and is the treatment of choice
for primary, secondary, or latent syphilis.
Adequate treatment requires the maintenance of serum
concentrations in excess of 0.03 units/mL for at least 10 days. A single
intramuscular dose of 0.6 mega units of aqueous procaine penicillin gives an
effective serum concentration for at least 24 h; in comparison, a single
intramuscular dose of 2.4 mega units of benzathine penicillin G maintains
effective levels for about 2 weeks. As this preparation may cause pain on
injection, 1.2 mega units are usually given in the upper and outer quadrant of
each buttock.
Treatment of late syphilis theoretically may require a
longer duration of therapy because organisms are dividing more slowly. The
penetration of aqueous procaine penicillin into the CSF (as into the aqueous
humour) is poor; that of erythromycin is poorer and that of benzathine
penicillin poorest of the three. For treatment of neurosyphilis, high dosages
of procaine penicillin, plus probenicid, should be considered. Desensitization
of penicillin‐allergic
patients is recommended.
Penicillin-allergic persons with syphilis who are not
pregnant and do not have neurosyphilis may be treated with doxycycline;
however, success is less assured than with penicillin. Azithromycin, given in
dosages of 500 mg daily for 10 days, or in a single 2 g dosage, has recently
been successful, but there are concerns about the emergence of antimicrobial
resistance.
All patients with syphilis should be offered screening
for other sexually transmitted infections and HIV. Serological testing for HIV
should be repeated after 3 months in those persons presenting with primary
syphilis who initially test negative.
Therapeutic ladder
Early syphilis (primary, secondary, and
early latent [acquired <1 year previously])
|
Recommended: 1. Benzathine
penicillin G, 2.4 million units IM
single dose or ×2 (days 1 and 8) 2. Procaine
penicillin G, 0.6 million units IM once daily for 10 days |
|
Alternative regimens
for penicillin-allergic patients: 1.
Doxycycline 100 mg orally twice daily
for 14 days 2.
Erythromycin 500 mg orally four times
daily for 14 days 3.
Azithromycin 500 mg orally daily for
10 days or Azithromycin, 2 g po as a single dose 4.
Ceftriaxone 500 mg IM daily for 10
days (if no anaphylaxis to penicillin) |
|
Late latent (acquired >1 year previously or of unknown
duration), cardiovascular and gummatous syphilis; retreatment of primary,
secondary or latent syphilis after failed initial treatment¶ |
|
Recommended: 1.
Benzathine penicillin G, 2.4 million
units IM weekly ×3 (days 1, 8 and 15) 2.
Procaine penicillin G, 0.6 million
units IM daily for 17 days |
|
Alternative regimens
for penicillin-allergic patients: 1.
Doxycycline 100 mg orally twice daily
for 28 days 2.
Amoxicillin 2 g orally three times
daily plus probenecid 500 mg orally four times daily for 28 days ¶ E.g. if RPR/VDRL titers fail to
decrease fourfold or symptoms persist/progress; must first examine the CSF to
exclude neurosyphilis. |
|
Neurosyphilis and ocular syphilis |
|
Recommended: 1.
Procaine penicillin G, 2.4 million
units IM daily plus probenecid 500 mg orally four times daily, both for 17
days (probenecid increases brain concentrations
of penicillin less than it increases CSF
concentrations, but avoid using it if the patient has a history of serious
allergy to sulfonamides) 2.
Aqueous penicillin G, 18–24 million
units daily, given as 3–4 million units IV every 4 h for 17 days |
|
Alternative regimens
for penicillin-allergic patients: |
|
1.
Ceftriaxone, 2 g im or iv qd for 10–14 days 2. Doxycycline 200 mg orally twice daily for 28
days 3.
Amoxicillin
2 g orally three times daily plus probenecid 500 mg orally four times daily
for 28 days 4.
Consider desensitization |
Pregnant women: only penicillin‐based
regimens have documented. Pregnant women who are penicillin-allergic must be
desensitized to and treated with penicillin, which is the only drug that is
known to cross into the placenta and treat infection in the fetus. Those women
who have had documented treatment for syphilis in the past do not need
retreatment in current or subsequent pregnancies so long as there is no
clinical evidence of syphilis, and the VDRL or RPR titer is negative.
|
Recommended: |
|
1.
Benzathine penicillin G, 2.4 million units IM weekly
for two (early syphilis) or three (late syphilis) doses or 2.
Procaine penicillin, regimen appropriate for the stage
of syphilis |
|
In the case of
penicillin allergy: |
|
1.
Desensitization to penicillin or 2.
Alternative regimens*: 1.
Azithromycin, 500 mg qd for 10 days or 2.
Ceftriaxone, 1 g IM or IV qd for 10–14 days |
* Limited data; not recommended by the Centers for
Disease Control (CDC) but included in the World Health Organization (WHO) and
European Branch of the International Union against Sexually Transmitted
Infections (IUSTI) guidelines.
HIV‐seropositive individuals: it
is recommended that CSF examination be performed in all patients with syphilis
who are HIV seropositive. Generally, recommended regimens are the same as those
in HIV‐negative
individuals if CSF examination is normal. Ceftriaxone has been successfully
used.
Complications of
Treatment
The Jarisch–Herxheimer reaction is a self-limited
clinical syndrome consisting of fever, headache, and flare of mucocutaneous
lesions, tender lymphadenopathy, pharyngitis, malaise, myalgias, and
leukocytosis. It occurs within 12 hours of initiating therapy and resolves
within 24–36 hours. The fever peaks 6–8 hours after the onset, usually around
39°C (102.2°F), but it can be as high as 42°C (107.6°F). It must be
differentiated from penicillin allergy. Patients should be warned about the
possibility of developing this reaction before receiving treatment. Acetaminophen can
be used to attempt to diminish the reaction, although very little evidence of
its effectiveness exists. The patient should be encouraged to rest, maintain
fluid intake, and seek medical attention if symptoms are severe. The
pathogenesis of the Jarisch–Herxheimer reaction is unknown, but is thought to
result from cytokine release mediated by the release of lipoproteins from dying
T. pallidum organisms. In pregnant patients, the Jarisch–Herxheimer reaction
may lead to premature contractions or loss of fetal movement, events that
should prompt the patient to seek evaluation. In late neurosyphilis and
cardiovascular syphilis, the Jarisch–Herxheimer reaction can be more serious
and may be associated with life‐threatening sequelae. Many
clinicians advocate a short course of corticosteroids to lessen its effects in
these patients. One such regimen is to prescribe oral prednisolone 30–60 mg
daily for 3 days, beginning syphilis treatment 24 h after the first dose.
Anaphylaxis from administration of penicillin injection
is a life-threatening emergency that is managed by intramuscular injection of epinephrine and
diphenhydramine
with hydrocortisone
intravenously along with emergent transfer to a monitored setting. If
penicillin is used in patients with a history of allergy, it is advisable to
keep the patient under observation for 15–20 min after the injection. An
emergency kit should always be available.
At the time of initial treatment, patients should be
educated to distinguish an allergic reaction, which precludes further treatment
with penicillin or related drugs, from a Jarisch–Herxheimer reaction, which
does not.
CDC Recommendations for Treatment and Follow-Up of Adults with
Primary, Secondary, or Early Latent Syphilis
|
Stage of Disease |
HIV Status of Person |
Recommended Treatment |
Alternative Treatment for
Penicillin-allergic Persons (Non-Pregnant Women Only A) |
Schedule for Follow-up After
Treatment B |
Timeframe to Expect Fourfold
Decline in Titer C |
|
Primary or secondary |
HIV-uninfected |
Benazthine penicllin G, 2.4 million
units, administered intramuscularly in a single dose |
Doxycycline 100 mg orally twice daily for 14 days |
6 and 12 months |
6–12 months |
|
HIV-infected |
Benazthine penicllin G, 2.4 million
units, administered intramuscularly in a single dose |
Doxycycline 100 mg orally twice daily for 14 days |
3, 6, 9, 12, and 24 months |
6–12 months |
|
|
Early latent |
HIV-uninfected |
Benazthine penicllin G, 2.4 million
units, administered intramuscularly in a single dose |
Doxycycline 100 mg orally twice daily for 14 days |
6, 12, and 24 months after treatment |
12–24 months |
|
HIV-infected |
Benazthine penicllin G, 2.4 million
units, administered intramuscularly in a single dose |
Doxycycline 100 mg orally twice daily for 14 days |
6, 12, 18, and 24 months |
12–24 months |
A. Pregnant
women must not be treated with doxycycline.
If allergic to penicillin, pregnant women must be desensitized and then treated
with benzathine penicllin G.
B.
In practice, many experts advocate follow-up every 3 months for all persons.
Additionally, some persons (e.g., MSM or women who become pregnant) should be
screened appropriately in addition to being followed at the recommended
intervals to assess clinical and serologic response to treatment.
C.
If titers have not declined fourfold after the stated time frame, consider
reinfection, treatment failure, or neurosyphilis. If at any time after
treatment signs or symptoms of syphilis appear, also consider those same three
possibilities.
Note
that initial treatment is the same for HIV-uninfected and HIV-infected persons.
Post treatment
evaluation of syphilis
Serologic
response to treatment
Clinical and
serologic follow-up is important to monitor response to treatment. Treatment
success is generally defined as a fourfold decline in serologic nontreponemal
titer (or reversion to nonreactive result) following appropriate treatment, in
the absence of persistent signs or symptoms of syphilis, and within a specified
timeframe depending on stage of infection and HIV infection status of the
infected person. The lower the serologic titer before treatment, the quicker
the blood test result will revert to normal. Patients with their first attack
of primary syphilis will have a nonreactive RPR result within 1 year. Patients
with secondary syphilis will have a nonreactive RPR test result within 2 years.
Patients with early latent syphilis of less than 1-year’s duration will have
negative serologic findings within 4 years. Of patients with late latent
syphilis, 45% will have negative serologic test results in 5 years, and the
remainder will have reagin fast reactions.
In about 5%
of successfully treated patients, who are described as being ‘reagin fast’, low
titer positivity in these tests may persist for life.
Frequency
of follow-up serologic tests
All patients treated for syphilis must
be followed to assess the effectiveness of initial treatment. Quantitative
nontreponemal tests (VDRL or RPR) to be performed at 3 and 6 months following
antibiotic treatment of early syphilis, then every 6 months for up to 2 years
post treatment. At least a four-fold decrease in titer (e.g. a 1:64 titer
declining to 1:16 or lower, or a 1:16 titer declining to 1:4 or lower) would be
expected 6 -12 months after therapy for patients with primary or secondary
syphilis and 12–24 months after therapy for patients with early latent
syphilis. Persons whose titers do not decline HIV testing (if HIV status is
unknown) and CSF evaluation are recommended.
Treatment failure should be considered for any patient who has a sustained
a fourfold increase in titer (i.e. compared with the baseline titer at the time
of treatment) or when an initially high titer does not show a fourfold decrease
after the stated time frame and the development of symptoms or signs
attributable to syphilis. These patients should receive additional clinical and
serological follow-up. If additional follow-up cannot be ensured, re-treatment
is recommended. Because treatment failure might be the result of unrecognized
CNS infection, CSF examination can be considered in such situations. HIV
testing should also be recommended. In the setting of abnormal CSF findings, a
CSF examination is recommended at 6-month intervals until cell counts are
normal and the CSF-VDRL is negative. For re-treatment, weekly injections of
benzathine penicillin G 2.4 million units IM for 3 weeks are recommended.
Evaluation of late syphilis at 6-month intervals for up to 3 years is
recommended.
Management of sexual
contacts
Clinicians should routinely encourage persons diagnosed
with syphilis to inform their sex partners of exposure to syphilis and
follow-up with patients to assure that disclosure has occurred. Identifying
which sex partners are at risk of infection depends both on the elapsed time
since last exposure and stage of infection in the source patient. This risk
period is 3 months plus duration of symptoms for primary syphilis, 6 months
plus duration of symptoms for secondary syphilis, and 1 year for early latent
syphilis and latent syphilis of unknown duration.
Management of at-risk sex partners of persons diagnosed
with syphilis also depends on elapsed time since exposure. Many clinicians
recommend presumptive treatment of all sexual contacts within the 90‐day
period preceding patient presentation of early syphilis if serological test
results are not immediately available and if follow‐up
cannot be assured.
