bubble_chart Overview

This disease is a chronic sexually transmitted infection caused by the Treponema pallidum, also known as the syphilis spirochete. It can invade the skin, mucous membranes, and various other tissues and organs, presenting with diverse clinical manifestations. During its course, the disease may sometimes remain in an asymptomatic latent state. The pathogen can be transmitted to the fetus through the placenta, leading to congenital syphilis.

bubble_chart Epidemiology

Syphilis patients are the only source of infection. Sexual contact accounts for 95% of transmissions. The infection primarily occurs through sexual intercourse via damaged areas, with syphilis spirochetes abundantly present on the surfaces of skin and mucous membrane lesions, as well as in saliva, breast milk, semen, and urine. Untreated patients are most infectious within the first year of infection, with infectivity decreasing over time. Those with a disease duration exceeding four years are no longer infectious through sexual contact. The bacteria can also invade through dry skin and intact mucous membranes. A small number of cases may result from close contact such as kissing or breastfeeding, but only if syphilis spirochetes are present at the contact site. Since syphilis spirochetes are anaerobic, they struggle to survive outside the body and are highly sensitive to drying, making indirect transmission through objects extremely rare. Blood transfusion from a syphilis-infected donor can transmit the disease to the recipient. Congenital syphilis occurs when an infected pregnant woman transmits the bacteria to the fetus through placental blood flow. Typically, during the first four months of pregnancy, the protective role of the trophoblast prevents syphilis spirochetes from crossing, so the fetus remains uninfected. After this period, as the trophoblast atrophies, the spirochetes can cross the placenta and infect the fetus.

bubble_chart Pathogen

The syphilis spirochete is difficult to stain due to its transparency and is therefore called Treponema pallidum. It can be stained pink with Giemsa stain. It is a type of treponema, appearing as a soft, slender spiral resembling metal shavings, measuring 6–12 μm in length and 0.09–0.18 μm in width, with 8–12 evenly spaced spirals. Under dark-field microscopy, the spirochete floats in tissues and exhibits three characteristic movements: (1) rotational, where it spins along its long axis and moves forward or backward—this is the primary mode of invasion into the human body; (2) extension and contraction of the spiral intervals, elongating its body, attaching one end, and then contracting the spiral distance to advance; and (3) serpentine, bending like a crawling snake—the most common movement, which helps distinguish it from other spirochetes in the genital region. Morphologically, the syphilis spirochete cannot be distinguished from the yaws spirochete or the pinta spirochete.

The syphilis spirochete should be differentiated from other spirochetes in the genital region, primarily Borrelia refringens and Borrelia balanitidis. The key distinguishing features are that these two spirochetes are thicker, have fewer coarse spirals, and are less motile than the syphilis spirochete. Although Borrelia gracilis has finer and denser spirals, the spacing between its spirals is not as tight as that of the syphilis spirochete, nor does it exhibit the typical movement patterns of the syphilis spirochete. Normal oral mucosa also harbors various spirochetes, the most common being Treponema microdenticum around the gums, which resembles the syphilis spirochete and can easily be confused with it.

Under electron microscopy, the syphilis spirochete appears as a small, unevenly stained snake-like structure with two bundles of filaments (filamenta) at each end, winding around the bacterial body. Each bundle consists of three separate fibril strands located in the cytoplasm at either end of the bacterium. When the spirochete contracts, it generates movement. These filaments were previously mistaken for "flagella," but it has now been confirmed that they are an artifact caused by the rupture of fibril bundles. The syphilis spirochete is surrounded by a thin membrane and contains cytoplasm (periplast), a sac-like structure (capsula stractula), and a treponemal cyst. These are easily observed in cultured strains and can also be seen in virulent strains, though their significance remains unclear.

The syphilis spirochete has three layers of cytoplasmic membranes externally, enveloped by a soft yet relatively sturdy mucoprotein to maintain its structure. This membrane possesses a certain strength, with its outer layer rich in lipids and containing small amounts of protein. Six internal flagella rotate in the space between the inner cell wall and the outer cytoplasmic membrane, likely serving as the contractile components responsible for movement. The surface of the syphilis spirochete carries specific antigens that stimulate the body to produce specific agglutinating antibodies and treponemal immobilizing or lysing antibodies, which cross-react with non-pathogenic treponemes. Group-specific antigens stimulate the production of complement-binding antibodies, which also cross-react with non-pathogenic treponemes.

The reproductive mode of the syphilis spirochete depends on its living environment. Recent electron microscopy observations show that under culture conditions or in a suitable in vivo environment, it reproduces by transverse fission, splitting the body into longer and shorter segments. Its generation time for division is 30–33 hours. Under unfavorable conditions, it reproduces via budding, where the spirochete produces buds along its body. Once detached from the parent, under favorable conditions, filamentous sprouts emerge from the buds and develop into spirochetes.

The virulent strain of syphilis spirochete (Nichols strain) can be propagated by inoculation in rabbit testes or anterior chambers of the eye, requiring approximately 30 hours to divide once while maintaining virulence. If transferred to rabbit testicular tissue fragments supplemented with various amino acids and cultured under anaerobic conditions, using a special medium containing albumin, sodium bicarbonate, pyruvate, cysteine, and serum ultrafiltrate, the spirochetes can retain motility for 4-7 days at 25°C in an anaerobic environment. Although the syphilis spirochete can grow and reproduce under these conditions, it loses its pathogenicity, and this strain is called the Reiter strain. Both the Nichols strain and Reiter strain have been widely used as diagnostic antigens for various syphilis serological tests.

The successful artificial cultivation of syphilis spirochetes was achieved in 1981 by Fieldsteel and others, building upon previous research. They used a monolayer of cotton-tail rabbit epithelial cells and cultured them in an atmosphere with 1.5% oxygen. After 9 to 12 days of incubation, the number of spirochetes increased by an average of 49 times compared to the initial inoculation. The DNA strain of the spirochetes retained its virulence in rabbits. Within the epithelial cell monolayer, the spirochetes tightly adhered to the surface and proliferated, forming microcolonies. This adhesion could be inhibited by specific immune serum. Dead syphilis spirochetes or non-pathogenic spirochetes were unable to adhere to the monolayer of epithelial cells.

Syphilis spirochetes are anaerobic organisms that can survive for long periods in the human body but struggle to survive outside it. Drying, soapy water, and common disinfectants such as 1:1000 phenol, benzalkonium bromide, and diluted alcohol can kill them within a short time. They die after 1–2 hours of drying. In blood stored at 4°C, they perish after 3 days, so blood stored in a blood bank refrigerator for more than 3 days is no longer infectious. Temperature also greatly affects syphilis spirochetes: they can survive for 1–2 hours at 41–42°C, lose infectivity after just half an hour at 48°C, and die immediately at 100°C. They are highly resistant to cold, surviving for 48 hours at 0°C. If a syphilis-infected specimen is stored in a refrigerator, it can still cause infection after a week. When preserved at low temperatures (-78°C), they can maintain their morphology, motility, and virulence for several years. In sealed physiological saline-diluted tissue fluid, they can survive for about 10 hours. They can also survive for several hours on damp utensils or wet towels. Syphilis spirochetes are extremely sensitive to drying and die rapidly in dry environments.

Syphilis spirochetes only infect humans, making humans the sole source of syphilis infection. Currently, there is no evidence that syphilis spirochetes produce endotoxins or exotoxins. Some researchers believe that two substances may be related to their pathogenicity: mucopolysaccharides and mucopolysaccharidase.

Mucopolysaccharides: The capsule-like mucopolysaccharides on the surface of spirochetes protect them from harmful environmental factors. An intact capsule-like mucopolysaccharide layer is essential for the reproduction and survival of syphilis spirochetes. Swin et al. placed pathogenic treponemes in a culture medium lacking the substances required for capsule formation, leading to the degradation of the capsule-like mucopolysaccharides on the spirochete surface, causing the spirochetes to die without reproducing. In the body, the syphilis spirochete capsule prevents large molecules (such as antibodies) from penetrating, thereby protecting the organism. Additionally, the capsule has anti-phagocytic effects.

Mucopolysaccharidase: This enzyme acts as a bacterial receptor, adhering to the hyaluronic acid on host cell membranes. The mucopolysaccharidase of syphilis spirochetes is closely related to their adhesion to tissue cells, the decomposition of tissue matrix, and the synthesis of the syphilis spirochete capsule. Animal experiments have found that in testicular and skin tissues infected with syphilis spirochetes, many actively motile spirochetes adhere to tissue cells at their ends. Tissue culture studies show that various cells can adsorb syphilis spirochetes, with each cell capable of adsorbing up to 200 spirochetes. Mucopolysaccharidase can decompose the mucopolysaccharide matrix of tissues, providing raw materials for the synthesis of the syphilis spirochete capsule and causing tissue injury. Research confirms that syphilis spirochetes first tightly adhere to the inner walls of capillaries, decompose the matrix mucopolysaccharides, and then mucopolysaccharidase disrupts the integrity of the supporting mucopolysaccharides around the blood vessels.

Different strains of syphilis spirochetes exhibit variations in virulence. The more virulent strains form lesions containing more mucoid substances, and these highly virulent strains show higher mucopolysaccharidase activity, enabling better adhesion to cells. Syphilis spirochetes require tissues rich in mucopolysaccharides to adhere, survive, reproduce, and cause disease. Mucopolysaccharides can affect nearly all tissues in the body. However, since mucopolysaccharide content varies among tissues, the degree of syphilis spirochete proliferation differs across tissues. Syphilis spirochetes exhibit higher affinity for tissues such as skin, aorta, eyes, placenta, and umbilical cord because these tissues contain abundant mucopolysaccharide matrices. Consequently, syphilis lesions predominantly occur in tissues with high mucopolysaccharide content, demonstrating a certain tissue tropism. Additionally, the transmission of syphilis spirochetes from mother to fetus only occurs after 18 weeks of pregnancy, as the placenta and umbilical cord are fully developed by then and contain large amounts of mucopolysaccharides.

In summary, the pathogenic nature of syphilis spirochetes is attributed to the mucopolysaccharide capsule-like structure on their surface, which contains N-acetyl-D-galactosamine that the spirochetes cannot synthesize on their own and must obtain from host cells. The syphilis spirochetes adhere to mucopolysaccharide receptors on the surface of host tissue cells via their mucopolysaccharidase, breaking down the host cells' mucopolysaccharides to acquire the materials needed for capsule synthesis. Since mucopolysaccharides are crucial matrix components of host tissues and vascular scaffolds, their degradation by syphilis spirochetes leads to tissue injury and destruction, resulting in vascular collapse, impaired blood supply, and subsequent conditions such as obliterative endarteritis, periarteritis, necrosis, and ulcers.

bubble_chart Pathogenesis

After the syphilis spirochete enters the human body through intact mucous membranes or abraded skin, it invades nearby lymph nodes within hours and disseminates throughout the body via the bloodstream within 2–3 days. Therefore, systemic infection and metastatic sexually transmitted disease lesions occur long before the appearance of a hard chancre, making the blood of patients in the latent stage or early syphilis infectious. The length of the incubation period is inversely proportional to the number of inoculated pathogens. Generally, clinical lesions appear only when the number of spirochetes reaches at least 10^7 per gram of tissue. If 10^6 spirochetes are injected intradermally, lesions often appear within 72 hours. Volunteer inoculation studies calculated the median infective dose (ID50) to be 57 pathogens, and an average inoculation of 500–1,000 infectious pathogens can cause the disease. Experimental inoculations in humans and rabbits show that the time from inoculation to the appearance of primary sexually transmitted disease lesions rarely exceeds six months. During this incubation period, treatment regimens below curative doses can delay the onset of hard chancre, but whether they reduce the ultimate progression of systemic lesions remains uncertain.

After entering the human body, syphilis undergoes a 2–3 week incubation period (called the first latent period), followed by skin lesions (typically hard chancre), marking the initial stage [first stage] syphilis. After skin lesions appear, the body produces antibodies. Studies on experimental rabbit syphilis demonstrate that the histological feature of initial stage [first stage] syphilis is mononuclear cell infiltration, with lymphocytes appearing by the 6th day of infection, peaking at 13 days, followed by macrophages. The infiltrating lymphocytes in the lesions are predominantly T-cells. At this stage, syphilis spirochetes are found in the intercellular spaces of the hard chancre’s epithelial cells, as well as in inward invasions or phagosomes of epithelial cells, or between fibroblasts, plasma cells, small capillary endothelial cells, and in lymphatic vessels and local lymph nodes. Due to immune responses, syphilis spirochetes are rapidly cleared from the lesion middle consumptive thirst. By the 24th day of infection, immunofluorescence tests no longer detect syphilis spirochetes. Most spirochetes are killed, the hard chancre naturally disappears, and the infection enters an asymptomatic latent period, known as initial stage [first stage] latent syphilis. Previously, latent syphilis was mainly detected via serological tests, but now genetic diagnosis allows for rapid and accurate detection.

Unkilled spirochetes continue to multiply in the body. After about 6–8 weeks, large numbers of spirochetes enter the bloodstream and disseminate throughout the body, causing intermediate stage [second stage] early syphilis, damaging the skin, mucous membranes, bones, eyes, and the nervous system. Spirochetes of intermediate stage [second stage] syphilis can be found in many tissues, such as skin rashes, lymph nodes, aqueous humor, and cerebrospinal fluid. As the body’s immune response strengthens, producing large amounts of antibodies, most spirochetes are killed again, and intermediate stage [second stage] early syphilis naturally disappears, re-entering a latent state, now termed intermediate stage [second stage] latent syphilis. Although clinically asymptomatic at this stage, residual spirochetes may have the opportunity to multiply again. When the body’s resistance declines, spirochetes re-enter the bloodstream, causing intermediate stage [second stage] recurrent syphilis. Before the antibiotic Suwen era, patients could experience one or multiple systemic or localized skin and mucous membrane recurrences, with 90% of recurrences occurring within the first year. Subsequently, as immunity fluctuates, the disease alternates between activity and latency. When immunity strengthens, spirochetes may become granular or spherical. When immunity declines, spirochetes invade certain body parts again, leading to recurrence. After about two years of such cycles, approximately 30–40% of patients progress to advanced stage syphilis.

In advanced stage syphilis, typical gummas appear. If there are no symptoms, and chest, heart blood vessel imaging, and cerebrospinal fluid tests are negative, with only positive syphilis serological tests and PCR detection, it is termed advanced stage latent syphilis. Advanced stage syphilis often affects the skin, mucous membranes, bones, heart blood vessels, and the nervous system. Some patients may experience a decline in syphilis serum titers, eventually turning negative, with PCR tests also negative, indicating natural recovery.

The above describes the typical progression without any treatment, but due to immune differences and therapeutic interventions, clinical manifestations vary greatly. Some patients may remain latent for life, while others exhibit only initial stage [first stage] symptoms without intermediate stage [second stage] manifestations, or solely present late stage [third stage] syphilis symptoms.

Pathophysiological studies indicate that syphilis is a chronic disease. Although there are large numbers of Treponema pallidum in the initial lesions, syphilis is not a simple inflammatory reaction caused directly by the release of toxic or inflammatory substances or by the presence of Treponema pallidum in the tissues. In the cellular infiltration of the primary injury, mononuclear cells dominate the acute inflammatory response, while polymorphonuclear leukocytes play a secondary role. In the initial stage [first stage] of syphilis infection, a large number of Treponema pallidum are present outside the cells near the proximal bleeding vessels.

Another prominent feature of syphilis is the absence of a fever response. Initial stage [first stage] syphilis does not present with fever, while intermediate stage [second stage] syphilis may exhibit grade I fever. Treponema pallidum is highly sensitive to temperatures slightly above normal human body temperature, which is why it does not produce pyrogenic substances. This is also essential for the survival of Treponema pallidum.

The immunity of syphilis is not yet fully understood. It is currently believed that there is no innate immunity to syphilis, and acquired immunity is generally weak, unable to prevent reinfection. The immunity in syphilis is pestilential immunity, meaning that immunity exists only when the body is infected with the spirochete. It is generally thought that after the initial stage [first stage] chancre develops, the body's immunity to syphilis also emerges and increases, reaching its peak during the intermediate stage [second stage] rash period, and then slightly declining. After the initial stage [first stage] chancre appears and before the intermediate stage [second stage] syphilis rash emerges, there is no reaction to reinfection, and no hard chancre develops. During the active phase of the intermediate stage [second stage], the body's immunity reaches its highest level, potentially leading to a clinically latent period. However, if the body's immunity declines due to internal or external environmental factors, recurrent rashes may appear. Generally, the longer the infection persists, the more stable and prolonged the latent period becomes, and the fewer the recurrences. In advanced stage syphilis, due to the lower number of spirochetes in the lesions, the immune stimulation is weaker, leading to slower immune development. Consequently, the lesions persist longer, and the reaction to reinfection is less pronounced, with no hard chancre developing. If syphilis is completely cured, reinfection can result in a hard chancre.

The humoral and cellular immune responses that appear early in syphilis play a crucial role in clearing Treponema pallidum, while the cellular immune responses that emerge in the advanced stage cause tissue damage. At all stages of infection, the host can produce antibodies against various Treponema pallidum polypeptide antigens and certain autoantigens, sometimes forming immune complexes. Syphilis infection also exhibits varying degrees of immunosuppression.

Treponema pallidum is a highly complex microorganism containing numerous antigenic substances. Under electron microscopy, the outermost layer of Treponema pallidum is the outer membrane, inside which lies the cytoplasmic membrane, with flagella located between the two. The flagella and outer membrane polypeptides of Treponema pallidum are highly antigenic. Surface polypeptide antigens of Treponema pallidum, such as the 190, 47, and 25–28 KD antigens, can induce strong antigenic reactions, indicating their important role in protective immune responses.

The surface protein antigens of pathogenic spirochetes can be divided into genus-, species-, and type-specific antigens, all of which are specific and termed specific antigens. Pathogenic spirochetes also possess lipid antigens, which are nonspecific. Treponema pallidum antigens include only lipid antigens, which are nonspecific. Only a few Treponema pallidum antigens are specific, while most are nonspecific, meaning they are identical to those of non-pathogenic spirochetes. Therefore, it is speculated that the slow emergence of weak protective immunity in syphilis is due to the low concentration of specific antigens. This speculation is supported by clinical observations, such as the fact that individuals with extensive intermediate stage [second stage] syphilis lesions generally do not develop active advanced stage syphilis, whereas those with mild intermediate stage [second stage] syphilis symptoms or chronic sexually transmitted lesions may progress to late stage [third stage] syphilis.

After entering the human body, the spirochete can produce many antibodies, which may target different components of the syphilis spirochete. The humoral immune response to syphilis manifests as follows: (1) Specific antibodies: Patients with intermediate stage [second stage] syphilis produce specific anti-syphilis spirochete antibodies in their serum, mainly IgM and IgG. In the early stage, both IgM and IgG are present, while in the advanced stage, only IgG remains, which can persist for life. Although the titer of specific antibodies in the serum is high during intermediate stage [second stage] syphilis, the spirochetes continue to proliferate and spread, indicating the limited effectiveness of these antibodies. The FTA-ABS test can detect spirochete-specific antibodies. (2) The syphilis spirochete immobilization antibody is another specific antibody, first used clinically by Nelson et al. in 1949. Under anaerobic conditions with complement, this antibody can inhibit the movement of live syphilis spirochetes and kill them. The titer of immobilization antibodies in early-stage patients is higher than in normal individuals, with the antibody class being IgM. It peaks during intermediate stage [second stage] syphilis, slightly decreases in the advanced stage, and can persist for life. This antibody can be detected using the TPI test. (3) Anti-cardiolipin antibodies, also known as reagin, are only useful for syphilis serological diagnosis and lack protective effects. VDRL antibodies targeting cardiolipin are primarily IgM, with a small amount of IgG. The antigen triggering the cardiolipin antibody response may be released from mitochondrial membranes of injured cells in infected tissues or may originate from cardiolipin within the syphilis spirochete itself, thereby stimulating the immune response. In early-stage syphilis patients who receive adequate treatment, cardiolipin antibodies can gradually disappear. In untreated early-stage patients progressing to the advanced stage, some may also experience a reduction or disappearance of these antibodies. (4) Partially transferable antibodies between animals. Rabbit syphilis studies found that 9–15 days after intratesticular inoculation of TP, rabbits produced anti-syphilis spirochete mucopolysaccharide antibodies. These antibodies inhibit the breakdown of host mucopolysaccharides by mucopolysaccharidases, thereby limiting the source of N-acetyl-D-galactosamine. This disruption impairs the synthesis of the syphilis spirochete's capsular membrane, which is essential for its survival. Thus, anti-syphilis spirochete mucopolysaccharidase antibodies may be a key factor in inhibiting spirochete proliferation and promoting lesion healing. (5) Serum neutralizing factors. Experimental syphilis immune serum contains a serum neutralizing factor that inactivates the toxicity of syphilis spirochetes, conferring resistance upon re-exposure. This factor is closely related to immunity against syphilis reinfection. Some believe the neutralizing factor and syphilis spirochete immobilization antibody may be the same antibody detected by different methods or two distinct but associated antibodies. (6) Immune adherence phenomenon. Nelson's experiments demonstrated that immune adherence enhances phagocytosis. Immune serum and complement also promote the phagocytosis of Cr-labeled syphilis spirochetes by guinea pig polymorphonuclear leukocytes. Immune adherence and opsonization are both antibody-mediated immune responses. (7) Syphilis spirochete polypeptide antibodies. Syphilis patients have antibodies against spirochete polypeptides, revealing the relationship between humoral immunity and disease stages at the molecular level. All syphilis patients have IgG antibodies against at least 4–6 syphilis polypeptides. Intermediate stage [second stage] and early latent syphilis patients additionally produce 16 more anti-syphilis spirochete polypeptide antibodies. However, when the disease progresses to latent advanced or advanced stages, 4–5 of these antibodies are specifically lost. This loss may contribute to disease progression. (8) Immune complexes and IgE binding to syphilis spirochetes. Studies show that syphilis patients' sera contain immune complexes with spirochete antigens. Circulating immune complexes are involved in syphilis pathology, including the Jarisch-Herxheimer reaction during treatment, congenital syphilis, and kidney damage in intermediate stage [second stage] syphilis.

There have been reports of IgE in the serum of syphilis patients. IgE binds to syphilis spirochetes, causing degranulation of mast cells and basophils, releasing histamine, slow-reacting substances, chemotactic factors, and platelet-aggregating factors, which may be related to local tissue lesions in syphilis.

Cellular immunity plays an active role in syphilis infection. The manifestations include: (1) Inoculating experimental animals with dead syphilis spirochetes does not induce immunity; only attenuated live syphilis spirochetes can confer protective immunity against syphilis spirochetes, indicating that syphilis immunity is cell-mediated. In the early stages of syphilis infection in rabbits, spleen and lymph node cells exhibit 100–600 times higher reactivity to ConA and syphilis spirochete antigens compared to uninfected animals, and this has been identified as a T-cell response. However, in the early stages of syphilis infection, lymphocytes sensitized to syphilis spirochetes are mainly confined to the spleen and lymph nodes of rabbits, with very few in the peripheral blood. Therefore, the reactivity of peripheral blood lymphocytes to syphilis spirochetes often does not correlate with that of the spleen and lymph nodes. (2) Monocytes are closely related to syphilis immunity. In syphilis-infected individuals, peripheral blood monocytes increase in number and size, with enhanced phagocytic activity. Indirect fluorescence microscopy reveals engulfed syphilis spirochetes displaying bright fluorescence within macrophages. Electron microscopy shows swelling of the protoplasmic cylinder, disappearance of ribosomes, fragmentation of axial filaments, and increased electron-dense material and lipid vacuoles in syphilis spirochetes within macrophages. Experimental studies in rabbits have shown that the histological hallmark of primary syphilis is mononuclear cell (lymphocytes and macrophages) infiltration. Lymphocyte infiltration begins as early as day 6 post-infection, peaks on day 13, and is predominantly composed of T cells. Due to the action of cellular immunity, syphilis spirochetes are rapidly cleared from the lesions. By day 24 post-infection, immunofluorescence examination of the lesions no longer detects syphilis spirochetes.

The depletion of lymphocytes in the spleen of congenital syphilis patients and syphilis-infected suckling rabbits, as well as in the paracortical regions of lymph nodes in syphilis patients, further underscores the importance of cellular immunity in syphilis. The gummatous lesions of late-stage syphilis exhibit granulomatous pathology, with cellular reactions resembling delayed-type hypersensitivity. Syphilis spirochetes are rarely seen in these lesions, which are primarily caused by cellular infiltration. Cellular immune responses are also evident systemically, such as lymphadenopathy, increased peripheral blood monocytes, and enhanced phagocytic activity. In vitro, these cells exhibit proliferative responses to syphilis spirochete antigens. Early syphilis spirochete antigen skin tests show no delayed-type hypersensitivity in secondary syphilis patients, but such reactions appear in late-stage and latent syphilis patients. Thus, cellular immunity plays a major role in the immune response against syphilis spirochete infection.

The reactivity of peripheral blood lymphocytes to mitogens is reduced in syphilis patients. Immunoglobulins in the patients' serum can inhibit the activity of natural killer cells in healthy individuals. The consequence of this immunosuppression is the promotion of syphilis spirochete dissemination. Studies have found that syphilis patients or syphilis-infected rabbits exhibit lower proliferative responses to mitogens (such as ConA, PHA, and PWM) and syphilis spirochete antigens compared to normal subjects.

Early immunosuppression phenomenon. Rich et al. reported that after inoculating rabbits with 500 syphilis spirochetes, local infiltration of lymphocytes and plasma cells occurred within 48 to 72 hours. Lesions formed at the inoculation site after 18 days, but it took 30 days for the lesions to heal. Immunosuppression may explain the early presence of these temporarily ineffective immune cells. Injecting rabbits with cortisone found an increase in the number of syphilis spirochetes within the lesions and delayed healing, which may be related to the immunosuppressive effects of cortisone. Capsular membrane mucopolysaccharides: Inoculating infected animals with syphilis rabbit testicular fluid containing large amounts of capsular membrane mucopolysaccharides shed by syphilis spirochetes can reverse and worsen the healing of syphilis lesions. Intermediate stage [second stage] syphilis plasma contains a factor that inhibits the transformation of normal lymphocytes. This inhibitory factor is a mucopolysaccharide that can inactivate B cells, plasma cells, TH and Tc cells, and macrophages, and can interfere with the production of spirochete mucopolysaccharidase antibodies. This inhibitor appears in the body fluids of rabbits infected with syphilis spirochetes within 10 days and can persist for 6 months. Intermediate stage [second stage] syphilis may be caused by the immunosuppressive effect of syphilis spirochete capsular membrane polysaccharides, which favors the proliferation of syphilis spirochetes.

The immune response to syphilis is extremely complex. During different stages of Treponema pallidum infection, both cellular immunity and humoral immunity are partially involved. Their synergistic action can protect the body against reinfection while also being associated with the variable clinical symptoms of syphilis.

bubble_chart Pathological Changes

The fundamental pathological changes of syphilis primarily include: ① vasculitis, with endothelial cell swelling and proliferation; ② perivascular inflammation, characterized by extensive infiltration of lymphocytes and plasma cells. In advanced-stage syphilis, in addition to the aforementioned changes, there are granulomatous infiltrations of epithelioid cells and giant cells, sometimes accompanied by necrosis.

1. Hard chancre: Exhibits perivascular infiltration, predominantly involving lymphocytes, including CD8+ and CD4+ cells, plasma cells, and histiocytes, accompanied by capillary endothelial proliferation, followed by small vessel occlusion. Additionally, Treponema pallidum is found in the intercellular spaces of the epithelium, capillaries, and around lymphatic vessels and regional lymph nodes in the chancre.

2. Intermediate-stage [second-stage] syphilis macules and papules: Characterized by epidermal hyperkeratosis, infiltration of polymorphonuclear neutrophils into the dermal papillae, and perivascular mononuclear cells, plasma cells, and lymphocytes in the deep dermis.

3. Condyloma latum: Early stages show epidermal verrucous hyperplasia, while the advanced stage features central tissue necrosis, elongated papillae, and inflammatory infiltration in the dermis. There is prominent perivascular plasma cell infiltration arranged in a cuff-like pattern, capillary proliferation, and intra- and extracellular edema. Silver staining reveals Treponema pallidum in approximately one-third of condyloma latum cases, mainly located within the epidermis and a few around superficial blood vessels.

4. Late-stage [third-stage] syphilis: Primarily manifests as granulomatous lesions, with vascular changes being milder than in the intermediate stage [second stage]. The granulomas consist of epithelioid cells and macrophages, sometimes with caseous necrosis in the center, surrounded by abundant lymphocytes and plasma cells, along with some fibroblasts and histiocytes. Vascular endothelial cells often exhibit proliferation and swelling, sometimes leading to luminal occlusion.

5. The distinction between nodular syphilid and gumma lies in the extent of the lesions and their depth. Nodular syphilid granulomas are confined to the dermis, with minimal or absent caseous necrosis, and large vessels are unaffected. Gummas, however, involve extensive lesions that may extend into the subcutaneous tissue, exhibit significant caseous necrosis, and often affect large blood vessels.

bubble_chart Clinical Manifestations

I. Secondary Syphilis

(1) Primary Stage Syphilis

The average incubation period is 3 to 4 weeks, with the typical lesion being a hard chancre (Hard Chancre, Ulcus Durum). Initially, a small red papule or induration appears at the site of spirochete invasion, which later erodes to form a superficial ulcer. The ulcer is firm, painless, round or oval, with clear boundaries, neat edges, and a raised, dike-like border surrounded by a dark red infiltration. It has a characteristic cartilage-like hardness, a flat base, and no pus. The surface is covered with a thin fibrin-like membrane that is difficult to remove. When slightly squeezed, a small amount of serous exudate containing numerous syphilis spirochetes may be released, making it a significant source of infection. Hard chancres are mostly solitary, but 2–3 may occasionally occur. The above describes a typical hard chancre. However, if it occurs on preexisting erosions, lacerations, or herpetic or balanitic lesions, the hard chancre may take on the same shape as the original lesion. In such cases, syphilis spirochete testing should be performed. Since hard chancres are transmitted through sexual contact, the lesions often appear on the external genitalia or areas of sexual contact. In males, they commonly occur on the glans, coronal sulcus, frenulum, inner foreskin, penis, penile root, urethral orifice, or inside the urethra (the latter is easily misdiagnosed). Hard chancres are often accompanied by foreskin edema. Some patients may develop lymphangitis on the dorsal side of the penis, presenting as a firm, linear lesion. In females, hard chancres are frequently found on the labia majora, labia minora, clitoris, urethral orifice, or mons pubis, with the cervix being a particularly common site, often leading to misdiagnosis as a fistula. Extra-genital hard chancres may appear on the lips, tongue, tonsils, fingers (healthcare workers may develop finger chancres due to occupational exposure), breasts, eyelids, or external ears. In recent years, anal and rectal hard chancres have also become more common. These chancres are often accompanied by severe pain, difficulty defecating, and a tendency to bleed. Rectal chancres are easily misdiagnosed as rectal cancer. Extra-genital hard chancres are often atypical, so syphilis spirochete testing and genetic diagnostic testing should be performed. Hard chancres have the following characteristics: ① The lesion is usually solitary; ② Cartilage-like hardness; ③ Painless; ④ The lesion surface is clean.

One week after the appearance of the hard chancre, nearby lymph nodes may swell. The swelling is painless, without redness or adhesion to surrounding tissues, and does not ulcerate, known as painless bubo (painless lymphadenitis). Without treatment, the hard chancre may heal on its own in 3–4 weeks. With effective treatment, it heals quickly, leaving a superficial atrophic scar. Two to three weeks after the appearance of the hard chancre, syphilis serological tests begin to show positive results. In addition to the hard chancre, a few patients with primary syphilis may develop firm edema on the labia majora, foreskin, or scrotum, resembling elephant hide, known as indurated edema (Edema Induratum). If the patient is also infected with Haemophilus ducreyi (causing soft chancre) or sexually transmitted lymphogranuloma venereum (causing phagedenic ulcer), it is called a mixed chancre.

Diagnostic criteria for primary syphilis: ① History of unprotected sexual intercourse with an incubation period of 3 weeks; ② Typical symptoms, such as a solitary, painless hard chancre, mostly occurring on the external genitalia; ③ Laboratory tests: PCR detection of syphilis spirochete genes is positive, or dark-field microscopy identifies syphilis spirochetes from the hard chancre; syphilis serological tests are positive. A positive result in any one of these three tests is sufficient for diagnosis.

Differential diagnosis: Diseases that need to be distinguished from primary syphilis include:

① Genital herpes: Begins as slightly raised erythema, forming clustered small blisters within 1–2 days, accompanied by itching and pain. The lesions are not firm and resolve within 1–2 weeks but are prone to recurrence. Tissue culture identifies herpes simplex virus, Tzank smear is positive, and PCR detects herpes virus DNA.

② Chancriform pyoderma: Caused by Staphylococcus aureus or Streptococcus. The skin lesions resemble hard chancres but lack the typical cartilage-like hardness and dark red infiltration. There is no history of unprotected sexual intercourse, and syphilis spirochete tests are negative. Nearby lymph nodes may swell but subside after the skin lesions heal.

③ Soft chancre: Also one of the sexually transmitted diseases, with a history of sexual contact, caused by Haemophilus ducreyi. The incubation period is short (3-4 days), onset is acute, inflammation is significant, painful, with a soft texture, skin lesions are often multiple, with purulent discharge on the surface, Haemophilus ducreyi can be detected, and syphilis serological tests are negative.

④ Subcutaneous nodule ulcer: Also commonly seen on the penis and glans. The skin lesion is also a single, isolated, superficial round ulcer, often with crusting on the surface. Symptoms are mild, and subcutaneous nodule bacilli can be detected. Often accompanied by visceral subcutaneous nodules.

⑤ Behçet’s disease: Ulcers may occur on the external genitalia, and in females, they may also appear in the vagina and cervix. The ulcers are deeper, with mild cutaneous pruritus. The lesions lack the characteristics of a hard chancre and are often accompanied by oral ulcers, eye lesions (iritis, hypopyon, etc.), erythema nodosum on the legs, and migratory arthritis. Syphilis serology is negative.

⑥ Acute vulvar ulcer: The chancre-like type resembles a hard chancre but is not indurated, with significant inflammation and pain. Large bacilli can be found in the secretions.

⑦ Fixed drug eruption: May appear on the inner foreskin of the penis, coronal sulcus, etc., as bright red erythema, which can develop into superficial erosions. It is pruritic but not painful, lacks the characteristics of a hard chancre, and has a history of medication use. Syphilis serology is negative.

(2) Intermediate stage [secondary stage] syphilis

This is the generalized phase of syphilis. The period from the disappearance of the hard chancre to the appearance of intermediate stage [secondary stage] syphilis rash is called the second latent period. Intermediate stage [secondary stage] syphilis rashes typically appear 3–4 weeks after the resolution of the hard chancre, corresponding to 9–12 weeks post-infection. Intermediate stage [secondary stage] syphilis results from the spread of Treponema pallidum through the lymph nodes into the bloodstream, causing widespread systemic damage. In addition to skin lesions, it can also affect internal organs and the nervous system.

Before the rash appears, intermediate stage [secondary stage] syphilis may present with flu-like symptoms (headache, low-grade fever, limb soreness). These prodromal symptoms last about 3–5 days and subside once the rash appears.

The skin lesions of intermediate stage [secondary stage] syphilis can be classified as macular and papular, papular, or pustular, with the latter being rare nowadays.

Macular and papular rash, also known as roseola (rose rash), is the most common, accounting for 70–80% of intermediate stage [secondary stage] syphilis cases. The early-onset type resembles the roseola of cold-damage disease. It presents as light red, round or oval erythematous patches of varying sizes (approximately 0.5–1.0 cm in diameter), with relatively clear borders. The lesions blanch under pressure, remain discrete, and do not merge. They appear symmetrically, typically first on the trunk and gradually spreading to the limbs, covering the entire body within days (though rarely on the neck or face). Symptoms are mild and often overlooked (difficult to see in warm environments but more visible in cooler temperatures). On the palms and soles, the rash may present with psoriasiform scales and a flesh-red base that does not blanch under pressure, which is characteristic. Over several days or 2–3 weeks, the rash color changes from light red to brown or yellowish-brown before fading, sometimes leaving residual pigmentation. Treatment with anti-syphilis medications leads to rapid resolution. Recurrent macular and papular rash usually occurs 2–4 months post-infection, though it may be delayed up to 6 months or 1–2 years. The lesions are larger than the early-onset type (about the size of a fingernail or coin), fewer in number, and arranged in localized clusters with distinct borders, often appearing on the extremities (e.g., lower limbs, shoulders, forearms, and perianal area). This type persists longer and may recur if untreated. During progression, the center may fade while the edges expand, forming annular lesions (annular roseola).

During this stage, syphilis serology is strongly positive. PCR testing for Treponema pallidum DNA is also positive.

Diagnosis and differential diagnosis: Based on the appearance of characteristic rashes 9–12 weeks post-infection, lack of subjective symptoms, self-resolution, history of initial stage [primary stage] syphilis, strongly positive syphilis serology, and positive PCR for Treponema pallidum DNA, the diagnosis can be confirmed. It should be differentiated from the following conditions:

① Drug rash: History of medication use, rapid onset, acute course, resolution after discontinuation of the drug, no history of sexual contact, negative syphilis serology and PCR results.

② Pityriasis rosea: Lesions are oval, with the long axis aligned with skin lines. They have fine scales and irregular, often serrated edges. A larger herald patch (mother patch) often precedes the generalized rash. Pruritus is present. Lymph nodes are not enlarged, and syphilis serology is negative.

In addition, differentiation should also be made from the roseola of cold-damage disease and measles. The rashes of these two diseases closely resemble the early roseola of intermediate stage [second stage] syphilis, but the former present with pronounced systemic symptoms and often occur in epidemics, though they are now extremely rare. Measles is mostly seen in children (but can also occur in adults who did not contract measles in childhood), with marked systemic symptoms such as fever, upper respiratory tract infection, catarrhal rhinitis, conjunctivitis, and oral mucosal involvement. In recent years, due to vaccination, it has also become extremely rare.

Papules and maculopapular rashes are also clinically common, accounting for approximately 40% of intermediate-stage [second-stage] syphilis cases. They appear slightly later than macules and papules. Based on their symptoms and clinical progression, they can be divided into large papules and small papules.

Large papules: These are hemispherical, infiltrative papules with a diameter of about 0.5–1 cm. The surface is smooth, ranging in color from dark brown to copper-red. Over time, the center of the rash may absorb, become depressed, or develop scaling. They commonly occur on the sides of the trunk, abdomen, flexor surfaces of the limbs, scrotum, labia majora and minora, anus, and groin. Some may have scales, referred to as papulosquamous syphilid or psoriasiform syphilid. These lesions feature large scaly patches with white or adherent crusts, beneath which superficial erosions may be found, surrounded by a red halo, resembling psoriasis. They frequently appear on the trunk and limbs.

Small papules, also known as syphilitic lichen or millet-seed-sized papules, are typically the size of hair follicles, conical in shape, firm, and pointed. They are brownish-red and may cluster or form lichenoid patterns. These appear later, usually within 1–2 years after infection, and persist for a long time, often not resolving without treatment for 2–3 months. Some papules may arrange in annular or arcuate patterns, termed annular syphilid. They commonly occur on the scrotum and nape of the neck, where Treponema pallidum can be detected, and syphilis serology is strongly positive.

Diagnosis and differential diagnosis rely on medical history, skin lesion characteristics, dark-field microscopy for Treponema pallidum, and serological tests. It should be differentiated from the following conditions:

① Lichen planus: Presents as purplish-red, slightly polygonal, flat papules with a waxy, smooth surface. Under magnification, Wickham striae may be visible. It causes intense cutaneous pruritus, progresses slowly, and is rarely generalized. Annular lesions on the scrotum should be distinguished from annular syphilid. Detection of Treponema pallidum and syphilis serology can aid differentiation.

② Psoriasis vulgaris should be differentiated from palmar and plantar hyperkeratotic syphilid. The clinical features of psoriasis, along with Treponema pallidum testing and syphilis serology, facilitate differentiation.

③ Condyloma acuminatum, another sexually transmitted disease caused by a virus, shares similar predilection sites with condyloma latum. However, the lesions are raised, cauliflower-like, with a pedunculated base and a pale red color, lacking the copper-red infiltration. Both Treponema pallidum and syphilis serology are negative.

Pustular syphilid: Now rare, it may occur in malnourished individuals, those with weak constitutions, alcoholics, or drug users. Large lesions resemble impetigo, ecthyma, or rupia, while small lesions may mimic smallpox or acne. Patients often present with fever and general malaise. The lesions typically exhibit copper-red infiltration. Diagnosis is based on medical history, Treponema pallidum testing, and syphilis serology, distinguishing it from common acne or impetigo. Rupioid lesions are distinctive due to their characteristic oyster-shell-like appearance.

Intermediate-stage [second-stage] syphilis mucosal lesions may occur alone or alongside other syphilitic rashes. Isolated lesions are easily overlooked. Smokers, alcoholics, those consuming excessively hot or spicy foods, and individuals with poor dental hygiene are more prone to developing or relapsing. Common lesions include mucous patches (leukoplakia, mucous patches), often found on oral or genital mucosa, or anal mucosa. Anal lesions may cause pain during defecation and even bleeding. The lesions are round or oval, well-demarcated, with superficial erosions and slightly raised grayish-white or milky-white patches surrounded by dark red infiltration. They range in size from a fingernail or larger and may increase in size or coalesce into garland-like or irregular shapes. Some may progress to ulcers with a black, thin membrane base that is difficult to detach; upon removal, the base appears uneven and bleeds easily. Asymptomatic initially, ulcers become painful. Mucous patches harbor large amounts of Treponema pallidum, making them significant sources of contagion.

syphilitic alopecia areata: occurs in approximately 10% of intermediate stage [second stage] syphilis patients. This is caused by syphilitic infiltration of hair follicles and blockage of microvessels in the hair-bearing area, leading to poor blood supply. It manifests as syphilitic patchy alopecia or diffuse alopecia areata. The former presents as alopecic patches about 0.5cm in size, appearing moth-eaten. Diffuse alopecia areata covers a larger area, with sparse and uneven hair length. It commonly affects the temporal, parietal, and occipital regions, and may also involve the eyebrows, eyelashes, beard, and pubic hair. In intermediate stage [second stage] syphilis, Treponema pallidum is present in the alopecic areas. The locations of Treponema pallidum and cellular infiltration are largely consistent, suggesting that syphilitic alopecia may be related to the sites of Treponema pallidum invasion. Treponema pallidum does not invade the hair papilla but rather the upper part of the hair follicle, which is why incomplete alopecic patches are predominant in syphilitic alopecia. However, syphilitic alopecia areata is not permanent. With timely treatment, hair can regrow within 6–8 weeks, and may even regrow spontaneously without treatment.

Syphilitic leukoderma is more common in female patients. It typically appears 4-5 months or 1 year after infection, predominantly on both sides of the neck, but may also occur on the chest, back, breasts, limbs, armpits, external genitalia, perianal area, and other regions. The affected areas show complete loss of pigmentation with increased pigmentation around them, resembling vitiligo. The lesions vary in size and may coalesce into large patches with a reticular pattern in the center, where pigmentation is lost. Syphilitic leukoderma often coexists with syphilitic alopecia areata. It tends to persist for a long time, stubbornly resisting disappearance, and may last for 7-8 years, extending into late-stage (third-stage) syphilis. It is frequently associated with neurosyphilis or may appear before the onset of neurosyphilis. Abnormal changes are observed in the cerebrospinal fluid. The syphilis serological test is positive. Differentiation from vitiligo can be made based on medical history, the presence of syphilitic symptoms in other areas, and a positive syphilis serological test.

Intermediate-stage (second-stage) syphilis can also affect the nails, leading to paronychia, onychia, and other abnormal changes, which resemble non-syphilitic nail disorders. Syphilitic paronychia may present with dark red infiltration around the nail. Intermediate-stage (second-stage) syphilis can also cause osteitis, periostitis, arthritis, iridocyclitis, retinitis, and may involve the nervous system without clinical symptoms, termed asymptomatic neurosyphilis in the intermediate stage. Additionally, syphilitic meningitis, cerebrovascular syphilis, and meningovascular syphilis may occur, accompanied by headaches and corresponding neurological symptoms.

The serological reactions in overt intermediate-stage (second-stage) syphilis are often strongly positive. The lesions of intermediate-stage (second-stage) syphilis are generally asymptomatic, though mild itching may occasionally occur. Pain may be experienced if periostitis or osteitis develops, typically worsening at night and subsiding or disappearing during the day. Without treatment, the symptoms may resolve in 1-2 months, but they disappear rapidly with antisyphilitic therapy.

In intermediate-stage (second-stage) syphilis, early eruptions and recurrent eruptions can be distinguished. The first to appear are early eruptions, characterized by numerous, smaller, and symmetrically distributed skin lesions, often on the trunk and extensor surfaces of the limbs. Recurrent eruptions, which appear after the initial lesions subside, are fewer in number, larger in size, and often clustered unilaterally in annular, hemispherical, or irregular patterns, commonly affecting the extremities, such as the head, face, perianal area, external genitalia, palms, soles, or flexor surfaces of the limbs. Differentiating between early and recurrent eruptions is significant for treatment and prognosis. Early syphilitic eruptions generally have a shorter course, respond well to treatment, and have a better prognosis, whereas recurrent eruptions have a longer course and poorer treatment outcomes and prognosis.

Diagnostic criteria for intermediate-stage (second-stage) syphilis: ① History of unclean sexual intercourse or hard chancre; ② Various rashes such as roseola, maculopapular lesions, mucous membrane lesions, moth-eaten alopecia areata, general malaise, and lymphadenopathy; ③ Laboratory findings: Treponema pallidum detected under dark-field microscopy from mucous membrane lesions; positive syphilis serological tests; positive PCR detection of Treponema pallidum DNA.

(3) Late-stage (third-stage) syphilis (advanced-stage syphilis)

This stage typically occurs 2 years after the onset of the disease but may take longer, up to 3-5 years. It predominantly affects individuals aged 40-50. The main causes include inadequate or insufficient antisyphilitic treatment, as well as imbalances in the body's internal and external environment. Excessive alcohol consumption, smoking, physical weakness, and the presence of chronic sexually transmitted diseases such as subcutaneous nodules are associated with a poor prognosis.

The characteristics of late-stage (third-stage) syphilis are as follows: ① Late onset (2-15 years after infection), with a prolonged course that may last 10-20-30 years or even a lifetime if untreated; ② Complex symptoms that can involve any tissue or organ, including the skin, mucous membranes, bones, joints, and internal organs, with a tendency to affect the nervous system, making diagnosis difficult due to similarities with other diseases; ③ Few Treponema pallidum organisms in the body and lesions, with low infectivity but strong tissue-destructive potential, often causing tissue defects, organ damage, disability, or even life-threatening conditions; ④ Although antisyphilitic treatment is effective, it cannot repair already damaged tissues or organs; ⑤ Syphilis serological reactions are unstable, with a negative rate exceeding 30%, and cerebrospinal fluid often shows abnormalities.

Late stage [third stage] syphilis skin and mucous membrane lesions account for 28.4% of advanced stage benign syphilis cases, mostly occurring within 3 to 10 years after infection. Clinically, it can be divided into nodular syphilid, gumma, and juxta-articular nodules. The skin lesions have the following characteristics: ① Few in number, isolated or clustered rather than symmetrical, often occurring in areas prone to trauma; ② Mild systemic symptoms, skin lesions lack subjective symptoms, but pain may occur if bones or periosteum are involved, especially at night; ③ Gummatous infiltrative induration, with ulcers forming after rupture still showing firm induration at the base, resolving very slowly, often taking several months or more; ④ Ulcers have a distinctive kidney-shaped or horseshoe-shaped appearance; ⑤ Ulcers may heal centrally while the edges often continue to expand; ⑥ Few Treponema pallidum are present on the lesion surface, making dark-field microscopy difficult to detect, but inoculation tests may be positive; ⑦ Strong tissue-destructive capability, healing may result in scar formation.

Nodular syphilid: Mostly occurs within 3–4 years after infection, with lesions commonly found on the head, shoulders, back, and extensor surfaces of the limbs. These are a group of infiltrative nodules about 0.3–1.0 cm in diameter, appearing copper-red in color, with a smooth surface or covered with thin scales, and are firm in texture. Patients experience no subjective symptoms. The evolution of the nodules may have two outcomes: one is flattening and absorption, leaving small atrophic patches with long-lasting deep brown pigmentation. The other outcome is central necrosis, forming small abscesses that ulcerate, resulting in nodular ulcerative syphilid, which heals to leave superficial scars. The scars are surrounded by pigmentation, and the atrophic areas are smooth and thin, with new lesions potentially appearing at the margins. This is a characteristic feature of the condition. Old and new rashes may alternate, with new ones appearing continuously, potentially persisting for several years.

Gumma is commonly seen in late-stage (third-stage) syphilis, accounting for about 61% of cases. It manifests as deep subcutaneous indurations, initially pea-sized and gradually enlarging to the size of a broad bean, plum, or larger. They are hard and movable upon palpation, with varying numbers. Initially, the color matches normal skin, but as the nodules grow, the color gradually changes to light red, dark red, or even purplish-red. The nodules are prone to necrosis, softening, and ulceration, discharging a gum-like secretion, forming distinctive round, oval, or horseshoe-shaped ulcers with well-defined borders, raised edges like embankments, and surrounded by brown-red or dark-red infiltration that feels hard to the touch. Often, one end heals while the other continues to spread in a serpentine pattern. Subjective symptoms are mild, but pain may occur if bones or periosteum are involved, especially at night. Gummas can appear anywhere on the body but are more common on the head, face, and extensor surfaces of the lower legs. The course is prolonged, lasting from months to years or longer, healing with scar formation surrounded by a pigmented band. Gummas may invade bones and cartilage, with bone lesions often manifesting as long tubular bone inflammation or osteoperiostitis. In the head, they may destroy the skull, while in the palate or nose, they may perforate the hard palate or nasal bones, creating a passage between the nose and palate. If near major blood vessels, they may erode them, leading to severe hemorrhage. With antisyphilitic treatment, gummas may resolve without scarring. Some may not ulcerate but form well-defined superficial infiltrations.

Late-stage (third-stage) syphilis may also present with localized or diffuse alopecia areata and paronychia, with clinical manifestations similar to intermediate-stage (second-stage) syphilis.

Late-stage (third-stage) syphilis can also affect mucous membranes, primarily in the oral cavity and tongue, where nodular eruptions or gummas may occur. On the tongue, they may appear as localized single gummas or diffuse gummatous infiltrations, the latter often progressing to chronic interstitial glossitis, presenting as fissured tongue of varying depth—a precancerous condition requiring close monitoring and adequate antisyphilitic treatment. Some superficial lesions may exhibit loss of papillae, leaving a smooth, red surface. Tongue lesions are asymptomatic but may cause pain when exposed to hot or acidic foods.

Juxta-articular nodules may appear near the extensor surfaces of large joints such as the hip, elbow, knee, and sacrum. These are firm, painless nodules with no inflammatory changes in the overlying skin, appearing normal or slightly darker in color. They progress slowly and do not ulcerate. Treponema pallidum can be detected within the nodules, often coexisting with other syphilitic signs, and syphilis serology is positive. Antisyphilitic treatment leads to easy resolution. Some believe these nodules are caused by a variant of Treponema pallidum with a special affinity for connective tissue. Late-stage (third-stage) syphilis may also involve ocular lesions, such as iridocyclitis, retinitis, or keratitis. When the cardiovascular system is affected, it may lead to simple aortitis, aortic valve insufficiency, aortic aneurysm, or coronary artery disease. It may also invade the digestive, respiratory, or urinary systems, though without specific symptoms, requiring relevant examinations based on medical history. Late-stage (third-stage) syphilis frequently affects the nervous system. Apart from asymptomatic neurosyphilis, where cerebrospinal fluid abnormalities are present without clinical symptoms, it may also manifest as meningovascular syphilis or parenchymatous neurosyphilis.

Diagnostic basis for late-stage [third-stage] syphilis: ① History of unclean sexual intercourse or early-stage syphilis; ② Typical symptoms such as nodular syphilid, gumma, aortitis, aortic valve insufficiency, aortic aneurysm, tabes dorsalis, and general paresis; ③ Laboratory tests: Syphilis serological tests, approximately 66% positive in non-treponemal antigen serological tests; positive in treponemal antigen serological tests. Cerebrospinal fluid examination shows increased white blood cells and protein levels, with a positive Venereal Disease Research Laboratory test (VDRL).

Regarding the diagnosis of neurosyphilis, no single test can definitively diagnose all cases of neurosyphilis. Diagnosis can be based on the following conditions, such as positive syphilis serological tests, abnormal cerebrospinal fluid cell count and protein levels, or a positive cerebrospinal fluid VDRL (without performing a cerebrospinal fluid RPR test), with or without clinical symptoms. The cerebrospinal fluid VDRL is the standard serological method for cerebrospinal fluid. If the cerebrospinal fluid VDRL is positive after excluding serum contamination, neurosyphilis should be considered. However, the cerebrospinal fluid VDRL can also be negative in cases of neurosyphilis.

Latent syphilis: Latent syphilis refers to patients who have been diagnosed with syphilis but, during a certain period, show no abnormal findings in the skin, mucous membranes, or any organ systems, including cerebrospinal fluid examination. Physical examinations and chest X-rays lack clinical manifestations of syphilis, cerebrospinal fluid tests are normal, and only the syphilis serological reaction is positive. Alternatively, there may be a clear history of syphilis infection without any clinical manifestations. This is termed latent syphilis. The diagnosis of latent syphilis also depends on a history of primary [first stage] or secondary [second stage] syphilis, contact with syphilis, or a history of giving birth to an infant with congenital syphilis. Previous negative syphilis serological test results and disease or contact history help determine the duration of latent syphilis. Infections within 2 years are classified as early latent syphilis, while those lasting more than 2 years are classified as advanced latent syphilis. Another category is latent syphilis with an unclear disease duration. The absence of symptoms in latent syphilis is due to strong immune responses or temporary suppression of the spirochetes through treatment. During latent syphilis, the spirochetes intermittently appear in the blood. Pregnant women with latent syphilis can infect the fetus in the uterus, and it can also be transmitted to blood recipients through blood donation.

Previously, it was believed that untreated advanced latent syphilis could persist for life, progress to advanced syphilis, or resolve spontaneously with serological conversion to negative. However, with modern, more sensitive anti-spirochetal antibody tests, seroreversion is rare. Nearly 70% of untreated latent syphilis cases do not clinically progress to advanced symptomatic syphilis, but the possibility of natural cure remains questionable.

Before the antibiotic era, about one-third of untreated latent syphilis cases progressed to advanced symptomatic syphilis. As mentioned, the diagnosis of latent syphilis cannot rely solely on serological reactions but must combine disease history, physical examination, and exclusion of false-positive serological results. Suwen Early latent syphilis can be comprehensively diagnosed based on the following criteria: ① Sequential changes in syphilis serological tests, i.e., whether non-treponemal test titers increase fourfold or more; ② A history of symptoms of primary [first stage] or secondary [second stage] syphilis; ③ Whether the sexual partner has primary [first stage], secondary [second stage], or latent syphilis with a disease duration of less than 2 years; ④ Positive genetic testing for syphilis spirochete DNA for confirmation. Apart from early latent syphilis, most other cases are classified as latent syphilis with an unclear disease duration, which should be managed as advanced latent syphilis. For children diagnosed with latent syphilis after the neonatal period, a thorough analysis of the mother’s medical history and the child’s birth circumstances is necessary to determine whether the syphilis is congenital or acquired. All patients with latent syphilis should be examined for manifestations of late [third stage] syphilis, such as aortitis, neurosyphilis, gummas, and iritis.

Pregnancy syphilis: Syphilis and pregnancy can mutually influence each other. Pregnancy syphilis can infect the fetus through the placenta. Due to the obstruction of placental blood vessels caused by pregnancy syphilis, fetal nutrition is affected, leading to a higher likelihood of late abortion, premature labor, or stillbirth. Although full-term childbirth may occur, approximately 64.5% of fetuses are already infected with syphilis, resulting in congenital syphilis, of which 15%–20% are early-onset congenital syphilis. Syphilis also significantly impacts pregnancy. Although women with syphilis can conceive, the pregnancy rate is markedly reduced. The infertility rate for active syphilis is 23%–40%, which is 1–5 times higher than normal. Pregnancy syphilis greatly affects the health of pregnant women, potentially causing weight loss, lack of strength, nutritional depletion, and reduced resistance to diseases. In cases of early syphilis, the impact on health is even more severe. In addition to the aforementioned symptoms, fever, night sweats, anemia, and susceptibility to bone and joint involvement may occur, including bone decalcification and arthralgia. Due to placental vascular infarction, there is an increased risk of placental abruption, leading to late abortion, premature labor, or stillbirth.

In addition to the aforementioned vascular changes, the placenta in syphilis often increases in weight, with a swollen and pale maternal surface. The number of villi is significantly reduced due to vascular infarctions within them, and the density of stromal cells increases. Syphilis spirochetes can be detected within the placenta.

When diagnosing pregnancy syphilis, it is essential to inquire in detail about the patient's and their spouse's history of syphilis, as well as any history of late abortion or premature labor. Pregnant women with syphilis must undergo syphilis serological testing: ① Once during early pregnancy and once during the intermediate stage [second stage] (or advanced stage) (avoid testing a few days before or after childbirth, as false-positive reactions may occur). ② If the husband has syphilis but the woman shows no syphilis symptoms and the serological reaction is negative, but the child develops advanced-stage syphilis symptoms before the age of 10, the mother should be treated as having latent syphilis. ③ A small number of pregnant women may also exhibit biological false-positive reactions (mostly weakly positive). If neither the pregnant woman nor her spouse has a history or symptoms of syphilis, nor any suspicious past history, and two serological tests show one as suspicious and a follow-up as weakly positive, continued observation is necessary. Anti-syphilis treatment should be withheld temporarily, with serological tests repeated every 2–3 weeks, along with quantitative serological tests to monitor for rising titers. A thorough physical examination should be conducted, and the umbilical cord and placenta should be checked for abnormalities during childbirth. If suspicious, scrape the umbilical vein wall and fetal side of the placenta for dark-field microscopy to