bubble_chart Overview

Congenital syphilis is transmitted from a syphilitic pregnant woman to the fetus through the bloodstream via the placenta during pregnancy, hence also called congenital syphilis. Typically, around four months of pregnancy, the placenta becomes infected, leading to fetal death or late abortion. If the mother has been infected with syphilis for more than five years, fetal infection in the uterus becomes less likely. Early congenital syphilis occurs within the first two years of life, while advanced-stage congenital syphilis occurs after the age of two. Its characteristics include the absence of hard chancres, with early-stage lesions being more severe than acquired syphilis, while the advanced stage is milder. Cardiovascular involvement is rare, whereas the skeletal and sensory systems, such as the eyes and nose, are more commonly affected.

bubble_chart Etiology

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 foci occur long before the appearance of a hard chancre, making the blood of patients in the latent period or early-stage syphilis infectious. The length of the incubation period is inversely proportional to the number of pathogens inoculated. 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 500-1000 infectious pathogens can cause the disease. Experimental inoculations in humans and rabbits showed that the time from inoculation to the appearance of primary sexually transmitted disease lesions rarely exceeds 6 months. During this incubation period, treatment regimens below curative doses can delay the appearance of hard chancres, but whether they reduce the ultimate progression of systemic lesions remains uncertain.

After syphilis invades the body, following a 2-3 week incubation period (referred to as the first latent period), skin lesions (typically hard chancres) appear, marking initial stage [first stage] syphilis. After skin lesions develop, the body produces antibodies. Studies on experimental syphilis in rabbits demonstrate that the histological hallmark of initial stage [first stage] syphilis is mononuclear cell infiltration. By the 6th day of infection, lymphocyte infiltration occurs, peaking on the 13th day, followed by the appearance of 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 epithelium, within epithelial cells as inward invasions or phagosomes, or among fibroblasts, plasma cells, small capillary endothelial cells, lymphatic vessels, and local lymph nodes. Due to immune responses, syphilis spirochetes are rapidly cleared from the lesion sites. By the 24th day of infection, immunofluorescence tests no longer detect the presence of syphilis spirochetes. Most spirochetes are killed, the hard chancre naturally disappears, and the infection enters an asymptomatic latent phase, known as initial stage [first stage] latent syphilis. Previously, latent syphilis was primarily detected through serological tests, but now genetic diagnostics enable rapid and accurate detection.

Unkilled spirochetes continue to multiply in the body, and after approximately 6-8 weeks, large numbers enter the bloodstream, disseminating throughout the body and causing intermediate stage [second stage] early syphilis, damaging the skin, mucous membranes, bones, eyes, and the nervous system. Spirochetes in 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 quantities 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 fluctuated, the disease alternated between active and latent phases. When immunity strengthened, spirochetes transformed into granular or spherical forms. When immunity declined, spirochetes invaded certain body sites again, leading to recurrences. After repeated cycles, about 30%-40% of patients progressed to advanced stage syphilis within two years.

In advanced stage syphilis, typical gummas appear. If no symptoms are present, and chest, cardiovascular 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, cardiovascular system, and nervous system. Some patients experience declining syphilis serum titers, eventually turning negative, with PCR tests also negative, indicating natural recovery.

The above describes the typical changes without any treatment. However, due to immune differences and the effects of treatment, clinical manifestations vary greatly. Some patients may remain latent for life, while others may only exhibit initial stage [first stage] symptoms without intermediate stage [second stage] manifestations, or only show late stage [third stage] syphilis symptoms.

Pathophysiological studies indicate that syphilis is a chronic disease. Although there are a large number of syphilis spirochetes present in the initial lesions, syphilis is not a simple inflammatory reaction caused directly by the release of toxic or inflammatory substances or the presence of syphilis spirochetes 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. During the initial stage [first stage] of syphilis infection, a large number of syphilis spirochetes 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. Syphilis spirochetes are highly sensitive to temperatures slightly above normal human body temperature, and it is for this reason that syphilis spirochetes do not produce pyrogenic substances. This is also essential for the survival of syphilis spirochetes.

bubble_chart Clinical Manifestations

Early congenital syphilis, in cases where symptoms appear shortly after birth, often occurs in premature infants who are malnourished, have low vitality, are underweight, and have a thin, frail physique. Their skin is pale and loose, with an aged facial appearance, often accompanied by mild fever. The rash is similar to that of acquired intermediate-stage [second-stage] syphilis, including macules and papules, macular papules, papules, and pustular eruptions. Macules and papules or macular papules on the buttocks often merge into dark red infiltrative patches, which may have scaling or slight moisture on the surface. Those around the mouth often appear seborrheic, surrounded by a dark red halo. In the perianal area, external genitalia, and flexural surfaces of the limbs, moist papules and condylomata lata are common. Pustular eruptions are frequently seen on the palms and metatarsus, with pea-sized pustules and a dark red or coppery-red infiltrated base, which may ulcerate into erosive surfaces. Moist papules, condylomata lata, and the erosive surfaces of ruptured pustules all contain large numbers of syphilis spirochetes. A few patients may develop flaccid bullae, also known as syphilitic pemphigus, containing seropurulent fluid with a dark red infiltrated base. Nail involvement may include paronychia and onychia. Oyster-shell-like lesions or ecthyma-like ulcers may also occur. Swelling of the inferior turbinate with purulent discharge and crusting can obstruct the nasal passages, making breathing and suckling difficult—a characteristic feature of congenital syphilis in infants. If the condition progresses, it may destroy the nasal bones and hard palate, leading to saddle nose and palatal perforation. Involvement of the larynx and vocal cords may cause hoarseness.

Systemic lymphadenitis may accompany the condition. In slightly older children with syphilis, skin lesions resemble those of acquired recurrent syphilis, being larger and more numerous, often clustered, with condylomata lata being common. Mucous membranes may also be affected, and a few children may develop gummas. Bone lesions and injuries are the most common manifestations of early congenital syphilis. Syphilitic dactylitis causes diffuse fusiform swelling, affecting one or several fingers, sometimes accompanied by ulcers. Osteomyelitis is common, often occurring in long bones, along with osteochondritis and periostitis, causing pain and immobility of the limbs, resembling paralysis—hence the term syphilitic pseudoparalysis.

Visceral damage may include hepatosplenomegaly. Kidney involvement can lead to proteinuria, casts, hematuria, and edema. Additionally, orchitis and epididymitis may occur, often accompanied by scrotal edema. Ocular manifestations include syphilitic chorioretinitis, iridocyclitis, retinitis, and optic neuritis. The nervous system may also be affected, leading to cerebral softening, cerebral edema, epileptic-like seizures, and pathological changes in the cerebrospinal fluid.

Advanced stage congenital syphilis typically begins to manifest between the ages of 5-8, with multiple symptoms appearing successively by 13-14 years old. Delayed onset symptoms may occur around the age of 20. Advanced stage congenital syphilis primarily affects the skin, bones, teeth, eyes, and nerves. (1) Skin and mucous membrane lesions: Gummas may develop, leading to perforation of the hard palate and nasal septum, as well as saddle nose (collapse of the nasal bridge with a widened, upturned tip resembling a saddle). Patients with saddle nose may also exhibit widened interocular distance and everted nostrils. Saddle nose usually appears at 7-8 years old and becomes pronounced by 15-16 years old. (2) Bones: Periostitis, osteitis, and bone pain, especially severe at night. Periostitis often affects the tibia, causing thickening and forward bowing of the bone, known as saber shin (thickening of the mid-tibia with anterior convexity). Joint effusions, typically bilateral knee effusions, may occur, with grade I stiffness, painlessness, and characteristic features. (1) Frontal bossing; Hutchinson's teeth (notched incisors), characterized by narrow free edges of the permanent central incisors with a central crescent-shaped defect. Affected teeth are short, with increased anteroposterior diameter, rounded edges, and irregular alignment. The first molars are smaller, with cusps concentrated in the center of the occlusal surface, resembling a mulberry fruit, hence termed mulberry molars. The simultaneous presence of interstitial keratitis, syphilitic labyrinthitis, and Hutchinson's teeth is known as Hutchinson's triad. (2) Interstitial keratitis: About 50% of advanced congenital syphilis cases exhibit this condition. Approximately 95% of interstitial keratitis cases are syphilitic. It is usually bilateral but may initially affect one eye before the other. The progression is slow, the course prolonged, and resistant to antisyphilitic therapy, making prognosis uncertain. Younger patients in good health with adequate treatment have a better prognosis; otherwise, blindness may result. (3) Nerve deafness: Caused by labyrinthitis due to labyrinth involvement. Most common in patients under 15, it typically affects both ears, with sudden onset and fluctuating severity, often accompanied by dizziness and tinnitus. It is resistant to antisyphilitic therapy, often progressing to deafness. Syphilitic labyrinthitis is difficult to distinguish from non-syphilitic forms.

Congenital latent syphilis: No clinical symptoms, positive syphilis serological reaction is congenital latent syphilis.

Diagnostic basis of congenital syphilis: (1) Family history of maternal syphilis; (2) Presence of typical lesions and signs; (3) Laboratory tests detecting Treponema pallidum from lesions, nasal secretions, or placental umbilical cord; (4) Positive syphilis serological test; (5) Genetic testing positive for Treponema pallidum DNA.

Syphilis co-infected with HIV: In recent years, many cases of syphilis patients co-infected with HIV have emerged, altering the clinical course of syphilis. Because genital ulcers in syphilis patients are a significant risk factor for acquiring and transmitting HIV infection; and HIV can cause meningeal lesions, making it easier for Treponema pallidum to cross the blood-brain barrier and cause neurosyphilis.

Due to HIV infection and immune impairment, early syphilis may not present with skin lesions, arthritis, hepatitis, or osteitis. Patients, lacking an immune response, may appear lesion-free on the surface but could actually be in an active syphilis stage. Because of immunodeficiency, syphilis progresses rapidly and can quickly advance to late-stage [tertiary] syphilis. Severe outbreaks may even occur, such as fulminant malignant syphilis (Lues Maligna). HIV infection can also accelerate the progression of syphilis to early neurosyphilis. In cases of syphilis with neurological involvement, penicillin treatment is less effective. In the 1960s and 1970s, cases of neurosyphilis recurring after standard penicillin treatment were rare. However, in recent years, a large number of syphilis patients co-infected with HIV have developed acute meningitis, cranial nerve abnormalities, and cerebrovascular accidents.

bubble_chart Treatment Measures

1. History and Current Status:

Syphilis is an ancient sexually transmitted disease. In the course of combating syphilis, humanity has accumulated extensive experience and attempted numerous treatment methods. In ancient China, there were records of using mercury-based treatments for syphilis. The treatment of syphilis can be divided into three developmental periods, from mercury-based treatments to the use of penicillin:

(1) The Mercury Treatment Era (1497–1907): Widmann was the first to use mercury-based treatments for syphilis, achieving significant therapeutic effects. Through repeated improvements in dosage forms and administration methods during clinical application, mercury became the only effective treatment for syphilis at the time. Intramuscular injection was commonly used, with typical mercury preparations including (1) water-soluble mercury, such as 20% mercuric cyanide and 20% mercuric chloride (corrosive sublimate); (2) mercury oil suspensions, such as 10% mercuric salicylate oil suspension; and (3) mercury ointment, containing 50% mercury, absorbed through topical application. Mercury inhibits the syphilis spirochete but is highly toxic and is no longer used. During this period, iodine was also introduced for treating syphilis, typically as a 5%–10% potassium iodide solution, with a daily dose of 1–3 grams or more. Iodine does not kill the spirochete but helps resolve granulomas, often used for late-stage [third-stage] syphilitic gummas. Its mechanism involves enhancing capillary permeability and reducing blood antitrypsin levels, thereby increasing the dissolution of fibrous tissue by trypsin in inflammatory lesions. Historically, iodine was only an adjunct therapy for advanced syphilis.

(2) The Arsenic Treatment Era (1907–1943): In 1907, Ehrlich developed trivalent arsenic, arsphenamine (also known as 606). Later, in 1912, Ehrlich introduced neoarsphenamine (914). Subsequent arsenic-based treatments included sulfur 914, arsenic oxide, and pentavalent arsenic compounds such as acetarsone. Arsenic effectively kills the syphilis spirochete and other spirochetes. Bismuth-based treatments for syphilis also emerged during this period, with bismuth nitrate powder being a notable example. Bismuth proved more effective than mercury in treating syphilis.

(3) The Penicillin Treatment Era (1943–Present): In 1943, Mahoney, Arnold, and Harris pioneered the use of penicillin for syphilis, ushering in a new era of treatment. Penicillin strongly inhibits the syphilis spirochete, with early-stage syphilis showing eradication of most spirochetes within 16 hours, rapid resolution of skin lesions, and subsequent seronegativity. Long-term use has demonstrated penicillin's rapid efficacy, minimal side effects, and thorough spirochete eradication, making it the ideal treatment for syphilis. To date, no penicillin-resistant syphilis spirochetes have been identified. Since the 1950s, other antibiotics have also been introduced for syphilis treatment.

2. Antibiotic Treatment:

With the advent of penicillin, older treatments such as mercury, iodine, arsenic, and bismuth gradually fell out of use. Today, penicillin remains the first-line treatment for syphilis due to the spirochete's high sensitivity to it. The replication cycle of the syphilis spirochete is 30–33 hours, and a serum concentration of 0.032 IU/mL is sufficient to kill it, provided this concentration is maintained for at least 7–10 days without reduction.

Penicillin Treatment Regimens for Syphilis (Based on the World Health Organization’s 1981 Guidelines for Sexually Transmitted Diseases):

(1) Early Syphilis: Includes primary [first-stage], secondary [second-stage], and latent syphilis with a duration of less than two years. Recommended treatment is intramuscular penicillin, 1.2 million units per buttock (total 2.4 million units), administered once. Alternatively, procaine penicillin G suspension can be given intramuscularly once daily for 10 days (total 6 million units). Follow-up clinical and serological examinations should be conducted twice within a year post-treatment. To eliminate sources of infection, not only should early syphilis patients receive adequate treatment, but their sexual contacts should also be thoroughly examined and treated.

(II) Advanced stage syphilis: Includes patients with late stage [third stage] skin, mucous membrane, and bone damage, latent syphilis with a disease duration of over two years, cardiovascular syphilis, and neurosyphilis. For benign advanced stage syphilis (vascular, mucous membrane, and bone, etc.), procaine penicillin G can be administered via intramuscular injection once daily, 600,000 units each time, for a total of 15 doses, with a cumulative dose of 9 million units. Alternatively, benzathine penicillin can be injected intramuscularly once a week, 2.4 million units each time, for a total of three doses, with a cumulative dose of 7.2 million units.

For cardiovascular and central nervous system syphilis, procaine penicillin is used instead of benzathine penicillin, administered intramuscularly once daily at 600,000 units per dose for at least 20 doses, with a total dose exceeding 12 million units.

After treatment for advanced-stage or latent advanced-stage syphilis, a significant proportion of patients may not show marked serological improvement. Post-treatment, annual check-ups are necessary. For neurosyphilis patients, cerebrospinal fluid should be examined yearly until satisfactory improvement is achieved. Generally, cell counts and protein levels recover earlier, while serological reactions in the cerebrospinal fluid improve later.

Spouses of advanced-stage syphilis patients and children born before treatment should be examined.

(3) Treatment for pregnant syphilis patients: Early-stage syphilis patients treated promptly can prevent congenital syphilis.

In syphilis-endemic areas, pregnant women at risk should undergo serological testing at least once during the first three months of pregnancy and again in the last three months before delivery. If positive, and if medical history and physical examination confirm syphilis, penicillin treatment should be administered according to the stage of syphilis.

(4) Treatment for early congenital syphilis: Infants born to treated syphilitic mothers should undergo clinical and serological examinations until serological tests turn negative or remain negative for at least three months. Treatment is required if clinical symptoms appear, radiological findings indicate bone syphilis lesions, serological titers rise by two or more dilutions or remain elevated, or if the mother received inadequate penicillin treatment or the infant cannot be thoroughly examined. Treatment involves intramuscular procaine penicillin once daily at 50,000 units per kilogram of body weight for ten consecutive days, totaling 1.5 to 3 million units. For early congenital syphilis infants with normal cerebrospinal fluid who cannot receive continuous injections, a single intramuscular dose of benzathine penicillin at 50,000 units per kilogram may be administered.

(5) Treatment for advanced congenital syphilis: For children over two years old, treatment follows the regimen for adults of the corresponding stage, with doses not exceeding adult levels.

Penicillin is highly effective against Treponema pallidum, killing the spirochete at serum concentrations above 0.03 units/mL. However, massive spirochete death after penicillin injection releases foreign proteins, potentially causing a Jarisch-Herxheimer reaction. In early-stage patients, this reaction typically manifests within 3–12 hours as fever, weakness, and worsening skin or bone membrane inflammation symptoms, usually resolving within 24 hours. In advanced syphilis, focal reactions may occur, such as angina, arrhythmias, or even aortic aneurysm rupture in cardiovascular syphilis patients, or worsened neurosyphilis symptoms like increased deafness or headaches. Some recommend starting prednisone 2–3 days before penicillin treatment for cardiovascular or neurosyphilis to mitigate the Jarisch-Herxheimer reaction. The dosage is 20–30 mg daily, tapered or discontinued after 2–3 days if no or mild reactions occur.

Other antibiotics: Several non-penicillin antibiotics are used against Treponema pallidum, including macrolides (e.g., azithromycin, roxithromycin, erythromycin), tetracyclines (e.g., doxycycline, oxytetracycline), and streptomycin. In recent years, ceftriaxone and cefotaxime have also shown good clinical efficacy.

III. Treatment Principles

Early-stage syphilis must be cured completely to eliminate the source of infection, while advanced-stage syphilis requires symptom control, organ function preservation, life extension, and improved work capacity.

Treatment must be early, adequate, standardized, and completed as planned, followed by post-treatment monitoring to detect relapse. Systematic examination is essential before treatment.