Syphilis: Clinical Guidelines

List of Abbreviations

HIV – human immunodeficiency virus

WHO – World Health Organization

DNA – deoxyribonucleic acid

STI – sexually transmitted infections

EIA – enzyme immunoassay

CT – computed tomography

ICD – International Classification of Diseases

MRI – magnetic resonance imaging

PCR – polymerase chain reaction

TPI – Treponema pallidum immobilization test

FTA – fluorescent treponemal antibody test

FTA-CSF _– fluorescent treponemal antibody test of cerebrospinal fluid

RCT – randomized controlled trial

RPR – rapid plasma reagin test

RNA – ribonucleic acid

TPHA – Treponema pallidum hemagglutination assay

RPR – rapid plasma reagin test

ESR – erythrocyte sedimentation rate

AIDS – acquired immunodeficiency syndrome

US – ultrasound examination

CNS – central nervous system

ECG – electrocardiography

Echo-CG – echocardiography

CD4 cells – T helper lymphocytes

IgG – immunoglobulin(s) G

IgM – immunoglobulin(s) M

VDRL – Venereal Diseases Research Laboratory test

Terms and Definitions

Congenital syphilis – an intrauterine infection transmitted to the fetus via the transplacental route from a mother with syphilis; manifestations of congenital syphilis may first appear in the fetus during the first months of life, a year later, or even in adolescence and adulthood.

Delayed seronegativization of non-treponemal serological reactions – a situation where, within 12 months after the completion of specific therapy for early syphilis, a gradual decrease in non-treponemal test positivity and/or antibody titer is observed (by at least 4-fold), but complete seronegativization does not occur.

Clinical relapse – the re-emergence of clinical manifestations of syphilis after the completion of specific therapy.

Neurosyphilis – symptom complexes arising from damage to the nervous system by *Treponema pallidum*, which transform into one another as the disease progresses or coexist as a dynamic state; these lesions vary in pathomorphological picture, pathogenesis, clinical presentation, course, and prognosis, and are united solely by their etiology.

Serological resistance – the persistent retention of positive non-treponemal tests without a downward trend in antibody titers for 12 months after the completion of specific therapy for early syphilis.

Serological relapse – the re-positivization of non-treponemal tests that had temporarily become negative after the completion of specific therapy, in the absence of evidence of reinfection.

Prozone phenomenon – in the presence of an excess of antibodies in the test serum, false-negative or weakly positive results may occur due to the blocking of the normal antigen-antibody reaction course, whereas upon dilution of the serum, the results become strongly positive.

Depot preparation – a long-acting drug.

Preventive treatment – therapy administered to individuals who have had sexual or close household contact with patients having early syphilis, provided that no more than 2 months have elapsed since the contact.

Treponemal tests - Detection of antibodies to Treponema pallidum by Treponema pallidum hemagglutination assay (TPHA) (qualitative and semi-quantitative test) in blood serum; Detection of antibodies to Treponema pallidum by Treponema pallidum hemagglutination assay (TPHA) (qualitative and semi-quantitative test) in cerebrospinal fluid; Detection of antibodies to Treponema pallidum by enzyme-linked immunosorbent assay (ELISA); Detection of antibodies to Treponema pallidum by immunoblotting; Detection of antibodies to Treponema pallidum in blood serum/cerebrospinal fluid by fluorescent treponemal antibody test (FTA), including FTA-abs and FTA-200 modifications); Treponema pallidum immobilization test (TPI); Immunochemiluminescent assay; Immunochromatographic test.

Non-treponemal tests - Detection of antibodies to Treponema pallidum in non-treponemal tests (RPR, VDRL) (qualitative and semi-quantitative test) in blood serum/cerebrospinal fluid; Venereal Disease Research Laboratory test (VDRL)

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Syphilis is an infectious disease caused by Treponema pallidum, transmitted predominantly sexually, characterized by lesions of the skin, mucous membranes, nervous system, internal organs, and musculoskeletal system, and distinguished by a staged, relapsing, progressive course.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The causative agent of syphilis belongs to the order Spirochaetales, family Spirochaetaceae, genus Treponema, species Treponema pallidum, subspecies pallidum (syn. Spirochaeta pallidum). Treponema pallidum is a spiral-shaped microorganism that stains poorly with aniline dyes due to the large number of hydrophobic components in the cytoplasm. It does not cultivate on artificial nutrient media. It is unstable outside the body, dying upon heating, drying, exposure to most antiseptics, and in acidic and alkaline environments. It is stable at low temperatures and in a moist environment.

In addition to the spirillar form, the microorganism can also exist as cysts, L-forms, and polymembranous phagosomes. The cyst is a survival form of Treponema pallidum under unfavorable environmental conditions, regarded as a dormant stage of T. pallidum, and possesses antigenic activity. The L-form is a survival mode of Treponema pallidum and has weak antigenic activity. Polymembranous phagosomes are the result of incomplete phagocytosis of T. pallidum. Encystment, L-transformation, and incomplete phagocytosis are the cause of prolonged asymptomatic persistence of T. pallidum. Reversion of treponemes from survival forms to the pathogenic spiral form is the cause of syphilis relapses

The pathogenesis of syphilis is characterized by the following:

Incubation period begins with the introduction of the syphilis causative agent through damaged skin or mucous membrane and ends with the appearance of the primary chancre. On average, the duration of the incubation period ranges from 2 weeks to 2 months; this period can shorten to 8 days or, conversely, lengthen to 190 days. Shortening of the incubation period is observed in reinfection and upon the introduction of the syphilis causative agent into the body from multiple entry sites, which accelerates the generalization of the infection and the development of immune changes in the body. Lengthening of the incubation period is observed as a result of the use of small doses of systemic treponemocidal antibacterial drugs for intercurrent diseases.

Intensive multiplication of T. pallidum begins at the inoculation site; the characteristics of the local tissue reaction to the treponeme determine the clinical features of syphilids.

Within a few minutes, T. pallidum can invade the bloodstream and then attach to host cells, including epithelial, fibroblast, and endothelial cells. Rapid dissemination via lymphatic and blood vessels occurs, along with penetration through the blood-brain and placental barriers, which determines the ability of T. pallidum to disseminate and leads to the spread of infection to various human tissues and organs—manifestations of syphilis remote from the primary affect.

In syphilis, an infectious (non-sterile) immunity develops, caused by the presence of Treponema pallidum in the body and disappearing shortly after its elimination as a result of treatment. Therefore, after microbiological cure of syphilis, reinfection is possible.

The interaction between the pathogen and the patient's immune defense factors determines the stage-wise, wave-like course of the syphilitic infection with alternating periods of manifestation and latency, as well as the progradient nature of the disease — a gradual shift in the clinical and pathomorphological picture toward increasingly adverse manifestations;

The combination of the virulence properties of the pathogen and the specific immune response to its introduction accounts for the wide variety of clinical manifestations and the chronic relapsing course of the disease.

1.3 Epidemiology of the Disease or Condition

According to official state statistical reporting, the epidemiological situation regarding syphilis is characterized by a gradual decrease in incidence across the Russian Federation as a whole (in 2000 — 164.5 cases per 100,000 population; in 2010 — 44.9 cases; in 2020 — 10.4 cases). Against the background of declining overall syphilis incidence, there is an increase in the proportion of late forms of the disease (in 2010 — 2.5 cases per 100,000 population; in 2019 — 4.6 cases). The proportion of patients with specific nervous system lesions in the overall structure of syphilis morbidity increased from 0.9% in 2008 to 5.9% in 2018. Furthermore, patients with late neurosyphilis accounted for 65.6% of the total number of identified neurosyphilis cases in 2008, and already 85.1% in 2018 [1]. In 2021, a total of 21,152 newly diagnosed cases of syphilis were registered, with the incidence rate for all forms of syphilis being 14.5 per 100,000 population (in 2020 — 15,313 cases, incidence rate 10.5 per 100,000 population). A significant increase in the syphilis incidence rate can be noted in 2021, amounting to 38.1% compared to 2020, as a result of which the incidence rate almost reached the level of 2019 (15.0 per 100,000 population) [47]

Syphilis is a strict anthroponosis. The sources of infection are most frequently patients with early forms of syphilis (within the first two years after infection) who have weeping rashes on the skin and mucous membranes. Routes of transmission:

1. Contact:

• direct (immediate) contact with an infected person:

– sexual (the most frequent and typical route of infection; transmission occurs through damaged skin or mucous membranes);

– domestic/household (occurs predominantly in children through household contact with parents who have syphilitic rashes on the skin and/or mucous membranes);

– occupational (infection of laboratory personnel working with infected experimental animals, as well as obstetrician-gynecologists, surgeons, dentists, pathologists, and forensic medical experts in the line of duty);

• indirect (mediatized) contact — via contaminated objects;

2. Transplacental — transmission of infection from an infected mother to the fetus via the placenta, leading to the development of congenital syphilis;

3. Transfusion — through blood transfusion from a donor infected with any form of syphilis.

A woman with syphilis who has specific rashes on the nipple and areola can infect her child during breastfeeding. The infectivity of breast milk has not been proven. Other contagious biological fluids include saliva and semen from patients with syphilis exhibiting clinical manifestations in the respective localizations. No cases of transmission via sweat or urine have been observed.

1.4 Features of Coding the Disease or Condition

ICD-10:

A50 Congenital syphilis

A50.0 Early congenital syphilis, symptomatic

Any congenital syphilitic condition specified as early or manifesting within the first two years of life.

Early congenital syphilis:

– cutaneous;

– of skin and mucous membranes;

– visceral.

Early congenital syphilitic:

– laryngitis;

– oculopathy;

– osteochondropathy;

– pharyngitis;

– pneumonia;

– rhinitis.

A50.1 Early congenital syphilis, latent

Congenital syphilis without clinical manifestations, with a positive serological reaction and negative cerebrospinal fluid examination results, manifesting within the first two years of life.

A50.2 Early congenital syphilis, unspecified

Congenital syphilis (without further specifications) manifesting within the first two years of life.

A50.3 Late congenital syphilitic oculopathy

Late congenital syphilitic interstitial keratitis (H19.2).

Late congenital syphilitic oculopathy (H58.8).

Excludes Hutchinson's triad (A50.5).

A50.4 Late congenital neurosyphilis [juvenile neurosyphilis]

Juvenile general paralysis.

Juvenile:

– progressive paralysis;

– tabes dorsalis;

– taboparesis.

Late congenital syphilitic:

– encephalitis (G05.0);

– meningitis (G01);

– polyneuropathy (G63.0).

Use an additional code, if necessary, to identify any associated mental disorder.

Excludes: Hutchinson's triad (A50.5).

A50.5 Other forms of late congenital syphilis, symptomatic

Any congenital syphilitic condition specified as late or manifesting two years or more after birth.

Clutton's joints (M03.1).

Hutchinson's:

– teeth;

– triad.

Late congenital:

– cardiovascular syphilis (I98.*);

– syphilitic:

- arthropathy (M03.1);

- osteochondropathy (M90.2).

Syphilitic saddle nose.

A50.6 Late congenital syphilis, latent

Congenital syphilis without clinical manifestations, with a positive serological reaction and a negative cerebrospinal fluid test, manifesting at age two years or older.

A50.7 Late congenital syphilis, unspecified

Congenital syphilis without additional specifications, manifesting at age two years or older.

A50.9 Congenital syphilis, unspecified

A51 Early syphilis

A51.0 Primary genital syphilis

Syphilitic chancre without additional specifications.

A51.1 Primary anal syphilis

A51.2 Primary syphilis of other sites

A51.3 Secondary syphilis of skin and mucous membranes

Condyloma latum.

Syphilitic:

– alopecia (L99.8);

– leukoderma (L99.8);

– mucous membrane patches.

A51.4 Other forms of secondary syphilis

Secondary syphilitic:

– female pelvic inflammatory disease (N74.2);

– iridocyclitis (H22.0);

– lymphadenopathy;

– meningitis (G01);

– myositis (M63.0);

– oculopathy not elsewhere classified (H58.8);

– periostitis (M90.1).

A51.5 Early syphilis, latent

(Acquired) syphilis without clinical manifestations, with a positive serological reaction and a negative cerebrospinal fluid test, of less than two years' duration after infection.

A51.9 Early syphilis, unspecified

A52 Late syphilis

A52.0 Cardiovascular syphilis

Cardiovascular syphilis without additional specifications (I98.0).

Syphilitic:

– aortic aneurysm (I79.0);

– aortic incompetence (I39.1);

– aortitis (I79.1);

– cerebral arteritis (I68.1);

– endocarditis, unspecified (I39.8);

– myocarditis (I41.0);

– pericarditis (I32.0);

– pulmonary insufficiency (I39.3).

A52.1 Symptomatic neurosyphilis

Charcot's arthropathy (M14.6).

Late syphilitic:

- acoustic neuritis (H49.0);

- encephalitis (G05.0);

- meningitis (G01);

- optic atrophy (H48.0);

- polyneuropathy (G63.0);

- retrobulbar neuritis (H48.1).

Syphilitic parkinsonism (G22).

Tabes dorsalis.

A52.2 Asymptomatic neurosyphilis

A52.3 Neurosyphilis, unspecified

Gumma (syphilitic).

Central nervous system syphilis (late) without additional specifications.

Syphiloma.

A52.7 Other symptomatic late syphilis

Syphilitic glomerulonephropathy (N08.0).

Gumma (syphilitic) of any site, except those classified in categories A52.0–A52.3.

Late or tertiary syphilis.

Late syphilitic:

- bursitis (M73.1);

- chorioretinitis (H32.0);

- episcleritis (H19.0);

- inflammatory disease of female pelvic organs (N74.2);

- leukoderma (L99.8);

- oculopathy not elsewhere classified (H58.8);

- peritonitis (K67.2).

Syphilis (without specification of stage):

- bone (M90.2);

- liver (K77.0);

- lung (J99.8);

- muscle (M63.0);

- synovial (M68.0).

A52.8 Late latent syphilis

Syphilis (acquired) without clinical manifestations, with a positive serological reaction and a negative cerebrospinal fluid test, two years or more after infection.

A52.9 Late syphilis, unspecified

A53 Other and unspecified forms of syphilis

A53.0 Latent syphilis, unspecified as early or late

Latent syphilis without additional specifications.

Positive serological test for syphilis.

A53.9 Syphilis, unspecified

Infection caused by Treponema pallidum, without additional specifications. Syphilis (acquired) without additional specifications.

Excluded: syphilis without additional specifications as the cause of death at an age under two years (A50.2).

Comments: A51.4 (other forms of secondary syphilis) includes early involvement of the nervous system, internal organs, and musculoskeletal system. There is no division of asymptomatic neurosyphilis into early and late; consequently, all patients with an asymptomatic course of neurosyphilis, regardless of the disease duration, are classified as late syphilis (A52.2). ICD-10 codes ending in 9 (A50.9; A51.9, A52.9, and A53.9), as well as A50.2 and A50.7, reflect forms of infection not confirmed by laboratory diagnostic methods.

1.5 Classification of the disease or condition

Currently, the traditional clinical classification of syphilis is widely used [2].

I. Acquired syphilis

After the incubation period, the following occur:

1. Primary syphilis:

a. Primary seronegative syphilis (syphilis primaria seronegativa) – diagnosed in the presence of a primary chancre and negative results of nonspecific serological tests.

b. Primary seropositive syphilis (syphilis primaria seropositiva) – diagnosed in the presence of a primary chancre and positive (even weakly positive) results of nonspecific serological tests (A51.0, A51.1, A51.2) [1A91.0, 1A91.1, 1A91.2].

In case of a rare localization of the primary chancre outside the genital organs, the word "extragenital" is added to the diagnosis of "primary syphilis".

2. Secondary syphilis:

a. Recent secondary syphilis (syphilis secundaria recens) – the first eruption of the secondary period, diagnosed in the presence of abundant, small, symmetrical secondary syphilids (most commonly roseolae, less commonly papules) and remnants of the primary chancre (A51.3, A51.4) [1A91.3].

b. Recurrent secondary syphilis (syphilis secundaria recidiva) – the second and subsequent "waves" of eruptions of the secondary period, diagnosed in the presence of fewer, larger, grouped secondary syphilids (most commonly papular) and the absence of a primary chancre (A51.3, A51.4) [1A91.3].

3. Tertiary syphilis:

a. Active tertiary syphilis (syphilis tertiaria activa) – a period characterized by the presence of nodular or gummatous syphilids (A52.7) [1A92.22].

b. Latent tertiary syphilis (syphilis tertiaria latens) – diagnosed in patients who have undergone active manifestations of the tertiary period of syphilis and have traces in the form of pathognomonic scars at the time of examination (A52.7) [1A92.22].

4. Latent syphilis:

a. Early latent syphilis (syphilis latens praecox) – diagnosed in patients who have not previously received antisyphilitic therapy, in the absence of clinical manifestations of the disease, with positive results of nonspecific and specific (or only specific) serological tests and a disease duration of up to 2 years (A51.5) [1A91.5].

b. Late latent syphilis (syphilis latens tarda) – diagnosed in patients who have not previously received antisyphilitic therapy, in the absence of clinical manifestations of the disease, with positive results of nonspecific and specific (or only specific) serological tests and a disease duration of more than 2 years (A52.8) [1A92.Y].

c. Unspecified latent syphilis (syphilis latens ignorata) – diagnosed in patients who have not previously received antisyphilitic therapy, in the absence of clinical manifestations of the disease, with positive results of nonspecific and specific (or only specific) serological tests and an undetermined disease duration (A53.0) [1A93].

5. Neurosyphilis:

a. Early nervous system syphilis (neurosyphilis praecox) – diagnosed in patients with a confirmed diagnosis of syphilis in the presence of neurological/psychiatric symptoms corresponding to exudative-inflammatory and proliferative processes in the meninges and blood vessels, and pathological changes in the cerebrospinal fluid, or in the presence of CSF pathology alone (asymptomatic early neurosyphilis) and a disease duration of up to 5 years (A52.1, A52.2, A52.3) [1A91.2, 1A91.4, 1A91.Y].

b. Late nervous system syphilis (neurosyphilis tarda) – diagnosed in patients with a confirmed diagnosis of syphilis in the presence of neurological/psychiatric symptoms corresponding to degenerative-dystrophic processes in the brain and/or spinal cord parenchyma, and pathological changes in the cerebrospinal fluid, or in the presence of CSF pathology alone (asymptomatic late neurosyphilis) and a disease duration of more than 5 years (A52.1, A52.2, A52.3) [1A92.0, 1A92.00, 1A92.01, 1A92.20, 1A92.0Z].

6. Syphilis of internal organs and the musculoskeletal system:

a. Early visceral syphilis (with indication of the affected organ) (syphilis visceralis praecox) – diagnosed in patients with a confirmed diagnosis of syphilis in the presence of clinical symptoms of damage to the corresponding organ based on the detection of lymphoplasmacytic infiltration in a biopsy sample during pathomorphological examination and/or positive dynamics of the process during specific therapy (A52.0) [1A91.2, 1A91.4, 1A91.Y].

b. Late visceral syphilis (syphilis visceralis tarda) – diagnosed in patients with a confirmed diagnosis of syphilis in the presence of clinical symptoms of damage to the corresponding organ based on the detection of granulomatous inflammation in a biopsy sample during pathomorphological examination and/or positive dynamics of the process during specific therapy (A52.0) [1A92.1, 1A92.2, 1A92.21, 1A92.2Y, 1A92.2Z, 1A92.Y].

II. Congenital syphilis

I. Syphilis of the placenta and fetus

II. Early congenital syphilis (syphilis congenita praecox) – diagnosed in children under 2 years of age; it is subdivided into:

a) infant syphilis – from 0 to 1 year

b) early childhood syphilis – from 1 to 2 years.

Early congenital syphilis can be:

1. active (with clinical manifestations) (A50.0) [1A90.0, JB62.1] and

2. latent – without clinical manifestations, but with positive serological tests (A50.1) [1A90.1, JB62.1].

III. Late congenital syphilis (syphilis congenita tarda) – diagnosed in children over 2 years of age; it is divided into:

a) syphilis in children aged 2 to 5 years with signs of secondary syphilis

b) syphilis in children over 5 years of age and adults with signs of tertiary syphilis.

Late congenital syphilis can be:

1. active (A50.3, A50.4, A50.5) [1A90.2, 1A90.3, 1A90.4] and

2. latent (A50.6) [1A90.5].

Comments: The division of syphilis into early and late forms is conventional. The 2-year mark from the moment of infection is accepted as the boundary between them because patients remain epidemiologically dangerous within 2 years, requiring adequate anti-epidemic measures. In addition, late clinical manifestations based on granulomatous inflammation (tubercles and gums) generally do not appear earlier than 2 years from the time of infection.

In the provided clinical classification, to assist the practicing physician, ICD-10 and ICD-11 codes are given in parentheses (ICD-10) and square brackets [ICD-11].

1.6 Clinical presentation of the disease or condition

Anamnestic data should take into account indications of skin and mucous membrane rashes, enlarged lymph nodes, etc., at a specific point in the past; the possibility of contracting syphilis during a certain period (presence of a source of infection); past serological tests for syphilis; a history of syphilis treatment; a history of systemic antibacterial therapy; information on past illnesses, dispensary monitoring by specialists of another profile, results of special studies and consultations with related specialists, if any were performed. In women, inflammatory processes of the reproductive organs and the number and outcome of previous pregnancies are taken into account.

Incubation period

On average, the incubation period lasts from 2 weeks to 2 months; this period may shorten to 8 days or, conversely, extend to 190 days, with no clinical manifestations. Primary syphilis begins at the end of the incubation period.

Primary syphilis (A51.0-A51.2)

At the site of *Treponema pallidum* introduction, a primary affect (hard chancre) develops—an erosion or ulcer ranging from 2-3 mm (dwarf chancre) to 1.5-2 cm or more (giant chancre) in diameter, round in shape, with smooth edges, a smooth, shiny base of pink or red, sometimes grayish-yellow color, saucer-shaped (ulcer), with scanty serous discharge, painless on palpation, and having a dense elastic infiltrate at the base. Depending on localization, genital, extragenital, and bipolar primary affects are distinguished. Chancres can be single or multiple, typical (erosive, ulcerative) and atypical. Atypical chancres include: amygdaloid chancre (unilateral enlargement and induration of the palatine tonsil), panaris chancre (painful ulcer on the edematous terminal phalanx of a finger), and indurative edema (unilateral enlargement of the labium majus in women or edema of the prepuce in men). The primary affect is accompanied by unilateral or bilateral regional lymphadenitis, less commonly lymphangitis. Enlarged lymph nodes are painless and have a dense-elastic consistency. When a secondary infection joins, complications of the primary affect develop: impetiginization, balanoposthitis, vulvovaginitis, phimosis, paraphimosis, gangrenization, and phagedenism. The average duration of the primary period of syphilis is 6-7 weeks. At the end of the primary period, polyadenitis and general infectious symptoms (intoxication syndrome) appear.

Complaints and anamnesis

Patients may have no complaints or may complain of rashes on the skin and mucous membranes, and enlargement of regional lymph nodes. Towards the end of the primary period, complaints of general malaise, fever, and nighttime pain in the bones, joints, and muscles may appear.

Clinical signs on physical examination

Clinical signs of a hard chancre of genital or extragenital localization. The appearance, shape, localization of the hard chancre, and the presence of secondary infection are evaluated. Palpation reveals a dense-elastic infiltrate at the base of the ulcer; palpation is painless.

Clinical signs of lymphadenitis and/or lymphangitis upon palpation of regional lymph nodes; palpation is painless.

Secondary syphilis (A51.3)

The secondary period of syphilis occurs on average 2-3 months after infection, is caused by hematogenous dissemination of the infection against the background of developing infectious immunity, and manifests as rashes on any areas of the skin and/or mucous membranes. Roseolous (macular) rashes are most common, followed by papular (nodular), less commonly papulo-pustular (pustular), and very rarely vesicular rashes. On mucous membranes, localized and confluent roseolous and papular syphilids are observed; the latter evolve from opalescent papules to erosive, vegetative, ragadiform, and rarely ulcerative syphilids. Manifestations of the secondary period of syphilis also include syphilitic leukoderma and alopecia—diffuse, microfocal, and mixed. In the secondary period, residual manifestations of primary syphilis may persist, as well as involvement of internal organs, the musculoskeletal system, and the nervous system (A51.4) [1A91.4]. The course is undulating.

Complaints and anamnesis

Patients may have no complaints or may draw attention to widespread rashes on the skin and mucous membranes. There may also be complaints of fever, headache, fatigue, sore throat, as well as diffuse or focal hair loss.

Clinical signs on physical examination

Rash, residual signs of the primary affect — the prevalence of the rash, localization, and the elements it is represented by are evaluated.

The scalp is examined to identify signs of focal or diffuse alopecia. On the skin of the anterior and anterolateral surfaces of the neck, the condition of the skin is assessed during examination to diagnose leukoderma.

Tertiary syphilis (A52.7)

It may develop immediately following secondary syphilis, but in most cases a latent period is observed between the secondary and tertiary periods. The appearance of symptoms of tertiary syphilis is possible many years after infection with an asymptomatic course of the infection. It manifests as rashes on any area of the skin and/or visible mucous membrane (tubercular and gummatous syphilids, Fournier's tertiary roseola). Tertiary period syphilids frequently lead to defects in the surrounding tissues. In the tertiary period of syphilis, involvement of internal organs, the musculoskeletal system, and the nervous system is frequently observed (A52.0-A52.7)

Complaints and anamnesis

Patients may have no complaints, or after a prolonged latent period (years after infection), complaints of rashes on the mucous membranes and skin (tubercular and gummatous) appear. Patients may present complaints similar to those of various somatic diseases, depending on the affected organ system.

Clinical signs on physical examination

Clinical signs of tertiary period rash (gumma) upon examination of the skin and visible mucous membranes

Clinical signs of musculoskeletal system involvement, such as synovitis and/or osteoarthritis, upon palpation and examination of the joints.

Latent syphilis (A51.5, A52.8, A53.0)

Early latent (A51.5) (up to 2 years from the moment of infection), late latent (A52.8) (more than 2 years from the moment of infection), and unspecified as early or late (A53.0) latent syphilis are distinguished. It is characterized by the absence of clinical manifestations.

Complaints and anamnesis

Patients, as a rule, have no complaints.

In some cases, the diagnosis of early latent syphilis is assisted by physical examination data (a scar at the site of the former primary syphiloma, enlargement of lymph nodes), as well as the appearance of a temperature flare-up reaction (Jarisch-Herxheimer reaction) after the initiation of specific treatment. Establishing a diagnosis of latent syphilis requires examinations by specialist physicians (neurologist, ophthalmologist, therapist), as well as cerebrospinal fluid analysis, echocardiography, and a biochemical blood test to rule out specific lesions of the nervous system and internal organs.

Clinical signs on physical examination

Clinical signs are not detected.

Congenital syphilis (A50).

Early congenital symptomatic syphilis (A50.0). Characterized by 3 groups of symptoms: 1) pathognomonic for congenital and absent in acquired syphilis (syphilitic pemphigus, Hochsinger's diffuse cutaneous infiltration, specific rhinitis (dry, catarrhal, and ulcerative stages), and Wegener's osteochondritis of long tubular bones (grades I, II, and III, detected by X-ray examination; grade I has no diagnostic significance, as similar changes can also be observed in rickets); 2) typical manifestations of syphilis found not only in early congenital but also in acquired syphilis (papular rash on the extremities, buttocks, face, sometimes all over the body; in macerated areas — erosive papules and condylomata lata; roseolous rash (rarely observed), raucedo, alopecia, bone lesions in the form of periostitis, osteoporosis and osteosclerosis, bone gummas; internal organ involvement in the form of specific hepatitis, glomerulonephritis, myocarditis, endo- and pericarditis, etc., central nervous system involvement in the form of specific meningitis, hydrocephalus, etc.); 3) general and local symptoms also found in other intrauterine infections: "senile appearance" of the newborn (skin wrinkled, flabby, dirty-yellow); low birth length and weight with features of hypotrophy up to cachexia; hypochromic anemia, leukocytosis, elevated ESR, thrombocytopenia; hepatosplenomegaly; chorioretinitis (type IV); onychia and paronychia. The placenta in syphilis is enlarged and hypertrophied; its weight is 1/4–1/3 (normally 1/6–1/5) of the fetal weight.

Late congenital symptomatic syphilis (A50.3; A50.4). Characterized by definite signs (Hutchinson's triad: interstitial keratitis, labyrinthine deafness, Hutchinson's teeth), probable signs (saber shins, chorioretinitis, nasal deformities, radiating scars around the mouth, natiform skull, dental deformities, syphilitic gonitis, nervous system lesions in the form of hemiparesis and hemiplegia, speech disorders, dementia, cerebral palsy, and Jacksonian epilepsy), and dystrophies (thickening of the sternal end of the right clavicle, cranial bone dystrophies in the form of "Olympic" brow, high "gothic" or vaulted palate, absence of the xiphoid process of the sternum, infantile little finger, widely spaced upper incisors, tubercle on the chewing surface of the upper first molar). In addition, specific lesions on the skin and mucous membranes in the form of tubercular and gummatous syphilids of the skin and mucous membranes, involvement of organs and systems, especially the bone system (periostitis, osteoperiostitis, gummatous osteomyelitis, osteosclerosis), liver and spleen, cardiovascular, nervous, and endocrine systems are characteristic.

Neurosyphilis (A51.4, A52.2, A52.1, A52.3)

Asymptomatic and symptomatic neurosyphilis are distinguished. Depending on the time elapsed since infection, neurosyphilis is conventionally divided into early (up to 5 years from infection) and late (more than 5 years from infection). This division does not fully define all aspects of nervous system involvement, since the clinical manifestations of neurosyphilis represent a unified dynamic system combining symptoms of both early and late forms.

Asymptomatic neurosyphilis (A51.4; A52.2) is characterized by the absence of clinical manifestations. The diagnosis is based on pathological changes detected during cerebrospinal fluid examination.

Symptomatic neurosyphilis. Manifests with any neurological or psychiatric disorders that develop acutely or subacutely and progress over several months or years. Most commonly among early forms of neurosyphilis (A51.4) is meningovascular syphilis, in the clinical picture of which symptoms of meningeal and cerebral vascular involvement predominate: syphilitic meningitis (acute convexital, acute basal, acute syphilitic hydrocephalus), syphilitic uveitis (chorioretinitis, iritis), vascular neurosyphilis (ischemic, less commonly hemorrhagic stroke), spinal meningovascular syphilis (syphilitic meningomyelitis). Late forms of neurosyphilis include general paresis, tabes dorsalis, taboparesis, optic atrophy (A52.1), and gummatous neurosyphilis (A52.1), in the clinical picture of which symptoms of brain parenchyma involvement predominate.

In the early stage of the disease (usually in secondary syphilis), syphilitic uveitis may be observed: anterior with involvement of the iris and ciliary body (iritis/iridocyclitis), posterior involving the choroid, vitreous body, and retina (choroiditis/chorioretinitis), or panuveitis. In posterior uveitis or syphilitic basal meningitis, optic neuritis may develop. The outcome of optic neuritis is secondary optic atrophy.

In late forms of syphilis, chronically progressive optic neuritis or its outcome — secondary optic atrophy — may be detected. In the late stages of neurosyphilis, primary optic atrophy may also develop without preceding neuritis. This form of the disease can be part of the tabes dorsalis symptom complex or an independent manifestation of late neurosyphilis.

Complaints and anamnesis

In neurosyphilis, the patient may be troubled by headache, dizziness, nausea, vomiting, visual, hearing, or speech impairment, loss of consciousness, seizures, paresthesia, coordination and gait disorders, pelvic organ dysfunction, memory and intellect decline, and psychiatric disorders.

Clinical signs on physical examination

Clinical signs of neurological symptoms: localization, unilateral/bilateral process, and severity are evaluated.

Syphilis of internal organs and the musculoskeletal system (A51.4, A52.0, A52.7).

Depending on the time from infection, it is conventionally divided into early (up to 2 years from infection) and late (more than 2 years from infection) forms. In early forms (A51.4), predominantly functional disorders of the affected organs develop. The pathological process mainly involves the heart (early cardiovascular syphilis), liver (anicteric or icteric forms of hepatitis), stomach (transient gastropathy, acute gastritis, formation of specific ulcers and erosions), kidneys (asymptomatic renal dysfunction, benign proteinuria, syphilitic lipoid nephrosis, syphilitic glomerulonephritis). The earliest symptom of musculoskeletal involvement is nocturnal bone pain in the long tubular bones of the extremities. The pain is not accompanied by any objective bone changes. Specific synovitis and osteoarthritis may be observed.

In late forms (A52.0; A52.7), destructive changes in internal organs are observed. Specific lesions of the cardiovascular system are most frequently registered (mesaortitis, aortic valve regurgitation, aortic aneurysm, coronary ostial stenosis, gummatous myocarditis, endo- and pericarditis), less frequently — late hepatitis (limited (focal) gummatous, miliary gummatous, chronic interstitial, and chronic epithelial), and even less frequently — other late visceral syphilitic lesions (A52.7).

Late manifestations of musculoskeletal pathology include tabetic arthropathy and gummatous lesions of bones and joints (A52.7).

Complaints and anamnesis

In visceral syphilis, patients may present with pressing chest pain, pain in the right upper quadrant, epigastric, or lumbar region, nausea, vomiting, scleral icterus, and peripheral edema. In musculoskeletal syphilis, patients may complain of nocturnal pain in the tubular bones of the extremities.

Clinical signs on physical examination

Clinical signs of internal organ dysfunction (e.g., during liver palpation), taking into account the patient's complaints.

Clinical signs of musculoskeletal system involvement.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Absolute proof of the disease is the detection of Treponema pallidum in samples obtained from lesion sites using dark-field microscopy or direct immunofluorescence, as well as the detection of specific DNA and RNA of the causative agent by polymerase chain reaction using test systems approved for medical use in the Russian Federation.

Diagnosis of syphilis in pregnant women has no specific features and is carried out in accordance with the recommendations given below for other patient groups.

2.1 Complaints and Anamnesis

See 1.6 Clinical picture of the disease or condition (group of diseases or conditions).

2.2 Physical Examination

Clinical signs of the disease detected during physical examination — see 1.6 Clinical picture of the disease or condition (group of diseases or conditions).

2.3 Laboratory Diagnostics

Direct and indirect methods are used for the laboratory diagnosis of syphilis. Direct diagnostic methods detect the causative agent itself or its genetic material, which is absolute proof of the presence of the disease.

Direct methods are used for the diagnosis of early forms of the disease (primary and secondary syphilis) with clinical manifestations (erosive and ulcerative lesions), as well as to confirm congenital syphilis (umbilical cord tissue, placenta, fetal organs, nasal mucosa discharge, blister contents, discharge from the surface of papules).

Indirect diagnostic methods for syphilis are tests that detect antibodies to the causative agent of syphilis in blood serum and cerebrospinal fluid; the term serological laboratory tests is also used.

The main diagnostic methods for syphilis are the detection of antibodies against *Treponema pallidum* using serological methods—non-treponemal and treponemal tests [2-6].

─ Determination of antibodies to Treponema pallidum using nontreponemal tests (RPR, VDRL/USR) (qualitative and semi-quantitative assay) in blood serum / cerebrospinal fluid;

─ Venereal Disease Research Laboratory test (VDRL) [3-6, 22].

GRC CLOE 5Grade of Recommendation – C (Level of Evidence 5)

Comments: General characteristics of nontreponemal tests: a nontreponemal antigen is used (standardized cardiolipin antigen); become positive 1-2 weeks after the formation of the primary chancre; have low sensitivity (up to 70-90% in early forms of syphilis and down to 30% in late forms) and can yield false-positive results (3% or more).

Advantages of nontreponemal tests: low cost; technical simplicity of performance; rapid result turnaround time.

Disadvantages of nontreponemal tests: low sensitivity in primary (75-80%) and late syphilis (30-75%), potential for false-positive results (up to 7%).

─ Detection of antibodies to Treponema pallidum in the Treponema pallidum hemagglutination assay (TPHA) (qualitative and semi-quantitative test) in blood serum

─ Detection of antibodies to Treponema pallidum in the Treponema pallidum hemagglutination assay (TPHA) (qualitative and semi-quantitative test) in cerebrospinal fluid;

─ Determination of antibodies to Treponema pallidum by enzyme-linked immunosorbent assay (ELISA);

─ Determination of antibodies to Treponema pallidum by immunoblotting;

─ Determination of antibodies to Treponema pallidum in blood serum / cerebrospinal fluid by fluorescent treponemal antibody absorption test (FTA-ABS), including FTA-ABS and FTA-₂₀₀ modifications;

─ Treponema pallidum immobilization test (TPI);

─ Immuno-chemiluminescent assay;

─ Immunochromatographic assay [2-8,22].

GRC CLOE 5Grade of Recommendation – C (Level of Evidence 5)

Comments: General characteristics of treponemal tests: an antigen of treponemal origin is used; sensitivity is 70-100% (depending on the test type and stage of syphilis); specificity is 94-100%.

Brief description of methods:

1. Determination of antibodies to Treponema pallidum by Treponema pallidum hemagglutination assay (TPHA) is a highly sensitive and specific test. The sensitivity of the method in primary syphilis is 76%, in secondary syphilis 100%, in latent syphilis 94-97%, and specificity is 98-100%.

2. Determination of antibodies to Treponema pallidum by enzyme-linked immunosorbent assay (ELISA) is a highly sensitive and specific test. Sensitivity in primary and secondary syphilis is 98-100%, specificity is 96-100%. It allows for both differentiated and combined detection of IgM and IgG antibodies to the causative agent of syphilis.

3. Determination of antibodies to Treponema pallidum by immunoblotting is a modification of ELISA. Sensitivity and specificity are 98-100%. It can be used to confirm the diagnosis, especially in cases of ambiguous or contradictory results from other treponemal tests. It allows for differentiated and combined detection of IgM and IgG antibodies to the causative agent of syphilis.

4. Determination of antibodies to Treponema pallidum by fluorescent treponemal antibody test (FTA), including FTA-abs and FTA-₂₀₀ modifications, is a sufficiently sensitive test across all stages of syphilis. Sensitivity in primary syphilis is 70-100%, in secondary and late syphilis 96-100%, and specificity is 94-100%. FTA is used to differentiate latent forms of syphilis from false-positive syphilis test results.

5. Treponema pallidum immobilization test (TPI) is a classical test for detecting specific treponemal antibodies; sensitivity (combined across syphilis stages) is 87.7%; specificity is 100%. It is a labor-intensive and technically complex test requiring significant resources to perform. The scope of TPI use is narrowing, but it retains its position as a "reference test" in the differential diagnosis of latent forms of syphilis versus false-positive serological reactions.

6. Immuno-chemiluminescence assay has high sensitivity and specificity (98-100%), enables quantitative determination of antibody levels against the causative agent of syphilis, and can be used for confirming syphilitic infection and for screening.

7. Immunochromatography method has a sensitivity of 99-100% and a specificity of 97-99.5%. The simplicity of the procedure and result interpretation, along with the lack of need for complex equipment, allow this method to be used as an additional test.

FTA, ELISA, and immunoblotting become positive approximately from the 3rd week after infection or earlier, TPHA from the 4th week, and TPI from the 7th-8th week.

Advantages of treponemal tests: high sensitivity and specificity.

Disadvantages of treponemal tests: cannot be used to monitor treatment efficacy, occasionally may yield false-positive results.

Depending on the objectives, serological screening of the population for syphilis is carried out using various methods.

2.3.1 Screening laboratory tests

─ pregnant women, including those referred for artificial termination of pregnancy;

─ blood, sperm, and tissue donors;

─ psychiatric, neurological, cardiological, ophthalmological, and otolaryngological patients;

─ HIV-infected individuals [2-6].

GRC CLOE 5Grade of Recommendation – C (Level of Evidence 5)

2.3.2 Laboratory tests performed for diagnostic purposes

─ microscopic examination of specific lesions for Treponema pallidum;

─ pathological anatomical examination of biopsy (surgical) material of skin and mucous membranes (immunohistochemical study);

─ molecular biological study (determination of Treponema pallidum DNA) in discharge (serous exudate) from erosive and ulcerative lesions of the skin and mucous membranes for Treponema pallidum by PCR using diagnostic test systems approved for medical use in the Russian Federation [3-6].

GRC CLOE 5Grade of Recommendation – C (Level of Evidence 5)

─ microscopic examination of specific lesions for Treponema pallidum;

─ pathological anatomical examination of biopsy (surgical) material of umbilical cord tissue, placenta, and fetal organs (immunohistochemical study);

─ molecular biological study (detection of Treponema pallidum DNA) in discharge (serous exudate) from erosive and ulcerative skin and mucous membrane lesions for Treponema pallidum (Treponema pallidum) in blood by PCR using diagnostic test systems approved for medical use in the Russian Federation [3-6].

GPP CLOE 5Grade of Recommendation – C (Level of Evidence 5).

Comments: Indications for nontreponemal tests: screening; determination of infection activity (assessment of positivity degree and antibody titers); monitoring treatment efficacy (determination of antibody titers).

Indications for treponemal tests: confirmation of positive results of nontreponemal tests; confirmation in cases of discordance between the screening treponemal test and the subsequent nontreponemal test, as well as between the screening and confirmatory treponemal tests; screening of specific population groups for syphilis using ELISA, TPHA, or chemiluminescence immunoassay methods (blood donors, pregnant women, patients in ophthalmological, psychoneurological, and cardiological inpatient departments, and individuals infected with the human immunodeficiency virus).

Treponemal tests cannot be used to monitor treatment efficacy, as antitreponemal antibodies circulate in the patient's body for a long time after recovery from a syphilitic infection; treponemal tests yield positive results in non-venereal treponematoses and spirochetoses; treponemal tests may yield false-positive reactions in patients with autoimmune diseases, leprosy, oncological diseases, endocrine disorders, and certain other conditions.

Symptomatic neurosyphilis is diagnosed based on a combination of clinical manifestations with positive results of cerebrospinal fluid serologic tests and changes in its composition (cell count and protein level); latent neurosyphilis is diagnosed based on laboratory detection of pathological cerebrospinal fluid changes.

Comments: Indications for lumbar puncture and cerebrospinal fluid analysis are:

1. Presence of neurological, ophthalmological, otological symptoms, and psychiatric disorders in patients with syphilis (regardless of the disease stage)

2. Coexistence of syphilis and HIV infection, especially if

– blood CD4+ T-lymphocyte count is ≤350/mm³ and/or

– serum RPR/USR titer is ³1:32 and/or

– the patient is not receiving antiretroviral therapy

3. Latent and late forms of syphilis

4. Malignant course of early syphilis (even in the absence of neurological symptoms)

5. Secondary syphilis manifesting as leukoderma, alopecia (especially when combined)

6. Presence of early and late specific visceral lesions

7. Suspected congenital syphilis

8. Failure of nontreponemal tests to become negative after specific treatment for early forms of syphilis

9. Increase in positivity degree or titer of serological tests during clinical and serological monitoring (follow-up) after treatment of late and unspecified forms of syphilis

10. Discharge from follow-up of patients with neurosyphilis and serological resistance.

Pleocytosis and elevated protein levels in the CSF are not specific for neurosyphilis, but they are of major diagnostic importance as criteria for the development of meningeal inflammation and organic brain tissue lesions. The presence of more than 5 lymphocytic cells per 1 mm³ of CSF indicates pathological changes in the nervous system. The normal CSF protein content in adults ranges from 0.16 to 0.45 g/L. The specificity of nontreponemal tests using cerebrospinal fluid is close to 100%, but their sensitivity is insufficiently high, and the frequency of negative results in various forms of neurosyphilis ranges from 30 to 70%. In contrast, treponemal tests have high sensitivity (90-100%), but are insufficiently specific and may be positive with CSF in forms of syphilis not accompanied by nervous system involvement; however, negative results of treponemal tests with cerebrospinal fluid rule out neurosyphilis.

Currently, there is no universal test that can definitively confirm or refute the diagnosis of neurosyphilis, nor can it distinguish antitreponemal antibodies passively penetrating into the central nervous system from the serum versus those locally synthesized. The diagnosis is established based on a set of criteria.

The diagnosis of neurosyphilis is considered confirmed if the cerebrospinal fluid RPR (USR and other analogues) test is positive, regardless of the presence of neurological/psychiatric/ophthalmological/otological symptoms. Due to the low sensitivity of nontreponemal CSF tests, a negative result does not rule out the diagnosis of neurosyphilis. A negative result of cerebrospinal fluid treponemal tests rules out the diagnosis of neurosyphilis. According to some experts, VDRL is a more sensitive test than RPR when performed on cerebrospinal fluid. Therefore, it is advisable to use VDRL rather than RPR or USR for CSF analysis.

When cerebrospinal fluid RPR (USR, VDRL) is negative, regardless of the presence of clinical symptoms, the diagnosis of neurosyphilis is confirmed by a combination of positive treponemal test results with elevated protein content (greater than 0.45 g/L) and/or pleocytosis (greater than 5 cells per 1 µL of CSF, typically with a predominance of lymphocytes), which cannot be attributed to other diseases.

Positive cerebrospinal fluid treponemal test results in the absence of pleocytosis and hyperproteinorachia do not allow confirmation of the diagnosis of neurosyphilis, since antibodies detected in these tests may appear in the CSF due to passive transport from the serum across the blood-brain barrier or due to blood contamination of the cerebrospinal fluid during a traumatic lumbar puncture. There is a viewpoint that low treponemal test titers in the cerebrospinal fluid (TPHA titer ≤ 1:160) argue against intrathecal antibody synthesis and, consequently, neurosyphilis, whereas a CSF TPHA titer > 1:320 makes intrathecal antibody production probable. To prove the presence of neurosyphilis in such cases, it is necessary to assess the permeability of the blood-brain barrier by determining the TPHA index or ITPA.

where

Under normal conditions, the albumin quotient can range from 140 to 400 depending on the patient's age and averages about 220. A decrease in the quotient indicates increased blood-brain barrier permeability.

A TPHA index above 100 indicates neurosyphilis. This index is also a good evaluation test to confirm the efficacy of ongoing therapy: if treatment is ineffective, the numerical values of the index do not decrease. However, the value of the TPHA index in the diagnosis of late and especially latent forms of neurosyphilis is low.

Due to the high risk of nervous system involvement, cerebrospinal fluid examination is indicated for HIV-infected patients with syphilis in the following cases:

– in the presence of neurological, ophthalmological, or otological symptoms;

– if the RPR/USR serum titer is ≥ 1:32 (in this case, the risk of neurosyphilis increases 6-fold);

– if the blood CD4+ T-lymphocyte count is ≤ 350 cells/µL (in this case, the risk of developing neurosyphilis increases 3-fold);

– if the HIV-infected patient is not receiving highly active antiretroviral therapy.

When interpreting cerebrospinal fluid test results in HIV-infected individuals, the following principles should be guided:

– a positive RPR result confirms the diagnosis of neurosyphilis, while a negative result does not rule it out due to the low sensitivity of non-treponemal tests with CSF;

– a negative result of treponemal tests with CSF rules out the diagnosis of neurosyphilis, whereas a positive result does not confirm the diagnosis, but merely reflects the fact of infection;

– with a negative RPR result, diagnostic criteria for neurosyphilis should include pleocytosis of more than 20 cells/µL (in patients receiving antiretroviral therapy, more than 10 cells/µL) and a protein level greater than 0.45 g/L (in the absence of pleocytosis, the diagnostic significance of this parameter is questionable).

Normal ITPA index values range between 0.5 and 2, and a result above 2 indicates neurosyphilis [9].

Comments:

Criteria for diagnosing early visceral syphilis:

- presence of serologically proven syphilis in the patient;

- presence of clinical symptoms of the corresponding organ involvement;

- detection of lymphohistioplasmacytic inflammatory infiltration and Treponema pallidum in the biopsy sample by pathomorphological examination (using immunohistochemical staining or silver impregnation) – evidence of the specific nature of the lesion;

- positive dynamics of the process during specific therapy (not always achieved).

Criteria for diagnosing late visceral syphilis:

- presence of serologically proven syphilis in the patient;

- presence of clinical symptoms of the corresponding organ involvement;

- detection of granulomatous inflammation in the biopsy sample by pathomorphological examination – evidence of the specific nature of the lesion;

- positive dynamics of the process during specific therapy.

Comments: According to WHO criteria (1999), a case of congenital syphilis is considered confirmed if T. pallidum is detected by dark-field microscopy, PCR, or immunohistochemistry in material obtained from rash discharge, amniotic fluid, placental tissue, umbilical cord, or autopsy samples.

Stillbirth due to congenital syphilis is defined as fetal death occurring after 20 weeks of gestation or with a body weight of more than 500 grams, in the presence of untreated or inadequately treated syphilis in the mother.

Congenital syphilis is considered probable if: the newborn's mother received no treatment or inadequate treatment (after 32 weeks of gestation or with system-acting reserve antibacterial drugs) during pregnancy (regardless of the presence of signs of the disease in the child); with a positive result of treponemal tests in the child and the presence of at least one of the following criteria: manifestations of congenital syphilis during physical examination or radiography of long bones; positive CSF RPR, pleocytosis, or hyperproteinorachia (in the absence of other causes); detection of IgM by ELISA or immunoblotting.

When diagnosing early symptomatic congenital syphilis, it should be borne in mind that grade I osteochondritis without other signs of congenital syphilis cannot serve as an indicator of congenital syphilis, as similar changes can be observed in other diseases and even in healthy children.

The diagnosis of early congenital syphilis must be established taking into account the following main criteria:

detection of clinical manifestations of the disease in the child;

detection of Treponema pallidum using direct laboratory methods;

positive results of serological tests in the child (blood is drawn simultaneously with the mother's blood and tested using the same assays, RPR/VDRL and TPHA in quantitative format);

presence of cerebrospinal fluid abnormalities;

presence of radiologically confirmed changes in long bones;

detection of macroscopic and pathomorphological signs of changes in the placenta, umbilical cord, and internal organs;

detection of manifest or latent syphilis in the mother, confirmed by direct and/or serological diagnostic methods.

It must be remembered that in newborns, serum antibody levels are low, and even in the presence of overt clinical signs of early congenital syphilis, some serological reactions may be negative.

Serological reactions may remain negative for 4–12 weeks of the newborn's life if the infection occurred in the late stages of intrauterine development. At the same time, positive results of serological reactions may be the result of passive transplacental transport of maternal antibodies. These antibodies disappear within 3–6 months after birth, and serological reactions gradually become negative.

If the RPR/VDRL titer with the newborn's serum is 4-fold or higher than the titer of these reactions with the mother's serum, or if a minimum 4-fold increase in the RPR/VDRL titer compared to baseline is observed during the first 3 months of the child's life, this is considered an indicator of congenital syphilis. However, this situation is observed in only 30% of children with early congenital syphilis; therefore, the absence of a non-treponemal test titer in the child that exceeds the maternal titer by 4 times does not rule out congenital syphilis. Specific anti-treponemal IgM antibodies are detected by IgM-ELISA, IgM-immunoblot, IgM-FTA-abs in only 75–80% of newborns with clinically manifest early congenital syphilis. Therefore, negative results of IgM tests also do not rule out congenital syphilis.

Late congenital syphilis can be diagnosed taking into account: clinical manifestations of the disease (each of the manifestations included in Hutchinson's triad has diagnostic significance; probable signs and dystrophies [dysmorphogenetic stigmata] are considered in combination with definitive ones or in conjunction with serological examination data and medical history. The identification of dystrophies alone, without any other signs of syphilis, does not allow confirming the diagnosis, as dystrophies can be a manifestation of other chronic diseases and intoxications in parents [alcoholism, toxoplasmosis, endocrine disorders, etc.] and children [tuberculosis, rickets, etc.], as well as in practically healthy individuals), positive results of serological reactions: non-treponemal tests are positive in 70–80% of patients, treponemal tests in 92–100%, the presence of a late form of syphilis in the mother, the mother's medical and obstetric history, as well as the results of examination of the father and other children in the family.

2.3.3 Interpretation of serological test results in HIV-positive patients

Comments: If the HIV test result is negative, repeat testing is performed after 6 months.

If HIV antibodies are detected in a patient, they are referred for further evaluation, treatment, and ongoing follow-up at the regional AIDS Center with appropriate recommendations for syphilis treatment.

In the majority of HIV-infected patients, syphilis presents typically, but in a very small percentage of cases against the background of moderate and especially pronounced immunodeficiency (in the absence of highly active antiretroviral therapy), the disease progresses rapidly and is characterized by a specific clinical picture described by the term "malignant syphilis". In HIV-infected patients with syphilis, the likelihood of specific lesions of the nervous system, organs of vision and hearing is 3–6 times higher compared to HIV-negative individuals. Developing against the background of HIV-induced immunosuppression, neurosyphilis is often characterized by clinical polymorphism, atypical clinical manifestations, and rapid progression.

Existing serological tests diagnose syphilis with sufficient reliability in patients with HIV infection and evaluate treatment efficacy. Although cases of false-negative serological reactions and delayed seroconversion against the background of HIV infection are known, such cases are rare (3–11% for nontreponemal tests and 0.7% for treponemal tests). Much more frequently, HIV-infected patients with syphilis exhibit strongly positive nontreponemal and treponemal tests with high antibody titers. The mean antibody titer in nontreponemal tests among HIV-positive patients is significantly higher than in HIV-negative individuals. It has been established that in HIV-infected individuals, nontreponemal test titers do not correlate with disease duration, severity, or CD4+ T-lymphocyte count. False-positive results of nontreponemal tests occur in 1–6% of HIV-infected individuals. However, overall, the results of serological screening practically do not depend on the patients' HIV status, and the interpretation of serological reactions in HIV-infected individuals should follow the same algorithms as in uninfected persons.

2.3.4 False-positive laboratory results

False-positive, or nonspecific, reactions for syphilis are defined as positive results of serological tests for syphilis in individuals who do not have a syphilitic infection and have no history of syphilis. They may be caused by technical errors during testing and individual physiological characteristics. Conventionally, they are divided into acute (<6 months) and chronic (>6 months).

False-positive reactions can be observed during pregnancy and menstruation, after vaccination, following a recent myocardial infarction, in many infectious diseases (leprosy, malaria, respiratory infections, influenza, chickenpox, viral hepatitis, HIV infection) and dermatoses, in autoimmune diseases, systemic connective tissue diseases, oncological diseases, chronic liver and biliary tract pathologies, cardiovascular and endocrine disorders, blood disorders, chronic lung diseases, intravenous drug use, in old age, etc.

False-positive reactions in treponemal and nontreponemal tests can occur in endemic treponematoses (yaws, pinta, bejel), borreliosis, and leptospirosis. A patient with positive serological tests for syphilis who has arrived from a country with endemic treponematoses must be screened for syphilis and prescribed anti-syphilitic treatment if it has not been administered previously.

Chronic false-positive reactions may serve as preclinical manifestations of severe diseases.

The number of false-positive reactions increases with age. In the 80-year-old age group, their prevalence reaches 10%.

False-negative serological tests for syphilis can be observed in secondary syphilis due to the prozone phenomenon when testing undiluted serum, as well as when evaluating individuals with immunodeficiency states, such as HIV-infected patients.

2.3.5 Other laboratory tests

2.4 Instrumental Diagnostics

Comments: The results of non-invasive neuroimaging studies in neurosyphilis are nonspecific.

Comments: A presumptive diagnosis of late cardiovascular syphilis can be established based on echocardiography data. Important echocardiographic signs include:

– dilatation of the aorta, particularly in its ascending portion (conventionally — diameter greater than 4 cm);

– thickening of the aortic wall, calcification in the area of its root and wall;

– thickening and compaction of the aortic valve, deformation and calcification of its cusps, aortic regurgitation starting from grade I (normally aortic regurgitation is absent) up to grade III–IV, which indicates pronounced aortic regurgitation;

– in some cases — a decrease in left ventricular ejection fraction (according to Teichholz, the norm is 55% and higher).

In patients who have suffered a myocardial infarction, a decrease in regional myocardial contractility of the corresponding localization is noted. Stenosis of the ostia and the proximal part of the coronary arteries may be observed; coronarography provides a more detailed picture of the degree of stenosis. In the diagnosis of aortic aneurysms, it is necessary to use radiography, computed tomography, and magnetic resonance imaging. Aneurysms of large vessels — branches of the aorta — may be observed, in the detection of which ultrasound duplex scanning of brachiocephalic vessels is of primary importance.

If signs of cardiovascular syphilis are detected based on echocardiography results, the patient undergoes a comprehensive cardiovascular assessment using appropriate diagnostic tests.

2.5 Other Procedures

─ in the presence of neurological, ophthalmological, otological symptoms, or psychiatric disorders in patients with syphilis (regardless of the disease stage);

─ in latent and late forms of syphilis;

─ in malignant courses of early syphilis (even in the absence of neurological symptoms);

─ in secondary syphilis presenting with leukoderma or alopecia (especially when combined);

─ in the presence of early and late specific visceral lesions;

─ when congenital syphilis is suspected;

─ in the absence of non-treponemal test seroconversion (negativation) after specific therapy for early forms of syphilis;

─ in case of an increase in the degree of positivity or titer of serological tests during clinical and serological monitoring (follow-up) after treatment of late and unspecified forms of syphilis;

─ when deregistering patients with neurosyphilis and serological resistance [3-6].

GRC CLOE 5Grade of Recommendation – C (Level of Evidence 5)

• Due to the high risk of nervous system involvement, it is recommended to perform a lumbar puncture followed by cerebrospinal fluid analysis in HIV-infected patients with syphilis in the following cases:

─ in the presence of neurological, ophthalmological, or otological symptoms;

─ if the RPR/VDRL titer with serum is ≥ 1:32 (in this case, the risk of neurosyphilis increases 6-fold);

─ if the blood CD4+ T-lymphocyte count is ≤ 350 cells/µL (in this case, the risk of developing neurosyphilis increases 3-fold);

─ if the HIV-infected patient is not receiving highly active antiretroviral therapy [3-6].

GRC CLOE 5Grade of Recommendation – C (Level of Evidence 5)

─ cytological examination of cerebrospinal fluid cells;

─ protein level determination in the cerebrospinal fluid;

─ a combination of several available immunological tests to detect antibodies against T. pallidum: RPR, VDRL, FTA-abs_csf (fluorescent treponemal antibody absorption test with whole cerebrospinal fluid), TPHA, ELISA_IgM+IgG, immunoblotting [3-6].

GRC CLOE 5Grade of Recommendation – C (Level of Evidence 5)

Comments: Pleocytosis and elevated protein levels in the cerebrospinal fluid are not specific to neurosyphilis, but they are of great diagnostic importance as criteria for the development of inflammatory processes in the meninges and organic lesions of the brain parenchyma. The presence of more than 5 lymphocytic cells per 1 mm³ of cerebrospinal fluid indicates pathological changes in the nervous system.

The normal cerebrospinal fluid protein concentration in adults ranges from 0.16 to 0.45 g/L.

The specificity of non-treponemal tests using cerebrospinal fluid is close to 100%, but their sensitivity is insufficiently high, and the rate of negative results in various forms of neurosyphilis ranges from 30 to 70%. Treponemal tests, in contrast, have high sensitivity (90–100%), but lack sufficient specificity and may be positive with cerebrospinal fluid in forms of syphilis not accompanied by nervous system involvement; however, negative treponemal test results in the cerebrospinal fluid rule out neurosyphilis.

When interpreting cerebrospinal fluid test results in HIV-infected individuals, the following principles should be guided:

– a positive RPR result confirms the diagnosis of neurosyphilis, while a negative result does not rule it out due to the low sensitivity of non-treponemal tests with CSF;

– a negative result of treponemal tests with CSF rules out the diagnosis of neurosyphilis, whereas a positive result does not confirm the diagnosis, but merely reflects the fact of infection;

– with a negative RPR result, diagnostic criteria for neurosyphilis should include pleocytosis of more than 20 cells/µL (in patients receiving antiretroviral therapy, more than 10 cells/µL) and a protein level greater than 0.45 g/L (in the absence of pleocytosis, the diagnostic significance of this parameter is questionable).

─ ophthalmologist, neurologist, general practitioner – for all patients with acquired syphilis;

─ ophthalmologist, neurologist, otorhinolaryngologist – for children with suspected congenital syphilis;

─ if specific involvement of internal organs or the musculoskeletal system is suspected, specialist consultations should be provided in accordance with the patient's complaints and/or instrumental examination findings [3–6].

GGR CLOE 5Grade of Recommendation – C (Level of Evidence 5)

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

Preventive treatment is administered to prevent syphilis in individuals who have had sexual or close household contact with patients with early forms of syphilis, provided that no more than 2 months have elapsed since the contact.

Specific treatment is carried out with the goal of etiological cure by establishing a treponemicidal concentration of a systemic antibacterial agent in the blood and tissues, and in neurosyphilis, in the cerebrospinal fluid.

• For the treatment of syphilis, it is recommended to use the following medications:

1. Beta-lactam antibacterial drugs: penicillins (hereinafter referred to as penicillins):

─ Benzathine benzylpenicillin** (long-acting);

─ Benzathine benzylpenicillin + Procaine benzylpenicillin (4:1) (long-acting);

─ Benzylpenicillin** (active substance: benzylpenicillin procaine/novocaine salt);

─ Benzylpenicillin** (active substance: benzylpenicillin sodium salt);

2. Tetracyclines: Doxycycline** (in the official product insert, the indicated indications include only primary and secondary syphilis).

3. Macrolides: Erythromycin.

4. Third-generation cephalosporins: Ceftriaxone**.

The drug of first choice for the treatment of syphilis is benzylpenicillin**. [2, 4, 5, 10, 15–18].

GRC CLOE 5Grade of Recommendation – C (Level of Evidence 5)

Comments: Contraindications for prescribing beta-lactamase-sensitive penicillins (penicillin group drugs):

─ hypersensitivity to benzylpenicillin**, its long-acting preparations, and semi-synthetic derivatives;

─ beta-lactamase-sensitive penicillins should be prescribed with caution to patients with severe hypertension, a history of myocardial infarction, endocrine disorders, acute gastrointestinal diseases, active tuberculosis, and blood disorders. [2, 4, 5, 10, 15–18].

Treatment of syphilis in patients with concurrent HIV infection is carried out in accordance with the same algorithms and methods adopted for HIV-negative patients [2, 4, 5, 10, 15–18].

3.1 Preventive treatment

─ Benzathine benzylpenicillin** 2.4 million IU intramuscularly as a single dose [4, 5, 15, 17, 18].

GRC CLOE 5Grade of Recommendation – C (Level of Evidence 5)

Comments: The drug is administered as 1.2 million IU into each gluteus maximus muscle [4, 5, 15, 17, 18].

─ Benzathine benzylpenicillin + Procaine benzylpenicillin

GRC CLOE 5Grade of Recommendation – C (Level of Evidence 5)

Comments: According to global data, the drug is prescribed at 1.5 million IU twice a week intramuscularly, for a total course of 2 injections [2, 15, 18].

─ Benzylpenicillin** (active substance: benzylpenicillin procaine salt).

GRC CLOE 5Grade of Recommendation – C (Level of Evidence 5)

Comments: According to global data, the drug is administered at 600,000 IU twice daily intramuscularly for 7 days [2, 15, 18].

The drug of choice is long-acting penicillin (benzathine benzylpenicillin**) administered as a single dose: treatment failures have not been described, and the drug also offers the greatest convenience of use [26, 27].

3.2 Treatment of syphilis in adults

─ Benzathine benzylpenicillin**.

Comments: According to global data, the drug is administered at 2.4 million IU once every 5 days intramuscularly, for a course of 3 injections [2, 5, 15–18, 41].

or

─ Benzathine benzylpenicillin + Procaine benzylpenicillin

Comments: According to global data, the drug is administered at 1.5 million IU twice a week intramuscularly, for a course of 5 injections [2, 15, 18, 41].

or

─ Benzylpenicillin** (active substance: benzylpenicillin procaine salt)

Comments: According to global data, the drug is administered at 600,000 IU twice daily intramuscularly for 14 days [2, 15, 18, 41].

or

─ Benzylpenicillin** (active substance: benzylpenicillin sodium salt) [4, 15–18].

GRC CLOE 5Grade of Recommendation – C (Level of Evidence 5)

Comments: the drug is administered at 1 million IU every 4 hours (6 times a day) intramuscularly for 14 days [4, 15–18].

The drug of choice is benzathine benzylpenicillin** (long-acting penicillin) as it is the most convenient to use. Benzylpenicillin** (active substance: benzylpenicillin procaine salt); benzylpenicillin** (active substance: benzylpenicillin sodium salt) are indicated when inpatient treatment is necessary (complicated disease course, somatically burdened patients, etc.) [26, 27].

─ Benzylpenicillin** (active substance: benzylpenicillin sodium salt) [2, 4, 5, 15–18, 41].

GRC CLOE 5Grade of Recommendation – C (Level of Evidence 5)

Comments: according to global practice, the drug is used at 1 million IU every 4 hours (6 times) a day intramuscularly for 28 days [2, 4, 5, 15–18, 41].

or

─ Benzylpenicillin** (active substance: benzylpenicillin procaine salt) 600,000 IU twice daily intramuscularly for 20 days [2, 15, 18, 41].

GRC CLOE 5Grade of Recommendation – C (Level of Evidence 5)

Comments: according to global practice, the drug is used at 600 thousand IU twice daily intramuscularly for 28 days [2, 15, 18, 41].

or

─ Benzathine benzylpenicillin** 2.4 million IU once every 5 days intramuscularly, for a course of 6 injections [2, 4, 5, 15–18, 41].

GGR CLOE 5Grade of Recommendation – C (Level of Evidence 5

or

─ Benzathine benzylpenicillin + Procaine benzylpenicillin 1.5 million IU twice a week intramuscularly, for a course of 10 injections [36, 41, 46, 48]

GRC CLOE 5Grade of Recommendation – C (Level of Evidence 5)

Comment: Benzathine benzylpenicillin + Procaine benzylpenicillin is used when the duration of the disease is no more than 6 months (clinical classification: early secondary syphilis). In patients with a disease duration of more than 6 months, the drugs of choice are benzylpenicillin** (active substances: benzylpenicillin sodium salt or benzylpenicillin procaine salt).

─ Benzylpenicillin** (active substance: benzylpenicillin sodium salt) 1 million IU every 6 hours intramuscularly for 28 days [2, 4, 5, 15–18].

GRC CLOE 5Grade of Recommendation – C (Level of Evidence 5)

Comments: according to global practice, 1 million IU every 4 hours intramuscularly for 28 days [2, 4, 5, 15–18].

or

─ Benzylpenicillin** (active substance: benzylpenicillin procaine salt) 600,000 IU twice daily intramuscularly for 28 days [2, 15, 18, 56].

GRC CLOE 5Grade of Recommendation – C (Level of Evidence 5)

─ Benzylpenicillin** (active substance: benzylpenicillin sodium salt)

GRC CLOE 5Grade of Recommendation – C (Level of Evidence 5)

Comments: According to global data, the drug is used at 1 million IU every 4 hours (6 times a day) intramuscularly for 28 days, followed in 2 weeks by a second course of treatment with benzylpenicillin** (active substance: benzylpenicillin sodium salt) in similar doses for 14 days [2, 15, 18].

or

─ Benzylpenicillin** (active substance: benzylpenicillin procaine salt)

GRC CLOE 5Grade of Recommendation – C (Level of Evidence 5)

Comments: the drug is administered at 600,000 IU twice daily intramuscularly for 28 days, followed by a 2-week interval, then a second course of treatment with benzylpenicillin** (active substance: procaine benzylpenicillin) at a similar dose for 14 days [2, 15, 18].

GRC CLOE 5Grade of Recommendation – C (Level of Evidence 5)

Comment: treatment of patients with late forms of syphilis using oral systemic reserve antibacterial drugs is less effective compared to parenterally administered drugs and frequently results in the development of serological resistance. Oral tablet formulations are permissible to prescribe only in cases of intolerance to all parenterally administered systemic antibacterial drugs.

─ Benzylpenicillin** (active substance: benzylpenicillin sodium).

GRC CLOE 5Grade of Recommendation – C (Level of Evidence 5)

Comments: According to international data, the drug is used at 1 million IU every 4 hours (6 times a day) intramuscularly for 28 days [2, 4, 5, 15-18].

─ Benzylpenicillin** (active substance: procaine benzylpenicillin) [2, 15, 18].

GRC CLOE 5Grade of Recommendation – C (Level of Evidence 5)

Comments: According to international data, the drug is used at 600,000 IU twice daily intramuscularly for 28 days [2,15,18]

— Benzylpenicillin** (active substance: benzylpenicillin sodium) [2, 4, 5, 15-18].

GRC CLOE 5Grade of Recommendation – C (Level of Evidence 5)

Comments: According to international data, the drug is used at 1 million IU every 4 hours (6 times a day) intramuscularly for 28 days, followed by a 2-week interval, then a second course of treatment with benzylpenicillin** at a similar dose for 14 days [2, 4, 5, 15-18].

or

— Benzylpenicillin** (active substance: procaine benzylpenicillin) [2, 15, 18].

GRC CLOE 5Grade of Recommendation – C (Level of Evidence 5)

Comments: According to international data, the drug is used at 600,000 IU twice daily intramuscularly for 28 days, followed by a 2-week interval, then a second course of treatment with benzylpenicillin** at a similar dose for 14 days [2, 15, 18]. Treatment of patients with late forms of syphilis using oral systemic reserve antibacterial drugs is less effective compared to parenterally administered drugs and frequently results in the development of serological resistance. Oral tablet formulations are permissible to prescribe only in cases of intolerance to all parenterally administered systemic antibacterial drugs.

3.3 Treatment of neurosyphilis

In cases of ocular and auditory organ involvement in syphilis patients, intravenous antibiotic therapy according to the neurosyphilis treatment regimen (early or late) should be initiated immediately upon diagnosis, regardless of cerebrospinal fluid examination results. The cerebrospinal fluid in sensory organ involvement may be pathological (more frequently) or normal.

─ Benzylpenicillin** (active substance: benzylpenicillin sodium)** [2, 4, 5, 7, 8, 15-18].

GRC CLOE 5Grade of Recommendation – C (Level of Evidence 5)

Comments: according to international data, the drug is used at 12 million IU twice daily as an intravenous infusion for 20 days. A single dose of the drug is diluted in 400 ml of isotonic sodium chloride solution** and administered intravenously over 1.5–2 hours. Solutions must be used immediately after preparation [2, 4, 5, 7, 8, 15-18].

or

─ Benzylpenicillin** (active substance: benzylpenicillin sodium salt)

GRC CLOE 5Grade of Recommendation – C (Level of Evidence 5)

Comments: 4 million IU 6 times a day as an intravenous bolus injection for 20 days. A single dose of the drug is diluted in 10 ml of isotonic sodium chloride solution** and administered slowly intravenously over 3–5 minutes into the cubital vein [2, 4, 5, 7, 8, 15-18, 56].

Treatment of patients with clinically manifest forms of neurosyphilis is carried out in a neurological/psychiatric inpatient setting due to the need for active participation of a neurologist or psychiatrist in the patient's treatment and monitoring, the severity of their condition, and the likelihood of exacerbation or development of neurological symptoms during antibacterial therapy. Specific treatment is prescribed by a dermatovenereologist.

Patients with asymptomatic neurosyphilis can receive full medical care in a dermatovenereological inpatient setting. The issue of preparatory and symptomatic therapy is decided jointly by a dermatovenereologist, neurologist, psychiatrist, and, if necessary, an ophthalmologist.

─ Benzylpenicillin** (active ingredient: benzylpenicillin sodium) [7, 8, 15, 39, 49].

Comments: according to international data, the drug is used at 12 million IU twice daily as an intravenous drip for 20 days. A single dose of the drug is diluted in 400 ml of isotonic sodium chloride solution** and administered intravenously over 1.5–2 hours. Solutions are used immediately after preparation. Two weeks later, a second course of treatment is administered according to a similar regimen [7, 8, 15, 39, 49].

─ Benzylpenicillin** (active ingredient: benzylpenicillin sodium) [7, 8, 41, 44, 49]

Comments: According to international data, the drug is prescribed at 4 million IU 6 times a day intravenously as a bolus for 14 days. A single dose of the drug is diluted in 10 ml of isotonic sodium chloride solution** and administered slowly intravenously over 3–5 minutes into the cubital vein. Two weeks later, a second course of treatment is administered according to a similar regimen [7, 8, 41, 44, 49]

GRC CLOE 5Grade of Recommendation – C (Level of Evidence 5)

Comments:

Concurrently with antibiotic therapy, the patient must receive symptomatic treatment and be monitored by an ophthalmologist or otolaryngologist. Follow-up examinations by the relevant specialist are carried out at the following intervals after treatment: 6 months, 1 year, and then upon deciding whether to discontinue monitoring.

─ Ceftriaxone** – 2.0 g once daily intravenously for 20 days; in severe cases (syphilitic meningoencephalitis, acute generalized meningitis), the daily dose may be increased up to 4 g. Two courses of treatment are administered according to the same regimen with an interval of 2 weeks between courses [4, 5, 15–19, 44, 49].

GRC CLOE 5Grade of Recommendation – C (Level of Evidence 5)

Comment: treatment of patients with late forms of syphilis using oral systemic reserve antibacterial drugs is less effective compared to parenterally administered drugs and frequently results in the development of serological resistance. Oral tablet formulations are permissible to prescribe only in cases of intolerance to all parenterally administered systemic antibacterial drugs.

3.4 Treatment of syphilis in pregnant women

Comments: Currently, due to the availability of effective and short-term treatments, the detection of syphilis is not a medical indication for pregnancy termination. The decision to continue or terminate the pregnancy is made by the woman. The role of the physician is to provide timely and adequate treatment (which must be initiated before 32 weeks of gestation and administered with drugs: benzylpenicillin** [active ingredients: benzylpenicillin sodium or benzylpenicillin procaine], broad-spectrum penicillins [semi-synthetic penicillins], or ceftriaxone**) and to provide psychological support to the pregnant woman [30, 31, 32].

Preventive treatment is carried out to prevent congenital syphilis in:

a) pregnant women who received treatment for syphilis before pregnancy, but who retain positive results in non-treponemal serological tests

b) pregnant women who underwent specific treatment for syphilis during pregnancy [31, 32].

3.5 Treatment of patients with congenital syphilis

— benzylpenicillin** (active substance: benzylpenicillin sodium salt)

• for infants under 1 month of age: 100,000 IU per kg of body weight per day, divided into 4 injections (every 6 hours), intramuscularly;

• for infants aged 1 to 6 months: 100,000 IU per kg of body weight per day, divided into 6 injections (every 4 hours), intramuscularly;

• for infants aged 6 to 12 months: 75,000 IU per kg of body weight per day, intramuscularly;

• for children older than 1 year: 50,000 IU per kg of body weight per day, intramuscularly.

The duration of administration for children is 28 days for both manifest and latent early congenital syphilis, including cases with central nervous system involvement confirmed by positive cerebrospinal fluid serological reactions [2, 15–18].

Level of Recommendation CLevel of Evidence 5Level of recommendation C (level of evidence 5)

— benzylpenicillin** (active substance: benzylpenicillin sodium salt) 50,000 IU per kg of body weight per day, divided into 6 injections (every 4 hours) intramuscularly for 28 days; 2 weeks later, a second course of treatment with benzylpenicillin** (active substance: benzylpenicillin sodium salt) at a similar dose for 14 days [2, 4, 5, 15, 18, 41].

or

— Benzylpenicillin** (active substance: benzylpenicillin procaine salt) [2, 15, 18, 41].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

• In manifest or latent late congenital syphilis, the duration of the first course of treatment is 28 days; 2 weeks later, a second course of treatment with ceftriaxone** is administered at a similar dose for 14 days [17–19].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments: specific treatment of acquired syphilis in children is carried out according to the adult treatment methodology in accordance with the diagnosis, based on age-appropriate doses of systemic antibacterial drugs. The dosage of benzylpenicillin** for treating children is calculated based on the child's body weight: for children under 6 months of age, benzylpenicillin** (active substance: benzylpenicillin sodium salt) is used at a dose of 100,000 IU per kg of body weight per day; for those older than 6 months, at 75,000 IU per kg of body weight per day; and for those older than 1 year, at 50,000 IU per kg of body weight per day.

The daily dose of benzylpenicillin** (active substance: benzylpenicillin procaine salt) as a single dose calculated at 50,000 IU per kg of body weight [15, 41].

Taking into account the anatomical and physiological characteristics of the urinary system in newborns and infants in the first month of life, reducing the frequency of benzylpenicillin** administration to 4 times a day is permissible. To avoid toxic reactions due to the mass destruction of Treponema pallidum following the initial administrations of benzylpenicillin** (Jarisch-Herxheimer reaction), the single dose of benzylpenicillin** on the first day of treatment should not exceed 5,000 IU per injection. After each injection on the first day, control thermometry and monitoring of the child's somatic condition are required.

Preventive treatment is indicated for all children under 3 years of age. For older children, the decision regarding treatment is made individually, taking into account the form of syphilis in the contact adult, the localization of rashes, and the degree of the child's contact with the infected person.

It is carried out according to the adult preventive treatment methodology, based on age-appropriate doses of systemic antibacterial drugs.

Prophylactic treatment is administered to prevent congenital syphilis in newborns born without manifestations of syphilis from mothers who were untreated or inadequately treated during pregnancy (specific treatment started after 32 weeks of pregnancy, with violations or modifications of approved treatment regimens), as well as in newborns whose mothers, in the presence of indications, did not receive prophylactic treatment during pregnancy. Drugs, single doses, and administration frequencies correspond to those used in specific treatment.

The duration of therapy is 14 days for newborns whose mothers did not receive prophylactic treatment or received inadequate treatment during pregnancy, and 28 days for newborns born without manifestations of syphilis from an untreated mother.

For children born to mothers who received specific treatment before pregnancy and prophylactic treatment during pregnancy, whose non-treponemal tests remain positive at delivery with persistently low titers (RPR <1:2, VDRL <1:4), prophylactic treatment is not indicated if the child's non-treponemal tests are negative or their titers do not exceed those of the mother. Confirmation of maternal treatment should be considered the presence of medical documentation of therapy performed in a medical facility in accordance with the clinical form, with strict adherence to single and course dosages and the frequency of administration of systemic antibacterial drugs.

Comments: The diagnosis of reinfection is based on a set of criteria, the first four of which are mandatory:

1. the fact of the primary disease is confirmed by medical documentation;

2. full treatment was administered for the primary disease, as confirmed by medical documentation;

3. during the primary treatment, timely resolution of rashes (if present) occurred;

4. within 12 months after completion of treatment for the primary disease, there was at least a fourfold decrease in titers, a decrease in positivity, or seroreversion of non-treponemal tests (RPR or its analogues);

5. upon reappearance of syphilitic rashes (if any), Treponema pallidum was detected in their discharge using dark-field microscopy;

6. recurrent positive results of previously negative non-treponemal tests or at least a fourfold increase in their titer compared to the baseline are observed;

7. antitreponemal IgM antibodies were detected by IgM-EIA or IgM-IB methods;

8. a new source of infection was identified in whom an early form of syphilis has been proven.

— benzylpenicillin** (active substance: benzylpenicillin sodium salt) 12 million IU 2 times a day intravenously as an infusion for 20 days [2, 4, 5, 15–18].

or

— benzylpenicillin** (active substance: benzylpenicillin sodium salt) [2, 4, 5, 15–18].

Level of Recommendation CLevel of Evidence 5Level of recommendation C (level of evidence 5)

Comments: Additional treatment is prescribed in the following cases:

- if one year after full treatment of early forms of syphilis, a fourfold decrease in the RPR/VDRL titer has not occurred;

- if 1.5 years after full treatment of early forms of syphilis, there is no tendency towards a further decrease in titers/degree of positivity of RPR/VDRL;

- if 2 years after full treatment of early forms of syphilis, complete seroreversion of RPR/VDRL has not occurred;

- if 6 months after full treatment of early congenital syphilis, a 4-fold decrease in the RPR/VDRL titer has not occurred;

- in case of clinical or serological relapse.

Before additional treatment, repeat examinations by specialist physicians (dermatovenereologist, ophthalmologist, neurologist, general practitioner, otolaryngologist), cerebrospinal fluid analysis (even in the absence of clinical neurological symptoms), echocardiography (EchoCG) and electrocardiography (ECG), as well as clinical and serological examination of the sexual partner are indicated. If specific pathology of the nervous system and internal organs is detected, a diagnosis of neurosyphilis or visceral syphilis is established, and appropriate specific treatment is administered according to the protocols for these forms.

Additional treatment in children is carried out according to the adult treatment methodology based on age-appropriate doses of systemic antibacterial drugs.

Indications for an additional course of therapy after treatment for neurosyphilis:

– progression or relapse of clinical manifestations;

– if pleocytosis in the cerebrospinal fluid does not decrease within 6 months and does not completely normalize within 2 years, or, having returned to normal, increases again;

– no decrease in the positivity of the VDRL / RPR tests in the cerebrospinal fluid is observed within 1 year;

– no significant decrease in the cerebrospinal fluid protein level is observed within 2 years.

Additional treatment in this case is administered according to neurosyphilis treatment regimens.

The protein level in the cerebrospinal fluid changes more slowly than pleocytosis and serological reactions, and up to 2 years may sometimes be required for its normalization. Persistence of an elevated but decreasing protein level in the presence of normal pleocytosis and negative serological test results is not an indication for an additional course of therapy.

3.6 Surgical Treatment

Surgical treatment of syphilis as treatment of the underlying disease is not provided; it is performed to treat complications of late cardiovascular syphilis (aortic aneurysm, aortic regurgitation) in accordance with clinical guidelines for these diseases and conditions [13, 14].

3.7 Adverse effects and complications of therapy

Patients should be warned about a possible bodily reaction to treatment. Medical organizations where therapy is administered must have emergency care supplies available.

1. Jarisch-Herxheimer reaction (Herxheimer reaction)

The exacerbation reaction is observed in 30% of patients with early syphilis. In the majority of patients, clinical manifestations of the reaction begin 2–4 hours after the first administration of a systemic antibacterial drug, reach maximum intensity within 5–7 hours, and the condition normalizes within 12–24 hours. The main clinical symptoms are chills and a sharp increase in body temperature (up to 39°C, sometimes higher). Other symptoms include general malaise, headache, nausea, muscle and joint pain, tachycardia, tachypnea, decreased blood pressure, and leukocytosis. In secondary syphilis, roseolous and papular rashes become more numerous, vivid, edematous, and elements sometimes merge due to their abundance (so-called local Jarisch-Herxheimer reaction). In some cases, against the background of the reaction, secondary syphilids appear for the first time in areas where they were not present before treatment. Occasionally, patients may develop psychosis, stroke, convulsive syndrome, or liver failure.

A rapidly transient exacerbation reaction usually does not require any special treatment. However, the development of a pronounced reaction should be avoided:

─ in pregnant women, as it can provoke premature birth, toxic fetal disorders, and stillbirth;

─ in patients with neurosyphilis, as the reaction may provoke the progressive development of neurological symptoms;

─ in patients with ocular involvement;

─ in patients with visceral syphilis, especially syphilitic mesoarteritis.

2. Nicolau syndrome – a symptom complex of complications following intra-arterial administration of long-acting penicillin preparations or other drugs with a crystalline structure.

It is characterized by sudden ischemia at the injection site, the development of painful cyanotic uneven patches (livedo) followed by blister formation and skin necrosis. In some cases, flaccid paralysis of the limb into which the drug was injected develops, and in rare cases, transverse paralysis. Macrohematuria and bloody stools are observed as long-term complications. Blood tests show leukocytosis. To date, cases have only been reported in pediatric practice.

1. Neurotoxicity – seizures (more common in children) with the use of high doses of benzylpenicillin**, especially in renal impairment.

2. Electrolyte imbalance – in patients with heart failure receiving high doses of benzylpenicillin** (active substance: benzylpenicillin sodium salt), worsening of edema is possible (1 million IU of the drug contains 2.0 mmol of sodium).

3. Allergic reactions – toxicoderma, urticaria, angioedema, headache, fever, joint pain, eosinophilia, etc. – occur in 5% to 10% of patients upon administration of penicillins. The most dangerous complication is anaphylactic shock, which accounts for up to 10% mortality.

4. Anaphylactic shock is characterized by a sense of impending doom, a feeling of warmth throughout the body, loss of consciousness, skin pallor, cold clammy sweat, sharp facial features, frequent shallow breathing, thready pulse, and low blood pressure.

3.8 Other treatment

Diet therapy is not indicated.

Pain management is not performed.

3.9 Evaluation of treatment outcomes

Comment: FTA-ABS, ELISA, and TPHA results become negative after treatment extremely infrequently. Persistence of positive FTA-ABS, ELISA, and TPHA with negative non-treponemal tests in a person who has had syphilis is not considered treatment failure. TPI seroconversion may occur in adequately treated syphilis patients, but this usually happens no earlier than 2–3 years after the completion of therapy.

─ normalization of pleocytosis within 6 months after completion of therapy;

─ decrease or normalization of protein levels within 2 years after completion of treatment;

─ disappearance from the cerebrospinal fluid of antibodies detected by non-treponemal tests within 6–12 months after completion of therapy. Sometimes production of these antibodies may continue for more than a year; in such cases, it is important to consider whether there is a decrease in the positivity of these tests;

─ absence of new neurological symptoms and lack of progression of existing neurological symptoms [4, 5, 37].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comment: if within 12 months after completing specific therapy for early forms of syphilis, the positivity of non-treponemal tests and/or antibody titers gradually decreases (by at least 4-fold), but complete seroconversion is not observed, it is termed delayed seroconversion of non-treponemal serological reactions. Clinical and serological follow-up of such patients is extended to 2 years, after which the issue of the advisability of prescribing additional treatment is decided.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Not provided.

5. Prevention and Dispensary Observation

5.1 Prevention

5.1.1 Prevention of acquired syphilis

Individual prevention is ensured by using barrier methods of contraception (condoms). After accidental unprotected sexual intercourse, self-prophylaxis can be carried out using individual preventive products (e.g., benzyldimethyl[3-(myristoylamino)propyl]ammonium chloride monohydrate).

─ individuals who have had sexual or close household contact with a patient with early forms of syphilis, in whom no more than 2 months have passed since the contact, are indicated for preventative treatment using one of the above regimens.

─ individuals in whom 2 to 4 months have passed since contact with a patient with early syphilis undergo a two-time clinical and serological examination at 2-month intervals; if more than 4 months have passed since contact, a single clinical and serological examination is performed.

─ preventative treatment of a recipient who received a transfusion of blood from a patient with syphilis is carried out using one of the regimens recommended for the treatment of primary syphilis, if no more than 3 months have passed since the transfusion; if this period is between 3 and 6 months, the recipient is subject to clinical and serological monitoring twice at 2-month intervals; if more than 6 months have passed since the blood transfusion, a single clinical and serological examination is performed [15].

GRC CLOE 5Grade of Recommendation – C (Level of Evidence 5)

5.1.2 Prevention of congenital syphilis

Prevention of congenital syphilis is carried out antenatally and postnatally.

Antenatal prevention includes: working with healthy individuals, providing information on the possibility of intrauterine transmission of syphilis and the need to start prenatal care early; triple serological screening of pregnant women (upon registration at the antenatal clinic, at 28–30 weeks, and 2–3 weeks before delivery); and, if syphilis is detected, appropriate specific and preventive treatment.

Postnatal prevention of congenital syphilis consists of prophylactic treatment of infants.

5.2 Clinical and serological monitoring (follow-up)

Comment: In case of sustained negativity of non-treponemal tests over 12 months, clinical and serological control (follow-up) of the patient may be discontinued. Patients with late forms of syphilis, in whom non-treponemal test results often remain positive after treatment (including additional treatment), must remain under clinical and serological control (follow-up) for at least 5 years.

The decision to discontinue clinical and serological control (follow-up) of these patients after 5 years or to continue clinical and serological control (follow-up) beyond 5 years is made individually after consultation with a neurologist, ophthalmologist, physician (internist), examination of cerebrospinal fluid, and performance of echocardiography and ECG.

Comments: If pathological changes in the cerebrospinal fluid (positive non-treponemal tests) persist, additional treatment is administered. Following additional treatment, the issue of extending the follow-up period beyond 5 years is decided individually in consultation with a neurologist. Sustained normalization of cerebrospinal fluid composition (two normal CSF test results performed at 1-year intervals), even with persistent residual clinical manifestations, is an indication for the termination of clinical and serological control (follow-up).

Comments: The first clinical and serological examination is performed at the age of 3 months and includes a pediatric examination, consultations with a neurologist, ophthalmologist, otorhinolaryngologist, and a comprehensive serological workup. If the serological results are negative and there are no clinical symptoms of the disease, the examination is repeated before de-registration at the age of 1 year. In other cases, examinations are performed at 6, 9, and 12 months of age.

For children who received specific treatment, clinical and serological control is carried out for 3 years.

5.3 Completion of clinical and serological monitoring (follow-up)

At the end of the follow-up period, a complete clinical and serological examination is performed, including RPR (or equivalent), TPHA, ELISA, and, if necessary, FTA-ABS, TPI, alongside consultations with a physician/pediatrician, neurologist, and ophthalmologist.

To terminate clinical and serological control, all patients treated for neurosyphilis, visceral syphilis, or late and unspecified forms of the disease must undergo cerebrospinal fluid examination, echocardiography, as well as a comprehensive blood biochemistry panel including liver enzymes, bilirubin, creatinine, lipid profile, and other tests as indicated.

Individuals who have undergone a full course of specific treatment for syphilis are allowed to work in childcare facilities and public catering establishments after the regression of clinical symptoms of the disease (in cases of manifest syphilis).

Children receiving specific treatment for syphilis may attend childcare facilities after the disappearance of clinical manifestations and the completion of the course of specific treatment.

In patients with positive non-treponemal test results, clinical and serological control may be discontinued if the following conditions are met:

1) a full course of specific and additional treatment has been administered;

2) clinical and serological follow-up was carried out for 5 years;

3) cerebrospinal fluid parameters are normal prior to de-registration;

4) there are no signs of cardiovascular syphilis on echocardiography of the heart and aorta;

5) there is no specific clinical pathology according to specialist consultations (neurologist, ophthalmologist, otorhinolaryngologist, physician/pediatrician).

The issue of extending the follow-up period beyond 5 years in the presence of persistent positive non-treponemal test results is decided on an individual basis.

6. Organization of Medical Care

Indications for hospital admission to a medical organization:

- pregnant women with syphilis in need of specific and preventive treatment;

- children with congenital syphilis;

- children with acquired syphilis up to middle school age (up to 10 years) and/or with somatic pathology, in conjunction with relevant specialists;

- patients with syphilis requiring regular therapeutic procedures.

Indications for discharging a patient from a medical organization:

1) completion of a full course of specific therapy according to the stage and form of syphilis;

2) resolution of infectious manifestations of syphilis.

Treatment of patients with visceral syphilis is best carried out in a dermatovenereology inpatient unit or a therapeutic/cardiology department (taking into account the severity of the lesion). Treatment is administered by a dermatovenereologist prescribing specific therapy, in conjunction with a physician/cardiologist recommending concomitant and symptomatic therapy.

7. Additional Information

If a patient with syphilis is found to have HIV antibodies, they are referred for further evaluation, treatment, and ongoing follow-up to the regional AIDS Center with appropriate recommendations for syphilis treatment.

Treatment of HIV-infected patients with syphilis is carried out using the same regimens as for uninfected individuals. The development of optimal antibiotic therapy regimens requires further research based on evidence-based medicine principles. The efficacy of alternative treatment regimens used for patients with penicillin allergy has not been sufficiently studied. Limited data indicate the efficacy of ceftriaxone**, administered intravenously at a dose of 1–2 g/day for 10–14 days [15], in the treatment of neurosyphilis in HIV-infected patients with penicillin allergy.

Non-treponemal tests in HIV-positive patients often remain positive within standard timeframes after specific antisyphilitic therapy, and in many patients remain positive for life (serological resistance develops).

After completing the course of treatment, HIV-infected patients with neurosyphilis require clinical and serological follow-up with cerebrospinal fluid examination every 6 months for 3 years or until CSF parameters normalize. Normalization of cerebrospinal fluid composition in HIV-positive patients occurs more slowly.

Criteria for Evaluating the Quality of Medical Care

Criteria (indicators) for evaluating the quality of inpatient medical care

Criteria (indicators) for evaluating the quality of outpatient medical care.

References

Appendix A1. Working Group Composition

1. Kubanov Alexey Alekseevich – Academician of the RAS, President of the All-Russian Public Organization "Russian Society of Dermatovenerologists and Cosmetologists" (RODVC), Director of the State Research Center of Dermatovenereology and Cosmetology of the Russian Ministry of Health, Head of the Department of Dermatovenereology and Cosmetology at the Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health, Moscow;

2. Sokolovskiy Evgeny Vladislavovich – Head of the Department of Dermatovenereology with Clinic at the First Pavlov State Medical University of St. Petersburg, Doctor of Medical Sciences, Professor, St. Petersburg.

3. Krasnoselskikh Tatyana Valeryevna – Professor of the Department of Dermatovenereology with Clinic at the First Pavlov State Medical University of St. Petersburg, Doctor of Medical Sciences, St. Petersburg.

4. Katunin Georgy Leonidovich – Candidate of Medical Sciences, Dermatovenereologist at the Consultative and Diagnostic Center of the State Research Center of Dermatovenereology and Cosmetology of the Russian Ministry of Health, Moscow.

5. Plakhova Ksenia Ilyinichna – Doctor of Medical Sciences, Scientific Secretary, Acting Head of the Department of Sexually Transmitted Infections, State Research Center of Dermatovenereology and Cosmetology of the Russian Ministry of Health, Moscow.

6. Mavlyutova Guzel Irekovna – Candidate of Medical Sciences, Associate Professor of the Department of Dermatovenereology and Cosmetology, Kazan State Medical Academy, Kazan.

7. Gorlanov Igor Alexandrovich – Head of the Department of Dermatovenereology, Saint Petersburg State Pediatric Medical University of the Russian Ministry of Health, Doctor of Medical Sciences, Professor, Saint Petersburg.

8. Frolova Zoya Vladimirovna – Deputy Chief Medical Officer for Medical Affairs, Regional Clinical Skin and Venereological Dispensary, Khabarovsk.

9. Arshinsky Mark Ivanovich – Chief Medical Officer, Regional Clinical Skin and Venereological Dispensary, Khabarovsk.

Conflict of interest: the authors declare no conflict of interest

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Medical specialists: dermatovenereologists, obstetrician-gynecologists, urologists, pediatricians;

2. Residents and trainees of continuing professional education cycles in the specified specialties.

Table 1. Level of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Level of Evidence (LoE) grading scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Grade of Recommendation (GoR) scale for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix B. Physician Action Algorithms

Diagnostic algorithm for neurosyphilis in HIV-negative patients

Diagnostic algorithm for neurosyphilis in HIV-positive patients

Management algorithm for children with suspected congenital syphilis

Appendix C. Patient Information

Syphilis is a sexually transmitted infection. Syphilis is often called the "great imitator" because it has numerous manifestations and is difficult to distinguish from other diseases. Most transmissions occur from people with syphilis who are not aware of their infection. Transmission occurs through direct sexual contact (vaginal, oral, or anal sex). The bacterium enters through mucous membranes or damaged skin upon contact with syphilitic sores. Sores can be located on the external genitalia, in the vagina, anus, and rectum, as well as on the lips and in the mouth. Pregnant women can transmit the infection to their child.

Syphilis is not transmitted through toilet seats, door handles, swimming pools, clothing, or eating utensils.

Sometimes symptoms of syphilis do not appear for years, but this does not reduce the risk of developing serious late complications.

The primary stage of syphilis typically manifests as one or more sores (known as chancres). The incubation period from infection to the appearance of clinical symptoms ranges from 10 to 90 days (averaging 21 days). Typically, a chancre is small, round, firm, red, and painless. The chancre appears at the site where Treponema enters the human body. Chancres in the vagina and rectum may go undetected for a long time. Chancres can easily transmit HIV infection (if the patient is infected) to a healthy person and also serve as an "entry portal" for the virus, increasing the risk of HIV acquisition up to 5-fold. In the primary stage of syphilis, lymph nodes on the inner thigh and in the groin enlarge and become firm. The chancre persists for 3 to 6 weeks and heals without treatment, but if left untreated, the infection progresses to secondary syphilis.

Secondary syphilis presents with a rash on the body or visible mucous membranes. The lesions are non-pruritic, typically red or red-brown, and most commonly appear on the palms and soles. The rash resolves without treatment within 2–6 weeks. In addition to the rash, symptoms may include low-grade fever, lymphadenopathy, patchy alopecia, sore throat, headaches, myalgia, and arthralgia. At this stage, the disease is highly contagious. If left untreated at this stage, it progresses to late syphilis.

The late (latent) stage of syphilis begins 1–2 years after infection. Without treatment, patients remain carriers of the disease even in the absence of clinical manifestations. In the late stage, the brain, nerves, eyes, heart, blood vessels, and liver are affected. Damage may manifest many years after infection.

Signs of late-stage syphilis include impaired coordination, paralysis, loss of sensation, progressive blindness, and dementia. These manifestations are most often irreversible and lead to death.

If a pregnant woman has syphilis, it can cause severe complications for her fetus/child:

- in 25% of cases, stillbirth ("missed abortion") is recorded;

- in 30% – neonatal death immediately after birth.

Infants infected in utero may be born without signs of the disease, but without treatment, they experience developmental delays, and in many cases, the child dies. Therefore, all pregnant women are screened for syphilis.

To diagnose syphilis in a patient, a blood sample is taken. Antibodies against Treponema pallidum are detected in the blood of an infected person no earlier than 1 to 4 weeks after the appearance of the chancre. Low levels of antibodies may persist in the blood months and years after successful treatment.

Syphilis is easily curable in its early stages. A course of penicillin is typically used. Patients with a penicillin allergy are treated with alternative medications. Antibiotics eradicate Treponema and prevent the development of complications.

There are no home remedies or unapproved medications effective against syphilis!

Important to know:

- Individuals with frequent casual sexual partners should undergo periodic screening for syphilis.

- Patients undergoing treatment for syphilis must abstain from sexual contact until chancres and other skin lesions are completely healed.

- Individuals diagnosed with syphilis must inform their sexual partners so that they can undergo full evaluation and treatment.

- Persons cured of syphilis are not immune to reinfection.

- Without laboratory tests, sexual partners cannot be certain of each other's health status.

- The best prevention of syphilis is mutually faithful sexual relations with a single uninfected partner.

- Avoiding alcohol and drug use prevents syphilis transmission by reducing risky sexual behavior.

- Male latex condoms reduce the risk of syphilis transmission via genital ulcers and chancres.

- Lubricated condoms are ineffective in protecting against STIs. Recent scientific studies have shown that they cause damage to mucous membranes and facilitate the entry of HIV and other STIs, including Treponema pallidum.

- Transmission of STIs, including syphilis, cannot be prevented by washing the genitals, urinating, or taking a shower after sex.

Any symptoms such as discharge or an unusual rash, particularly in the groin area, serve as a signal to cease sexual contact and seek immediate evaluation at a specialized clinic. This will reduce the risk of complications and prevent reinfection.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

None.