Secondary syphilis can present with a very broad range of symptoms. However, the hallmark of this stage of infection is the appearance of a maculopapular rash. The diameter of lesions, which are red-to-brown in color, ranges from 3-10 mm and initially appear on the trunk, followed by their dissemination to the extremities, including the palms and soles, which is one of the main distinguishing features [9]. Condylomata lata is a term that describes the development of raised grayish or white papillary skin lesions in intertriginous areas, which are also specific features for secondary syphilis. Macules and papules may progress into pustules. Mucous patches, grayish oval-shaped erosions or ulcerations are also commonly observed in patients during this stage.

Apart from skin lesions, patients may exhibit symptoms related to virtually any organ. Constitutional symptoms, such as fever, malaise, weight loss, myalgia, and arthralgia may precede the rash. Generalized lymphadenopathy, involving cervical, axillary and inguinal regions, is frequently present. Gastrointestinal involvement may result in symptoms such as vomiting, abdominal pain. Ocular involvement, including the development of keratitis, uveitis, retinitis, optic neuritis may occur [10]. Periostitis, meningitis, hepatitis and pharyngitis may also be encountered in variable percentages.

Lues maligna is a rare, but severe presentation of secondary syphilis, which presents with generalized progressive polymorphic ulcers accompanied with the poor systemic condition [4].

The initial diagnosis of syphilis in the secondary stage can be made based on properly obtained patient history and thorough physical examination. Recent sexual behavior that may have posed a risk for contracting an STD, together with typical features such as disseminated rash including the palms and soles, condylomata lata, and the recent development of chancres (the hallmark of primary syphilis) can provide key elements in establishing the diagnosis. A confirmation of T. pallidum as the causative agent can be done using various tests [11]:

• Microscopical evaluation - Because T. pallidum cannot be visualized by classical light microscopy, special methods must be used. Darkfield microscopy is a method which includes an immediate examination of material scraped from skin lesions, which can detect viable spirochetes. However, because T. pallidum cannot survive laboratory transport, the direct fluorescent antibody (DFA) test is more commonly used, which comprises introduction of fluorescent anti-treponemal antibodies into the sampled material. Antibodies bind to spirochetes that are both motile and nonmotile, but more importantly, oral and rectal swabs can be examined by this method since darkfield microscopy may identify commensal spirochetes from these regions and make a falsely positive diagnosis [5].
• Serology - There are various tests that can be used for confirming syphilis. The serologic evaluation includes non-treponemal tests that confirm the presence of antibodies reacting with certain cellular components that bind to T. pallidum. Treponemal tests, on the other hand, detect T. pallidum-specific antibodies. Non-treponemal tests include Venereal Disease research Laboratory (VDRL) test and the Rapid Plasma Reagin (RPR) test, which are shown to be 100% sensitive in secondary stages of syphilis [5], but certain diseases, such as systemic lupus erythematosus (SLE) or antiphospholipid syndrome may present with positive VDRL and RPR levels. Fluorescent treponemal antibody-absorption (FTA-ABS) and Treponema pallidum particle agglutination (TP-PA) are two treponemal tests which are used in making a definite diagnosis [12]. The first include binding of fluorescent antibodies to T. pallidum, while TP-PA is a test in which agglutination of particles occurs if the inspected material contains T. pallidum antigens.

All patients with suspected syphilis should be tested for HIV infection, as well as hepatitis B and C and other STDs, including Chlamydia trachomatis and Neisseria gonorrhea because their coinfection is not uncommon.

The mainstay of treating patients in secondary syphilis, but in other stages as well, is the administration of penicillin. Administration of 2.4 million units as a single dose IM is the recommended regimen [13]. Alternative regimens include administration of ceftriaxone 1g either IM or IV q24h for 10-14 days, azithromycin 2g as a single dose PO, doxycycline 100 mg PO q12h for 14 days, or tetracycline 500 mg PO q6h for 14 days, depending on history of allergies or other factors which limit the use of penicillin, but virtually all regimens except azithromycin has shown inferior results to penicillin [14].

In rare cases, a systemic reaction that occurs 6-8 hours after administration of therapy, known as Jarisch-Herxheimer reaction, may occur and is most commonly observed in patients who are treated in the secondary stage of syphilis [4]. The cause involves the release of various components of treponemes that are being killed by antibiotics and are recognized by cells of the immune system. As a result, massive activation of pro-inflammatory cells and release of cytokines lead to development to either mild or severe and life-threatening symptoms. Fever, headache, hypotension and tachycardia usually appear and resolve within 24 hours, but patients in later stages of syphilis may develop life-threatening complications.

The prognosis of patients with secondary syphilis is very good if treatment is initiated, as complete recovery and cure may occur with timely treatment. However, without treatment, patients may progress into a latent stage and eventually develop tertiary syphilis, with cardiovascular and neurologic complications that can pose a significant risk to the patient. In very rare cases, severe variants of secondary syphilis (known as Lues maligna) may develop [4].

Treponema pallidum is a bacterial pathogen belonging to the group of spirochetes because of their coiled and helical shape. It is very thin (0.1-0.5 µm x 5-20 µm), which makes it undetectable under light microscopy. This bacteria thrives under anaerobic or microaerophilic (very low O2 concentrations) conditions, as it is extremely sensitive to oxygen. T. pallidum readily crosses the blood-brain barrier and the placental barrier, because of its potent virulence. It is able to move through tissues by using flagellar ligaments located in the periplasmic space, which extend virtually throughout the entire spirochete [4]. Its unique characteristics include the ability to maximally reduce expression of lipoproteins and other molecules on its outer membrane, which enables it to evade immune defenses and recognition by dendritic cells and macrophages.

Syphilis is diagnosed in all parts of the world with variable prevalence and incidence rates. Overall, it is estimated that 10.6 million new cases occurred annually in the year 2008, while more than 36.4 million individuals had active syphilis [2]. Incidence rates were highest in Africa, where it is established that syphilis occurred in approximately 8-9 per 1000 individuals, while the European regions reported incidence rates of less than 1 per 1000 [2]. In the United states, Syphilis is established to be the third most common STD, after Chlamydia trachomatis and Neisseria gonorrhea [5]. The main mode of transmission includes any form of sexual contact, but vertical transmission can also occur. More than 1.3 million pregnant women were estimated to have active syphilis worldwide [6], which presents a significant risk for fetal invasion of T. pallidum. A significant predilection toward male gender is established, with a 2-4:1 ratio, perhaps because the highest incidence rates of this STD is noted among men who are having sex with men (MSM population) [7].

The pathogenesis of syphilis invariably starts with the transmission of T. pallidum via direct contact from the infected host, primarily during sexual intercourse and its inoculation to the skin or mucosa. Once the bacteria reaches the new host, it is able to penetrate through the initial layers of the skin through breaks or abrasions, but it may penetrate through intact skin as well. As it reaches the subepithelial layers, it begins to rapidly multiply and disseminate through the blood vessels and the lymphatic system [4], which is the hallmark of secondary stage of syphilis, in which generalized dissemination leads to the development of a generalized rash. In order to achieve the process of multiplication, the bacteria uses several flagella located in its periplasmic space for movement and its tip serves for attachment to host structures. Several substances have been discovered to be key pieces in this process, including several hemolysins, fibronectin, and laminin, which are used for adherence and cleavage of various host components. Normally, the immune system should recognize foreign pathogens through recognition of pathogen-associated molecular patterns (PAMPs), but because of practically absent expression of components on the outer membrane of the bacteria, cells, and receptors of the immune system are unable to detect them. As a result, it is free to replicate and disseminate into all tissues and organs, including the central nervous system and at some point, for unknown reasons, dendritic cells are able to recognize the antigen and induce a proper immune response, including stimulation of Th1 CD4+ T-Helper cells and interferon gamma (IFN-γ) [8]. Why the infection then reaches latent stages and how it is able to survive in hosts and cause tertiary infections with life-threatening complications in some cases remains unknown.

Significant steps in terms of prevention can be made. Firstly, protection during sexual intercourse is shown to significantly reduce the possibility of transmission of syphilis, but other STDs as well [15]. Because syphilis can be transmitted by oral sex as well, reducing sexual contact that may be of risk is also an effective treatment strategy.

Syphilis is among the most common sexually transmitted diseases (STDs) diagnosed worldwide. It is caused by Treponema pallidum, which belongs to the group of spirochete bacteria [1]. Epidemiological data suggest that more than 30 million adults have this infection worldwide and more than 10 million new cases occur annually [2]. Humans are the only natural hosts and sexual contact is the primary mode of transmission of T. pallidum, while vertical transmission from mother to child is also possible. T. pallidum reaches the host through either intact or damaged skin and mucosa and is able to evade immune defenses through several mechanisms. The most important one, however, is the ability of bacteria to express very few molecules on their outer membrane, which limits the capacity of the innate immune system to recognize this pathogen and its antigens. As a result, the bacteria is able to roam freely in the extracellular space, make direct contact with host tissues and disseminate throughout the human organism. The clinical presentation of syphilis can be challenging due to the presence of many symptoms at various stages of the disease, but in general, this infection is classified into four stages. Primary syphilis includes development of a skin lesion (chancre) over the course of 10-14 days at the site where bacteria penetrated the tissues; Secondary syphilis reflects the dissemination of bacteria throughout the human body and is characterized by a maculopapular rash that initially develops on the trunk and extends to the extremities, including the palms and soles. The rash develops approximately 2-6 months after infection by T. pallidum and in addition to its maculopapular forms, several other skin lesions may be encountered. The development of pustules may be seen as the maculopapular rash further progress. In intertriginous areas, the maculopapular rash can progress into gray or white papillary formations known as condylomata lata [3]. Skin lesions may regress and then appear again within a few weeks, which is not uncommon. In addition to skin manifestations, various other symptoms may be present during this stage. Constitutional symptoms, such as nausea, vomiting, abdominal pain, weight loss, fever, myalgia, and arthralgia may be present, while cervical, axillary or inguinal lymphadenopathy may be encountered as well. The secondary stage is known to be the time when the patient is most infectious. In some patients, secondary syphilis can progress into a latent stage (third stage), and in rare cases, tertiary syphilis (fourth stage) may develop, which may cause severe, life-threatening cardiovascular and neurological manifestations. The diagnosis of patients with secondary syphilis can be made during the physical examination, aided by a thorough patient history, including recent sexual contact and previous exposure to carriers of syphilis. A definite diagnosis can be made by dark-field microscopy and through various serological tests. Human immunodeficiency virus (HIV) infection, but other STDs should be tested for as well in all individuals presenting with syphilis, as coinfection of these pathogens is frequent. Treatment of patients during the secondary stage of syphilis includes administration of benzathine penicillin G as a single dose of 2.4 million units intramuscularly, while alternative regimens exist for penicillin-allergic patients.

Syphilis is one of the most common sexually transmitted diseases worldwide and it is caused by a bacteria, Treponema pallidum. Global estimates suggest that more than 30 million people suffer from this infection and that every year, 10 million people contract this infection. It is almost exclusively transmitted by sexual intercourse, including oral, genital and anal, but transmission of syphilis from mother to child during pregnancy is also possible because the bacteria can breach the placental barrier and infect the fetus. However, syphilis is much more common among males, with most frequent rates observed among men who are having sex with men (MSM population). The course of this infection is divided into four stages: primary, secondary, latent stage and tertiary. The secondary stage of syphilis represents dissemination of bacteria throughout the body after their initial entry through the skin and subsequent spreading through blood vessels and the lymphatic system. It is the time period in which the infected individual is most prone to spreading the infection. The hallmark of secondary syphilis is the development of a rash over the entire body, which occurs between 2-6 months after contracting the spirochete. The rash firstly develops on the trunk and then spreads to the extremities. One of the main distinguishing features of this rash is that it spreads to the palms and soles as well. This rash is reddish-to-brown in color and consists of red-to-brown spots several millimeters in diameter. In intertriginous areas, such as the armpit, the area under the breasts, or the gluteal region, grayish-to-white elevations of the skin, known as condylomata lata, may develop. Flu-like symptoms, such as malaise, muscle and joint pain, fever and weight loss may appear a few days before the rash develops. Enlarged lymph nodes in the neck, armpits, and groins are frequently observed. In addition to the skin, secondary syphilis may cause symptoms related to hearing, vision, but also bone pain and gastrointestinal symptoms such as vomiting and diarrhea may develop. The diagnosis of syphilis in the secondary stage can be made through physical examination and observation of the rash that involves the palms and soles, but a definite diagnosis can be made by obtaining material from the rash for a specific microscopic evaluation called dark-field microscopy. This method implies investigation of bacteria through binding of fluorescent antibodies and their visualization in a dark field, as these bacteria cannot be seen in regular light microscopy. Other methods include detection of antibodies against Treponema pallidum in blood, as well as other tests that confirm their presence. Treatment includes administration of penicillin as a single dose intramuscularly, while patients who are allergic to penicillin may receive azithromycin, doxycycline or tetracycline. In very rare cases, a reaction to therapy, known as Jarisch-Herxheimer reaction, may develop and includes symptoms such as fever, flushing, headaches and blood pressure disturbances, which occurs as a result of interaction between the degrading bacteria and the host immune system. Significant steps in prevention can be made, through the use of protection during intercourse, but more importantly, avoiding sexual contact that may be of risk, since secondary syphilis may eventually cause life-threatening complications if it reaches the tertiary stage of the disease.

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