Syphilis in Men Infected with the Human Immunodeficiency Virus

1.1 Historical perspectives The origins of syphilis have been discussed for many centuries. Two main theories have been proposed: The new World or Columbian theory and the world or pre-Columbian theory. The Pre-Columbian theory purports that syphilis originated in central Africa and was introduced to Europe prior to the voyage by Columbus (Hudson, 1956). The former holds that syphilis was endemic in the part of the world now know as Haiti and was then acquired and carried to Europe by Columbus in the 1400s (Rothschild,2005). Bacteriological studies efforts the theory than the syphilis was introduced by Columbus to the Europe (Harper, 2008). In 1495 there was the first syphilis s epidemic in Europe (Knell, 2004). John Hunter in 1767 inoculated matter from a patient whom believed to have gonorrhea onto into the prepuce and glans of a recipient, who traditionally is believed to be himself. Ten days after the inoculation, a chancre appeared, followed by signs of secondary syphilis. (Oriel, 1994). It is now believed that the donor had both syphilis and gonorrhea, but Hunter was convinced that he had induced syphilis by inoculation of gonorrheal pus. In 1838 Philippe Ricord demonstrated conclusively that syphilis and gonorrhea were separate diseases on over 2500 human inoculations and he was the first to propose a scheme for the categorization of syphilis into primary, secondary, and tertiary stages, which is still used today. In 1905 Schaudinn y Hoffman demonstrated spirochetes in Giemsa-stained smears (Schaudinn, 1905), August von Wasermann devised a serum reaction test for syphilis (Wasermann, 1906). The treatments for syphilis included mercury, organic arsenical compounds (Sartin, 1995).In 1943 Mahoney (Mahoney, 1943) successfully treated the first four cases with penicillin (table 1).

. Historical aspects of syphilis.
syphilis. T.pallidum subsp. endemicum, which causes endemic syphilis (bejel), T.subsp.pertenue which causes yaws, and T.carateum, which is the etiologic agent of pinta (Tramont,2010). The T.pallidum is a spirochete varying from 0.10 to 0.18 um in diameter and from 6-20 um in legth, making it invisible by light microscopy, for the visualization the Dark-field microscopy is generally used (Creigton, 1990). T. pallidum, cannot be cultivated in vitro, although limited multiplication can be obtained in tissue cultures (rabbits are the laboratory animals most commonly used for maintaining virulent organism), for this reason is difficult to study and determine its metabolic, physical, and pathogenic features. There were few physiologic studies have previously shown that the organism has limited biosynthetic capabilities, requiring multiple nutrients from the host (Fraser, 1998). However, genomic sequencing has provided some insights by suggesting functional activities. This consists of a single circular chromosome of approximately 1,138,006 bases pairs, which places it close to the lowest end for the range of the bacteria. Unlike most pathogenic, its genome lacks apparent transponsable elements, suggesting that the genome is extremely conserved and stable. This is the likely explanation of why T.pallidum has remained exquisitely sensitive to penicillin for more than 70 year (Tramont, 2010).

Epidemiology 1.3.1 Transmission of disease
The primary mode of transmission is by sexual contact and the next common is transfer across the placenta (Singh, 1999). Kissing, blood transfusion, and accidental inoculation have also been reported as routes of transmission but are of minor importance today. The majority of infants with congenital syphilis are in uterus, but the newborn can also be infected by contact with an active genital lesion at the time of delivery (Fiumara, 1975). Today, the acquisition of syphilis through transfused blood or blood products is now rare, at least in the developed world, because of the low incidence of disease, the requirement that all blood donors have a nonreactive non-treponemal blood test, and because T.pallidum cannot survive longer than 24 to 48 hours under the current conditions of blood bank storage (Tramond,2010).
Accidental direct inoculation can occur by needlestick or during handling of infected clinical material. Syphilis of the fingers is most common in medical personnel (Palfi, 2008).

Occurrence of the disease
In USA, prior to the penicillin age, the incidence in 1947 of primary and secondary syphilis was reported at 66.4 cases per 100,000 persons. Rates declined in 1956 to 3.9 cases per 100,000 persons due to availability of penicillin, changes in sexual behaviour, and public health measures (Nakashima, 1996). The most recent epidemic was noted in 1990, with reported rates for primary and secondary syphilis at 20 per 100 000 persons, although no simple factor can explain this trend, and important contributing factor is crack cocaine use and the exchange of illegal drugs for sex (Rolf, 1990) (Fig.1). In USA, the rates fell to 2.1 cases per 100 000 in 2000, rising to 3 cases per 100 000 in 2005 (86% men). Actually the syphilis is a health problem with a prevalence of 12 million cases per year in worldwide (Hook, 2004 (Zetola, 2007). In Germany the rate is 75% (Ditzen, 2005). In Africa the prevalence of infection for HIV is 21% between MSM in comparation the 1-2% of general population (Wade, 2005). Some researchers have postulated that oral sex may now be more www.intechopen.com

Natural course of untreated syphilis
Descriptions of the natural history of untreated syphilis originate primarily from two large prospective studies and one study retrospective study. Boeck performed a prospective natural history of 1978 patients with early syphilis in 1891. His observations 20 years were then continued by Brusgaars, and this information was later termed the Oslo Study. Between 1949 and 1951, Gjestland undertook a follow up of 1404 of the original 1978 patients. The data were reviewed in 1955 and then recanalyzed in 1964 by Clark and Danbolt (Clark, 1964), the diagnoses were made clinically since neither serologic testing nor microscopy was available when the study began. The results indicate that approximately one-third of the patients developed tertiary manifestations of neurologic, cardiovascular, and gummatous (late benign) syphilis and that the probability of dying due to untreated syphilis was 17% and 8% in females (   (Rosahn, 1947). There was an increased overall mortality in syphilitic compared with nonsyphilitic populations.

Clinical manifestation
T.pallidum penetrates the intact mucous membrane or gains access through abraded skin, it enters the lymphatics and bloodstream and disseminates throughout the body. Clinical lesions appear when a concentration of approximately 10 7 organisms/mg of tissue is reached (Magnuson, 1956). The incubation period is directly proportional to the size of the inoculums (3-90 days approximately). In untreated cases, syphilis has traditionally been divided into the following stages: incubating, primary, secondary, early latent, late latent and late tertiary syphilis.

Primary syphilis
The classic primary chancre begins at the site of inoculations as a single, occasionally multiple, painless papule. The base is usually smooth; the borders are raised are raised and firm and have a characteristic cartilaginous consistency (Stokes, 1944). The size of the chancre varies from 0.3 to 3.0 cm, multiples chancres can occur especially in persons who are inmunosuppresed as those coinfected with HIV (Chapel,1978&Rompalo,2001. The localization, in men is the penis, more specifically the coronal sulcus and glans. Anorectal chancres are common in homosexual men (Horihan,2004). In women, the commonest locations of the lesions, in order of decreasing frequency, are the labia majora, labia minora, fourchette, and perineum. Regional lymphadenopathy consisting of moderately enlarged, firm, nonsuppurative, painless lymph nodes or satellite buboes usually accompanies the primary lesion (DiCarlo,1997).

Secondary syphilis
A rash of varying severity is the most common initial presenting symptom. This rash appears on the palms, soles, flanks, and arms and can range from macular to follicular and o c c a s i o n a l l y t o p u s t u l a r . A d d i t i o n a l l y u p t o 7 % o f p a t i e n t s m a y e x p e r i e n c e a l o p e c i a characterized by patchy hair loss of the scalp, beard, and lateral eyebrows, with is referred to as a moth-eaten appearance. Patients may also experience sore throats due to inflammatory involvement of the pharynx or the tonsils. Condiloma lata are found 5-22% of patients. Althoug the incidence of these effects is rare, syphilis can cause renal, ophthalmologic, hepatic, bone, and joint disease.

Latent (early and late) syphilis
Latent syphilis is a stage in which patients are seroreactive but asymptomatic. It occurs between the disappearance of secondary syphilis symptoms and the appearance of tertiary syphilis manifestations or therapeutic cure. About 90% of first relapses occur within 1 year , its defined early latent syphilis, and late latent syphilis is defined as occurring after 1 year (Gjestland, 1955).

Tertiary syphilis
Tertiary syphilis describes a broad range of manifestations but most commonly includes cardiovascular, gummatous, and/or neurological effects. Together, approximately 15% to 40% of individuals who are not treated will develop tertiary manifestations, with men at increased risk compared with women. Cardiovascular complications are the most common of the effects and typically present within 10 to 30 years of infection. They often involve the aortic arch and can lead to angina from coronary ostitis, aortic regurgitation, or aortic aneurysm. Gummas can present in any organ and can lead to complications, including ulcers of the skin, collapse of the palate or nasal septum, or organomegaly. It can develop any time after a year of infection, but incidence peaks at approximately 15 years.

Syphilis and HIV
The coinfection have shown no distinctive or unique clinical presentation or pathologic manifestations from those without concurrent HIV infection, they are at an increased risk to manifest a more protracted and malignant course, more constitutional symptoms, greater organ involvement, atypical and florid skin rashes, multiple genital ulcers in the 70% of patients (Rompalo,2010), 25% presented concomitant chancre during the secondary stage (Hutchinson, 1994), and a significant predisposition to develop symptomatic neurosyphilis (Tramont, 2010).  Table 4. Clinical phases of syphilis

Syphilis and HIV transmission
The two diseases can affect each other in a number ways. Studies epidemiologist showed that the syphilis increasing the likelihood of acquisition of HIV (Buchacz, 2004, Reynolds, 2006, Fleming 1999. The acquisition and transmission of each other but syphilis also upregulates CCR5 coreceptor expression (Sellati, 2000) and causes local inmune activation, thereby further increasing likelihood of adquisition of HIV, the stimulation of syphilis infected patient immune system might induce replication of the virus (Quinn TC, 2000), decrease CD4 T cell counts and induce lymphocyte and CD4 apoptosis (Buchacz, 2004). The pathogenic interaction between HIV and T. pallidum leading both to an immunodeficiency state may reduce the immunologic response to treponemal infection through a decrease in CMI, macrophage functional defects, and possibly immunomodulation of the humoral immunity response. Functional immunologic abnormalities may impair the host defense against syphilis, leading to more aggressive forms. The serologic tests for syphilis may be modified, often resulting in extremely high titers (11% HIV-infected persons have a biologic false-positive serologic test result) and a failure to decrease in response to adequate treatment unless successfully treated with HAART.

T.pallidum induce the expression of CCR5 on macrophages in syphilitic lesions Setalli, 2000
T.pallidum decreased CD4 T-cell counts and increased HIV viral load Buchacz, 2004 Syphilis increased HIV transmission 2-to9fold Chesson, 2003 First six months after exposure of syphilis, represent the of greatest risk for HIV infection Reynolds, 2006 Table 5. Syphilis and HIV transmission.

Clinical features of syphilis in HIV-infected patients
The majority of patients coinfected with HIV and syphilis have a primary syphilis similar to the population without HIV. However sometimes can show multiples chancres, larger and deeper and that heals more slowly (Hutchinson, 1994). The primary and secondary period overlap in 75% of cases (Rompalo, 2001). The signs of secondary syphilis can develop and succeed while chancres are still present. The rash may be more widespread and condylomata lata lesions more common than in patients without HIV. Unusual cutaneous manifestations, particularly the malignant lues are not uncommon in HIV patients. Acute syphilitic meningitis, ocular manifestations and losing hearing are more common in HIV patients (Tramont, 2005). The progression of tertiary syphilis is faster in HIV patients (Hutchinson, 1994)

Identification of T.pallidum (Lesion-Based Testing)
Direct fluorescent antibody test (DFA): A direct fluorescent antibody test can be performed on lesion exudate or tissue specimen. There are no differences in test performance characteristics among HIV-infected and non-infected patients. Darkfield microscopy: Examination of exudate from an ulcer base or a mucocutaneous lesion under darkfield microscopy can identify the spirochete (T. pallidum). This test is invalid for oral samples. There are no differences in test performance characteristics among HIV-infected and non-infected patients. Silver stain: Spirochetes may be seen in biopsy specimens of suspicious lesions such as palmar macular rash or gummatous lesions. There are no differences in test performance characteristics among HIV-infected and non-infected patients.

Serology
The serology in patients co-infected syphilis and HIV are similar; however there are least differents in the serology but very important in the diagnostic (Table 7).

Case report
A 42-year-old homeosexual man with chronic infection for HIV from 2003, in stadium A2 without antiretroviral therapy consulted at the outpatient infection department at Juan Ramon Jimenez Hospital for fever of 38,5 º C of three weeks of evolution, which the patient Reference False positive non-treponemal antibody test (RPR/VDRL). In one study, 4% of HIVinfected patients tested had false-positive RPR results Rompalo, 1992 Seroreactivity may be delayed or absent in HIV-infected patients. Rare cases have been reported of biopsy-proven secondary syphilis in HIV-infected patients with negative serology. Tikjob, 1991 Higher mean serologic serum nontreponemal antibody levels than non-HIVinfected Rolfs, 1997 Serum non-treponemal antibody levels may decline more slowly after treatment in HIVinfected patients than non-infected patients Rolfs, 1997, Yinnon 1996 Pro-zone reaction more commonly in HIVinfected persons Schöfer, 1996  relates to a "boil" perianal weeks before the beginning of the fever. On examination lymph nodes were palpable in the cervical, axillary and inguinal regions and skins lesions consisted of multiple erythematous present in his face, neck, trunk and extremities. One week after came back by persistence of the fever and pain of the throat. The laboratory studies revelead the following: Hemograme, glucose, urea, creatinine and ions were normal, GPT 71 U/l, GOT 50U/l, GGT 212 U/l, phosphatase alkaline 149 U/l. His CD4 cell count was 315/mm3 and his HIV viral load of 102.718 copies/ml. The Acid-fast bacilli stains, bacterial, fungal cultures and Lowenstein's culture in urine were all negative. The abdominal ultrasound scan was normal. Before the persistence of the clinic in absence of diagnosis the hospitable for continue the study. On examination, the patient was fever of 39 º C with stable vital signs. In mucous oral was presented whitish plates, didn't show ulcerative lesions or thrush ( fig.1), skins lesions in different stages in trunk ( fig. 2, panel A,B), face and neck, consisting of stains, papules, pustules with center necrotic and ulcerative scabs. He had and inguinal lymph node of 1-2 cm, and cardiac, lung and abdominal examinations are benign. Neurologically, the patient was grossly intact without focal deficits. The C reactive-protein was 3,9 mg/dl and the erhytrocyte sedimentation rate was 99 mm/hour. There were realized bacterial, fungal, mycobacterial culture and the blood detection of the antigen criptococo were normal. The Chest x-ray film was normal and the tomography thorax-abdominal didn't observe lesions in lung and in abdomen showed moderate enlargement hepatoesplenomegaly and lymphadenopathy in retroperitoneo, chains external ilíacas and inguinal approximately of 1,5 cm. The histological examination of the ganglionar biopsy showed reaction granulomatous giants cells without necrotic debris ( fig. 3, panel A), didn't observe acid-fast bacilli fast and the fungal culture was negative. The skin biopsy punch revelead infiltrated lymphocytes, histiocytes with extensive areas of necrosis and debris, (fig. 3, panel B), the culture of this one (conventional, fungi and mycobacterial) was negative. Warthin-Starry's stain was negative in both samples.  Treatment began with nistatine for the muguet. The presence of long fever, skin lesions, hepatoesplenomegaly and ganglionar affectation with noncaseating granuloma, suspected infection for Bartonella beginning treatment with azitromicina (500 mg c/ 24 hours) with fever and decrease of the size of the inguinal lymphadenopathy. The serology's bartonella was negative <1/256 (IFI). The information together with the persistence of the fever and the skins lesions in a patient HIV forced us to reject the diagnosis of malignant Syphilis. The cerebrospinal fluid was without cell (VDRL negative). Empirical treatment began with injection of intramuscular benzathine penicillin (2,4 million UI) in only dose, the fever defervesced over the next 24 hours, receiving in ambulatory regime two additional doses weekly. He didn't present Jarish-Herxheimer's reaction. There began antiretroviral treatment of high efficiency based on tenofovir 300mg with 200 mg of emtricitabina and efavirenz 600mg every 24 hours. He was discharged from the hospital with this therapy. It was checked 10 days later in consultation being afebril and asymptomatic. The oral lesion had disappeared and the skins lesions ones were showing clear improvement. The syphilis serology showed a positive RPR titer 1/32, the immunoglobulin G was positive and the immunoglobulin M negative. The liver function test was normal three months after of the beginning the therapy. To six months RPR titer had descended to 1/4. The rash approximately coincided months before with inconsistent condom use and several new sexual relationships.

Discussion 2.2.1 Definition
Lues maligna was first described by Bazin (1859) and Dubuc (1864), who applied this term based on the bizarre clinical features and progressive course of this variant of syphilis.
During some decades, there was controversy about whether lues malignt was a severe variant of secondary syphilis or an early manifestation of tertiary syphilis; a question clarified by Haslund andNeisser in 1896-1897. In contrast to tertiary syphilis, the lesions of lues maligna are multiple, have a round or oval configuration, with no tendency to central healing, and exhibit a lamellated, brown-black rupioid crust. Moreover, the early onset of necrotic ulcers in the disease is in contrast to the later occurring gummas of tertiary syphilis. Neisser identified five clinical features of malignant syphilis:


Short incubation period  Constitutional symptoms are pronounced  The skin and frequently the mucous membranes of the mouth and nose present multiple irregularity distributed lesions consisting of large pustules, ulcers, and rupioid ecthymatous lesions  The patient may have characteristics of the milder forms of the disease such as mucous membrane buccal patches, etc.
The skin lesions:  Pleomorphic  Papulopustules, beginning ulceration, deep ulceration, ulcers covered with crusts, healing lesions  Typically round or oval with a granulating base, and a lamellated, brown-black rupioid crust  The surrounding skin is little affected, showing only minimal erythema. Table 8. Criteria required for malign lues diagnosis (Neisser, 1896).
Compatible gross and microscopic morphology A high titer serologic test for syphilis Herxheimer reaction Dramatic response to antibiotic therapy Table 9. Criteria required for malign lues diagnosis (Fisher, 1969).

Risks factors for malignant lues
The risks factors for malignant lues are: constitutional symptoms. MSM, sex, syphilis previous. Shulkin proposed the HIV and the presence of opportunistic infections (Shulkin, 1988).

Incidence
The incidence of malignant lues in the cases of series were 0.36% (Haslund, 1987) in the age pre-HIV and 7.3% after of the co-infection (Schofer,1996).

Cases of ulceronodular syphilis in HIV patients
Shulkin published in 1988 the first case of malignant lues in British language. We checked the characteristics epidemiologist, diagnostic, evolutions and treatments in patients with coinfection ulceronodular syphilis-HIV from 1988 until 2010 (British and Spanish languages) including our case.