A 26-year-old HIV-positive, homosexual, Black male presented to his nurse practitioner (NP) for his quarterly HIV follow-up exam. During the review of systems, the patient reported having a long-standing tender rash on his right hand. The rash was evaluated at a previous visit and he was given an antimicrobial ointment that was ineffective. The rash continued to enlarge and became pruritic. Visual exam of the right palm revealed a single hyperpigmented erythematous peeling lesion on the thenar eminence; the lesion was 3 to 4 cm in length with an area of raised border. The lesion closely resembled a bite mark. Two 0.5- to 1 cm diameter satellite lesions with a similar appearance were present on his right palm near the base of the index and little fingers. The patient's history included three documented episodes of syphilis. The chart revealed that at the first presentation of the rash 4 months earlier, a rapid plasma reagin (RPR) and Treponema pallidum particle agglutination (TP-PA) were ordered. The RPR was reactive at a dilution of 1:32. The last documented case of syphilis occurred 1 year ago with an RPR of 1:512. Six months after treatment, his RPR had decreased to 1:16 (indicating full recovery from syphilitic infection (see Syphilis testing). The NP correctly interpreted the RPR of 1:32 as not indicating treatment because it was only a twofold increase from the patient's nadir. To confirm suspicion of a syphilitic gumma, the patient was referred to a dermatologist for a biopsy of the lesion. Given the patient's history of syphilis, the self-report of unprotected intercourse with potentially infected individuals, and the correlation between palmar rash and syphilis, an additional RPR and TP-PA were drawn in the office and a three-dose penicillin G benzathine (Bicillin L-A) treatment for syphilis was initiated. The last RPR was reactive at 1:64 indicating that he was experiencing his fourth documented case of syphilis. The rash resolved before he completed the dermatology consult.
Background
Syphilis has been called the Great Imitator. The NP caring for HIV-positive persons must obtain a precise history and carefully apply physical exam skills to differentiate the dermatologic, visceral, and somatic signs and symptoms that are frequently attributable to many different conditions. Syphilis greatly increases the risk of contracting HIV, and HIV alters the natural course of syphilis, but the exact mechanisms remain poorly defined.-3 The incidence of syphilis has increased in the United States and Europe since 2000 with a notable increase in incidence among HIV-infected individuals.1,3 It is essential for NPs interacting with HIV-positive patients, especially populations of men who have sex with men (MSM), to screen for syphilis yearly and evaluate risk for any sexually transmitted diseases (STDs) at each visit.4,5 This patient population is at higher risk for both HIV and syphilis infections than the general population.1,4
According to the CDC, 1990-2000 saw the rate of primary and secondary (P&S) syphilis decline 90%.6 However, the rate of P&S syphilis has been steadily increasing since 2001. This increase is seen predominantly in men although there is evidence of an increase in women as well.7 The CDC received 13,500 reported cases of P&S syphilis in 2008, the highest number since 1995. This equates to a rate of approximately 4.5 cases per 100,000, an 18% increase since 2007.7 The majority of reported cases (63%) occur in the MSM population, and there is an emerging problem among heterosexuals as well.6
A decrease in safer sex practices has been linked to the increased rate of syphilis among HIV-infected MSM.1,3 Recreational drug use (both prescription and illegal), success of HIV pharmocotherapeutics, finding sexual partners over the Internet, and the practice of serosorting (selectively having unprotected sex with partners of concordant HIV status or of only using condoms with HIV-discordant partners)8 may all contribute to the elevated rate of syphilis.1-3 An increase in the practice of oral sex (believed to have a lower risk of HIV transmission)9 may also be contributing to the increased rate of syphilis.3 Risk estimates related to HIV transmission through oral sex are not available.9 However, syphilis is easily transmitted during oral sex in either primary or secondary syphilis infections.10,11
Clinical presentation
An HIV-positive patient with syphilis coinfection may have a similar course of syphilitic disease as a non-HIV-infected patient.3 Some minor differences have been noted (HIV-infected patients may present with more than one chancre and have larger, deeper lesions, develop ocular syphilis, experience a more rapid progression to tertiary syphilis with lesser efficacy of standard therapy), however, large observational studies have not confirmed these variances.2,3,12
The causative agent in syphilis is a spirochete, also referred to as T. pallidum. This corkscrew-shaped motile bacteria bores through the skin and mucous membranes during sexual contact. The original site of entrance into the body is the location where the primary lesion arises. After the lesion heals, the bacteria penetrate the lymphatic system and migrate to regional lymph nodes where they enter the bloodstream and travel throughout the body. T. pallidum can migrate to the central nervous system (CNS) during any phase of a syphilis infection.11
Below is a general description of the different stages of syphilis with common presentations.
Primary syphilis: An infected patient with syphilis may present with a firm, round, indurated, painless ulcer or chancre on the genitalia or mouth that generally appears 10 to 90 days after infection. As long as the chancre is present, the patient is highly infectious. This open sore also allows for easier transmission of HIV. This lesion may heal in 1 to 6 weeks without treatment. Because the chancre is painless and heals without treatment, patients may delay seeking medical attention. Serologic tests may be negative during early syphilitic infection, but without treatment, the infection will progress to the secondary stage.4,11
Secondary syphilis: This stage is characterized by a nonpruritic, erythematous, hyperpigmented, macular rash that typically arises on the palms of the hands and the non-weight-bearing parts of the soles of the feet.4,11 The rash associated with secondary syphilis may also appear on other areas of the body including the back, trunk, abdomen, mouth, and scalp (see Rash with secondary syphilis). When located on other body parts, it may be papular and cause hair loss. Other symptoms that may occur with secondary syphilis include fever, lymphadenopathy, sore throat, headaches, weight loss, myalgias, and fatigue, in addition to condylomata lata, a form of genital warts caused by T. pallidum. The highest titers will be noted during this point of the infection.11
Latent syphilis:If the infection goes untreated, the host's immune system may be able to suppress the bacteria. When the spirochetes are suppressed, there are no dermatologic or systemic manifestations of the infection. The only sign of infection will be positive serologic tests (see Interpretation of syphilis serologies).
Tertiary syphilis: This late stage of syphilis is very rare in the United States due to the availability of antimicrobial therapy.11 Thirty percent of nontreated patients will progress to this stage of syphilis within 1 to 21 years of initial infection.11 Signs of tertiary syphilis include gummatous lesions (ulcerating and nonulcerating) and infection of the cardiovascular system.
Neurosyphilis:T. pallidum is able to disseminate into the CNS at any point during the infection and may be asymptomatic. Early neurosyphilis may occur anywhere within weeks to a few years of initial infection with clinical manifestations of acute syphilitic meningitis, meningovascular syphilis, and ocular involvement.4,11
Assessment and diagnosis
The precise interaction between syphilis and HIV remains controversial and is a topic of continued research. Syphilis is commonly believed to increase the HIV viral load and decrease CD4 cell counts in patients with concomitant infection. 2,3 The actual method of the effect is not well understood. "Syphilis infection may increase the immune activation of host cells and the secretion of cytokines, and thus enhance HIV replication".2
In obtaining a patient history, the NP should include questions regarding a past history of syphilis and results of previous serologic testing, syphilitic type symptoms within the last 12 months, and known contact with a person infected with syphilis.3,11 The patient should also be asked about drug and alcohol use and high-risk sexual behavior. The physical examination should include a thorough visual inspection of the mouth, palms and soles, torso, and genitals, palpation for lymphadenopathy, and a neurologic evaluation. Coinfected patients are more likely to present with secondary or latent infections.3,4 HIV-infected patients with neurologic symptoms should be referred to an infectious-disease specialist for evaluation of neurosyphilis. Mental status changes, stroke, meningitis, cranial nerve dysfunction, and loss of vibratory sense are all clinical signs of neurosyphilis.13
Patients who are coinfected with T. pallidum and HIV require the same serologic testing as those not infected with HIV. Treponemal and nontreponemal serologic tests can be interpreted in the normal manner for most patients coinfected with T. pallidumand HIV.13 If the interpretation of serologic tests is hindered by provider uncertainty, a lack of documented serologic history, or the tests are nonreactive in spite of clinical findings consistent with syphilis, diagnosis may be made by performing biopsy of lesions, darkfield exam, or direct fluorescent antibody (DFA) staining. These tests are not easily accessible and availability may be an issue.3
A definitive diagnosis is made with dark field exam and DFA test of primary lesion exudate, or tissue from a biopsy. A presumptive diagnosis can be made by serologic exam using nontreponemal and treponemal tests. The most commonly used nontreponemal tests are the Venereal Disease Research Laboratory (VDRL) and the Rapid Plasma Reagin (RPR). These tests detect the presence of nonspecific antibodies to cardiolipin (antibodies produced in the presence of tissue injury) and are equally valid assays.13 A reactive nontreponemal test is insufficient for diagnosis due to false-positive test results related to medical conditions unassociated to syphilis including autoimmune conditions, injection drug use, and older age.13 False positive also may occur in some parasitic infections including malaria and trypanosomiasis, or in the presence of spirochetal diseases such as leptospirosis or rat-bite fever.15 Typically, nontreponemal test titers go down after treatment. However, in some patients, nontreponemal antibodies persist for many years, even after adequate treatment. This response is called the serofast reaction.13 A patient in this situation will always test reactive with a low-level dilution such as 1:8 or 1:16.
A reactive nontreponemal test should be confirmed with treponemal-sensitive tests such as the fluorescent treponemal antibody absorbed (FTA-ABS) or the T. pallidum particle agglutination (TP-PA).13 These tests detect antibodies to T. pallidum. Therefore, most patients with a history of syphilis will have reactive treponemal tests for their entire lives, and future screening for syphilis involves following the reactivity and dilutions of an RPR or VDRL.
Additional information regarding serologic testing for syphilis can be found in the CDC Sexually Transmitted Diseases Treatment Guidelines, 2010. This resource can be found online at http://www.cdc.gov/std/treatment/default.htm
Treatment and follow-up care
Parenterally administered penicillin G 2.4 million units is the drug of choice for all stages of syphilis regardless of HIV status.13 According to the CDC, a single dose of penicillin G should be sufficient to cure primary, secondary, and early latent syphilis, even in the HIV-infected patient. However, some authors and providers recommend administering one or two additional weekly doses of penicillin G.1 The effectiveness of other medications (doxycycline, ceftriaxone, and azithromycin) in the treatment of syphilis has not been thoroughly studied in the HIV-infected patient population (see Guidelines for treating syphilis in the HIV-infected patient.) In several areas of the U.S., T. pallidum chromosomal mutations associated with azithromycin resistance and treatment failures have been documented. Azithromycin should not be used in MSM.13
It is important for the NP to use caution when prescribing the commonly used brand of penicillin G benzathine. Bicillin L-A is a preparation that contains the recommended 2.4 million units per dosage for syphilis treatment. This medication is also used in treatment of upper respiratory tract infections caused by susceptible streptococci. Bicillin C-R contains only 1.2 million units of penicillin G comprised of equal amounts of penicillin G as benzathine salt and procaine salt. Its efficacy in treating syphilis is unknown, but it is indicated for skin and respiratory tract streptococcal infection. In 2005, it was discovered that a clinic pharmacy in California had mistakenly begun dispensing Bicillin C-R for the treatment of syphilis in place of Bicillin L-A beginning in 1998. Nearly 600 patients were affected before a patient discovered the error while reading the package insert for Bicillin C-R, which clearly indicates it is not for the treatment of syphilis. Patients affected by this error were contacted and follow-up occurred.16
A patient is considered cured when follow-up serologic tests show a fourfold decrease in RPR or VDRL 6 months after treatment. Assessment of treatment response should not be measured with treponemal test antibody titers.13 If the HIV-infected patient being treated for syphilis in a primary care practice setting does not exhibit serologic signs of cure, it is essential that the NP refer this patient to an infectious-disease specialist experienced in treating HIV and syphilis coinfection. HIV-infected patients, who experience treatment failure (persistent or recurring signs or symptoms, or a sustained fourfold increase in nontreponemal test titer) or whose nontreponemal test titers do not see a fourfold decrease within 6 to 12 months of therapy, are recommended to be evaluated for neurosyphilis. This evaluation is performed by testing cerebrospinal fluid (CSF) obtained by lumbar puncture.1,13 The CSF in a syphilis/HIV coinfected patient may show elevated white blood cells, elevated protein, and less glucose than the non-HIV-infected patient.4 However, determining which patients should undergo CSF evaluation remains one of the most controversial issues in the treatment of coinfected patients.3
Patients need to be evaluated for treatment failure at 3, 6, 9, 12, and 24 months after penicillin therapy.3,13 This evaluation should include both clinical and serologic exams. Because treatment failure is difficult to distinguished from reinfection with T. pallidum, it is recommended that a CSF analysis be performed.13 Unless CSF exam indicates that neurosyphilis is present, retreatment with three weekly injections of penicillin G benzathine 2.4 million units is indicated.
Patient education and screening
Although the primary care NP may not manage the care of HIV syphilis coinfection, he or she can act as an information source for patients. Methods of HIV and syphilis transmission, in addition to methods of protection, must be discussed with all patients and is especially important to populations participating in high-risk sexual behaviors. Risks of acquiring syphilis associated with multiple sexual partners, the practice of serosorting, and inconsistent condom use should also be discussed. Describing the risks and complications of contracting syphilis include clearly explaining the decreased risk of transmitting HIV via oral sex, but the high risk of transmitting syphilis during this same type of sexual encounter. It is also important for the NP to explain to HIV-positive patients that they are most contagious to sex partners during the P&S stages of syphilis, regardless of their partners' HIV status.
Nationally, both healthcare providers and labs are obligated to participate in the mandatory reporting process for both syphilis and HIV infections.17 Patients should be provided explanation about the local county and state processes of reporting syphilis, including required contact information about previous sexual partners so they can be contacted to ensure early diagnosis and treatment.
As with any antibiotic, patients should be instructed to complete the prescribed dose of antibiotics regardless of symptom resolution. Skipping doses of medication decreases likelihood of cure, and increases the chance that an earlier stage of syphilis will progress to tertiary, or neurosyphilis. A reminder phone call may be warranted to assist patients in remembering their appointments for additional in-office doses of penicillin.
HIV-infected patients should also have annual screenings for syphilis (and other curable STDs) as recommended by the CDC.13
Conclusion
By being aware of the signs and symptoms of syphilis and frequency of coinfection with HIV, the NP was able to initiate treatment based on CDC guidelines. This patient should have a follow-up RPR and TP-PA 3 months after completion of therapy with subsequent tests at 6, 9, 12, and 24 months until there is a fourfold decrease in titers. However, this patient may benefit from having a lumbar puncture to verify the absence of neurosyphilis. Upon resolution of this current syphilis infection, this patient should have regular syphilis screening as part of his routine HIV monitoring serologic tests.
Syphilis testing13
An RPR and TP-PA in an uninfected patient would be nonreactive. A reactive RPR or VDRL with a fourfold dilution increase, in addition to a reactive TP-PA or FTA-ABS, is required for a presumptive diagnosis of syphilis. Treatment should be given in this case.
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