Hospital Medicine

Secondary syphilis

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I. What every physician needs to know.

Syphilis is a complex disease, with innumerable clinical presentations. As is well known, syphilis is a sexually transmitted disease caused by the spirochete Treponema pallidum. Here we will discuss secondary syphilis, which, despite its name, is an early stage of syphilis.

A chancre, or painless ulcerated lesion, is the most common clinical sign of primary syphilis. It develops in the location of the initial sexual exposure after an incubation period of approximately 3 weeks. Multiple lesions are sometimes seen, and they can be tender, contradicting the common medical lore of non-tender initial ulcerations. The fact that most are painless, however, can lead to delayed diagnosis. As a result, patients may present for medical care with secondary, not primary, syphilis. It is estimated that approximately 25% of patients with untreated primary chancres will develop secondary syphilis.

Secondary syphilis usually presents 4-10 weeks after initial chancre as a systemic illness, including a rash, fever, and generalized lymphadenopathy. Other frequent areas of involvement are the eye and the liver. Patients with HIV at times present with a more severe ulcerative rash. Patients with HIV are more likely to have syphilitic hepatitis, with liver function test (LFT) abnormalities.

Precise understanding of the pathophysiology of syphilis is compromised by the inability to grow the spirochete in culture, and therefore it has been studied in animal models and in some controversial human studies, for example, the Tuskegee study in the 1930s. The initial infection is transmitted via sexual intercourse, through areas of skin breakdown and mucous membranes. Within minutes of inoculation, the spirochete replicates in the tissues, activating a neutrophilic and then T-cell immune response and then entering the blood stream.

The chance of primary syphilis appears at the location of the initial exposure, and it is often associated with regional lymphadenopathy. With or without treatment, the chancre usually resolves with a local immune response. However, the organism continues to replicate in the regional lymph nodes, setting up the latent infection that becomes secondary syphilis.

Neurosyphilis develops as a result of invasion of the treponema into the cerebrospinal fluid (CFS) early in infection. CSF invasion is extremely common, but usually transient and spontaneously clears. In a subset of patients, particularly those with HIV, neurologic symptoms develop subsequently, both in the early phases of syphilis, including secondary syphilis, with meningitis and ocular symptoms, and at the later stages with tabes dorsalis and paresis.

The mainstay of treatment remains benzathine penicillin G. Treatment also includes patient counseling as well as partner notification. Syphilis reflects a growing public health problem; the greatest rates of increase appear to have been in men who have sex with men.

II. Diagnostic Confirmation: Are you sure your patient has secondary syphilis?

  • Appropriate clinical suspicion

  • Known sexual exposure

  • Characteristic rash, lymphadenopathy, fatigue, malaise, anorexia

  • Ocular symptoms

A. History Part I: Pattern Recognition:

There are myriad presentation of secondary syphilis, hence its moniker, "the great pretender." A typical patient today would be a young man, who has sex with other men, with a diffuse macular rash, often on the palms and soles, with generalized lymphadenopathy, malaise and anorexia. See Figure 1 for a typical palmar rash. Salient key features are as follows, with percentages from case series:

Figure 1.

Typical palmar rash of secondary syphilis. Image courtesy of Paul Aronowitz, CPMC, San Francisco, CA

Dermatologic findings

  • Rash - Macular, papular, pustular, annular, lichenoid rashes are all described, but never vesicular. A rash is present in 80% of all patients.

  • Mucosal lesions - Rounded, raised areas, covered with a pink exudate, which ulcerate when unroofed. They can occur on any mucous membrane, including anywhere in the oral cavity and in the genital area (60% more in women).

  • Condyloma lata - These are large whitish grey lesions on the genital mucous membranes, sometimes near the location of a prior chancre, with high organism burden (approximately 10%).

  • Alopecia - moth-eaten appearance with scattered hair loss.

Systemic findings

  • Constitutional symptoms - Fever/malaise/sore throat

  • Lymphadenopathy - Firm, rubbery. Often symmetric and wide spread (approximately 50%).

Neurologic findings

  • Neurologic symptoms - visual changes, headaches, confusion

  • Visual changes (less than 10%) - anterior or posterior uveitis

Abdominal findings

  • Hepatitis: transaminitis, usually self-resolving

  • Bowel ulcerations

B. History Part 2: Prevalence:

Prevalence

Syphilis is increasing in prevalence, particularly among men who have sex with men. The major burden of US disease is in the HIV infected population. The nadir of prevalence was in 2000, but since that time, the prevalence has steadily risen. According to data from the Centers for Disease Control (CDC), the US prevalence in 2013 was 5.3/100,000, double the rate in 2005. The predominant burden of disease is in men, and specifically, men who have sex with men. Much recent growth has been in the southern states. Now it is estimated that approximately 60% of newly diagnosed syphilis is in men who have sex with men.

Reasons for the recent increase are multiple, but originate predominantly in a decrease in safe sexual practices among the population of men who have sex with men in the era of HAART as well as illegal substance abuse around sexual activity.

Predisposing factors

  • Male homosexual sex

  • Illegal drug abuse

  • History of prior STDs

Effect of HIV

There is a high correlation of patients with HIV and patients with syphilis, and there is evidence to support that having HIV facilitates both transmission and acquisition of syphilis. Epidemiologic studies in San Francisco, Seattle and New York City, however, have not found an increase in HIV coincident with the significant growth of syphilis in those urban centers.

C. History Part 3: Competing diagnoses that can mimic secondary syphilis.

For diffuse rash

  • Rocky Mountain Spotted Fever - in tick-endemic areas rash is similar to syphilis, can also be on hands and soles, pink to red macules

  • Pityriasis - herald patch, macular, usually itchy

  • Viral exanthems - most often with associated viral syndrome history

  • Disseminated herpes simplex - usually vesicular, more painful

  • Tinea versicolor

  • Erythema multiforme

For genital lesions (chancres)

  • Chancroid (painful, purulent deep genital ulcers with painful localized lymphadenopathy in 50% of cases)

  • Herpes simplex (often multiple, grouped vesicles which can ulcerate, on erythematous base)

For oral lesions

  • Candidiasis

  • Leukoplakia

For lymphadenopathy and constitutional symptoms

  • HIV - more often associated with cytopenias, less prominent rash

  • EBV - again, rash less likely, different demographic often

  • Lymphoma - lymphadenopathy more prominent, less associated with rash

D. Physical Examination Findings.

  • Rash: myriad rashes. Macular or papular, erythematous, diffuse, often includes palms and soles. Never vesicular.

  • Lymphadenopathy: diffuse, symmetric, inguinal, cervical, epitrochlear, axillary. Minimally tender, firm/rubbery.

  • Alopecia: moth eaten (patchy)

  • Condyloma lata: flat greyish mucosal lesions, highly infectious, usually near location of initial chancre.

  • Eye: conjunctivitis with injected conjunctiva or uveitis. Considered neurosyphilis.

  • Neurologic signs and symptoms: change in mental status, focal weakness, numbness, visual or hearing changes.

  • Abdominal symptoms: right upper quadrant pain, jaundice, nausea, vomiting.

E. What diagnostic tests should be performed?

Detailed skin, lymphatic and genital exam.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Serologic testing

Serologic testing is the mainstay for diagnosis of syphilis. Direct examination of exudate from a chancre, using dark field microscopy, has fallen out of favor due to the technical difficulties and user variability. Serologic testing is a two-step process:

Step 1

Non-treponemal tests (venereal disease research laboratory [VDRL] test and rapid plasma reagin [RPR]). Both test serum against a cardiolipin-cholesterol-lecithin antigen. These tests reflect antibodies to lipids on the surface of T. pallidum and are reported as an antibody titer, i.e. 1:32. There is a high degree of false positivity, but the test is easy to perform.

  • False positive RPRs are found in pregnancy, tuberculosis, other treponemal diseases, endocarditis.

  • False negative RPRs are associated with immunodeficiency, including advanced HIV.

Step 2

If non-treponemal test is positive, it needs to be confirmed with a treponemal-specific test, which tests for reactivity to specific treponemal antigens. These are reported as reactive or non-reactive. The four most common tests are listed below. A reactive test confirms the diagnosis.

  • Treponema pallidum particle agglutination assay (TP-PA) - best test

  • Microhemagglutination test for antibodies to Treponema pallidum (MHA-TP) - less sensitive than TP-PA

  • Treponema pallidum enzyme immunoassay (TP-EIA) - most commonly done in state health departments.

  • Fluorescent treponemal antibody absorption (FTA-ABS) - technically difficult, infrequently used.

Complications in test interpretation - prozone phenomenon

With very high titers, RPR tests are sometimes falsely negative, due to agglutination of the antibodies. Serum must be diluted for the test to function properly. Labs need to be advised to dilute the serum if clinical suspicion is sufficiently high.

Some patients have a delayed antibody response, and therefore their RPR/VDRL (rapid plasma reagin/venereal disease research laboratory) will be negative. If clinical suspicion is sufficiently high, the test should be repeated in 1-2 weeks.

Lumbar puncture

Lumbar puncture (LP) is controversial, as many patients have transient treponemal CSF infection which resolves spontaneously. LP should be performed on patients with neurologic symptoms, with or without HIV, including ocular symptoms, or in HIV-infected patients diagnosed with syphilis of unclear duration, late latent syphilis or patients who fail treatment.

The 2-pronged approach

Step 1: CSF-VDRL. A reactive CSF-VDRL diagnoses syphilis, but there are false positives with blood-tinged CSF and/or high serum RPR titers, and false negatives are frequent.

Step 2: CSF FTA-ABS is sensitive but not specific. If a patient has CSF pleocytosis, with negative VDRL and negative CSF FTA-ABS, then neurosyphilis is ruled out.

In addition, interpretation of CSF pleocytosis is affected by the patient's HIV status, as with HIV infection, particularly when untreated, both CSF protein and white cell count is elevated.

Other tests

  • Complete blood count (CBC)

  • LFTs

  • HIV serotesting

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

No imaging studies necessary.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

None

III. Default Management.

  • Diagnostic testing with serology. LP in certain cases, as described above.

  • Treatment with penicillin.

  • Follow up with repeat non-treponemal tests to ensure decreased titer (4 fold) over 6-12 months after treatment.

A. Immediate management.

  • Benzathine penicillin (penicillin G) 2.4 million units IM once

In penicillin-allergic patients

  • Doxycycline 100mg po bid for 14 days

  • Ceftriaxone IM 1g for 8-10 days

For neurosyphilis

Treatment for neurosyphilis should be done as possible in consultation with an infectious disease physician.

Common regimens:

  • Aqueous Penicillin G 18-24 million U per day, administered every 4 hours, or continuously for 14 days, followed by benzathine penicillin (Penicillin G) 2.4 million units IM once

  • Procaine penicillin G 2.4 million U IM for 14 days, plus probenecid 500mg PO every 6 hours for 14 days

  • Ceftriaxone 2g IV/IM for 14 days, followed by benzathine penicillin (Penicillin G) 2.4 million units IM once

HIV

Recommendations for HIV-infected patients are the same as for uninfected patients. There are reports of higher treatment failures with standard regimens, but strong evidence is not available to support alternative treatment.

Other notes

  • Penicillin-allergic patients should be desensitized to penicillin, with the assistance of an allergist, for treatment of neurosyphilis.

  • Azithromycin should not be used, due to high rates of resistance.

B. Physical Examination Tips to Guide Management.

Monitor for Jarisch-Herxheimer reaction. This is an acute febrile reaction characterized by vasodilation, myalgias, fevers, flushing and occurs in up to 30% of patients, more frequently in patients without HIV.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

After treatment, RPR titers are followed to ensure sero-reversion, or disappearance of antibody. This is key for long-term follow-up. There is not usually changes to treatment based on repeat in-hospital testing.

The same non-treponemal test (RPR or VDRL) as checked on initial diagnosis should be checked at 1 week, and then 1, 3, 6 and 12 months after treatment. A four-fold decrease in titer (i.e. 1:32 to 1:8) is considered evidence of cure.

If RPR or VDRL does not decrease, patients should be re-treated, and tested for HIV and neurosyphilis with lumbar puncture. This occurs in 15% of patients.

D. Long-term management.

One year follow-up is focused on determination of cure. Long-term management hinges decreasing risk of further infections and following for evidence of reinfection.

E. Common Pitfalls and Side-Effects of Management

The most frequent problem with management is poor patient follow through, with many patients lost to follow-up and few tests to document cure.

IV. Management with Co-Morbidities

N/A

A. Renal Insufficiency.

No change in standard management.

B. Liver Insufficiency.

No change in standard management.

C. Systolic and Diastolic Heart Failure

No change in standard management.

D. Coronary Artery Disease or Peripheral Vascular Disease

No change in standard management.

E. Diabetes or other Endocrine issues

No change in standard management.

F. Malignancy

No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc).

Treatment is the same for HIV-infected patients. Higher suspicion for neurosyphilis is needed. Titers should be followed for 12 months.

H. Primary Lung Disease (COPD, Asthma, ILD)

No change in standard management.

I. Gastrointestinal or Nutrition Issues

No change in standard management.

J. Hematologic or Coagulation Issues

No change in standard management.

K. Dementia or Psychiatric Illness/Treatment

No change in standard management.

A. Sign-out considerations While Hospitalized.

No specific sign-out considerations.

B. Anticipated Length of Stay.

Unpredictable, except with neurosyphilis when 14 days of IV or IM antibiotics must be administered, sometimes in the hospital but usually in an extended care facility.

C. When is the Patient Ready for Discharge.

When appropriate discharge planning has been performed.

D. Arranging for Clinic Follow-up

Patients should have one week follow up for repeat serologic testing.

1. When should clinic follow up be arranged and with whom.

Depending on geographic preference, patients should have one week follow-up, either with a primary care physician or with an infectious disease physician.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

None

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

Repeat VDRL or RPR.

E. Placement Considerations.

Not relevant.

F. Prognosis and Patient Counseling.

Secondary syphilis has a good prognosis with treatment.

The key elements of counseling surrounds partner notification and testing, as well as counseling around safe sexual activity and substance abuse. Given the recent rise in syphilis incidence and prevalence, public health efforts are necessary to control the continued growth of the infection. Therefore, partners should all be contacted by the patient and tested. Novel public health strategies, using social media, have been used in some cities to raise awareness about the epidemic.

In all states, syphilis must be reported to the state. Most laboratories directly report their results to the state Department of Public Health.

A. Core Indicator Standards and Documentation.

None

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

None.

What's the evidence?

Blank, LJ,, Rompalo, AM,, Erbelding, EJ,, Zenilman, JM,, Ghanem, KG. "Treatment of syphilis in HIV-infected subjects: a systematic review of the literature.". Sexually transmitted infections. vol. 87. 2011. pp. 9-16.

Celum,, CL. "Sexually transmitted infections and HIV: epidemiology and interventions. Topics in HIV medicine". International AIDS Society USA. vol. 18. 2010. pp. 138-142.

Crum-Cianflone, N,, Weekes, J,, Bavaro, M. "Syphilitic hepatitis among HIV-infected patients.". International journal of STD & AIDS. vol. 20. 2009. pp. 278-284.

Eccleston,, K,, Collins,, L,, Higgins,, SP. "Primary syphilis.". International journal of STD & AIDS. vol. 19. 2008. pp. 145-151.

Farhi, D,, Benhaddou, N,, Grange, P,, Zizi, N,, Deleuze, J,, Morini, JP,, Gerhardt, P,, Krivine, A,, Avril, MF,, Dupin, N. "Clinical and serologic baseline and follow-up features of syphilis according to HIV status in the post-HAART era". Medicine. vol. 88. 2009. pp. 331-340.

Li, JZ,, Tucker, JD,, Lobo, AM,, Marra, CM,, Davis, BT,, Papaliodis, GN,, Felsenstein, D,, Durand, ML,, Yawetz, S,, Robbins, GK. "Ocular syphilis among HIV-infected individuals. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America". vol. 51. 2010. pp. 468-471.

Miller, AC,, Rashid, RM,, Khachemoune, A. "Secondary syphilis". The Journal of emergency medicine. vol. 35. 2008. pp. 83-85.

Mullooly, C,, Higgins, SP. "Secondary syphilis: the classical triad of skin rash, mucosal ulceration and lymphadenopathy". International journal of STD & AIDS. vol. 21. 2010. pp. 537-545.

Zetola, NM,, Engelman, J,, Jensen, TP,, Klausner, JD. "Syphilis in the United States: an update for clinicians with an emphasis on HIV coinfection". Mayo Clinic proceedings Mayo Clinic. vol. 82. 2007. pp. 1091-1102.

Zetola, NM,, Klausner, JD. "Syphilis and HIV infection: an update. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America". vol. 44. 2007. pp. 1222-1228.

Patton,, ME. "Center for Disease Control and Prevention: Primary and Secondary syphilis - United States, 20015-2103.". MMWR Morb Mortal Wkly Rep. vol. 63. 2014. pp. 402-6.

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