Secondary Syphilis with Ocular Manifestations in Older Adults
- 1United States Naval Medical Research Center Detachment, Lima, Peru; and Departments of Medicine and Pathology, University of California, San Diego
- 2Medicine and Pathology, University of California, San Diego
- 3Pathology, University of California, San Diego
- 4Veterans Administration San Diego Healthcare System, San Diego, California
- Reprints or correspondence: Dr. Ryan Maves, Naval Medical Research Center Detachment, Unit 3800, APO AA 34031 USA (Ryan.Maves{at}med.navy.mil).
Abstract
We describe 4 patients (age, >50 years) with secondary syphilis. All patients presented with ocular syphilis, and 2 presented with syphilis-negative rapid plasma reagin titers due to a prozone phenomenon. Three male patients reported sildenafil use. The presentation of these patients with ocular syphilis suggests the need for additional clinical studies involving older patients.
Rates of syphilis in the United States are increasing [1]. Much of this increase has occurred among men who have sex with men (MSM) and in association with the HIV epidemic [1], but the occurrence of infection in patients aged >50 years has been less well described. If patients are presumed to be in low-risk groups, delays in diagnosis and therapy may be likely. This is particularly true when such patients present with atypical symptoms and misleading diagnostic test results.
We identified 4 cases of secondary syphilis in HIV-uninfected, older patients at our institutions during a 2-year period. All patients presented with ocular symptoms, and the diagnoses of 2 of the 4 cases were delayed by false-negative rapid plasma reagin (RPR) test results due to the prozone phenomenon. All patients recovered after receiving treatment with penicillin. We describe the history of one of the patients in detail below; data concerning all 4 patients are summarized below and in table 1. This report serves to increase awareness about infectious syphilis, including its risks and manifestations, in older patients.
Table 1
Clinical and demographic characteristics of 4 older adult patients with secondary syphilis.
Case report. A 67-year-old white man presented in December 2006 for evaluation of epigastric pain that was accompanied by frequent loose stools. He also reported a perirectal “lump” that self-resolved. He initially denied having any high-risk sexual contacts. The findings of a physical examination were initially normal. A liver function panel test revealed elevated transaminase levels (alanine aminotransferase, 427 IU/L; aspartate aminotransferase, 390 IU/L) and a serum alkaline phosphatase level of 400 IU/L.
The patient's abdominal pain persisted during the subsequent month, and he lost 9 kg (20 lb) of weight as a result of diminished appetite. The patient's alkaline phosphatase level peaked at 1046 IU/L. A maculopapular eruption developed over his face, trunk, and extremities but spared his soles and palms. The result of a RPR test was negative, and the results of other serologic and radiologic tests were unrevealing. The patient's pain resolved spontaneously after 2 months, with normalization of his liver function panel findings.
In February 2007, the patient presented for evaluation of new-onset blurry vision, ocular pain, and photophobia. His rash had begun to fade. Visual acuity was 20/80 bilaterally. He had bilateral retinal papillitis and anterior chamber synechiae, which were consistent with panuveitis. Treatment with topical corticosteroids and cycloplegics was prescribed, with a decrease in ocular pain.
Two weeks later, his visual acuity had improved to 20/50 in the right eye and 20/63 in the left eye. The result of an additional RPR test was again interpreted to be negative. The result of a Treponema pallidum particle agglutination assay, requested by the consulting ophthalmologist because of a high suspicion for syphilis, was positive. Serial dilutions of the patient's serum specimen revealed a titer of >1:1024, with the prior studies yielding false-negative results because of a prozone phenomenon.
The patient was admitted to the hospital with diagnoses of syphilitic uveitis and resolved syphilitic hepatitis. The patient now admitted to a long history of unprotected casual sexual encounters with men, the most recent of which occurred 1 month before his initial presentation in December. An evaluation of a CSF specimen yielded normal findings. Intravenous penicillin G (24 million IU per day) was administered for 14 days, followed by 3 weekly injections of intramuscular benzathine penicillin (2.4 million IU). Two months later, the patient's visual acuity was 20/20 bilaterally, with no residual photophobia.
Results. We identified 4 patients aged >50 years who had secondary syphilis. Three of the patients were men. Two of the 3 men were MSM, and the third was an exclusively heterosexual man who was the sex partner of the female patient in the series. She, however, had a prior history of intercourse with MSM. All 3 men were users of sildenafil. The male patients were aged 60–67 years, and the female patient was aged 52 years.
All 4 patients presented with various ocular findings, which are detailed in table 1. Three of the 4 patients presented with rash, and 2 of the 4 presented with elevated serum alkaline phosphatase and bilirubin levels, which were consistent with cholestatic hepatitis.
Serum RPR titers were high; the lowest documented value was 1:1024. In 2 of the 4 cases, the diagnosis was delayed because of a false-negative RPR test result associated with a prozone phenomenon. Three of the 4 patients had abnormal CSF cellularity or protein levels, but only 1 of these 3 patients had a detectable CSF Venereal Disease Research Laboratory titer. All 4 patients tested negative for HIV infection by ELISA (table 1).
Discussion. Syphilis is reemerging in the United States. A total of 9756 cases of primary and secondary syphilis in the United States were reported to the Centers for Disease Control and Prevention in 2006 [1], a rate of 3.3 cases per 100,000 population and an increase from 2.1 cases per 100,000 population in 2000 [2]. In San Diego County, California, rates of syphilis have increased even more dramatically, with 7.6 cases per 100,000 population reported in 2006 [3]. These increases have been concentrated among MSM, with HIV coinfection present in 50%–60% of patients [4]. Because HIV and T. pallidum can facilitate each other's spread, this increase in the rate of infection has significant public health implications beyond syphilis control alone [5].
All of our patients had evidence of ocular syphilis. Ocular disease may occur during either the early or late stages of syphilis and can affect most of the components of the eye, with effects ranging from interstitial keratitis to retinal vasculitis and necrosis. Uveitis appears to be the most common form of syphilitic eye disease, occurring in 2.5%–5% of patients with tertiary syphilis [6] and in 9% of HIV-coinfected patients receiving potent antiretroviral therapy [7].
Presentations of syphilitic uveitis vary depending on the involved portion of the eye. Ocular pain, redness, and photophobia are more common with inflammation of the anterior uvea (the iris and ciliary body). Posterior uveitis involving the choroid is often painless, although visual loss may be severe. In addition, syphilitic meningitis and other CNS manifestations have been more frequently reported in association with posterior uveitis, particularly during early infection [8]. There are few data on the incidence of ocular syphilis among older patients, but 3 recent cases involved ophthalmic involvement as a presenting syphilitic syndrome in patients aged >65 years [9, 10]. The true incidence of ocular syphilis among older patients is unknown.
Rates of sexually transmitted infection are increasing among older men. The incidence of primary and secondary syphilis among men aged 55–64 years in the United States increased from 0.9 cases per 100,000 population to 2.3 cases per 100,000 population in 2006, with similar increases noted for men aged >65 years [1]. More than 10% of new cases of AIDS in the United States occur in patients aged >50 years, and the incidence of AIDS is increasing in this age group, despite stable rates among persons aged 30–49 years [11]. Similar increases in the rate of sexually transmitted infection among older patients have been reported in The Netherlands and Canada [12, 13].
The reasons for this increase in the rate of sexually transmitted infection are uncertain, although one article has suggested that the use of erectile dysfunction medications (such as sildenafil) may play a role [14]. Sildenafil use has been associated with high-risk sexual behavior among MSM, including unprotected and serodiscordant anal intercourse [15, 16]. Sildenafil use alone, however, was not independently associated with an increased risk of acquiring syphilis in other cohorts [17, 18]. Nevertheless, use of phosphodiesterase inhibitors is likely to be a necessary but not sufficient reason for older men with erectile dysfunction to acquire a sexually transmitted infection.
Older patients may consider themselves to be at low risk of acquiring sexually transmitted infections, even though a recent large survey of older adults in the United States revealed high rates of sexual activity [19]. These patients may be less likely to use condoms [20–22] and wait longer before presenting for care after the onset of symptoms [23, 24]. Older patients at risk of acquiring sexually transmitted infections may continue to engage in high-risk sexual practices at rates similar to those of younger patients; one survey reported that 33% of sexually active, HIV-infected adults aged >50 years in New York City had engaged in recent, unprotected sex (one-half of the time with HIV-negative partners) [25]. In spite of these findings, 73% of clinical trials of sexually transmitted infection prevention and therapy exclude patients aged >50 years, and 89% exclude patients aged >65 years [26].
The diagnosis of syphilis in 2 of our patients was delayed because of the prozone phenomenon, which is the result of high titers of nonspecific anti-cardiolipin antibodies. The RPR uses charcoal particles to accentuate the agglutination reaction between antibodies in the patient's serum specimen and cardiolipin antigen [27]. When the concentration of antibody is excessive, the lattice does not form, and a false-negative test result occurs. Dilution of the patient's serum specimen will overcome this phenomenon. Prior studies have estimated that 2% of patients with syphilis will have a prozone reaction. However, a large cohort of 4328 patients with a high incidence of syphilis (7.2%) identified only 1 such case from 312 confirmed infections, a rate of 0.3% [28]. Conversely, at our Veterans Administration hospital (where we have longitudinal follow-up data on nearly all of our patients), we identified 3 patients (from a total of 31 patients) with newly diagnosed infectious syphilis during a 12-month period for whom the RPR test result was initially interpreted to be negative because of a prozone reaction (J.F., unpublished data). Whether the prozone phenomenon occurs more frequently among older patients, as is suggested by 2 of our 4 cases, remains to be determined.
We recommend maintaining a high index of suspicion for syphilis when evaluating patients with a compatible clinical syndrome, regardless of their age or reported sexual activity. Additional studies are needed to better define the prevalence and manifestations of infectious syphilis in older patients. The limitations of the RPR test for diagnosis of secondary syphilis may be greater than has previously been recognized when testing is done in clinics without adequate patient follow-up.
acknowledgments
Potential conflicts of interest. All authors: no conflicts.
Footnotes
-
The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of Defense, Department of Veterans Affairs, or the US Government. R.C.M. and J.F. are employees of the U.S. Government. This work was prepared as part of their official duties. Title 17 U.S.C. §105 provides that Copyright protection under this title is not available for any work of the United States Government. Title 17 U.S.C. §101 defines a U.S. Government work as a work prepared by a military service member or employee of the U.S. Government as part of that person's official duties.
- Received December 26, 2007.
- Accepted February 1, 2008.
- © 2008 by the Infectious Diseases Society of America
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