Volume 119, Issue 5 , Pages 448.e21-448.e25, May 2006
Ocular Syphilis in HIV-Positive Patients Receiving Highly Active Antiretroviral Therapy
Article Outline
Abstract
Background
From October 2001 to October 2002, we have observed a surprisingly high incidence of ocular syphilis in human immunodeficiency virus-positive (HIV+) patients receiving highly active antiretroviral therapy at our clinic.
Methods
We conducted a retrospective chart and patient database review.
Results
From 1997 to 2002, 455 patients in our clinic were screened for syphilis; 320 were screened from 2001 to 2002; 7.3% of patients (33/455) were diagnosed with syphilis. During the past year, syphilis was diagnosed in 7.5% of patients (24/320), of whom 13% (3/24) had ocular syphilis. We estimate the prevalence of ocular syphilis in HIV+ patients on highly active antiretroviral therapy screened for syphilis to be 9% (3/33). Presenting symptoms included blurred vision, loss of vision, central scotomas, and bilateral ocular involvement. The most common ocular manifestation of syphilis was posterior chamber uveitis; one patient also had a retinal detachment. All patients demonstrated reactive rapid plasma reagin and fluorescent treponemal antibody absorption test results, cerebrospinal fluid pleocytosis, and elevated total protein. Each patient received a 21-day course of intravenous penicillin G (24 million units daily) with improvement of visual symptoms.
Conclusion
Our data demonstrate an unexpectedly high incidence of ocular syphilis in our HIV+ patients receiving highly active antiretroviral therapy during the past year. A diagnosis of ocular syphilis should be considered in any HIV+ patient who presents with visual symptoms, irrespective of the patient’s CD4 count.
Keywords: Syphilis , Ocular , HIV , Uveitis
The widespread use of highly active antiretroviral therapy in persons infected with human immunodeficiency virus (HIV) has resulted in decreased morbidity and mortality.1 In addition, treatment with highly active antiretroviral therapy has resulted in immunologic reconstitution, which has altered the clinical presentation and manifestations of several opportunistic infections.2 It has been recognized that coinfection with HIV can accelerate the natural course of syphilis and alter its clinical presentation.3 With the incidence of the most common ocular opportunistic infection (cytomegalovirus retinitis) declining and the number of syphilis cases in HIV-infected men who have sex with men increasing, clinicians must be sensitized to a changed clinical picture of HIV-associated eye disease.4, 5
Syphilitic ocular involvement is a well-recognized complication of infection with Treponema pallidum and was reported to be one of the most common causes of ocular inflammation in the pre-antibiotic era.6 The manifestations of ocular syphilis include uveitis, retinitis, neuroretinitis, optic neuritis, perineuritis, retinal detachment, and papillitis.7 In HIV-infected persons not receiving antiretroviral therapy, ocular syphilis is more severe and frequently bilateral and involves the posterior segment.7 In the post-antibiotic era, ocular syphilis is rarely observed and had an estimated incidence of 0.6% in HIV+ patients in the era before highly active antiretroviral therapy.7 Schlaegel and Kao8 estimated that uveitis developed in 1% of HIV seronegative patients with syphilis. From October 2001 to October 2002, we observed a surprisingly high incidence of ocular syphilis in HIV+ patients receiving antiretroviral therapy at our clinic. This prompted us to perform a retrospective chart review to identify factors, such as immune reconstitution, that could potentially explain this observation in the era after highly active antiretroviral therapy.
Patients and methods
We performed a retrospective chart and database review of 453 HIV+ patients at the Georgetown University Hospital Infectious Diseases Clinic. Inclusion criteria included HIV+ patients screened for syphilis by rapid plasma reagin between January 1997 and December 2002. Patients were excluded from the study if they had been treated for syphilis before 1997 and did not have any evidence of reinfection with syphilis. Patients with a reactive rapid plasma reagin and fluorescent treponemal antibody absorption test result were considered to have a diagnosis of syphilis. Of the 453 patients who were screened for syphilis, 33 had a positive rapid plasma reagin and a confirmatory fluorescent treponemal antibody absorption test result. Staging of syphilis was based on signs and symptoms as recorded in the medical record, using standard diagnostic criteria.9 A diagnosis of ocular syphilis was determined by funduscopic examination performed by an experienced ophthalmologist. A positive funduscopic examination included one or more of the following findings: uveitis, retinitis, neuroretinitis, optic neuritis, perineuritis, papillitis, retinal detachment, and optic nerve gumma.
Data collected included demographic data, clinical manifestations of syphilis, ophthalmologic findings, syphilis serology, results of cerebrospinal fluid examination, syphilis treatment, CD4 count, HIV RNA level, and antiretroviral therapy. All mean CD4 cell counts were calculated using the most recent CD4 count before the diagnosis of syphilis.
The demographic data and baseline characteristics were statistically analyzed using analysis of variance and chi-square test. All calculations were performed in SPSS version 11.5 (SPSS Inc, Chicago, Ill).
Results
In the era before highly active antiretroviral therapy from 1997 to 2002, 453 patients in our clinic were screened for syphilis; 221 were screened between 2001 and 2002. Of those screened, 318 (70%) were men and 135 (30%) were women. The estimated incidence of syphilis in our entire study population was 7.3% (33/453). Of the patients diagnosed with syphilis, 9% (3/33) met diagnostic criteria for ocular involvement. From 1997 to 2001, we identified 16 cases of syphilis, none of which had ocular involvement. Surprisingly, during our last year of observation (2001-2002) syphilis was diagnosed in 7.7% of patients (17/221), of whom 41% (7/17) had neurosyphilis (including ocular syphilis) and 17% (3/17) had ocular syphilis. All of the patients with ocular syphilis were male and reported having sex with other men. There were no statistically significant differences between the patients with ocular syphilis and the study population when evaluated for race, HIV risk factor, acquired immune deficiency syndrome, CD4 cell count, or the use of highly active antiretroviral therapy. The only statistically significant factor was male gender (P = .008). The patients with ocular syphilis had a median age of 42 years and were receiving antiretroviral therapy with well-controlled plasma viremia (Table 1). In our comparison of HIV+ patients with and without syphilis and with and without ocular syphilis, there was no statistically significant difference in mean CD4 count (P = .53). During the observational period from 2001 to 2002, the mean CD4 cell count was 476 cells/mm3 for patients with syphilis without ocular involvement, and the mean CD4 cell count was 408 cells/mm3 (range 388-594 cells/mm3) for patients with ocular syphilis. In addition, the patients with ocular syphilis did not have any evidence of HIV-associated opportunistic infections or any history of an acquired immune deficiency syndrome-defining illness.
Table 1. Clinical Characteristics of Ocular Syphilis Cases
| Patient | Age | Sex | Risk factor | Mean CD4 count cells/mm | HIV RNA copies/mL | Duration of symptoms | Symptoms |
|---|---|---|---|---|---|---|---|
| #1 | 45 | Male | MSM | 465 | <400 | 4 wk | Loss of vision, retinal detachment, rash |
| #2 | 38 | Male | MSM | 594 | 782 | 2 wk | Central scotoma, blurred vision |
| #3 | 42 | Male | MSM | 388 | <400 | 1 wk | Blurred vision; b/l red, painful eyes |
The four patients with neurosyphilis without ocular involvement had dermatologic or cognitive symptoms without any ocular symptoms. The most common presenting symptom of those patients diagnosed with ocular involvement was blurred vision; one patient developed progression to loss of vision. Other symptoms of ocular syphilis included central scotomas, bilateral involvement, and conjunctival injection. The common ophthalmologic finding of ocular syphilis in our cohort was bilateral posterior chamber uveitis in all three patients. One patient had retinal detachment, and one patient had both anterior chamber uveitis and optic neuritis (Figure 1, Figure 2). The time from onset of visual symptoms to diagnosis ranged from 1 to 4 weeks. The serum rapid plasma reagin ranged from 1:64 to 1:256, and fluorescent treponemal antibody absorption test was reactive in all three patients shown in Table 2. All patients demonstrated a cerebrospinal fluid pleocytosis ranging from 17 to 44 cells/mm3. The total protein was elevated in all 3 patients, ranging from 60 to 78 mg/dL. Only one of the 3 patients had a positive cerebrospinal fluid venereal disease research laboratory slide test result. Each patient received a 21-day course of intravenous penicillin G (24 million units daily) and oral or topical steroids with improvement of visual symptoms. Although all 3 patients noted improvement of vision after treatment, only 1 patient had complete resolution of symptoms and signs.
Figure 1.
Right eye with optic nerve edema and retinitis.
Figure 2.
Left eye with retinal detachment and vitreous inflammation.
Table 2. Clinical Manifestations of Ocular Syphilis Cases
| Patient | Serum RPR | FTA-Abs | CSF WBC (μL) | CSF TP (mg/dL) | CSF VDRL | Diagnosis | Treatment | Outcome |
|---|---|---|---|---|---|---|---|---|
| #1 | 1:256 | R | 42 | 71 | NR | Bilateral posterior chamber uveitis, retinal detachment | IV PCN, prednisone taper | Loss of vision in left eye, improved vision in right eye |
| #2 | 1:256 | R | 44 | 78 | NR | Bilateral posterior chamber uveitis | IV PCN | Resolution of symptoms |
| #3 | 1:64 | R | 17 | 60 | R 1:2 | Bilateral anterior and posterior uveitis, optic neuritis | IV PCN, prednisolone gtts | Improvement of vision |
Discussion
Cytomegalovirus retinitis has been reported as the most common ocular complication in persons with advanced HIV disease.4 During our observation period from October 2001 to October 2002, we identified a cluster of cases of ocular syphilis. During that same time frame, we identified no patients with newly diagnosed cytomegalovirus retinitis who attended our clinic. Because this was a retrospective chart review, a systematic approach of ruling out other causes of uveitis was not performed. On the basis of our demographic data, clinical and funduscopic findings, rapid plasma reagin serologies, cerebrospinal fluid findings, and response to therapy, we believe that ocular syphilis was the most likely diagnosis.
Ocular syphilis is an uncommon but well-recognized complication of T. pallidum infection. Patients present with decreased visual acuity, eye pain, or visual changes. Because ocular syphilis is associated with a cerebrospinal fluid pleocytosis, intravenous penicillin G therapy is warranted. Although the Centers for Disease Control recommends penicillin G 24 million units daily for 14 days, treatment failures have been reported in HIV-coinfected patients.10, 11 Therefore, a prolonged course of 21 days was chosen. There is no specific ophthalmologic finding pathognomonic for ocular syphilis, but often there is evidence of posterior chamber uveitis. In our study population, we demonstrated an increased incidence of syphilis cases in our patients with HIV in the era after highly active antiretroviral therapy, which most likely reflects a mini-epidemic of syphilis in men who have sex with men in the Washington, DC metropolitan area. We also documented a surprisingly high prevalence (3/33; 9%) of ocular syphilis in persons coinfected with T. Pallidum and HIV. Our study is consistent with a recent article on neurosyphilis in which Marra and colleagues12 reported a 6.0% prevalence of ocular syphilis in a cohort of HIV+ patients with syphilis. Male gender was the only statistically significant risk factor in our study for the development of ocular syphilis; however, only 2 of 135 women (1.5%) had syphilis compared with the 31 of 318 men (9.5%) with syphilis. The gender differences observed in our cohort most likely reflects the trend that men who have sex with men have an increased incidence of syphilis as reported by the Centers for Disease Control.5 All other demographic and baseline characteristics, including CD4 count and the use of highly active antiretroviral therapy, had no effect on the risk of the development of ocular syphilis.
The overall incidence of ocular syphilis over our 5-year observation period was 3 of 453 patients (0.7%). This is similar to that reported by Shalaby and colleagues,7 who estimated a 0.6% incidence of ocular syphilis in HIV+ patients who presented to their ophthalmology clinic. Their study was performed during the era before highly active antiretroviral therapy, and notably, the majority of these patients had a CD4 count less than 200 cells/mm3, with a mean CD4 count of 159 cells/mm3.7 Furthermore, all of our patients had low-level HIV-1 plasma viremia and were on antiretroviral therapy.
Our data suggest that ocular syphilis seems to be a clinical entity that occurs in the immunocompetent, as well as the immunosuppressed population. Therefore, immunologic reconstitution does not seem to be protective against syphilitic ocular involvement. In the era after highly active antiretroviral therapy, the increase in the number of syphilis cases in men who have sex with men may explain our surprisingly high incidence.
Although our study is limited by a relatively small number of cases, we believe that our clinical observations warrant consideration by the HIV practitioner. In an era in which cytomegalovirus retinitis cases have dramatically decreased, syphiitic uveitis may become the more common HIV-associated ocular complication.1 Therefore, clinicians should be vigilant and suspect a diagnosis of syphilis when an HIV+ patient presents with visual symptoms, regardless of the CD4 count.
References
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- . The response of symptomatic neurosyphilis to high dose intravenous penicillin G in patients with human immunodeficiency virus infection . N Engl J Med . 1994;331:1469–1473
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PII: S0002-9343(05)01083-1
doi:10.1016/j.amjmed.2005.11.016
© 2006 Elsevier Inc. All rights reserved.
Volume 119, Issue 5 , Pages 448.e21-448.e25, May 2006
