Share this article on:

Seronegative Syphilis in an AIDS Patient: Case Report and Review of the Literature

Rouphael, Nadine G. MD*; Moanna, Abeer MD*†; Rimland, David MD*†

Infectious Diseases in Clinical Practice: September 2008 - Volume 16 - Issue 5 - p 330-331
doi: 10.1097/IPC.0b013e3181637a23
Case Reports

Syphilis is increasing in the United States particularly among men having sex with men due to high-risk sexual practices. In AIDS patients, diagnostic dilemma can occur with false-negative serologic tests or delay in positive reactions. Accurate and timely diagnosis of syphilis is crucial in limiting its transmission along with other sexually transmitted diseases and preventing its long-term sequelae. We report a case of secondary syphilis in a patient with AIDS with initial negative serologic testing. A skin biopsy specimen revealed spirochetes and prompted treatment with resolution of symptoms.

*Division of Infectious Diseases, School of Medicine, Emory University, and †Atlanta Veterans Affairs Medical Center, Atlanta, GA.

Address correspondence and reprint requests to Nadine G. Rouphael, MD, Division of Infectious Diseases, Emory University, 69 Jesse Hill Jr Dr SE, Atlanta, GA 30303. E-mail:

Back to Top | Article Outline


A 30-year-old African American man with acquired immunodeficiency syndrome (AIDS) presented with a 3- to 4-week history of skin rash, myalgias, arthralgias, night sweats, and fever. The rash was pruritic, initially noted on the extremities and then involving the palms and soles and extending to the trunk. The patient was diagnosed with HIV infection in 1996; his most recent CD4 count and HIV viral load were 32 cells/μL and 208,608 copies/mL, respectively. He was off his antiretrovirals for the past 2 weeks. He was taking dapsone, azithromycin, and valacyclovir for Pneumocystis jiroveci pneumonia, Mycobacterium avium complex, and herpes simplex virus prophylaxis, respectively. The patient was also receiving metronidazole for giardiasis. His medical history is significant for rectal Kaposi sarcoma, gonococcal proctitis, herpes simplex virus and human papillomavirus anal infection, and parvovirus B19 infection. He has an allergy to sulfa and practiced unprotected homosexual intercourse. He denied any recent travel or tick exposure.

On examination, he appeared in mild discomfort with a temperature of 104°F. Skin examination revealed scattered mildly erythematous minimally infiltrated papules (3-6 mm) (Fig. 1) sparing the face, scalp, and genital area and involving the palms and soles (Fig. 2). There were no vesicles, pustules, or scales.





No peripheral eosinophilia was noted on his blood smear. Blood cultures were negative for bacteria, mycobacteria, and fungi. Initial rapid plasma reagin (RPR) was nonreactive in an undiluted specimen and at 1:1024 dilution ruling out a prozone effect. Liver function tests were mildly elevated, and a hepatitis B viral DNA was 2 million copies/mL. A parvovirus polymerase chain reaction, serum cryptococcal antigen, and toxoplasma immunoglobulin G were all negative.

A punch biopsy was performed and revealed interface dermatitis associated with lymphoplasmacytic infiltrates, and spirochetes were noted on Steiner stain (Fig. 3). One month later, repeated RPR was positive with a 1:32 dilution and the fluorescent treponemal antibody absorbed (FTA-ABS) test was also positive.



Patient was treated with intramuscular injection of 2.4 million units of benzathine penicillin resulting in resolution of his symptoms.

Back to Top | Article Outline


The patient had secondary syphilis with initial negative serologic testing. The high clinical suspicion for secondary syphilis in our patient despite an initial negative RPR and the absence of prozone effect prompted a skin biopsy to confirm the diagnosis.

Early syphilis is on the rise in men having sex with men due to an increase in unsafe practices likely favoring the transmission of other sexually transmitted diseases.1

Early diagnosis of syphilis is therefore important in a patient presenting with rash but can be difficult due to a broad range of differential diagnosis making syphilis the "great imitator." Treponema pallidum is a fastidious organism that does not grow in routine laboratory cultures. Therefore, the diagnosis usually relies on serologic testing. The diagnosis is made more difficult with initial false-negative serologic tests or delay in positive reactions particularly in HIV patients. Although nontreponemal tests are believed to be virtually 100% sensitive in secondary syphilis, this may not be applicable in a HIV setting particularly in the advanced stage of the disease.2 Due to a dysregulation of the humoral immune system in AIDS patients, response to T. pallidum antigens can be decreased resulting in a negative result or a delayed positive result.

To our knowledge, 9 other cases of seronegative syphilis in HIV patients have been described in the literature.3-9 The median age was 33 (range, 26-45) years. Seven were male and 2 were female. Seronegative secondary syphilis occurred mostly in the setting of AIDS, with CD4 counts ranging from 69 to 340 cells/μL. Three patients had a previous history of syphilis.6,8,9 A chancre was present in addition to the generalized skin rash in only 1 of the patients.3 Initial negative serology resulted in delayed diagnosis in all patients. Repeated serology was available in 6 patients3-7 and remained negative in 2 of them.6 Diagnosis was made by skin biopsy in all patients except one where the patient had multiple episodes of syphilis in the past and was treated empirically for secondary syphilis despite a negative RPR.6

Treatment of secondary syphilis prevents late complications of the disease as well as sexually transmitted diseases transmission in a high-risk group such as HIV patients. The treatment of secondary syphilis in HIV-infected patients does not differ when compared to non-HIVpatients. When follow-up was available on the 9 patients reported in the literature, all patients had resolution of their symptoms. Two patients experienced a Jarisch-Herxheimer reaction.6,7 It has also been reported that an initial negative RPR will become positive after penicillin therapy likely due to destruction of a large number of treponemes enhancing the production of reaginic antibodies.10

Physicians need to be aware of a negative or a delayed positive serology in early syphilis especially in the setting of an immunocompromised state. A high index of suspicion is required and a skin biopsy is often needed to establish the diagnosis.

Back to Top | Article Outline


The authors thank Dr Jeannette Guarner from the Department of Pathology and Dr Steven T. Prior from the Department of Medicine for their help.

Back to Top | Article Outline


1. Heffelfinger JD, Swint EB, Berman SM, et al. Trends in primary and secondary syphilis among men who have sex with men in the United States. Am J Public Health. 2007;97(6):1076-1083.
2. Hutchinson CM, Hook EW 3rd, Shepherd M, et al. Altered clinical presentation of early syphilis in patients with human immunodeficiency virus infection. Ann Intern Med. 1994;121(2):94-100.
3. Blum L, Bachmeyer C, Caumes E. Seronegative secondary syphilis in an HIV-infected patient. Clin Exp Dermatol. 2005;30(2):158-159.
4. Fowler VG Jr, Maxwell GL, Myers SA, et al. Failure of benzathine penicillin in a case of seronegative secondary syphilis in a patient with acquired immunodeficiency syndrome: case report and review of the literature. Arch Dermatol. 2001;137(10):1374-1376.
5. Hicks CB, Benson PM, Lupton GP, et al. Seronegative secondary syphilis in a patient infected with the human immunodeficiency virus (HIV) with Kaposi sarcoma. A diagnostic dilemma. Ann Intern Med. 1987;107(4):492-495.
6. Gregory N, Sanchez M, Buchness MR. The spectrum of syphilis in patients with human immunodeficiency virus infection. J Am Acad Dermatol. 1990;22(6 Pt 1):1061-1067.
7. Strobel M, Beauclair P, Lacave J. Seronegative syphilis in AIDS. Presse Med. 1989;18(29):1440.
8. Kingston AA, Vujevich J, Shapiro M, et al. Seronegative secondary syphilis in 2 patients coinfected with human immunodeficiency virus. Arch Dermatol. 2005;141(4):431-433.
9. Tikjob G, Russel M, Petersen CS, et al. Seronegative secondary syphilis in a patient with AIDS: identification of Treponema pallidum in biopsy specimen. J Am Acad Dermatol. 1991;24(3):506-508.
10. Dutta RK, Malik AK. An unusual case of seronegative secondary syphilis (case report). Indian J Dermatol. 1983;28(2):81-84.
© 2008 Lippincott Williams & Wilkins, Inc.