Infectious Disease Alert Updates
August 1, 2022
By Carol A. Kemper, MD, FACP
Clinical Associate Professor of Medicine, Stanford University, Division of Infectious Diseases, Santa Clara Valley Medical Center
Remaining Questions in Syphilis Treatment
SOURCE: Tuddenham S, Ghanem KG. Management of adult syphilis: Key questions to inform the 2021 Centers for Disease Control and Prevention Sexually Transmitted Infection Treatment Guidelines. Clin Infect Dis 2022;74(Suppl 2):S127-S133.
Eight leading experts on sexually transmitted diseases (STDs) convened to discuss key questions in the management of syphilis in adults with and without human immunodeficiency virus (HIV) infection based on a systematic review of the literature. More than 3,000 articles were screened, and the discussion focused on 95 relevant publications and three main topics, as follows:
1. Therapeutic management of early syphilis, including treatment options when penicillin is not an option.
No difference in serologic response or clinical outcome has been demonstrated in persons receiving one vs. three doses of benzathine penicillin G (BP) for the treatment of early syphilis (as demonstrated by several smaller prospective clinical studies and one larger retrospective study), including patients with well-controlled HIV infection. One larger prospective study, referenced in the 2015 Centers for Disease Control and Prevention guidelines, which has since been published, showed no difference between one and three doses of BP, although a subanalysis favored three doses. In patients with HIV infection and higher RPR titers (≥ 1:32) treated for early syphilis, 98.4% achieved serologic response by eight months (≥ four-fold drop in titer). Only one HIV-positive person later had evidence of clinically asymptomatic neurosyphilis. Another anticipated Phase IV study examining the question of one vs. three doses of BP for early syphilis, begun in 2018, has yet to be published.
Data also support the effectiveness of doxycycline or other tetracyclines for the treatment of early syphilis or latent syphilis when BP is not available or is contraindicated. On the other hand, macrolides no longer are recommended, based on observed resistance and treatment failures in the United States. A 10-day course of intramuscular ceftriaxone also is an effective alternative, based on one randomized clinical trial, although the data are more limited in support of 3 grams of amoxicillin plus probenecid. These data provide a good explanation for the not infrequent occurrence of persons with low or serofast RPR titers who declaim a history of syphilis, who likely have received inadvertent effective treatment.
2. The management of patients with serologic non-response or failure to respond to appropriate therapy.
It is apparent that a good number of people treated for syphilis never serorevert (become non-reactive) and another good number appear to have responded inadequately. Generally, treatment failure has been defined as a lack of a ≥ four-fold drop in RPR titer by six to 12 months of treatment for early syphilis and by 12-24 months of treatment for latent syphilis. The questions become what is a “serologic non-responder,” do they require cerebrospinal fluid (CSF) investigation or additional treatment, and if so, when? Keep in mind that earlier syphilis stage and higher baseline titers often increase the likelihood of serological cure and seroreversion, whereas older age and female gender are associated with a greater likelihood of a serofast response. In other words, it is likely the longer a person has been infected, the less likely those (often lower) RPR titers will serorevert in response to therapy.
Differences in the definitions of “treatment failure,” “serological non-response,” and “serofast” complicate any assessment of the literature. The experts attempted to provide some standardization for these terms and recommended that future publications stick to this: Serofast is defined as a “failure to achieve a ≥ four-fold drop in nontreponemal antibody titer after stage-appropriate therapy.” (Presumably, the authors also intended to convey this was a stable, persistent titer over some period of time.)
In such patients, two studies showed no further benefit in the serologic response when serofast patients received additional doses of BP, although clinical outcomes were not examined, and there are no data on the long-term clinical outcome when serofast persons receive additional treatment. One study suggested there was no difference in the proportion of asymptomatic people with neurosyphilis who were serofast and those who achieved a four-fold decline in titers — although another study of patients with HIV infection who were serofast at 12 months found that 5/12 (42%) had asymptomatic neurosyphilis.
3. Treatment of neurosyphilis, including ocular syphilis.
In neurosyphilis, serologic and clinical response predicts normalization of cerebrospinal fluid parameters in both non-HIV-infected persons and persons with well controlled HIV infection who receive appropriate treatment. Therefore, follow-up lumbar punctures in these two groups is not necessary to confirm therapeutic response.
The most common manifestations of ocular syphilis are panuveitis and posterior uveitis. Previously, it has been recommended that all such patients undergo CSF analysis, perhaps in part to confirm the diagnosis. The experts agreed that clinicians reasonably can assume that people with ocular and otic syphilis are likely to have neurosyphilis on CSF analysis and can treat as such without first obtaining a lumbar puncture. At least 10% to 60% of patients with ocular syphilis in one study had CSF abnormalities, and 50% had a positive VDRL. Unfortunately, despite appropriate intravenous penicillin therapy, visual outcomes will depend on the duration and severity of symptoms at presentation. There are no good data on alternative treatments for ocular syphilis, and no data on the use of steroids.
Discussion regarding antibacterial post-exposure prophylaxis for syphilis was deferred to the recently published clinical STD prevention guideline. And discussion regarding the utility of the reverse paradigm testing algorithm for diagnosis of syphilis will be published in the soon-to-be released Laboratory guidelines.
The only additional comment made by the convention was an observation that some clinical laboratories are reporting RPR titers as simply “> 1:32” without providing an endpoint. To provide appropriate treatment recommendations, a nontreponemal antibody endpoint is necessary, and laboratories should provide one.
The Great Imitator Imitates Again
SOURCE: Chang H, Tang TY, Kuo CF. Syphilitic pancolitis: A case report with literature review. Int J STD AIDS 2022;33:618-621.
With the nationwide increase in syphilis cases, we are seeing some interesting and unusual manifestations of syphilis — including a case of syphilitic gumma or osteomyelitis in the wrist and several cases of neurosyphilis and/or ocular syphilis with posterior uveitis. A recent case of severe secondary syphilis masqueraded as “long COVID” with three months with fatigue, lymphadenopathy, sore throat, headache, and progressive hair loss. Interestingly, an initial RPR was negative (possibly from prozone effect). The subsequent development of rash and a skin biopsy with immunohistochemical staining confirmed the diagnosis, and a repeat RPR was 1:256.
The authors described an unusual case of pancolitis due to secondary syphilis in a 64-year-old male with recent unprotected receptive anal intercourse two months earlier. He presented with one month of diarrhea and tenesmus, and weight loss. Stool studies were unremarkable, and an initial human immunodeficiency virus (HIV) test was negative. Colonoscopy revealed extensive pancolitis with mucosal ulcerations with mucous coating from the cecum to the rectum; the terminal ileum was spared. Histopathology of cecal and rectal biopsies showed chronic active inflammation with increased lymphoplasmocytic infiltrate with cryptitis and crypt abscesses. Immunohistochemical staining was positive for Treponema pallidum spirochetes. An RPR titer was 1:4. He converted his HIV testing on subsequent studies.
This case report serves as a reminder that even though pancolitis from secondary syphilis is rare, syphilitic proctitis is a not-uncommon manifestation of syphilis — and that syphilis can present as almost anything — even long COVID! Syphilitic proctitis may present similar to other sexually transmitted diseases (STDs) or enteritis, with painful defecation, rectal bleeding, and diarrhea — but at least you might be more likely to screen for STDs. A syphilitic pancolitis could fool you, and the pathology could easily be mistaken for inflammatory bowel disease —unless immunohistochemical staining or T. pallidum PCR is performed. A sexual history and RPR screening are important parts of the workup of “enterocolitis” or proctocolitis.
Remaining Questions in Syphilis Treatment; The Great Imitator Imitates Again
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