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HIV associated Fever of Unknown Origin

posted Apr 28, 2014, 5:53 AM by Ewa Rakowski

Monte Minute by Daniele Massera, PGY-3

 1.       The case

During a past CRS, we tried to solve the case of a 38-year-old man with HIV and a CD4 count of over 500 who presented with 3 weeks of fevers as high as 102°F, myalgias and generalized pruritus. He had recent unprotected receptive oral intercourse with a man, and had been treated with ciprofloxacin and azithromycin early in the course of his illness. His physical exam on presentation was notable for a temperature of 102.4°F, a heart rate of 111, and anal condylomata on genital exam. Initial workup included a normal CBC, electrolytes and renal function, a mild cholestatic picture on liver tests, and a sedimentation rate of 32 mm/hr. Subsequently, he developed a generalized pruritic maculopapular rash (which spared his palms and soles…). Despite an initially negative serum RPR test, he was ultimately diagnosed with secondary syphilis on (repeated) skin biopsy, which revealed spirochetes. His second serum RPR test was reactive at 1:64 dilutions. We were all pretty surprised by the conclusion of this FUO case.

I took this opportunity to review this confusing disease and to try to answer the following questions: How come our patient’s initial serum RPR test was negative? What does this mean for our clinical practice? And what is the prozone phenomenon?

        2.  Review of clinical manifestations of syphilis

I think we can all agree that diagnosing syphilis is not always straightforward. It occurs in four different stages, and is often difficult to recognize, especially in more advanced stages. The manifestation of primary syphilis is a painless indurated ulcer (= chancre) that occurs within three weeks at the site of inoculation with Treponema pallidum. During this stage, the diagnosis is made by dark-field microscopy or direct fluorescent antibody test of lesion exudates. Serology can be ne

Secondary syphilis or “the great imitator”: hematogenous dissemination of the organism happens within 6 weeks to 6 months of initial untreated infection and can manifest in a myriad of ways, including the characteristic generalized scaly maculopapular rash involving palms and soles, lymphadenopathy, hepatosplenomegaly, meningitis, uveitis, optic neuritis, glomerulonephritis, condylomata lata, alopecia, tonsillitis, aphthous ulcers, cranial nerve palsies, periostitis … Secondary syphilis also resolves spontaneously without treatment (which led our ancestors to believe that their obscure treatments with mercury, arsenic and different herbs were effective).

gative for 4 weeks and up to 90 days after formation of the ulcer. The ulcer is usually associated with enlargement of local lymph nodes and disappears spontaneously, even without treatment.

If left untreated again, the next stage is latent syphilis. It is characterized by seropositivity without clinical manifestations. The ultimate stage occurs in about 30% of infected individuals and is called tertiary syphilis. It can appear several decades after initial infection and presents as neurosyphilis, cardiovascular syphilis and/or visceral syphilis (= gummas). These manifestations include progressive paralysis, tabes dorsalis (syphilitic myelopathy leading to ataxia by loss of sensation and proprioception), dementia, seizures, Argyll Robertson pupils (bilateral pupillary constriction on accommodation but not on exposure to light), and vasculitis (infiltration of vasa vasorum leading to aneurysms of aorta and cerebral arteries, and stenosis of coronary arteries). Gummas are soft tissue tumors that can be found anywhere (skin, bone, liver, and other organs). They are benign, unless they obstruct hollow viscera like bile ducts or blood vessels. And when they grow in the brain, they cause trouble…

        3.       Treatment

Simplified treatment algorithm:


Benzathine penicillin G 2.4 million units IM x 1

Tertiary without neurological involvement

Benzathine penicillin G 2.4 million units IM weekly x 3

Tertiary with neurological involvement (=neurosyphilis)

IV penicillin G 3-4 million units every 4 hours x 10-14 days


        4.       Recent changes to the diagnostic algorithm

As we all know, we use non-treponemal and treponemal tests to diagnose syphilis. Non-treponemal tests include the venereal disease research laboratory (VDRL) test and the rapid plasma reaginine (RPR) test. They were thought to be decently sensitive until recently (though they admittedly are not so specific, leading to a lot of false positives necessitating a confirmatory test). There are several treponemal tests available, including the treponema pallidum particle-agglutination (TP-PA) test, the fluorescent treponemal antibody-absorbed (FTA-ABS) test, and the enzyme immunoassay (EIA) test. In medical school we learned that we first do a RPR (or VDRL), and when positive, we confirm the diagnosis with a treponemal test. However, this testing sequence has recently been challenged. The CDC conducted a study in New York City in which the test sequence was reversed. Samples were first tested with a treponema-specific EIA, followed by RPR and a second confirmatory treponemal test (TPPA or FTA-ABS). Surprisingly, 3% of samples that tested positive by EIA turned out to be RPR negative, leading to the assumption that many patients who tested negative by common clinical practice really did have syphilis. This could be one of the reasons why the incidence of syphilis has increased tremendously, especially among the HIV-infected population. Our own laboratory at Montefiore has adopted this new strategy of syphilis testing in 2012 (see attached figure).

        5.       The prozone effect and back to our patient

We can try to explain why our patient’s initial serum RPR was nonreactive in two ways: we can either invoke the prozone phenomenon, or postulate that the initial RPR was done at a too early stage of the disease. The prozone phenomenon occurs in 2% of patients (according to the attached Lancet ID review article from 2004), and is a scenario in which the RPR is nonreactive due to of a mismatch between very high antibody levels in the affected serum for the amount of antigen in the test reagent. The test is so to speak “overwhelmed”, and is read as falsely negative.

This is one possible explanation for our patient’s delayed diagnosis (combined with a false negative skin biopsy and a lot of bad luck); however, the diagnosis of syphilis gets even more complicated in the setting of HIV co-infection. As outlined in the attached review articles, false negative serologies are more common than in the non-HIV-infected population (both in primary and in secondary stages), and HIV-infected patients can present with both stages simultaneously in up to 25% of cases and have a more “malignant” course of the disease. There is some disagreement in the literature, but it seems that seroreactivity develops after 1-3 weeks or 4 weeks to 90 days after initial infection, depending on the source you believe. If we allow the patient to have progressed very quickly from primary to secondary syphilis, his initial RPR could have been still negative at the time of first presentation.

Also, it is important to note that both syphilis and HIV enhance transmission of one another. Recent epidemiological data show that the incidence of syphilis is on the rise – perhaps a good reason for us to be familiar with the multitude of possible presentations of this fascinating disease.

Ewa Rakowski,
Apr 28, 2014, 5:57 AM
Ewa Rakowski,
Apr 28, 2014, 5:55 AM
Ewa Rakowski,
Apr 28, 2014, 5:55 AM
Ewa Rakowski,
Apr 28, 2014, 5:56 AM