Immune reconstitution inflammatory syndrome associated with secondary syphilis

Introduction

Immune reconstitution inflammatory syndrome (IRIS) is a condition associated with paradoxical worsening and/or new onset of an opportunistic infection (OI) in HIV patients following the initiation of anti-retroviral therapy (ART) or switching to more potent ART regimen.^1,2 Although IRIS associated with tuberculosis, cryptococcosis, pneumocystis pneumonia (PCP), kaposi sarcoma, hepatitis B and C, cytomegalovirus (CMV) infections and progressive multifocal leukoencephalopathy (PML) has been well reported, syphilis has very rarely been mentioned in this regard. Here, we report a case of IRIS associated with secondary syphilis in an HIV patient after initiation of antiretrovirals.

Case presentation

A 52-year-old Chinese bisexual man, diagnosed with AIDS six weeks ago, presented to the infectious disease (ID) clinic with the disseminated non-pruritic painless skin rash. He denied any fever, cough, shortness of breath, and joint pain or swelling. The patient reported having protected sexual intercourse with several male partners six months ago and denied any other sexual contact after that. Patient had no other past medical illnesses.

At the time of HIV/AIDS diagnosis six weeks prior to this presentation, the patient had no skin rash, genital ulcer, urethral discharge, or inguinal swelling and his CD4 cell count and viral load were 40 cells/mm³ and 280,000 copies/ml, respectively. Screening tests for OIs including rapid plasma reagin test (RPR), quantiferon, cryptococcal antigen, and toxoplasma tests were negative. Treatment with emtricitabine (FTC)/rilpivirine (RPV)/tenofovir disoproxil fumarate (TDF), trimethoprim/sulfamethoxazole (TMP-SMX), and azithromycin was started. FTC/RPV/TDF was chosen as an initial treatment due to the patient’s preference on the low co-payment for his medical insurance provider. After three days of initiation of above medications, he developed the skin rash and returned to the ID clinic.

On physical examination on clinic visit, vitals were within normal range. Systemic examination was remarkable only for a maculopapular, non-blanching, slightly scaling skin rash over the whole body including palms and soles (Figure 1(a)). There were no genital ulcer and inguinal swelling. Repeat RPR test at this time was also negative. Due to the concern of possible drug allergy, TMP-SMX was switched to atovaquone and FTC/RPV/TDF was changed to abacavir (ABC)/dolutegravir (DTG)/lamivudine (3TC). As the rash still did not subside, a punch biopsy of skin was taken and enzyme immunoassay (EIA) was sent. The skin biopsy demonstrated lichenoid granulomatous infiltrate with swollen endothelial capillary walls (Figure 2(a)). The picture was suggestive of secondary syphilis. Treponema pallidum immunostain (Biocare Medical, Walnut Creek, CA) confirmed the presence of multiple spirochetes in the dermo-epidermal junction (Figure 2(b)). EIA demonstrated positive result. The patient was then referred to the emergency department (ED) for further management. OPEN IN VIEWER

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Figure 2.

(a) Histopathology picture of skin biopsy on hematoxylin and eosin (H&E) stain showing lichenoid granulomatous infiltrate with swollen endothelial capillary walls suggestive of secondary syphilis lesion; ×200. (b) Immunohistochemical stain for Treponema pallidum confirmed the presence of multiple spirochetes in the dermo-epidermal junction; ×200.

On ED visit, the repeated blood work showed mild normocytic anemia (Hb 10.2 gm/dL) and positive RPR test with a titer of 1:256. Repeat absolute CD4 cell count and viral load were 257 cells/mm³ and 5000 copies/ml, respectively. Cerebrospinal fluid (CSF) was negative for cell counts and venereal disease research laboratory (VDRL) test. The remaining chemistries, complete blood count (CBC), and urine testing were normal.

The clinical features, histopathology of the skin, and RPR test results were consistent with the diagnosis of secondary syphilis. An abrupt rise in CD4 cell count from 40 to 257 cells/mm³ in two weeks of HIV therapy with 3 log reduction of viral load was consistent with the diagnosis of IRIS. The patient responded well to the treatment with three doses of 2.4 million units of benzathine penicillin intramuscular and non-steroid anti-inflammatory drugs. His skin rashes faded away, leaving post-inflammatory hyperpigmentation (Figure 1(b)) and RPR titer trended down to 1:64 on three-month follow-up.

Discussion

The incidence of IRIS is varied in different studies ranging from 7.6% to approximately 25% of HIV patients within first three months following the initiation of ART.^3,4 The likelihood of IRIS is higher in ART-naïve patients who have a rapid initial decline in HIV-1 RNA levels. ⁵ Very limited number of IRIS associated with secondary syphilis cases are reported in the literature.^6–8 Other reported cases of IRIS associated with syphilis are rare cases of ocular and neurosyphilis. ⁹ The low CD4 cell count even in the absence of other OIs/conditions defined AIDS in this patient.

The pathophysiology of HIV-specific T-Lymphocyte responses that underlie IRIS is still incompletely understood. Studies have demonstrated that the likelihood and severity of IRIS correlate with the extent of pre-treatment CD4 cell counts suppression and the degree of immune recovery following the initiation of ART. ¹⁰ A low number of CD4 cells may lead to the higher numbers of the pathogen in immunosuppressed patient and more active inflammatory response in predisposed individuals. Patients prone to IRIS development likely have innate immune system impairment that causes their T-cells to produce a larger amount of pro-inflammatory cytokines with exuberant immunological responses to antigenic stimuli. ¹⁰

Co-infection with HIV and syphilis can result in unusual manifestations of syphilis such as rapid progression to neurosyphilis, seronegativity, relapse despite adequate treatment, and failure of penicillin therapy. ¹¹ Malignant syphilis is a nodular variant of syphilis characterized by papulopustular skin lesions often associated with mucosal involvement; however, spirochetes are usually not found in the lesions. ¹² In our case, there was no mucosal involvement and the skin manifestation presented as generalized maculopapular pruritic rash, which was more aggressive than the normal presentation of a secondary syphilis. There are no universally agreed-upon diagnostic criteria for IRIS (unmasking or paradoxical) yet; however, the presence of AIDS with a low pretreatment CD4 cell count, a positive virologic and immunological response to ART, the presence of clinical manifestation consistent with an inflammatory condition and a temporal association between ART initiation and the onset of the clinical features are well considered as IRIS. ¹³ The possibility of drug-resistant infection, bacterial superinfection, or drug allergy should essentially be ruled out before considering an IRIS.

Our observation added one more report of IRIS associated with syphilis to the literature. IRIS associated with syphilis should be kept in mind when the unusual rash appears after initiation of ART. Skin biopsy and T. pallidum immunostain are helpful tools to confirm the presence of Treponema in the tissue and to establish the diagnosis. That may be particularly useful in IRIS patients with early rash development when serological reactions are still negative, as was seen in our patient. Reverse sequence algorithm helps to detect early and treated infection that may be missed with traditional screening. ¹⁴ Ideally, EIA should be performed in all RPR test negative cases with high clinical suspicion of syphilis. In our case, initially there was a high suspicion for drug allergy or other skin problems as the manifestation was more aggressive than a normal presentation of syphilis. Skin biopsy and EIA were carried out concurrently which helped to diagnose secondary syphilis. Since the patient did not reveal clear sexual history in the past, he was treated with three doses of penicillin for diagnosis of secondary syphilis with unknown onset of the disease.

The presence of an IRIS response does not predict overall HIV or OI treatment responses, and discontinuation of ART is not generally recommended, as the benefits of treating HIV infection outweigh the risk associated with IRIS.