Lymphogranuloma venereum as a cause of persistent perianal ulcers

Abstract

Lymphogranuloma venereum (LGV) has been increasingly reported, and many clinicians are familiar with it as a cause of proctocolitis or inguinal adenopathy. On the other hand, LGV is less commonly considered as a cause of isolated genital ulcerative disease in comparison to other etiologies such as syphilis or herpes simplex. We report a case of persistent perianal ulcerations due to LGV in an HIV-positive patient, confirmed by nucleic acid amplification testing.

Background

Lymphogranuloma venereum (LGV) is a sexually transmitted infection (STI) caused by the L1–L3 serovars of Chlamydia trachomatis. LGV has received greater attention in Europe and North America since the early 2000’s, following recognition of an outbreak of proctitis among men who have sex with men (MSM) in the Netherlands.^1–3 Clusters have occurred among HIV-positive patients, and a high frequency of STI coinfections has been noted.⁴ In a recent study based at San Francisco City Clinic, nearly half of MSM diagnosed with rectal chlamydia were determined to have LGV.⁵ Given LGV’s prevalence, it is important for clinicians to be familiar with LGV’s common and less common clinical manifestations.

Case presentation

A transgender woman in her 50s with HIV, methamphetamine use disorder, psychotic disorder and history of anal cancer presented to our urgent care clinic with 1 week of perirectal pain and bleeding. She denied any sexual activity in the last year, but had a history of receptive anal intercourse. Her HIV was under good control with dolutegravir, emtricitabine and tenofovir alafenamide; her most recent CD4 lymphocyte count was 384 cells/µL and her HIV RNA viral load was less than 40 copies/mL. In regard to her oncological history, she had been diagnosed with stage 1 anal cancer 4 years previously. She had previously received radiation therapy in addition to chemotherapy with 5-flucytosine and mitomycin, but she had not received either chemotherapy or radiation in the last 4 years. She was felt to be doing well at time of her last oncology visit 8 months prior to her urgent care appointment, without evidence of any lesions on high-resolution anoscopy.

On physical examination, she was afebrile and in no apparent distress. She was found to have multiple perianal ulcers without active bleeding or discharge (figure 1). Anoscopy was deferred. Due to clinical suspicion for genital herpes simplex, she was empirically started on valacyclovir 1 g twice daily for a 7-day course. Swabs collected from her pharynx and rectum were both positive for Chlamydia trachomatis via nucleic acid amplification testing (NAAT, GEN-PROBE APTIMA), but were negative for Neisseria gonorrhoeae via NAAT. A swab of a perianal ulcer was negative for herpes simplex virus (HSV) by PCR, and her rapid plasma reagin (RPR) test was non-reactive.

Figure 1.

Multiple perianal ulcers at time of patient’s initial presentation to clinic.

Unfortunately, she could not be contacted until approximately 12 days subsequently, at which time she returned to clinic. On re-evaluation, she reported ongoing perirectal discomfort and noted that valacyclovir treatment had not seemed to help. Her physical examination was notable for persistent perianal ulcerations (figure 2), which were less erythematous than at her initial presentation but were otherwise similar in appearance. She did not have any palpable inguinal lymph nodes or other rash.

Figure 2.

Perianal ulcers at time of patient’s follow-up presentation to clinic, 12 days from initial presentation.

Investigations

PCR of a perianal ulcer was negative for HSV on repeat testing, and RPR was again negative.

Differential diagnosis

At the time of her return to clinic, multiple possibilities were considered as the cause for her persistent perianal ulceration. LGV was compelling given her known positive Chlamydia NAAT. Herpes simplex seemed less likely given her reported adherence to valacyclovir. In the absence of a history of HSV outbreaks and repeated acyclovir exposure, acyclovir-resistant HSV was unlikely. A false-negative HSV test was less likely given use of PCR (rather than less sensitive direct fluorescent antibody testing) and the ease of sampling her ulcers. Syphilis remained a consideration given its local prevalence. A false-negative RPR resulting from a prozone phenomenon was considered but excluded by the lab via sample dilution.⁶ Other sexually transmitted infections associated with genital ulcer disease such as chancroid or donovanosis were less compelling given the lower frequency of these etiologies. Malignancy, such as recurrence of anal cancer, was also less likely given the acuity of her presentation. She did not have any other known dermatological conditions or inflammatory/autoimmune disorders such as Crohn’s disease or Behçet’s disease.

Her perianal ulcer was found to be positive for LGV on real-time PCR run at the San Francisco Public Health Laboratory.

Treatment

She was treated with doxycycline 100 mg two times per day for 21 days.

Outcome and follow-up

At her follow-up visit 6 weeks later, she reported that her perianal discomfort was significantly improved. She had one residual perianal ulcer with surrounding erythema and induration. She declined to take additional doxycycline and was referred for wound care.

Discussion

In contrast to non-LGV serovars which typically cause infections limited to mucosal surfaces, LGV serovars can be tissue-invasive and associated with more severe manifestations. However, both symptomatic and asymptomatic LGV infections have been described.⁷ Following infection, patients may develop a self-limited primary lesion at the inoculation site which may be papular or ulcerative.^{8 9} Persons may then go on to develop an ‘inguinal syndrome’ characterised by tender, enlarged inguinal lymph nodes that may ultimately form abscesses and fistulae. Alternatively, patients may present with proctocolitis, experiencing symptoms such as rectal pain, bleeding, tenesmus or constipation.¹⁰ Systemic symptoms such as fever and malaise may be present. Without treatment, LGV may be complicated by genital or rectal strictures or by elephantiasis, though these complications are now uncommon.

In addition to these more frequently described presentations of LGV, other manifestations reported include persistent penile ulceration,¹¹ tongue ulceration,¹² pharyngitis⁴ and a neck mass.¹³ Persistent perianal ulcers due to LGV with or without concomitant inguinal lymphadenopathy have also been previously described.^{2 14 15} As in the case reported here, these patients were initially suspected of having other etiologies for their perianal ulcers such as HSV. Unfortunately, it is difficult to know the acuity of the patient’s LGV infection in this case due to the unreliability of her sexual history, though we speculate she may have had a more long-standing infection.

The diagnosis of LGV remains challenging in many settings due to limited access to specific diagnostics, and the diagnosis may often be clinical.¹ Serological testing has not been standardised, and few labs offer nucleic acid amplification testing specific for LGV. The NAAT used by the San Francisco Department of Public Health for the case patient reported here targets the pmp gene, encoding polymorphic protein H, and has been shown to be a highly-specific test for LGV.¹⁶

LGV is typically treated with 21 days of doxycycline, though it remains uncertain whether shorter course treatment might be sufficient, particularly in milder or asymptomatic cases.^{7 17} Alternatives to doxycycline such as azithromycin or fluoroquinolones remain poorly-studied in LGV.¹

In conclusion, we report a case of LGV presenting as persistent, isolated perianal ulceration, highlighting the importance of considering LGV in the differential diagnosis of genital ulcerative disease, particularly when other common etiologies such as syphilis and herpes simplex have been excluded. A positive NAAT for Chlamydia is an initial diagnostic clue and is more widely available than LGV-specific testing at present. Ongoing clinical follow-up, particularly for persons with immunocompromising conditions such as HIV, is important in these cases to ensure ulcer resolution. Biopsy should be pursued to exclude malignancy or other concomitant infection when the diagnosis is uncertain, and the ulceration persists.

Learning points.

• Lymphogranuloma venereum (LGV) is being increasingly recognised, and in addition to its association with proctitis and inguinal adenopathy, it can also cause genital ulcerative disease. LGV screening should be considered in these cases, particularly among persons at higher risk such as men who have sex with men.

• Access to LGV-specific testing remains limited and the diagnosis often remains clinical. Clinicians should have a low threshold to treat a patient with a positive Chlamydia test for LGV (ie, with 21 days rather than 7 days of doxycycline) in the presence of a compatible clinical syndrome.

• Sexually transmitted infection screening for persons with anorectal complaints should be strongly considered, even in the absence of reported recent sexual contacts.