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Abstract
Current lymphogranuloma venereum (LGV) guidelines mainly focus on anorectal infections. Inguinal LGV infections have been rare in the current epidemic among men who have sex with men (MSM), but might require a different approach not yet recommended in current guidelines for the treatment and diagnosis of LGV. We describe 4 inguinal LGV cases. Three MSM developed inguinal LGV infection several weeks after a previous consultation, of which two had received azithromycin after being notified for LGV. Three failed the recommended 21 days doxycycline treatment. These inguinal LGV cases highlight 3 pitfalls in the current standard management of LGV: 1) Urethral chlamydia infections in MSM can be caused by LGV biovars that in contrast to non-LGV biovars require prolonged antibiotic therapy. 2) The recommended one gram azithromycin contact treatment seems insufficient to prevent established infections. 3) Inguinal LGV may require prolonged courses of doxycycline, exceeding the currently advised 21 days regimen.
- Men who have sex with men
- Lymphogranuloma venereum
- Sexually transmitted infection
- Human immunodeficiency virus
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- Men who have sex with men
- Lymphogranuloma venereum
- Sexually transmitted infection
- Human immunodeficiency virus
Introduction
Lymphogranuloma venerum (LGV) in men who have sex with men (MSM) became apparent in 2003, first in the Netherlands and soon after in other European countries, North America and Australia.1 Most men were HIV seropositive2 and engaged in high-risk behaviour.3 LGV is an invasive ulcerative sexually transmitted disease caused by biovar L-type Chlamydia trachomatis (CT).
A short-lived ulcer on the site of entry characterises the first stage of an LGV infection and if inoculation occurs at an internal location such as the anal canal or the urethra, is easily missed.4 After transmission, the pathogen leaves the mucosal lining at the apical site, invades the underlying connective tissue layers and disseminates via the lymphatics towards loco-regional lymph nodes. A typical sign of secondary stage LGV is the occurrence of ‘buboes’, fluctuating painful swellings of infected lymph nodes that can suppurate spontaneously and cause chronic suppurating fistulae. The inguinal lymph nodes become involved in cases where the external genitalia are the site of inoculation, in what is often referred to as ‘the inguinal syndrome’.
In the current epidemic among MSM, the majority of LGV infections are anorectal and only a few urethral infections have been reported.5 Most current guidelines recommend partner treatment of LGV index patients with azithromycin 1000 mg once or doxycycline 100 mg twice a day for 7 days, a regimen considered sufficient to eliminate biovar non-L CT infections.6 ,7 The new BASHH guideline suggests extending the duration of partner treatment with doxycycline to 14 days.8 We showed previously that anorectal LGV can persist under doxycycline treatment for 16 days, which highlights the importance of prolonged treatment for at least 21 days.9
Here we describe a case series of four MSM who developed inguinal LGV to highlight: (1) pitfalls in the diagnosis of LGV; (2) the importance of correct partner treatment; and (3) the protracted course of some infections.
Methods
All data were obtained for routine purposes for which ethics clearance was not necessary. All patients consented to publication. All MSM who reported receptive anal contact in the previous 6 months were screened for anorectal chlamydia with the Aptima single CT test (Gen-Probe, California, USA). If C trachomatis was detected, the sample was further tested using an in-house developed genovar L specific assay to detect LGV.10 Gram stained smears of urethral and anorectal samples were used to exclude non-specific urethritis, non-specific proctitis (defined as the presence of >10 polymorphonuclear leucocytes (PMNL) per light microscopic high power field) and gonorrhoea infections (presence of Gram negative diplococci in PMNL). Presumptive therapy for non-specific proctitis and urethritis was doxycycline 100 mg twice daily for 7 days and azithromycin 1000 mg once, respectively. Syphilis, urogenital chlamydia and gonorrhoea, and undiagnosed HIV infections were excluded. Known HIV seropositive patients were screened for hepatitis C. Patients notified by a partner diagnosed with LGV were screened and treated presumptively with 1000 mg azithromycin if the index patient could be identified in the electronic patient file or if the notified partner could show a notification slip. More details on the notification system have been provided elsewhere.11
Results
All four patients reported high-risk behaviour such as unprotected receptive anal and oral intercourse with multiple partners, and all had been diagnosed with multiple bacterial sexually transmitted infections (STI) in the past.
Patient A was a 45-year-old HIV positive, hepatitis C negative MSM who was receiving antiretroviral therapy (ART). He visited the outpatient clinic upon partner notification for LGV. He reported no complaints or signs, and the Gram stained smears were negative. He received the LGV contact treatment of 1000 mg azithromycin once. A week later all screening results came back negative. Seven weeks after the consultation, he visited his general practitioner (GP) with a painful fluctuating swelling in the groin region (figure 1). Aspirate of this inguinal bubo proved LGV positive. The GP prescribed doxycycline 100 mg twice a day for 21 days, after which the inguinal bubo disappeared and no further abnormalities were observed.
Timeline of the cases of four men who have sex with men (MSM) who developed bubonic lymphogranuloma venereum (LGV). Tx, treatment.
Patient B was a 26-year-old HIV and hepatitis C positive MSM; ART had not yet been commenced. Like patient A, an LGV positive partner had notified him. At his visit he had no signs or symptoms and the Gram stained smears were negative. He was treated with 1000 mg azithromycin once, and 1 week later all his screening results came back negative. He returned to the clinic for a routine screening (no complaints were reported) 16 weeks after this episode. Urogenital chlamydia was diagnosed and treated with 1000 mg of azithromycin once. One week later (17 weeks after his first presentation), he returned to the clinic with a painful swollen penis, and swollen bilateral inguinal lymph nodes. Therapy with 100 mg doxycycline twice a day was started. One week later, patient B returned with five inguinal buboes, of which three had erupted spontaneously and two had increased in size. Urine samples collected then and the week previously, plus bubo pus, all proved LGV positive. The buboes subsided after 3 weeks of continuous therapy. Nonetheless, doxycycline was continued for another 2 weeks.
Patient C was a 39-year-old HIV positive, hepatitis C negative MSM who was receiving ART. A partner diagnosed with LGV had notified him, but this could not be confirmed, so he was not presumptively treated with azithromycin. He complained of painful urination which had lasted several weeks, had no STI related signs upon physical examination, and the Gram stain smears were negative. A week later all STI screening results proved negative. Six weeks after his STI clinic consultation, he visited his GP with an inguinal bubo. An aspirate proved LGV positive and CT RNA positive, suggesting live replicating infections.9 Antibiotic therapy with doxycycline 100 mg twice a day was started. Despite the doxycycline, the inguinal bubo did not subside and the antibiotic regimen was extended. Five weeks after the first LGV positive aspirate, a second aspirate still proved LGV positive. The doxycycline regimen was prolonged for 12 weeks by which time the inguinal bubo had finally disappeared.
Patient D was a 33-year-old HIV and hepatitis C negative MSM. He visited the STI outpatient clinic for a solitary painful fluctuating inguinal lymph node lasting 3 weeks. All Gram stained smears were negative. Doxycycline 100 mg twice a day was started under the suspicion of inguinal LGV. A week later the aspirate proved LGV DNA positive. After 3 weeks the bubo had not decreased in size and a second aspirate was again LGV positive. Doxycycline twice daily was continued for 6 weeks by which time the bubo had subsided.
Discussion
Here we describe two men (A and B) who received a single dose of azithromycin after exposure to CT biovar L. Patient C was also exposed to biovar L, but did not receive presumptive antibiotic treatment. In all three patients, urethral and anorectal LGV was ruled out by routine screening. Subsequently, in all three patients, inguinal LGV was diagnosed respectively 7, 16 and 6 weeks after the initial presentation.
Patients C and D did not respond to the advised course for inguinal LGV of doxycycline 100 mg twice a day for 21 days. Both had persisting LGV DNA positive bubo aspirates after receiving 5 and 3 weeks of doxycycline, respectively. Subsequently, doxycycline courses were prolonged for another 12 and 6 weeks, respectively, by which time the buboes had subsided.
Pitfalls in the diagnosis of LGV
Patients A, B and C were all partners of LGV patients, but none had a urethral CT infection when they visited the clinic after being notified. Presumably the infection had spread into the lymphatic system and had left the epithelial layers. Moreover, two of the three were treated with azithromycin once, but still developed inguinal LGV a few weeks later. This finding supports the suggestion that LGV contacts should be treated with an extended course of doxycycline instead of the now widely recommended single dose of azithromycin.
Azithromycin for partner treatment
There is insufficient evidence concerning the effectiveness of azithromycin for LGV.11 Azithromycin is currently recommended in many guidelines as presumptive therapy for the partners of LGV patients.6 ,7 Here we describe two partners of LGV patients (A and B) who were treated with azithromycin 1000 mg once as presumptive therapy but who were diagnosed with LGV infections after 7 and 16 weeks, respectively. The new BASHH guideline suggests partner treatment with doxycycline for 14 days. In 2009 we reported that anorectal LGV can persist for up to 16 days during treatment with doxycycline.9 The treatment of notified LGV partners with doxycycline, possibly for 21 days, seems warranted.
Protracted course of inguinal LGV infections
Treatment with 21 days of doxycycline is recommended for LGV infections. The duration of therapy is mainly based on clinical experience, and not on evidence.4 ,12 Moreover, chlamydia biovar L-type organisms are able to survive under doxycycline therapy for a longer period than chlamydia non-LGV biovars, so a prolonged course of doxycycline is warranted to successfully eradicate LGV.9 Patients C and D had persisting CT RNA positive and LGV DNA positive bubo aspirates following the recommended 21 days of doxycycline. Both patients confirmed they used the antibiotic therapy as prescribed. Symptoms only subsided upon extension of the doxycycline course to 12 and 6 weeks, respectively. The therapeutic course of these two patients suggests that 21 days of antibiotic therapy is insufficient to completely eliminate inguinal LGV infections.13 Furthermore, it is important to aspirate persisting buboes in cases of inguinal LGV, since the penetration of antibiotics in abscess cavities is very poor. Clinical trials on the optimal treatment of LGV infections are warranted.
Strengths and weaknesses of this study
The strength of this case series is that it highlights shortcomings in the current clinical guidelines for the management of LGV, in particular the treatment of notified partners and patients with inguinal LGV. A weakness is the uncontrolled nature of any case descriptive study. Although both cases A and B denied having had sexual contact with the LGV indexes who had notified them after they had received partner treatment, it cannot be excluded that they were re-exposed to other LGV infected partners since they both reported considerable risk behaviour.
We conclude first that the diagnosis of inguinal LGV can be missed in the first stages of the infection when symptoms can be non-specific in the absence of buboes, mild or absent, and routine tests for CT can be negative. Clinicians dealing with STI patients should be aware that clinical manifestations of LGV have not been confined to proctitis14 and instruct patients notified for LGV to return to the STI clinic once anogenital symptoms occur, even if all STI test came back negative. Second, a 21-day regimen of doxycycline is considered sufficient to treat anorectal LGV infections. In cases of inguinal LGV with bubo formation, live replicating bacteria can be detected after 3 weeks of continuous doxycycline treatment. This could be caused by the sub-optimal penetration of the antimicrobial agent in the bubo cavity. It is therefore important to follow-up LGV patients with buboes and continue doxycycline treatment until symptoms have resolved. In cases of persisting buboes, their contents should be aspirated. Third, the effectiveness of the current recommended presumptive treatment of contacts notified for LGV with 1 g of azithromycin lacks evidence. In an analogy with the current treatment of LGV infections, prolonged courses of doxycycline seem better able to prevent established infections in contacts exposed to LGV.
Key messages
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Inguinal lymphogranuloma venereum (LGV) infections have been rare in the current epidemic among men who have sex with men (MSM) that may require a different approach not yet recommended in current guidelines for the treatment and diagnosis of LGV.
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Urethral chlamydia infections in MSM can be caused by LGV biovars that in contrast to non-LGV biovar infections require prolonged courses of antibiotic therapy.
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The recommended presumptive treatment of contacts notified for LGV with one gram of azithromycin seems insufficient to prevent established infections.
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Inguinal LGV with bubo formation may require prolonged courses of doxycycline, exceeding the currently advised 21 days regimen.
Supplementary materials
Abstract in Dutch
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Files in this Data Supplement:
- Abstract in Dutch - Online abstract
Footnotes
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Handling editor Jackie A Cassell
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Contributors EVO and NHNdV gathered the data from the electronic patient file. AdM provided information from his own general practice. HJCdV designed and supervised the study. The first draft was written by EVO and critically revised by NHNdV, AdM and HJCdV. All authors approved of the final version submitted.
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Competing interests None.
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Patient consent Obtained.
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Provenance and peer review Not commissioned; externally peer reviewed.