Among re-emerging sexually transmitted infections like hepatitis C virus and Mycoplasma genitalium, Lymphogranula venereum (LGV) has been particularly reported among men who have sex with men (MSM) as a relatively common cause of proctitis and occasional genital ulcerative disease.1–3 Primary LGV classically presents as a painless ulceration or chancre that heals within 1 week and often remains unnoticed. We hereby report 5 cases of atypical inflammatory LGV serovar L2b presenting initially with edema and persistent painful ulceration. To the best of our knowledge, no such cases had so far been reported at the initial phase of the disease.
Patients 1 and 2 were 37- and 41-year-old MSM, exclusively partnered with one another for 11 years, both were human immunodeficiency virus (HIV)-positive with undetectable viral loads. They presented together to our clinic for ongoing hyperalgic genital ulcerations of the foreskin with tender inguinal lymphadenopathy that started 25 and 14 days before, respectively; patient 1 also had a severe edematous stricture of the foreskin (Fig. 1). Patient 3 was a 64-year-old MSM, HIV-positive with undetectable viral load, who presented with an 8-day history of edema, induration and a painful genital ulceration of the foreskin with fever and tender lymphadenopathy. Patient 4 was a 52-year-old MSM, HIV-positive with undetectable viral load, complaining of an ulceration and an indurated and painful edema at the base of the penis that had started 2 days before. Patient 5 was a 27-year-old MSM, who presented with a 7-day history of 2 painful ulcerations of the foreskin with local painful edema and bilateral inguinal lymphadenopathy (Fig. 2). The number of sexual partners for patients 3, 4, and 5 was above 20 during the last 6 months. Information on sexual practice as the use of hyperosmolar lubricants and sex toys was not available. No proctitis was noted in any of the cases; diagnosis of LGV serovar L2b was made using the rapid Chlamydia trachomatis variant L2b-specific polymerase chain reaction (PCR) to circumvent laborious ompA gene sequencing, on urine and/or ulcer swab. Inhouse PCR for herpes simplex virus types 1 and 2 and for Treponema pallidum taken from the ulcers of all patients were negative; serology for syphilis was also negative in all patients. Patients received a 3-week course of doxycycline 200 mg/d for 3 weeks or azithromycin 2 g stat on days 1, 8, and 15, and their symptoms resolved completely. A summary of the patients' characteristics is found in Table 1.
Lymphogranula venereum, caused by serovars L1, L2, and L3 of C. trachomatis, is endemic in parts of Africa, Asia, South America, and the Caribbean.1 The primary stage of disease is classically characterized by a small painless papule that appears at the site of inoculation in 1% to 10% of cases and may ulcerate.3 The ulceration is self-limiting, may not always occur, and may pass unnoticed by the patient.4 Since 2003, an emergence of LGV serovar L2b has been observed in industrialized countries among HIV-positive MSM, presenting mostly as proctitis (approximately 96% of the cases in the United Kingdom, 91% in Netherlands, and 97% in France).5,6
In this report, we describe 5 cases of confirmed L2b LGV in MSM presenting with edema and persistent painful ulceration; 2 had systemic symptoms (fever or flu-like syndrome). To our knowledge, this L2b confirmed atypical and intensely inflammatory presentation of LGV has never been described before. Biological investigations ruled out other causes of sexually acquired genital ulcers, such as herpes and syphilis. Diagnosis of the serovar L2b was confirmed by PCR-based genotyping. Treatment with a 3-week course of doxycycline 200 mg/d or azithromycin 2 g on days 1, 8, and 15 was effective in all cases.
The pathophysiological pathways leading to either asymptomatic infection in some patients1–7 or to proctitis or painful genital ulcer in others are still unknown.1 The emerging clinical diversity of LGV has also been emphasized by Singhrao et al8 who reported 2 cases of HIV-infected patients presenting with isolated painful perianal ulcer disease, and by cases of reactive arthritis9 and atypical pneumonia10 that have also been associated with LGV.
Spenatto et al11 also reported a case of classic second stage “bubonulus” evolving into local acute inflammatory lymphoedema. A recent report of 2 cases of LGV-induced penile ulcers among HIV-infected MSM in Michigan showed that LGV is a potential cause of genital ulceration across the Atlantic as well.12
Lymphogranula venereum is in fact known to be a virulent disease beyond the initial ulcerative stage. What struck us in this short series of patients is an aggressive initial stage. As serovar L2b was incriminated in all our patients, we raise the question of its higher virulence. Among possible causes for higher virulence, host-related or pathogen-related factors should be considered. The main host-related factor could be coinfection with HIV. Human immunodeficiency virus prevalence among LGV cases indeed ranges from 67% to 100%, with a significant association between HIV and LGV (odds ratio, 8.19; 95% confidence interval, 4.68–14.33).5 Likewise, in our cases, 4 of 5 patients were HIV-positive with preserved CD4 count (cf., Table 1). The role of the latter in modulating the clinical picture of LGV, as occurs with many infections associated with HIV, is yet to be established. Regarding pathogen-related factors, recent studies have shown that the chlamydial major outer membrane protein, which is involved in the chlamydial attachment-infectivity process, and Uridine diphosphate-diacylglucosamine hydrolase, which is involved in the lipid A biosynthetic pathway, may explain the different immunogenicity and adherence capacity to host cells, modulation of inflammation, and the high virulence of certain serovars of LGV.13 Clinical presentation of LGV could therefore reflect the influence of both the genovars' virulence and the host immune system. Further observational studies are warranted to substantiate this hypervirulent presentation of the initial stage of L2b LGV and, if confirmed, further fundamental work will be needed to shed light on the mechanisms involved.
In conclusion, our cases are the first reported L2b-confirmed LGV cases presenting with painful and edematous genital ulcer disease. They further illustrate that clinical manifestations of LGV in the current outbreak in MSM are not confined to proctitis. The need for awareness of LGV as a cause of genital ulceration is crucial. L2b serovar could have a particular high virulence profile. Microbiological and larger clinical studies are still needed to better understand its pathogenicity.
1. White JA. Manifestations and management of lymphogranuloma venereum. Curr Opin Infect Dis 2009; 22:57–66.
2. Lanjouw E, Ouburg S, de Vries HJ, et al. 2015 European guideline on the management of Chlamydia trachomatis
infections. Int J STD AIDS 2016; 27:333–348.
3. de Vries HJ, Zingoni A, Kreuter A, et al. 2013 European guideline on the management of lymphogranuloma venereum. J Eur Acad Dermatol Venereol 2015; 29:1–6.
4. Peuchant O, Baldit C, Le Roy C, et al. First case of Chlamydia trachomatis
L2b proctitis in a woman. Clin Microbiol Infect 2011; 17:E21–E23.
5. Rönn MM, Ward H. The association between lymphogranuloma venereum and HIV among men who have sex with men: systematic review and meta-analysis. BMC Infect Dis 2011; 11:70.
6. de Barbeyrac B. Current aspects of Chlamydia trachomatis
infection. Presse Med 2013; 42(4 Pt 1):440–445.
7. Stoner BP, Cohen SE. Lymphogranuloma venereum 2015: clinical presentation, diagnosis, and treatment. Clin Infect Dis 2015; 61(Supp. 8):S865–S873.
8. Singhrao T, Higham E, French P. Lymphogranuloma venereum presenting as perianal ulceration: an emerging clinical presentation? Sex Transm Infect 2011; 87:123–124.
9. Perry ME, White JA. Three cases of reactive arthritis secondary to lymphogranuloma venereum. J Clin Rheumatol 2015; 21:33–34.
10. Wood WH Jr, Felson H. A case of lymphogranuloma venereum associated with atypical pneumonia. Int J STD AIDS 2005; 16:771–772.
11. Spenatto N, Boulinguez S, de Barbeyrac B, et al. First case of “bubonulus” in L2 lymphogranuloma venerum. Sex Transm Infect 2007; 83:337–338.
12. de Voux A, Kent JB, Macomber K, et al. Notes from the Field: cluster of lymphogranuloma venereum cases among men who have sex with men—Michigan, August 2015-April 2016. MMWR Morb Mortal Wkly Rep 2016; 65:920–921.
13. Young HE, Zhao J, Barker JR, et al. Discovery of the elusive UDP-diacylglucosamine hydrolase in the lipid a biosynthetic pathway in Chlamydia trachomatis
. MBio 2016; 7:e00090.