Chronic epididymitis due to Chlamydia trachomatis LGV-L2 in an HIV-negative heterosexual patient: a case report.

Chlamydia trachomatis is an obligate intracellular pathogen and the leading bacterial cause of sexually transmitted infections worldwide. Chlamydia trachomatis genovars L1-L3 are responsible for lymphogranuloma venereum (LGV), an invasive sexually transmitted disease endemic in tropical and subtropical regions of Africa, South America, the Caribbean, India and South East Asia. The typical signs and symptoms of C. trachomatis LGV urogenital infections in men include herpetiform ulcers, inguinal buboes, and/or lymphadenopathies. Since 2003, endemic cases of proctitis and proctocolitis caused by C. trachomatis LGV emerged in Europe, mainly in HIV-positive men who have sex with men (MSM). Scarce data have been reported about unusual clinical presentations of C. trachomatis LGV urogenital infections. Herein, we report a case of a 36-year-old heterosexual, HIV-negative male declaring he did not have sex with men or trans women, who presented to the Urology and Andrology outpatient clinic of a healthcare center from Cordoba, Argentina, with intermittent testicular pain over the preceding 6 months. Doppler ultrasound indicated right epididymitis and funiculitis. Out of 17 sexually transmitted infections (STIs) investigated, a positive result was obtained only for C. trachomatis. Also, semen analysis revealed oligoasthenozoospermia, reduced sperm viability as well as increased sperm DNA fragmentation and necrosis, together with augmented reactive oxygen species (ROS) levels and the presence of anti-sperm IgG autoantibodies. In this context, doxycycline 100 mg/12 h for 45 days was prescribed. A post-treatment control documented microbiological cure along with resolution of clinical signs and symptoms and improved semen quality. Strikingly, sequencing of the ompA gene revealed C. trachomatis LGV L2 as the causative uropathogen. Remarkably, the patient did not present the typical signs and symptoms of LGV. Instead, the infection associated with chronic testicular pain, semen inflammation and markedly reduced sperm quality. To our knowledge, this is the first reported evidence of chronic epididymitis due to C. trachomatis LGV L2 infection in an HIV-negative heterosexual man. These findings constitute important and valuable information for researchers and practitioners and highlight that C. trachomatis LGV-L2 should be considered as putative etiologic agent of chronic epididymitis, even in the absence of the typical LGV signs and symptoms.

Towards a Deeper Understanding of Chlamydia trachomatis Pathogenetic Mechanisms: Editorial to the Special Issue "Chlamydia trachomatis Pathogenicity and Disease".

Chlamydia trachomatis, an obligate intracellular Gram-negative bacterium, is characterized by a wide range of different serotypes responsible for several local or systemic human diseases, including genital tract manifestations (D-K), trachoma (A-C), and lymphogranuloma venereum (L1-3) [...].

Use of real-time PCR as an alternative to conventional genotyping methods for the laboratory detection of lymphogranuloma venereum (LGV).

Lymphogranuloma venereum (LGV) can be differentiated from non-LGV chlamydial infection using Sanger sequencing or molecular assays, including those that are commercially-available internationally. Here, we describe the performance of a rapid real-time PCR (RT-PCR)-based strategy in differentiating Chlamydia trachomatis infections associated with LGV or non-LGV serovars. One hundred three rectal swabs, previously genotyped using Sanger sequencing of the ompA gene as a reference method, were tested in the RT-PCR assays. All non-LGV specimens were correctly identified, but the RT-PCR failed to detect 1 LGV specimen, resulting in a sensitivity of 87.5% for the non-LGV/LGV RT-PCR assay. Additional performance characteristics (e.g., specificity, accuracy, and reproducibility) were all between 93% and 100% with a limit of detection ≤100 copies/reaction. Thus, this rapid RT-PCR method for LGV detection in clinical specimens is comparable to the reference method.

Ongoing evolution of Chlamydia trachomatis lymphogranuloma venereum: exploring the genomic diversity of circulating strains.

Lymphogranuloma venereum (LGV), the invasive infection of the sexually transmissible infection (STI) Chlamydia trachomatis, is caused by strains from the LGV biovar, most commonly represented by ompA-genotypes L2b and L2. We investigated the diversity in LGV samples across an international collection over seven years using typing and genome sequencing. LGV-positive samples (n=321) from eight countries collected between 2011 and 2017 (Spain n=97, Netherlands n=67, Switzerland n=64, Australia n=53, Sweden n=37, Hungary n=31, Czechia n=30, Slovenia n=10) were genotyped for pmpH and ompA variants. All were found to contain the 9 bp insertion in the pmpH gene, previously associated with ompA-genotype L2b. However, analysis of the ompA gene shows ompA-genotype L2b (n=83), ompA-genotype L2 (n=180) and several variants of these (n=52; 12 variant types), as well as other/mixed ompA-genotypes (n=6). To elucidate the genomic diversity, whole genome sequencing (WGS) was performed from selected samples using SureSelect target enrichment, resulting in 42 genomes, covering a diversity of ompA-genotypes and representing most of the countries sampled. A phylogeny of these data clearly shows that these ompA-genotypes derive from an ompA-genotype L2b ancestor, carrying up to eight SNPs per isolate. SNPs within ompA are overrepresented among genomic changes in these samples, each of which results in an amino acid change in the variable domains of OmpA (major outer membrane protein, MOMP). A reversion to ompA-genotype L2 with the L2b genomic backbone is commonly seen. The wide diversity of ompA-genotypes found in these recent LGV samples indicates that this gene is under immunological selection. Our results suggest that the ompA-genotype L2b genomic backbone is the dominant strain circulating and evolving particularly in men who have sex with men (MSM) populations.

Lymphogranuloma venereum genovariants in men having sex with men in Italy.

OBJECTIVES: Lymphogranuloma venereum (LGV) is an STI caused by Chlamydia trachomatis serovars L1-L3. In Europe, the current epidemic is caused mainly by L2b genovariant, although increasing cases associated with other L2 variants have been reported. Here, we assessed the distribution of rectal LGV genovariants among men having sex with men (MSM) in Italy. METHODS: From 2016 to 2020, all the anorectal swabs collected from MSM attending the STI Clinic of St. Orsola-Malpighi Hospital in Bologna and positive for C. trachomatis were stored. LGV infection was confirmed by a pmpH PCR, and, subsequently, a fragment of the ompA gene was amplified and sequenced. Sequences were aligned to reference strains representing different LGV variants. RESULTS: LGV cases accounted for one-third of all chlamydial rectal infections with a total prevalence of 4.1% (76/1852). Total number of LGV cases per year remained constant. LGV was mainly found in symptomatic patients (>65%), older than 30 years, with a high burden of other STIs (63.7% HIV-positive, 35.5% with concurrent rectal gonorrhoea, 19.7% with early syphilis). A decreasing trend in HIV-LGV co-infection was noticed over time. Three main LGV genovariants were detected (L2f, 46.1%; L2b, 23.0%; L2-L2b/D-Da, 16.9%), together with other known L2b variants (mainly L2bV2 and L2bV4). Two novel L2b ompA variants with non-synonymous single-nucleotide polymorphisms were found. Over time, the percentage of L2f cases dropped gradually, with a significant increase in L2-L2b/D-Da cases (p=0.04). CONCLUSIONS: In our area, LGV is endemic among MSM with different circulating genovariants. Active surveillance and genotyping programmes are needed to reduce re-establishing of LGV infection.

Estudio clínico y epidemiológico del linfogranuloma venéreo en un hospital público del sur de España / Lymphogranuloma Venereum in a Public Health Service Hospital in Southern Spain: A Clinical and Epidemiologic Study

El linfogranuloma venéreo (LGV) es una enfermedad emergente en hombres que tienen sexo con hombres (HsH), con una incidencia en España de 1,15 casos por 100.000 habitantes en el año 2017. Suele cursar como una proctitis severa que puede ocasionar abscesos, fístulas y estenosis anal. Raramente se manifiesta con úlceras genitales o adenopatías inflamatorias inguinales. El objetivo de este trabajo fue describir una serie de pacientes con LGV de un hospital público de Andalucía. MATERIAL Y MÉTODOS: Estudio observacional descriptivo de una cohorte retrospectiva de casos diagnosticados de LGV. Se recogieron variables epidemiológicas, clínicas, microbiológicas, de tratamiento, así como los hábitos sexuales de los pacientes. RESULTADOS: Se seleccionaron los 17 casos diagnosticados entre octubre de 2016 y mayo de 2019 en HsH, 12 de ellos positivos para el VIH. Trece pacientes tuvieron una proctitis muy sintomática con ulceraciones en el canal anal y el recto. En 4 pacientes el LGV se manifestó en la forma genital o inguinal. Se identificaron prácticas sexuales de alto riesgo: un número elevado de parejas y sexo anal receptivo anónimo sin protección, búsqueda de sexo por Internet y sexo en grupo o fuera de nuestra comunidad. La Chlamydia trachomatis L2 se identificó en todos los casos, con una buena respuesta a la doxiciclina oral. Dos pacientes con la forma clásica necesitaron ciclos más prolongados de tratamiento y en 3 de ellos fue necesario tratamiento quirúrgico. CONCLUSIONES: Ante una proctitis sintomática en HsH con prácticas sexuales de alto riesgo debemos tomar muestras de exudado para identificar los serovares de LGV. Las úlceras genitales y los bubones inguinales son también muy sugerentes de la infección. La sospecha de LGV y el tratamiento precoz son fundamentales para prevenir las complicaciones y la transmisión de la enfermedad

Lymphogranuloma venereum (LGV) is an emerging disease in men who have sex with men (MSM): the incidence was 1.15 cases per 100,000 population in Spain in 2017. Patients with LGV characteristically have severe proctitis that can cause abscesses, fistulas, and anal stenosis. Genital ulcers and inflammatory inguinal adenopathy may occasionally be present. The aim of this study was to describe a series of patients with LGV treated in a public health service hospital in Andalusia, Spain. MATERIAL AND METHODS: Retrospective, observational description of a series of patients diagnosed with LGV. We gathered epidemiologic, clinical, microbiologic, and treatment data. Patients' sexual behaviors were also noted. RESULTS: We found 17 cases of LGV diagnosed in MSM between October 2016 and May 2019. Twelve of the patients were also infected with the human immunodeficiency virus, and 13 had severe proctitis with ulcers in the anal canal and rectum. Four patients had genital or inguinal manifestations. The following high-risk sexual behaviors were on record: a high number of sexual partners, receptive anal sex with strangers and without a condom, seeking sexual partners online, participation in group sex, and sex with partners from outside Andalusia. Chlamydia trachomatis serovar L2 was identified in all cases, and the infection responded well to oral doxycycline. Two patients with the most characteristic form of LGV required longer treatment cycles. Three required surgery. CONCLUSIONS: When symptomatic proctitis is found in MSM who engage in high-risk sex, the LGV exudate should be sampled and the C trachomatis serovar identified. Genital ulcers or inguinal buboes are also highly suggestive of LGV. Clinical suspicion and early treatment are the keys to preventing complications and disease transmissios

Reduction of non-typeable results using a plasmid oriented Lymfogranuloma venereum PCR for typing of Chlamydia trachomatis positive samples.

OBJECTIVES: Typing of Chlamydia trachomatis (CT) is traditionally performed by characterising the ompA gene, resulting in more than a dozen different genovars, A to L. Type L is associated with Lymphogranuloma venereum (LGV) and commonly screened for using PCR, targeting the chromosomal pmpH gene. We aimed to develop and validate a new CT/LGV plasmid-based typing assay targeting the pgp3 gene, to increase sensitivity and thus reduce the number of non-typeable results. METHODS: The new pgp3 PCR assay using LNA probes to detect point mutations was analytically and prospectively validated in a routine diagnostic laboratory setting. For the analytical tests, quantified nucleotide constructs (gBlocks) were used to perform limit of detection analyses. Quality control panel samples from 2018 and 2019 for CT were also tested. For the clinical study patient samples which were collected in two months in 2018 were tested simultaneously using the pmpH PCR and the pgp3 PCR. RESULTS: Analytically, the assay proved to be 100% specific relative to the previously used LGV typing assay targeting the single copy pmpH gene but it was much more sensitive to detect non-LGV CT. In the quality control panel 2 nonLGV samples and 7 LGV samples were solely positive with the pgp3 PCR and not with the pmpH PCR. None of the samples from analytical specificity panels were positive, indicating 100% specificity. In a prospective panel of 152 clinical samples, 142 (93%) were successfully typed with the pgp3 PCR compared to 78% with the pmpH PCR. The pgp3 PCR was fully concordant with the pmpH PCR to identify all LGV subtypes and detected an increased number of clinical samples of non-LGV subtype. CONCLUSION: We developed and validated a sensitive and specific plasmid-based typing assay to discriminate LGV from non-LGV CT subtypes. This is useful in a clinical setting to quickly determine the optimal treatment for Chlamydia trachomatis infections.

Prevalence of lymphogranuloma venereum among anorectal Chlamydia trachomatis-positive MSM using pre-exposure prophylaxis for HIV.

OBJECTIVES: We evaluated the prevalence of lymphogranuloma venereum (LGV) in anorectal Chlamydia trachomatis-positive French men who have sex with men (MSM) using pre-exposure prophylaxis (PrEP) for HIV. Here, we describe the clinical, biological and behavioural characteristics of these patients. METHODS: Laboratories throughout French metropolitan areas performing routine testing for C. trachomatis sent positive anorectal specimens to the National Reference Centre for bacterial STIs for LGV real-time PCR targeting the pmpH gene. Identification of the C. trachomatis genovar was performed by ompA gene sequencing. For each patient, clinical, biological and sexual behaviour data were collected after obtaining written informed consent. RESULTS: In 2017, 486 anorectal C. trachomatis-positive specimens from MSM PrEP users were analysed. A strain of genovar L was detected in 91 cases (18.7%). Patients with LGV were significantly more symptomatic, had more sexual partners and more concurrent syphilis compared with their non-LGV counterparts. OmpA gene sequencing, successful in two-thirds of anorectal C. trachomatis-positive specimens, showed that the LGV cases were mainly of variant L2b (n=33), followed by genovar L2 (n=27) and genetic L2b ompA variants (n=16). In 11 cases, the results indicated the occurrence of genetic exchange between L and non-L genovars. CONCLUSIONS: LGV was diagnosed in 18.7% of anorectal C. trachomatis-positive specimens from French MSM using PrEP. LGV testing should be carried out for MSM diagnosed with chlamydia and with a large number of sexual partners, high-risk practices and anorectal symptoms. These patients should be presumptively treated as having LGV. This is the first surveillance study of LGV among MSM PrEP users and monitoring should continue.

Substantial underdiagnosis of lymphogranuloma venereum in men who have sex with men in Europe: preliminary findings from a multicentre surveillance pilot.

OBJECTIVES: Understanding the public health impact of lymphogranuloma venereum (LGV) in Europe is hampered by inadequate diagnostics and surveillance systems in many European countries. We developed and piloted LGV surveillance in three European countries without existing systems and performed a preliminary investigation of LGV epidemiology, where little evidence currently exists. METHODS: We recruited STI or dermatovenereology clinics and associated laboratories serving men who have sex with men (MSM) in Austria, Croatia and Slovenia, using the UK for comparison. We undertook centralised LGV testing of Chlamydia trachomatis (CT)-positive rectal swabs collected between October 2016 and May 2017 from MSM attending these clinics. Stored specimens from Austria (2015-2016) and Croatia (2014) were also tested. Clinical and sociodemographic data were collected using a standardised proforma. The ompA gene of LGV-positive specimens was sequenced. RESULTS: In total, 500 specimens from CT-positive MSM were tested, and LGV positivity was 25.6% (128/500; 95% CI 22.0% to 29.6%) overall, and 47.6% (79/166; 40.1% to 55.2%) in Austria, 20.0% (3/15; 7.1% to 45.2%) in Croatia, 16.7% (1/6; 3.0% to 56.4%) in Slovenia and 14.4% (45/313; 10.9% to 18.7 %) in the UK. Proformas were completed for cases in Croatia, Slovenia and in the UK; proformas could not be completed for Austrian cases, but limited data were available from line listings. Where recorded, 83.9% (78/93) of LGV-CT cases were HIV-positive compared with 65.4% (149/228) of non-LGV-CT cases; MSM with LGV-CT were more likely to have proctitis (Austria, 91.8% vs 40.5%, p<0.001; Croatia, 100% vs 25%, p=0.04; UK, 52.4% vs 11.7%, p<0.001) than those with non-LGV-CT. Six different ompA sequences were identified, including three new variants; the L2 ompA sequence predominated (58.6%, 51/87). CONCLUSIONS: LGV is substantially underdiagnosed in MSM across Europe. Unified efforts are needed to overcome barriers to testing, establish effective surveillance, and optimise diagnosis, treatment and prevention.

Epidemiology of lymphogranuloma venereum in New South Wales, 2006-2015.

AIM: To describe the epidemiology of lymphogranuloma venereum (LGV) in New South Wales (NSW) from 2006 to 2015. METHODS: LGV notification data between 2006 and 2015 from New South Wales were analysed to describe time trends in counts and rates by gender, age group and area of residence, as well as anatomical sites of infection. A positivity ratio was calculated using the number of LGV notifications per 100 anorectal chlamydia notifications per year. Data linkage was used to ascertain the proportion of LGV cases that were co-infected with HIV. RESULTS: There were 208 notifications of LGV in NSW from 2006 to 2015; all were among men, with a median age of 42 years, and half were residents of inner-city Sydney. Annual notifications peaked at 57 (1.6 per 100,000 males) in 2010, declined to 16 (0.4 per 100,000 males) in 2014, and then increased to 34 (0.9 per 100,000 males) in 2015. Just under half (47.4%) of LGV cases were determined to be co-infected with HIV. CONCLUSION: The number of LGV notifications each year has not returned to the low levels seen prior to the peak in 2010. Continued public health surveillance is important for the management and control of LGV.

Orolabial Lymphogranuloma Venereum, Michigan, USA.

Orolabial lymphogranuloma venereum was diagnosed for a man in Michigan, USA, who had sex with men, some infected with HIV. High index of suspicion for lymphogranuloma venereum led to accurate diagnosis, successful therapy, and description of an L2b variant with a unique genetic mutation.

Infecciones por Chlamydia trachomatis (incluye linfogranuloma venéreo) y Mycoplasma genitalium / Infections caused by Chlamydia trachomatis (including lymphogranuloma venereum) and Mycoplasma genitalium

El incremento en las infecciones de transmisión sexual por Chlamydia trachomatis, incluyendo el linfogranuloma venéreo, y Mycoplasma genitalium registrado en la última década plantea nuevos retos para mejorar su control y reforzar su prevención. El diagnóstico clínico habitual (uretritis/cervicitis) debe completarse con una búsqueda activa de la infección en varones con disuria o proctitis, mujeres con enfermedad inflamatoria pélvica y contactos asintomáticos. El diagnóstico microbiológico debe basarse en técnicas moleculares, capaces de detectar Chlamydia trachomatis (diferenciando el genotipo L para linfogranuloma venéreo) y Mycoplasma genitalium (incluyendo idealmente la detección de cepas resistentes a macrólidos). Un diagnóstico más rápido y específico permitirá un tratamiento dirigido con la pauta antibiótica idónea. El manejo de estas infecciones de transmisión sexual debe incluir un estudio de los contactos sexuales y en ocasiones un test de cura. Finalmente, deben ser valorados los cribados de infección en grupos de población con mayor prevalencia

Sexually transmitted infections caused by Chlamydia trachomatis, including lymphogranuloma venereum and Mycoplasma genitalium have increased in last decade. This epidemiological scenario presents new challenges in order to improve and strengthen our control and prevention strategies. The routine clinical diagnosis of urethritis and cervicitis must be combined with the active search for the causal agent in men with symptoms of dysuria or proctitis, and in women with pelvic inflammatory disease. We should also include sexually transmitted infections screening in asymptomatic patients with sexual risk behaviours or sexual contact with patients diagnosed with an sexually transmitted infection. The microbiological diagnosis must be based on molecular techniques capable of detecting Chlamydia trachomatis (discriminating between L genotypes associated with lymphogranuloma venereum and other genotypes) and Mycoplasma genitalium (ideally including the identification of macrolide-resistant strains). A faster and specific diagnosis will allow for a targeted treatment with a suitable antibiotic regimen. We also recommend including contact tracing of sexual partners and, occasionally, a cure test. Finally, sexually transmitted infection screening must be widely implemented in those population groups with a high prevalence of sexually transmitted infections

Rectal Lymphogranuloma Venereum, Buenos Aires, Argentina.

Among 34 men with proctitis in Buenos Aires, Argentina, 16 (47%) had Chlamydia trachomatis infection, 11 (68.8%) of which were biovar lymphogranuloma venereum. The outbreak was probably local, as in Europe. In Argentina, lymphogranuloma venereum should be a suspected cause of proctitis in HIV-infected men who have had unprotected anal sex with men.

Lymphogranuloma venereum presenting as penile ulcer in two HIV-negative gay men.

An epidemic of lymphogranuloma venereum among men who have sex with men (MSM) has persisted in Australia for over a decade and virtually all diagnoses are made from rectal samples. We discuss two cases of human immunodeficiency virus-negative MSM who presented with a penile ulcer. The diagnosis can be made by ensuring a swab of any such ulcer is tested for Chlamydia trachomatis.