Chlamydia trachomatis anorectal infections by LGV (L1,L2 and L2b) and non-LGV serotypes in symptomatic patients in Buenos Aires,Argentina

Abstract

Background

Chlamydia trachomatis (CT) can infect the anorectum producing various signs and symptoms. There is scarce literature regarding the differences between LGV and non-LGV CT anorectal manifestations. We compare the clinical spectrum of LGV and non-LGV infections.

Methods

Patients over 18 years with presumptive infectious anorectal symptoms were examined in two healthcare centres in Buenos Aires. The patients were studied and treated according to current sexually transmitted infection guidelines. Anorectal swabs were collected to detect and genotype CT.

Results

A three-year-long study on 317 patients with anorectal symptoms showed 45.11% CT infection (85% LGV strains). Of 140 samples, 92 were sequenced: 80/119 LGV (L2b 45%, L1 32.5% and L2 22.5%) and 12/21 non-LGV. Older age and HIV+ status were significantly higher in the LGV group. Anal discharge, bleeding, severe proctitis and anal ulcers were more common in the LGV group. Multivariate logistic regression analysis revealed that HIV infection, anorectal bleeding and oro-anal sex are independent predictors of LGV infection.

Conclusions

In patients with anorectal symptoms, LGV serovars predominate over non-LGV ones. Clinical manifestations are not pathognomonic of a specific biovar. If genotyping is not available, having clinical predictors may help to presume an LGV infection and define length of treatment.

Keywords

LGV LGV L1 sexually transmitted infections HIV men who have sex with men proctitis anal ulcer

Introduction

Chlamydia trachomatis (CT) is an intracellular bacterium responsible for the annual infection of one hundred million people globally. Anorectal symptoms are frequently associated to sexually transmitted infections (STIs) in patients who practise anal sex, CT being among the most prevalent ones.

There are different genotypes of CT that can cause STIs. LGV biovar (genotypes L1, L2 and L3 and their variants) and non-LGV (genotypes D to K) can both infect different tissues, anorectal included, and cause diverse symptoms of varying severity. Non-LGV genotypes remain confined to the mucosa while LGV strains are invasive and can disseminate via underlying connective tissue and spread to regional lymph nodes. LGV biovar is responsible for lymphogranuloma venereum.¹ In 2003, an outbreak of rectal LGV was reported in the Netherlands,² followed by many other reports from different high-income countries.^3,4 Similarly, in 2018 an outbreak of anorectal LGV was reported in Argentina particularly among men who have sex with men (MSM) living with HIV (LHIV).⁵

There is scarce literature regarding the differences between LGV and non-LGV CT anorectal manifestations.⁶ In this study, we describe and compare the clinical spectrum of LGV and non-LGV infections in a symptomatic population in Buenos Aires and identify possible predictors of anorectal LGV.

Methods

Between 1 September 2017 and 1 October 2020, patients over 18 years of age from a public hospital and a private healthcare centre in Buenos Aires with anorectal symptoms (anal discharge, rectal bleeding, tenesmus, rectal urgency and proctalgia) and epidemiology suggestive of STIs were prospectively included. Patients were included only once and none of them was referred to by another patient in the study. Patients with inflammatory bowel disease (IBD) and pelvic radiation therapy were excluded. The study was approved by an Ethics Committee (nr 201723), and the patients provided written informed consent.

Personal data and information about anorectal disorders, sexual behaviour, number of sexual partners in the last 12 months and history of previous STIs in their lifetime were recorded from each patient. A general physical examination, including inguinal and anorectal evaluation, was performed. When symptoms allowed, proctoscopy was carried out to observe rectal mucosa.

Serological investigations for HIV and syphilis (non-treponemal test) were performed in all patients. Anorectal swabs were collected to detect CT and Neisseria gonorrhoeae. CT was detected after DNA extraction, using real-time PCR targeting a cryptic plasmid fragment (Alert PCR; ELITech Molecular Diagnostics, https://www.elitechgroup.com). Positive samples were first genotyped by ompA PCR-RFLP,⁷ and genotypes were then confirmed by ompA sequencing (Macrogen, Inc).

The patients were studied and treated according to current STI guidelines.^8,9 Patients were treated for 1 or 3 weeks with doxycycline 100 mg every 12 h according to their genotype. Clinical and proctoscopic assessment of treatment response was made after treatment finished.

Statistical analysis

Categorical variables are reported as number (percentage) and quantitative variables as mean ± standard deviation or median (interquartile range (IQR)). The two-sided chi square or Fisher exact test, as appropriate, was used for comparisons of categorical variables. Continuous variables were analysed using two-sided Student t tests or Mann–Whitney U tests depending on the variable distribution. One way-ANOVA or Kruskal Wallis was used to compare between more than two groups with quantitative variables. Multivariate analysis using a logistic regression model was performed to identify independent predictors of LGV infection (p value <0.05). Statistical tests were performed using STATAMP 13 version.

Results

During the study period, a total of 317 patients met our admission criteria. Of these, 281 were men (276 were MSM), 16 trans women and 20 cis women.

One hundred and forty-three CT infections were detected (45.11%) and 140 were genotyped (study population). Of these 140, 134 were MSM, 5 trans women and 1 cis woman. The median age of the study population was 34 years (IQR 18–59). All the patients reported having practised unprotected oro-anal or receptive anal sex. One hundred thirteen (80.71%) were people living with HIV. Genotyping showed 119 LGV (85%) and 21 non-LGV CT (15%) infections. Until now, 92 of the 140 samples were sequenced. Non-LGV genotypes identified were 12: 5 D, 3 J, 2 G, 1 F and 1 mixed infection involving Ja and a non-identifiable genotype. LGV genotypes were 36 L2b (45%), 26 L1 (32.5%) and 18 L2 (22.5%). The ompA sequences obtained were deposited in the GenBank (accession no. MN548736 to MN548759, MN537150 to MN537152 and MN563608 to MN563615).

Table 1 summarizes patients’ characteristics and clinical features.

Table 1.

Patients’ characteristics and clinical features of lymphogranuloma venereum (LGV) versus non-LGV Chlamydia trachomatis anorectal infection.

Chlamydia trachomatis (N = 140)	LGV (N = 119)		Non-LGV (N = 21)
	n	%	n	%	p value	Univariate OR (CI95%)
Age (mean ± SD)	34.9±8.4		30.5 ±9		0.03
Male	115	96.6	19	90.5	0.19
Cis women	0	0	1	4.75	0.01
Trans women	4	3.4	1	4.75	0.75
HIV positive	102	85.71	11	52.4	0.000	5.4 (1.75–16)
CD4 copies/ml (median, IQR 25–75)	619 (418–843)		614 (345–646)		0.84
CD4 < 500 copies/ml	25	31.2	4	36.4	0.73
N° of sexual partners in 12 months (median, IQ25–75)	6 (2–15)		7.5 (1–17.5)		0.91
Receptive anal sex exclusively	17	14.2	3	14.3	1.00
Insertive anal sex exclusively	6	5	0	0	0.59
Versatile	94	80	16	76.2	0.71
Oro-anal sex	114	96.6	18	85.7	0.03	4.7 (1.1–30.17)
Sex worker	4	3.3	1	4.75	0.75
Concomitant STI	52	42.4	11	52.4	0.39
Treponema pallidum	24	20.3	2	9.5	0.24
Neisseria gonorrhoeae	12	10.2	6	28.6	0.02	0.3 (0.08–0.99)
Herpes simplex virus	3	2.5	2	9.5	0.11
HPV-related lesions	22	18.6	8	38	0.04	0.4 (0.12–1)
Days of symptoms (median, IQ25–75)	21 (14–45)		21 (14–90)		0.96
Fever	6	5	0	0	0.59
Anorexy	12	4.8	2	9.5	0.43
Weight loss	20	16.8	2	9.5	0.52
Altered bowel movements	22	18.5	6	28.6	0.28
Tenesmus	76	63.8	13	62	0.86
Rectal urgency	19	16	2	9.5	0.44
Proctalgia	84	70.6	11	52.4	0.1
Rectal bleeding	91	76.5	8	38	0.000	5.3 (1.8–16.1)
Anal discharge	117	98.3	18	85.7	0.004	9.7 (1.01–120.8)
Proctoscopy	110	92.43	17	85	0.24
Non-endoscopic proctitis	7	6.36	3	15	0.18
Mild proctitis	18	16.36	10	50	0.001	0.2 (0.06–0.61)
Moderate proctitis	50	45.45	5	25	0.08
Severe proctitis	35	31.81	2	9.5	0.04	4.2 (0.91–38.9)
Rectal tumour	11	9.2	1	4.75	0.69
Days of symptoms (median, IQR 25–75)	21 (14–45)		21(14–90)		0.96
Anal ulcer	44	37	2	9.5	0.012	5.8 (1.2–51.1)
Anitis	19	16	3	14.3	0.84
Anal abscess	3	2.5	1	4.75	0.57
Fístula-in-ano	3	2.5	2	9.5	0.11
Anal inflammatory tumour	14	11.8	1	4.75	0.46
Palpable inguinal lymph nodes	59	50.8	10	47.6	0.78

SD: standard deviation; IQR: interquartile range; OR: odds ratio. HIV: human immunodeficiency virus; STI: sexually transmitted diseases; HPV: human papilloma virus. Bold numbers: statistically significant values.

PLHIV were significantly more frequent in the LGV group (85.71% vs. 52.40%, OR 5.4, CI 1.75–16, p < 0.001). The median CD4 count was similar in both groups. The median age of the non-LGV group was 30.5 ± 9 years, and the median age of the LGV group was 34.9 ± 8.4 years (p = 0.03).

The unique significant difference in sexual behaviour was oro-anal sex which was more frequent in the LGV group (96.6% vs. 85.7%, OR 4.7, CI 1.1–30.17, p = 0.03).

The most frequent anorectal STIs diagnosed within the CT infected group were syphilis, gonorrhoea, herpes simplex virus (HSV) and HPV-related lesions. Other detected anorectal infections were two Neisseria meningitidis and one Gardnerella vaginalis. There were no significant differences in the global percentage of concomitant STIs between the two groups (LGV 42.4% vs. non-LGV 52.4%, p = 0.39). However, gonorrhoea and HPV-related lesions were significantly more frequent in the non-LGV group (10.2% vs. 28.6%, p = 0.02 and 18.6% vs. 38%, p = 0.04). Although not statistically significant, syphilis was more common in the LGV group (20.3% vs. 9.5%, p = 0.24).

Rectal bleeding and anal discharge were significantly more frequent in the LGV group (76.5% vs. 38%, OR 5.3, CI 1.8–16.1, p < 0.001 and 98.3% vs. 85.7%, OR 9.7, CI 1.01–120.8, p = 0.004). It was possible to perform proctoscopy in 127 of 140 patients (90.71%). Almost all the patients had proctitis. Mild proctitis predominated in the non-LGV group (50% vs. 16.4%, p = 0.001), while severe proctidides were more common in the LGV group (31.8% vs. 10%, OR 4.2, CI 0.91–38.9, p = 0.04). One patient with severe proctitis had concomitant mild rectal stenosis.

Of the various anal lesions, ulcers were the only one significantly more common in the LGV group (37% vs. 9.5%, OR 5.8, CI 1.2–51.1, p = 0.012) (Figure 1).

Figure 1.

Anorectal manifestations of lymphogranuloma venereum: a-mild proctitis, b-severe proctitis, and c and d-anal ulcers.

All these clinical and endoscopic significant differences persisted when CT was the unique causative agent analysed (excluding those pathogens that can cause similar anorectal symptoms, such as syphilis, HSV or gonorrhoea) (Table 2).

Table 2.

Clinical and endoscopic features of Chlamydia trachomatis anorectal infection as a unique causative agent: lymphogranuloma venereum (LGV) versus non-LGV CT.

C. trachomatis infection (N = 99)	LGV (N = 86) 70/86 LHIV		Non-LGV (N = 13) 6/13 LHIV
	n	%	n	%	p value
Days of symptoms (median, IQR 25–75)	21 (14–43.5)		30 (14–120)		0.35
Fever	6	7	0	0	1
Anorexy	7	8.1	1	1 (7.7)	0.95
Weight loss	12	14	2	2 (15.4)	1
Altered bowel movements	12	14	4	4 (30.8)	0.12
Tenesmus	58	67.4	10	10 (77)	0.49
Rectal urgency	15	17	1	1 (7.7)	0.29
Proctalgia	61	71	6	6 (46.1)	0.07
Rectal bleeding	67	78	6	6 (46.1)	0.01
Anal discharge	85	98.8	11	11 (84.6)	0.005
Proctoscopy	80	91.4	11	84.6	0.44
Non-endoscopic proctitis	7	8.8	2	15.4	0.45
Mild proctitis	13	16.2	5	46.1	0.01
Moderate proctitis	32	40	3	31	0.52
Severe proctitis	28	35	1	7.7	0.04
Rectal tumour	7	8.1	1	7.7	1
Anal ulcer	32	37.2	1	7.7	0.05
Anitis	13	15.1	1	7.7	0.47
Anal abscess	1	1.2	1	7.7	0.11
Fístula-in-ano	1	1.2	1	7.7	0.24
Anal inflammatory tumour	12	14	1	7.7	1
Palpable inguinal lymph nodes	40	47	7	53.8	0.64

LHIV: living with HIV; IQR: interquartile range. Bold numbers: statistically significant values.

About 50% of the patients had palpable inguinal lymph nodes (LGV 50.8% vs. non-LGV 47.6%, p = 0.78). Only one patient showed the ‘groove sign’ with both anal and bubo samples positive for L2 genotype.

In all patients but one, the symptoms resolved with doxycycline treatment. The remaining patient was living with HIV and had 2 different CT serovars separated by 3 months. The first one was L1 (in association with gonorrhoea, syphilis and condylomas). After 3 weeks of treatment, although improved, the patient remained symptomatic. Mycoplasma genitalium was ruled out and a second swab for CT revealed an L2 genotype, requiring a second line course of treatment.

Perianal fistula-in-ano required additional surgical resolution and the rectal stenosis, endoscopic dilatation.

Multivariate logistic regression analysis revealed that HIV infection (OR 8.97, CI 2.12–37.95, p = 0.003), rectal bleeding (OR 6.90, CI 1.79–26.56, p = 0.005) and oro-anal sex (OR 10.42, CI 1.21–90.02, p = 0.033) were independent predictors of LGV infection (Table 3).

Table 3.

Multivariate logistic regression analysis for lymphogranuloma venereum risk factors.

Variable	OR	CI 95%	p value
HIV	8.97	2.12–37.95	0.003
Rectal bleeding	6.90	1.79–26.56	0.005
Anal discharge	5.71	0.43–76.67	0.188
Severe proctitis	3.27	0.56–19.19	0.189
Anal ulcer	4.66	0.75–28.96	0.098
Oro-anal sex	10.42	1.21–90.02	0.033
Concomitant STI	0.36	0.09–1.38	0.136

All the analysed variables are included in the table.

OR: odds ratio; HIV: human immunodeficiency virus; STI: sexually transmitted infection. Bold numbers: statistically significant values.

Discussion

In this study, CT was found in almost half of the patients with anorectal complaints presumably secondary to an STI, with a significant predominance of LGV strains. In 2018, our group reported an outbreak of LGV in Buenos Aires, Argentina,⁵ similar to the European ones. In Latin-America, there were only isolated cases published of anorectal LGV without genotyping until that year. In that context, the predominance of LGV biovar causing anorectal symptoms was an unexpected finding. But the most surprising fact was the detection of the L1 genotype,¹⁰ which had not been reported worldwide in literature since the 1980s.¹¹ In the present series, although L2b was the most frequent genotype diagnosed in North American and European countries,^12,13 L1 was detected in almost one-third of LGV positive patients, being more frequent than L2. This particular genotype’s profile on the Argentine outbreak highlights a different distribution pattern of anorectal LGV infection.

Background shows that in anorectal CT infections, the non-LGV genotypes predominate over the LGV ones, detecting LGV strains in 10–19% of the cases.^3,14,15 But, in general, these studies included the population attending an STI clinic, regardless of the presence of symptoms or not. In our series, we found the inverse proportion. This could be explained because we had studied only symptomatic patients.

Despite the low number of patients with non-LGV infection, there was a statistically significant difference in age, with those in the LGV group being older than those in the non-LGV group. The same finding was observed in other reports.¹⁶

According to the Argentine Health Authorities, the prevalence of HIV infection in MSM is 12–15%.¹⁷ Our data show that HIV infection was much more common both in LGV and non-LGV groups. As has been described in the literature, the majority of patients with LGV infection were MSM living with HIV who are used to having unprotected oro-anal or receptive anal sex. We found a strong association between HIV infection and anorectal LGV infection, as other authors also described.^18,19 Although there were 20 women with anorectal symptoms and epidemiology of STI, only one had CT and it was not an LGV biovar.

As already reported, we observed a high prevalence of co-infection with other STIs (nearly 50%), with syphilis, gonorrhoea and the presence of HPV-related lesions the most frequent ones.^3,20 This could reflect high risk sex practices and the dense networks in which these sexual infections are being transmitted. Foschi et al. found syphilis to be a strong predictor of LGV infection.¹⁸ In this series, even though syphilis was more common in the LGV group, the difference was not statistically significant.

The route of acquisition of anorectal LGV among MSM is not fully understood. Since urethral LGV infection is 15 times lower than anorectal infection, other routes of transmission – rather than insertive anal intercourse – are needed to explain anorectal LGV.²¹ In our study, oro-anal sex was an independent predictor of LGV infection. There is some evidence that oro-anal sex or using saliva as a lubricant is associated with the acquisition of different STIs in MSM, including CT.^22-24 Cornelisse et al.²³ found that the use of a partner’s saliva during receptive anal sex was a weak risk factor for anorectal CT in MSM, but they did not discriminate between biovars. Another possible explanation is that after oro-anal sex and subsequent oropharyngeal infection, LGV might pass through the gastrointestinal tract to cause anorectal LGV proctitis. As we did not discriminate between passive and active oro-anal sex, we cannot discard any of these hypotheses; however, our results show that oro-anal sex and saliva might have a role in the transmission of LGV to the rectum. Further studies are needed to better comprehend the acquisition of rectal LGV infection.

Anorectal clinical spectra of LGV and non-LGV CT infections are diverse and non-specific: anorectal pain, tenesmus, anal discharge and anal lesions.^1,18,25 Pallawela et al.²⁰ compared symptomatic LGV positive versus LGV negative patients, being only one-third non-LGV CT infections. They found that anal discharge, tenesmus, constipation and weight loss were more common in the LGV group. In the multivariate analysis, only tenesmus and constipation persisted as significant predictors suggestive of LGV. In our series, which only included CT symptomatic infections, anal discharge (as Hamill et al.⁶ reported) and rectal bleeding were significantly more common in the LGV group. We did not find differences in tenesmus or changes in bowel movements. Of the anorectal manifestations, multivariate logistic regression analysis revealed that only rectal bleeding persisted as a predictive factor for anorectal LGV detection.

Proctoscopy is a necessary step of diagnosis in every patient with anorectal symptoms because it not only allows detection of proctitis, but also identifies other causes of rectal syndromes. Although mild proctitis predominated in the non-LGV group and severe ones in the LGV group, the whole spectrum was seen in both: there were 10% of severe proctitis in the non-LGV group and 16.4% of mild ones in the LGV group. This emphasizes that the endoscopic appearance of proctitis alone is insufficient to determine the biovar involved. However, if a patient has risk factors for STI and the proctoscopy shows severe proctitis, LGV should be suspected.

The patient with proctitis and concomitant stenosis mimicking IBD had been wrongly treated in another institution for a year with mesalazine until IBD was ruled out. The clinical and endoscopic similarities between IBD and LGV compel consideration of LGV as a differential diagnosis in patients with proctitis, especially among MSM living with HIV.²⁶

Most of the literature has been focused on proctitis and it is relatively scarce regarding anal manifestations.^3,14,27 Diverse anal lesions as anitis, abscess, fistula-in-ano and inflammatory tumours were observed in both groups. Anal ulcers were significantly more common in the LGV group, not only when associated to other STIs (as syphilis, HSV or gonorrhoea) but also when CT was the unique causative agent detected (n = 25). This must be taken into consideration when studying a patient with an anal ulcer.^3,28 It is also interesting that only 8 of 26 syphilis cases had ulcers at the moment of diagnosis. All other cases were identified by serological testing. This emphasizes the importance of screening other STIs, particularly syphilis which is frequently associated with LGV and could be latent.^8,18

It is generally believed that in low- and middle-income countries, inguinofemoral lymphadenopathy is the classical presentation of LGV which has a secondary stage characterized by enlarged, unilateral, painful lymph nodes with inflammation, suppuration and abscesses.^14,25 That presentation is not what we have been seeing in our case series so far. Although almost half of the patients had palpable inguinal lymph nodes, all but one had minimal symptoms. Since anal area lymph vessels drain towards the groins,²⁹ it would be expected to find more significant inguinal compromise. The intense discomfort caused by anorectal symptoms may induce patients to seek therapy early in the course of the disease, making chronic inguino-femoral complications of LGV less usual, even in patients with anal lesions. In a globally connected world, it is expected that diseases may have clinical similarities with those detected in other countries.

As has been seen in the published evidence, doxycycline 200 mg every day for 21 days is a good treatment option for the majority of the cases of lymphogranuloma venereum.⁸ In this study, all patients but one resolved their symptoms after that treatment. The latter was cured after being administered moxifloxacin 400 mg every day for 21 days as reported.³⁰ In this patient’s case, although there is still some controversy on the relevance of Mycoplasma genitalium as an agent causing anorectal disease, due to the persistence of symptoms, it was ruled out.

This study was limited by the small size of the non-LGV group which may have influenced the result of the multivariate analysis. A future analysis including more patients could bring more robust evidence to support the found predictors.

The study is strengthened by prospective recruitment. Almost all the patients were studied by proctoscopy which allowed us to describe the severity of the proctitis and confirm the cure. Performing sequencing allowed us to identify the genotypes involved.

In conclusion, this research provides data on symptomatic anorectal CT infection in Buenos Aires, Argentina. To our knowledge, this study includes the most extensive case series of anorectal LGV in Latin-America which presents a unique profile with a high proportion of L1 serovar.

Anorectal symptoms associated with STIs epidemiology makes it necessary to rule out CT infection, particularly in MSM living with HIV who are used to having unprotected oro-anal or receptive anal sex with rectal bleeding or anal ulcers.

Given the clinical polymorphism of anorectal CT infection, clinicians should have a high index of suspicion. Even though there are some predictors of LGV infection, clinical manifestations are not pathognomonic of a specific biovar; therefore, genotyping becomes a useful tool to define the length of treatment. If genotyping is not available, empirical treatment for LGV should be considered, particularly in the context of an LGV outbreak.

Footnotes

Acknowledgments

We are indebted to Dr Brenda Mangariello for carrying out the statistical analysis and to Professor Silvina V. González Lorenzo (Medical-Scientific-Technical Translator Es-En) for her assistance with the English version of the manuscript.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was partly supported by the Secretaría de Ciencia y Técnica de la Universidad de Buenos Aires grants [UBACyT 20020150100223BA, UBACyT 20020190100357BA].

ORCID iD

Luciana La Rosa

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