ARTICLE
Auteur(s) : B
Halioua1, JM Bohbot1, L
Monfort1, N Nassar1, B de
Barbeyrac2, J Monsonego1, P
Sednaoui1
1Institut Alfred Fournier, Paris
2Laboratoire de Bacteriologie, Universite Victor Segalen
Bordeaux 2, 33076 Bordeaux Cedex, France. Centre Nationale de
Référence de Chlamydia
accepté le 16 Decembre 2005
Lymphogranuloma venereum (LGV) or Nicolas-Favre disease is a rare,
sexually transmitted disease caused by serotypes L1, L2, L2a and L3
of the obligate intracellular bacterium Chlamydia trachomatis that
causes inflammation and drainage of certain lymph nodes,
destruction and scarring of surrounding tissue. This disease is
endemic in some parts of Africa, South East Asia, South America,
and some Caribbean islands. In the western world, the incidence is
low and most cases were considered to be imported in the past two
decades [1]. In 1936, Raoul Bensaude described LGV for the first
time, as acute primary proctitis in homosexual men [2]. This
clinical entity was the subject of a large study by Arthur W Grace
in 1943 from a series of 276 cases [3]. Ano-rectal lymphogranuloma
venereum (ARLGV) almost disappeared in Europe, but caused a revival
of attention after Nieuwenhuis et al. reported of a case of ARLGV
in 2003 in a Dutchman who did not report travel overseas [4]. At
the beginning of 2004 [5], several men who had sex with men (MSM)
in the Netherlands were diagnosed with LGV. An alert was sent to
the Early Warning and Reporting System of the European Union and to
the European Surveillance of Sexually Transmitted Infections
Network (ESSTI). By 1 September 2004, 92 cases had been confirmed
(30 in 2003 and 62 during 2004) [6]. A series of outbreaks of LGV
in western Europe have been reported in 2004 in Antwerp [7] (27
cases), in Stockholm [8] and in Germany at the Hamburg Institut für
interdiziplinäre Infektiologie und Immunologie [9]. In July 2004,
CDC identified an L2 LGV strain on a rectal swab specimen from a
patient in the United States who had signs and symptoms similar to
those observed in the patients of the Netherlands [10]. These
outbreaks were concentrated in sexual networks of MSM in large
cities, and appear to have been associated with the sex party
scene. In May 2004, an alert of French Institut de Veille Sanitaire
(INVS) reported that some Dutch patients with ARLGV had had sexual
contacts in France [11]. Further to this alert, the STI center of
Institut Fournier in Paris decided to undertake a retrospective
study of CT rectal strains over a 28 month period (January 2002-May
2004) and a prospective study through May 2004 and August 2004.
Materials and methods
During the study period, 154 MSM were screened for anorectal
sexually transmitted infections (STIs). A total of 216 swabs of
rectal discharge were reviewed for the study. Some patients had
more than one rectal sample medical visit. Routine bacteriological
tests including gram staining and cultures were performed.
Anorectal CT infections were diagnosed by conducting polymerase
chain reaction (PCR) (Cobas Amplicor Roche) tests on rectal swab
specimens. Positive Rectal CT samples were sent to the national
laboratory for Chlamydiae in Bordeaux for subsequent restriction
endonuclease pattern analysis of the amplified outer membrane
protein A gene in order to determine the genotype. A confirmed case
of ARLGV was defined as : rectum specimen PCR positive for CT and
detection of serovar L2 through genotyping. Serological tests were
also performed for CT (Chlamydia IgG seroFIA, Chlamydia IgM
seriFIA, Savyon diagnostics) and for syphilis (VDRL, TPHA). We
reviewed the medical records of the study patients to obtain
clinical and epidemiologic data.
Results
Among 216 swabs of rectal discharge from 154 homosexual or bisexual
males, 32 (14.8%) were positive for C. trachomatis (3 patients in
2002, 11 in 2003 and 18 in 2004). C. trachomatis-positive specimens
were genotyped to detect the specific C. trachomatis serovars. Of
the 32 genotyped C. trachomatis rectal strains, 22 were revealed as
serovars L(2) (respectively 1 in 2002, 9 in 2003 and 12 in 2004).
10 were respectively of serotype Da, E , F, G, J. All 22
patients infected with serovar L-2 were homosexual men. The
patients with LGV ranged in age from 28 to 52 years (mean age 39.2
years). Twelve of 21 subjects with an LGV diagnosis were
seropositive for human immunodeficiency virus (HIV) (one not done).
The average time between the beginning of the symptoms and the
diagnosis is 40.2 days (1-131 days). All the patients presented a
proctitis which was severe in 16 cases. 6 patients presented
exudative rectal ulcers. 11 patients reported mucus stool and 6
bloody diarrhea. A spontaneous draining fistulae was noted in one
patient. Three patients had a significant problem with tenesmus
while two complained of fever. Of the 22 patients, 14 had Chlamydia
trachomatis serology and 13 showed high immunoglobulin (Ig) titers
(> 512) to C. trachomatis, suggesting an invasive
infection. An enlarged screening for sexually transmitted
infections among 22 patients revealed 8 positive cultures for
Neisseria gonorrhoeae, 1 herpetic infection (positive culture for
Herpes virus simplex 2), 3 positive tests for syphilis compatible
with a probable recent syphilis (VDRL > 32/TPHA > 1000)
(figures 1, 2, 3).
Discussion
The increase of C. trachomatis infection with serovar L2 between
2002 and 2004 in our STI clinic suggests the beginning of an
outbreak among MSM in Paris. Because of the retrospective nature of
this study, we were not able to identify sexual contacts among
these men or detailed travel histories. Chlamydia trachomatis
infects the anorectal mucosa via oral-genital and rectal insertive
intercourse. Whereas serovars A-K are largely confined to mucosal
columnar epithelial surfaces of the genital tract and eye, the L2
serovars predominantly infect monocytes and macrophages, pass
through the epithelial surface to regional lymph nodes, and may
cause disseminated infection [12]. Factors associated with an
increased risk of acquiring ARLGV include multiple and anonymous
partners and other sexual activities such as unprotected anal
intercourse or ‘fisting’, mainly take place in sex parties, in
‘leather scene’ bars or saunas, as suggested by Nieuwenhuis et al.
[13]. ARLGV presenting with an acute haemorrhagic proctitis occurs
after a 3 day to 6 week (on average 10-14 days) incubation period.
During the acute phase, symptoms are anorectal pain, tenesmus,
diarrhoea, rectal ulcer, proctitis, anal fissures and loss of
blood, often associated to pronounced systemic features (fever,
discomfort, chills, and weight loss). A study [14] of the
prevalence, clinical spectrum, and histopathology of Chlamydia
trachomatis rectal infections suggests that the presence of LGV
immunotypes of C. trachomatis in the rectum is associated with
severe acute proctitis that mimics Crohn’s disease, whereas the
non-LGV immunotypes are associated with a mild proctitis with or
without symptoms [15]. Lymphadenopathy develops in draining nodal
basins (iliac, perirectal, inguinal, femoral) several weeks after
the initial infection. Inguinal bubo is often absent [16].
Rectoscopy reveals a granular or ulcerative proctitis, resembling
ulcerative colitis, confined to the distal 10 cm of the
anorectal canal [17]. ARLGV may be histologically indistinguishable
from Crohn’s disease of the rectum, thereby creating a diagnostic
and therapeutic dilemma [18]. Without treatment, ARLGV can have a
number of serious complications including perforation with
perirectal abscess [19], fistula formation, rectal fibrosis
resulting in marked luminal narrowing and stenosing anal mass.
Perirectal sinus tracts and/or rectovaginal fistula are best
demonstrated by MRI and fistulography. Lymphogranuloma venereum of
the rectum has been described as a rare cause of rectal strictures
or stenosis in the western world [20]. Rectal stricture of LGV
resembles malignancy, trauma, tuberculosis, schistosomiasis or
actinomycosis [21]. Association with rectal adenocarcinoma has been
reported but is rare [22]. The incidence of rectal cancer in
patients with ARLGV rectal stricture ranges from 2% to 5% [23]. In
a study of 106 LGV patients who subsequently developed carcinoma
rectum, Rainey proposed a causal relationship between the two
conditions, hypothesizing that chronic irritation by LGV
predisposes the rectal strictures to malignant transformation [24].
Positive diagnosis of ARLGV is difficult, requiring a combination
of good clinical acumen and supportive investigations. In the past,
ARLGV was diagnosed by the Frei skin test, which consisted of an
intradermal injection of purified Chlamydia trachomatis antigen
obtained from culture in yolk sacs of chicken embryos. Due to its
poor sensitivity and specificity, this test was abandoned in 1974.
Clinical diagnosis of ARLGV is confirmed if the causative agent is
microbiologically determined as serotype L1, L2, or L3. When
available, histopathological examination of biopsy specimens can
also support the diagnosis. C trachomatis can be identified in bubo
fluid following aspiration, or in ulcer material. This causative
agent can be isolated in tissue culture, using HeLa-229 or McCoy
cell lines, but this technique is not widely available. DNA
amplification assays – for example, polymerase chain reaction (PCR)
or ligase chain reaction (LCR)–, which detect Chlamydia specific
genomic or plasmid DNA, are the most sensitive tests available for
the diagnosis of genital C trachomatis infection but have not been
well evaluated for the diagnosis of LGV [25]. PCR has been used to
diagnose LGV in samples taken from genital ulcers in the Bahamas
[26]. The determination of chlamydial serology with
microimmunofluorescence (MIF) tests allows the distinction of
infections due to C trachomatis from infections due to C psittaci,
and from the common respiratory pathogen C pneumoniae. A high
serology titre count of antibodies IgG >1:1024 is strongly
suggestive for invasive Chlamydia infection at least of a possible
case of LGV. This result suggests that serologic tests would
support the diagnosis of ARLGV in clinical conditions where ARLGV
could be part of the differential diagnosis. The diagnosis of ARLGV
in our patients was confirmed for all 22 cases in our study
according to the recently published [27] CDC classification of
ARLGV; cases are considered as confirmed if there are 1) proctitis
or contact with a patient confirmed with LGV; 2) a positive PCR
test for C. trachomatis on rectal specimen; and 3) L1, L2, or L3
genotype determined by PCR. A case is classified as probable of
ARLGV if there is a clinical evidence and a positive serologic test
for C. trachomatis, even if it does not meet the third criterion
(if specimens are not available for genotyping). A case is
classified as possible if there is only the first criterion and a
positive serologic test.
The routine STD screening undertaken in patients with ARLGV in
our study showed the frequent co-prevalence with anorectal
gonococcal infection. Documentation on LGV and concomitant HIV
infection is limited. Scieux et al. suggested that HIV infection
does not influence the clinical presentation of LGV [28]. However,
it has been reported that HIV infected patients (mean CD4+ count:
0.66 × 109/l) with genital ulcer disease (GUD) are more
likely to present deeper, larger, and multiple lesions [29].
Proctitis or inflammation of the rectum, is a condition that is not
uncommon among MSM. In HIV-negative men, it greatly increases the
risk of acquiring HIV infection [30]. Regarding the extremely
contagious character of this affection and the well-known link
between ARLGV and the risk of HIV transmission, the patients must
rapidly be treated. No controlled double blind treatment
trials have been published on LGV. The therapy of choice is
doxycycline 100 mg orally twice daily for 21 days [31]. In the
event of intolerance to the drug, erythromycin 500 mg four times
daily orally for 21 days can be used as an alternative. In one case
of ARLGV, a single dose of 1 g azithromycin was effective [32].
Lymphedema in later stages may not resolve despite elimination of
the micro-organism. Fluctuant buboes should be aspirated, not
incised. Late complications such as rectal stricture may be
improved by antibiotic treatment, which reduces the inflammatory
component, but does not correct damage due to fibrosis.
Rectovaginal fistula, abcesses and bowel obstruction require
surgical correction in association with antibiotics. People who
have had sexual contacts with an ARLGV patient within the 30 days
before the onset of the patient’s symptoms should be examined,
tested for chlamydial infection and treated. The patient should be
followed up after apparently successful treatment until the results
of chlamydial tests are negative and clinical recovery. ARLGV in an
HIV-negative man should be considered as a sentinel event,
necessitating education, risk-education counseling, HIV testing,
and follow-up HIV testing 3 months after diagnosis.
In conclusion, our report describes an outbreak of ARLGV among
MSM in Paris. Physicians and MSM in France should be aware of this
LGV outbreak, which is similar to STD increases (e.g., in syphilis,
rectal gonorrhea, and quinolone-resistant Neisseria gonorrhoeae and
including co-infections with HIV) that have been reported in recent
years among MSM. Several questions remain concerning the
recrudescence of cases of ARLGV in Paris. Is there a risk of
transmission of ARLGV from anus to mouth? Why do all the patients
only show rectal infection and no urethral infections? Does
asymptomatic carriage exist in the rectum? Is serologic testing for
Chlamydia effective for screening? Is it the beginning of an
important outbreak in MSM? What is the incidence and prevalence of
ARLGV in France? It is difficult to answer because this STD is not
nationally reportable, and the diagnosis is not straightforward.
The clinical presentation of LGV can easily be missed, as evidenced
by the large number of retrospective cases identified in our
center. Physicians must be informed about the misleading
symptomatology of ARLGV (constipation, anal pain, tenesmus,
abdominal discomfort, diarrhoeas, anal pruritus, fever and general
weakness). This disease, although rare, should not be forgotten in
the differential diagnosis of rectal problems in male
homosexuals.
Thanks to Doctors Fabienne Castano, Amanda Baldin, Isabelle
Faure, Vincent de Parades, Denis Soudan, Josée Bourguignon, Franck
Gigon, Tony Andreani, Pierre Periac, Virginie Retourné-Nizet,
Patrick Santoni.
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