Chapter 203 :: Lymphogranuloma Venereum

:: Rim S. ishak & Samer h. ghosn

LYMPHOGRANULOMA VENEREUM `AT A GLANCE
Systemic sexually transmitted disease caused by L Hematogenous spread with manifestations of
serovars of Chlamydia trachomatis. systemic infection.

Endemic in Africa, Southeast Asia, and South and Diagnosis by identification of organism and by
Central America, and rare in developed countries. serology or genotyping.

Recent outbreaks among men who have sex with Doxycycline or erythromycin treatment curative if
men in Europe and North America. given early.

Clinically manifest as inguinal and anorectal

syndromes, in three stages. 2505
32

EPIDEMIOLOGY
Lymphogranuloma venereum (LGV) is a sexually
transmitted disease due to specific Chlamydia vari- ants
that is rare in developed countries. It is endemic in
East and West Africa, India, Southeast Asia, South and
Central America, and some Caribbean Islands; and
2506 accounts for 7%–19% of genital ulcer diseases in areas
1,2
of Africa and India. The peak incidence occurs in
persons 15–40 years of age, in urban areas, and in
individuals of lower socioeconomic status. Men are six
times more likely than women to manifest clinical
3
infection. The incidence of LGV is low in the devel-
oped world where cases are usually limited to trav-
elers or military personnel returning from endemic
Se areas. Since 2003, however, outbreaks of LGV have
cti appeared in Europe, Australia, and North America,
on particularly in the form of proctitis, among human
32 immunodeficiency virus (HIV) positive men who have
4–11
:: sex with men (MSM).
Se LGV is contracted by direct contact with infectious
xu secretions, usually through any type of unprotected
all intercourse, whether oral, vaginal, or anal. Trans-
12,13
y mission efficiency is unknown. Sexual practices
such as fisting and sex-toy sharing may be other
Tr 4
routes of transmission. In a recent study that com-
an pared sexual behaviors in men with LGV and men
sm with non-LGV chlamydial proctitis, fisting was a
itt 14
major predisposing factor. An epidemic of LGV
ed has been reported among “crack” cocaine users in
15
Di the Bahamas.
se Due to underdiagnosis and underreporting, the
as epidemiology of LGV remains poorly understood.
es Common diagnostic laboratory methods are non-
specific and not readily available in endemic areas.
Even in industrialized countries, only a few labora-
tories offer specific assays to LGV serovars. Without
such assays, many LGV cases are misdiagnosed as
common chlamydial urogenital infection. Underdi-
agnosis of LGV is also largely due to the presence of
an asymptomatic carrier state. Women, in particu- lar,
may harbor asymptomatic persistent infection in
the cervical epithelium, thus serving as reservoirs of
the infection as they do for other urogenital chla-
mydial infections and gonorrhea. Recently, a large
study conducted in the United Kingdom found
that only 6% of MSM were asymptomatic carriers
of LGV Chlamydia serovars; the majority of cases of
16
LGV in the rectum and urethra were symptomatic.
Infectivity in men usually ceases after healing of the
primary mucosal lesion. Interestingly, most of the
detected cases in the recent outbreaks are in men who
practice receptive anal sex, suggesting that a high
proportion of men who practice insertive anal sex are
mis- or scarlatiniform exanthema may occur with any of these
21
undiagno stages.
sed. The
reasons ETIOLOGY AND PRiMARy STAgE. Three to 30 days after infection,
behind PATHOGENESIS 5- to 8-mm painless erythematous papule(s) or small
this are herpetiform ulcers appear at the site of inoculation
22
unclear (Fig. 203-1). Painful ulcerations and nonspecific ure-
LGV (tropical or climatic bubo, lymphopathia 23
but may thritis are less common. In males, the lesion is
venerea, Nicolas–Favre disease) is caused by
be usually
Chlamydia tracho- matis serovars (serologic variants)
organism 17 found on the coronal sulcus, prepuce, or glans penis;
L1, L2, and L3.
-related, and in females on the posterior wall of the vagina,
Most of the recent outbreaks are caused by a
host- vulva, or, occasionally, the cervix. Inoculation may
number of strains of C. trachomatis L2 serovar (L2b),
related also
suggesting that these outbreaks most likely represent
(sexual 7– be rectal or pharyngeal. The primary lesion is
increased awareness of a slowly evolving endemic.
practices 9,16,18,19 transient,
such as often heals within a few days, and may go unnoticed.
Chlamydiae are obligate intracellular bacteria charac-
fisting
terized by two distinct morphologic forms: (1) the SECoNDARy STAgE. A few weeks after the pri-
and the
small metabolically inactive and infectious elementary
use of mary lesion appears, marked LN involvement and
body, and (2) the larger metabolically active and
sex toys, hematogenous dissemination occur, manifested by
noninfectious reticulate body. (eFig. 203-0.1 in online
intraveno variable signs and symptoms, including fever, myal-
edition). C. tracho- matis has been subdivided into
us drug gia, decreased appetite, and vomiting. Photosensi-
several serovars that dif- fer in their major outer
use, HIV tivity may develop in up to 35% of the cases, often
membrane proteins, and which are associated with
status, 24
several diseases. Serovars A, B, and C are the causes 1–2 months after bubo formation. Less commonly,
etc.) or
of trachoma ocular infections, whereas serovars D-K patients may develop meningoencephalitis, hepato-
physician
are responsible for ocular, genital and respi- ratory splenomegaly, arthralgia, and iritis.
25,26
The lymphad-
-related 20
infections. In contrast to the A-K serovars that enitis episodes often resolve spontaneously in 8–12
(failure
remain confined to the mucosa, LGV serovars are weeks. Depending on the mode of transmission, two
to
more invasive and have a high affinity for major syndromes are distinguished.
diagnose 17
macrophages. After being inoculated onto the
genital
mucosal surface, the organisms replicate within
LGV).
macrophages, and find their way to the draining
The
lymph nodes (LNs), and cause lymphadenitis.
resurgenc
e of LGV
as a
health
CLINICAL
problem FINDINGS
may
simply
reflect CUTANEOUS LESIONS AND
increased RELATED PHYSICAL FINDINGS
awarenes
s rather Clinical manifestations are protean, depending on
than the sex of the patient, acquisition mode, and the
increased disease stage. Three clinical stages characterize LGV.
incidence Nonspe- cific cutaneous lesions such as erythema
. nodosum, erythema multiforme, urticaria, and
 32

Ch
Figure 203-3 Lymphogranuloma venereum: bilateral, apt
firm, immovable masses above Poupart’s ligament.
er
20
which may rupture and drain through the skin,
form- ing sinus tracts. Bilateral involvement occurs 3
in one- third of the cases (Fig. 203-3). Nodal ::
enlargement on either side of the inguinal ligament, Ly
the “groove sign,” is pathognomonic of LGV, but m
Figure 203-1 Lymphogranuloma venereum: soft painless 27
only presents in 10%–20% of cases and is rarely ph
erosion on the prepuce. 28
bilateral. In women, inguinal lymphadenitis is og
unusual because the lymphatic drainage of the ra
The acute genital syndrome (GS) or inguinal syn- vagina and cervix is to the deep nu
drome is characterized by inguinal and/or femoral pelvic/retroperitoneal LN. When these nodes are lo
LN involvement and is the major presentation in involved, low abdominal/back pain that exacerbates
m
men. Initially, the skin overlying the affected LN is upon lying supine and pelvic adhesions may ensue.
The acute anorectal syndrome (ArS) is character- a
erythematous and indurated. Over the subsequent Ve
1–2 weeks, the LN enlarge and coalesce to form a ized by perirectal nodal involvement, acute hemor-
rhagic proctitis, and pronounced systemic ne
firm and tender immovable mass (bubo) (Fig. 203-2),
symptoms. It is the most common presentation in re
women and in homosexual men who practice anal u
sex. The major source of rectal spread in women is
the internal lym- phatic drainage of the lower two-
thirds of the vagina. Patients may complain of anal
pruritus, bloody rec- tal discharge, tenesmus,
5,29
diarrhea, constipation, and lower abdominal pain.
In a recent study, 96% of MSM patients presented
30
with signs and symptoms of proctitis. Despite
affecting mostly HIV-positive MSM, LGV has not
behaved as an opportunistic infection in the recent
outbreak, and clinical features have not differed
31
between HIV-positive and HIV- negative cases.

TERTiARy STAgE. This stage is more seen in

women with untreated ArS, and includes rectal
strictures (most common) and abscesses, perineal
sinuses, rectovaginal fistulae (leading to “water-
ing can perineum”), and “lymphorrhoids” (perianal
outgrowths of lymphatic tissue). Esthiomene (Greek,
“eating away”) is a rare primary infection of the
exter- nal genitalia (mostly in women), leading to
Se
progres- sive lymphangitis and genital destruction.
cti Infertility and “frozen pelvis” are potential sequelae
on of ruptured deep pelvic nodes in women. Late
32 sequelae of the GS are less common and include
:: Figure 203-2 Early bubo consisting of unilateral en- urethral strictures and genital elephantiasis with
Selargement and coalescence of inguinal lymph nodes. The ulcers and fistulas (in 4% of cases).
32
Penile
xuoverlying skin is erythematous and indurated. Note the deformities such as the saxophone penis may also
allabsence of the primary lesion in this case. (Used with per-
occur.
33

y mission from Shukrallah Zaynoun, MD.) 2507

Tr Extragenito-anal inoculation of LGV

32
an
sm
itt
ed OTHER UNUSUAL MANIFESTATIONS
is rare. Oropha- ryngeal infection
may manifest initially as pinhead-
sized vesicles on the lip, and later on
as cervical lymphadenopathy with
Di constitutional symptoms, closely
se mimicking lymphoma. Tonsillitis,
as
 supracla- vicular and mediastinal lymphadenopathy,
34–38
and peri- carditis rarely occur. Ocular
autoinoculation of infected discharges may lead to
conjunctivitis with marginal corneal perforation, often
39
with preauricular lymphadenopathy. Inhalation of
LGV serovars L1 and L2 may accidentally occur in
laboratory workers and lead to pneumonitis with
40
mediastinal and supra- clavicular lymphadenopathy.
LABORATORY TESTS
Diagnosis of LGV may be difficult, but LGV should be
suspected in any patient with infected sexual contacts,
genital ulcer, perianal fistula, or bubo. The accuracy
of clinical diagnosis has been reported to be as low
41
as 20%. Therefore, laboratory tests are important to
establish the diagnosis and are usually divided into
two broad categories: (1) nonspecific tests that do not
distinguish between LGV and (2) non-LGV serovars,
and specific LGV tests. In practice, a positive test on
LN aspirate is considered diagnostic of LGV, in con-
trast to a positive test on primary genital lesion where
further specific testing is required to rule out common
chlamydial urogenital infections.
SPECIFIC TESTS FOR
LYMPHOGRANULOMA VENEREUM
Nucleic acid amplification using polymerase chain
reaction (PCR) may be performed on all specimens,
and has been the diagnostic method of choice in the
recent outbreak. Several generations of PCR analy-
sis have been developed over the past decade; how-
ever, most of them lacked the ability to differentiate
between LGV and non-LGV strains. In 2008, a new
diagnostic technique with a quadriplex reverse tran-
scriptase PCR assay was developed. This unique
technology can detect individual LGV and non-
LGV infection, as well as mixed infections in rectal
specimens. However its main disadvantage is that it
is available only in the Centers for Disease Control
42
and Prevention and in a few US laboratories. Other
newly introduced biomolecular techniques exploring
23 43,44
immune-mediated lysis, heparin sulfate lysis,
18
use of pooled antibody, and structural genetic dif-
45
ferences seem to be promising.
NONSPECIFIC CHLAMYDIAL TESTS
The complement fixation test is the most commonly
used test. Titers greater than 1:256 are highly sugges-
tive of LGV and titers below 1:32 exclude the diag-
46
nosis unless the disease is in its early stages. The
2508
Box 203-1
LyMPhogRANULoMA
SPECiFiC)
Primary stage
microimmunofluorescence test for the L-type serovar
is more sensitive & specific but less readily available.
47
In addition, culture studies may be preformed; how-
ever, they do not distinguish between LGV and non-
LGV serovars, are tedious, and require special growth
media. Nevertheless, a positive culture without cen-
trifugation is highly suggestive of LGV.
In addition, direct fluorescence microscopy using
conjugated monoclonal antibody against C.
trachomatis on smears from bubo material or genital
48
swab can be done. Serology assays are sensitive but
nonspecific due to cross reactivity with other
chlamydial infec- tions. In addition, they do not
differentiate current from prior infection. Frei test, the
earliest diagnostic modality to identify LGV, consists
of an intradermal skin test assessing delayed
hypersensitivity to chla- mydial antigens. It is no
longer used because of its low sensitivity and
limited specificity due to cross reaction with C.
17
trachomatis D-K. Finally, other non specific
laboratory findings include mild leukocytosis, false-
positive VDRL, cryoprecipitates, rheumatoid fac- tor,
and high serum levels of immunoglobulin A and
49
immunoglobulin G.
DIAGNOSTIC PROCEDURES
Bubo aspiration to obtain material for culture and
direct microscopy should be performed through a lat-
eral approach, and may require injection of 2–5 mL of
sterile saline before the aspiration due to the paucity
of milky fluid.48 Proctoscopic examination reveals, in
the setting of the ArS, multiple discrete and irregular
superficial ulcerations and friable granulation tissue,
usually confined to the distal 10 cm of the anorectal
canal.
50,51
HISTOPATHOLOGIC EXAMINATION
Primary lesions reveal nonspecific ulceration with
granulation tissue, and endothelial swelling. Organ-
isms are rarely demonstrated using Giemsa stain.
Biopsy of affected LN reveals suppurative granulo-
matous inflammation. Necrotic foci may enlarge into
stellate abscesses, which, in turn, may coalesce into
discharging sinuses. These findings are not specific to
LGV and can be found in chancroid, cat-scratch dis-
ease, tularemia, and some deep fungal infections. The
pathology of LGV-proctocolitis is similar to that of
Crohn disease and includes crypt distortion, submu-
cosal fibrosis, and follicular inflammation with occa-
50
sional granuloma formation.
DIFFERENTIAL DIAGNOSIS
(See Box 203-1)
In contrast to LGV primary stage, chancroid ulcers
are usually larger and more painful, and granuloma
inguinale ulcers have abundant friable granulation
tissue without associated lymphadenitis. Acute GS
may be hard to differentiate from chancroid. Buboes
DiFFERENTiAL DiAgNoSiS oF
VENEREUM (STAgE
 Ulcerogenital diseases (herpes simplex virus,

32 chancre, chancroid, granuloma inguinale)

Neisseria gonorrhoeae and/or common chlamyd-
ial urogenital infection
COMPLICATIONS 32
Noninfectious causes: trauma, Zoon balanitis, In addition to the complications seen in the tertiary
fixed drug eruption stage, the ulcerative nature of LGV may facilitate the
Secondary stage acquisition and transmission of blood-borne pathogens
52 17
such as HIV and hepatitis C. LGV may also lead to
Acute genital syndrome
immune disturbances ranging from mild gammaglobu-
Ulcerogenital diseases with lymphadenopathy linemia to rare but fatal immunoblastic lymphoma.
53

(syphilis, chancroid, herpes simplex virus) Recently several case reports have described an
incarcerated inguinal hernia associa- tion between LGV and sexually acquired
Reactive inguinal lymphadenitis to a lower reactive arthri- tis (SARA) in HLA-B27 positive
54,55
individuals.
extremity focus of infection
Bubonic plague (in endemic areas)
Acquired immunodeficiency syndrome PROGNOSIS AND CLINICAL
Kaposi sarcoma
COURSE Ch
Tularemia apt
Mycobacterial infections er
Antibiotic treatment, if given early, is curative, with
Acute anorectal syndrome the acute ArS responding more dramatically than the
20
inflammatory bowel disease acute GS. 3
oropharyngeal lymphogranuloma venereum ::
Ly
Lymphoma
infectious mononucleosis
TREATMENT m
ph
Cat-scratch disease Oral doxycycline, 100 mg twice daily for 3 weeks, is og
Tertiary stage the treatment of choice. When contraindicated, oral ra
Malignancy eryth- romycin base, at a dose of 500 mg four times a nu
Filariasis and other parasitic infections day for lo
Pseudoelephantiasis (no lymphadenitis) of 3 weeks, may be given. Treatment with azithromycin m
56
(1 g once weekly for 3 weeks or in a single dose) is a
tuberculosis and granuloma inguinale likely curative but still lacks data regarding its efficacy
Deep fungal infection and safety in pregnancy. It should be noted that the
Ve
hidradenitis suppurativa duration of treatment needed to eradicate C. trachoma- ne
Trauma tis is longer for the LGV serovars compared with the re
other less invasive serovars of C. trachomatis. There- u
fore, when in doubt about the Chlamydia serovar, a
3-week course of antibiotics is advised. Therapy may
be prolonged in HIV-positive patients and, in general,
containing little or no pus are, however, more likely to should not be stopped until the complete resolution of
44
be caused by LGV. Suspecting LGV proctitis in HIV- all signs and symptoms (Box 203-2).
positive MSM who present with signs and symptoms Surgery is often required in late stages and includes
of Crohn’s disease is important, even in the absence lateral aspiration of buboes through intact skin (direct
of LGV pathognomonic findings. Both conditions incision has a high risk of fistula formation), rectal
have similar proctoscopic findings; however, Crohn’s stricture dilatation, abscess drainage, rectovaginal
dis- ease is more proximally localized. fistula repair, genital reconstruction, and colostomy.
Avoidance of sexual activity until complete resolution
57
of signs and symptoms is important.

PREVENTION
LGV seems to be a rapidly spreading universal prob-
lem. Effective control should include periodic evalua-
tion of high-risk individuals, reinforcement of health

Box 203-2 TREATMENT oF LyMPhogRANULoMA VENEREUM

First line oral doxycycline 100 mg bid 3 weeks
Second line oral erythromycin 500 mg qid 3 weeks
Third line oral azithromycin 1 g once weekly 3 weeks
2509
treated. LGV case reporting should
be mandatory by law for more
reliable monitoring of prevalence
8
education aiming at early recognition and counsel- trends.
ing, improving community and clinician awareness of
LGV, and increasing the availability of specific diag-
nostic tests. All sexual contacts should be traced and KEY REFERENCES
 Full reference list available at
www.DIGM8.com 8. Blank S, Schillinger JA, Harbatkin D: Lymphogranu-
loma venereum in the industrialised world. Lancet
DVD contains references and additional content 365(9471):1607-1608, 2005
16. Ward H et al: The prevalence of lymphogranuloma vene-
2. Goeman J, Piot P: The epidemiology of sexually transmit- reum infection in men who have sex with men: Results
ted diseases in Africa and Latin America. Semin of a multicentre case finding study. Sex Transm Infect
Se Dermatol 85(3):173-175, 2009
cti 9(2):105-108, 1990 17. Kapoor S: Re-emergence of lymphogranuloma venereum.
on J Eur Acad Dermatol Venereol 22(4):409-416, 2008
32 42. Chen CY et al: A real-time quadriplex PCR assay for the
diagnosis of rectal lymphogranuloma venereum and non-
:: lymphogranuloma venereum Chlamydia trachomatis in-
Se fections. Sex Transm Infect 84(4):273-276, 2008
xu 57. Workowski KA, Berman SM: Centers for Disease Control
all and Prevention sexually transmitted diseases treatment
y guidelines. Clin Infect Dis 44(Suppl 3):S73-S76, 2007
Tr
an
sm
itt
ed
Di
se Chapter 204 :: Granuloma Inguinale
as
es :: Abdul-ghani Kibbi, Ruba F. Bahhady,
& Myrna El-Shareef
3
nantly affects sexually active individuals. Moreover,
GRANULOMA INGUINALE donovanosis, being an ulcerative disease, increases the
AT A GLANCE risk of human immunodeficiency virus (HIV) trans-
4–6
mission. Transvaginal transmission of donovanosis
Granuloma inguinale or donovanosis is a during delivery has been reported, with an apparent
7,8
chronic ulcerative debilitating disease that predilection to ear structures of the newborn.
mainly affects the genital organs. Patients tend to belong to the low socioeconomic
9–11
classes. No racial predilection has been proved, and
both male and female predominance have been
Caused by the Gram-negative bacteria 5,6,11
reported.
Klebsiella granulomatis.
Afflicted people are likely to delay seeking medical
attention due to the painless nature of the ulcers and
Affects mostly people of lower the possible embarrassment or fear from medical or
socioeconomic status living in the tropical surgical intervention. Late cases can be very debilitat-
and subtropical areas. ing and are much more difficult to manage.
12

GI is endemic in warm, moderately humid areas

Diagnosis is made by demonstrating like South Africa, India, Southern China, and Brazil.
5,13

intracellular Donovan bodies on histology. There are new endemic areas of donovanosis, mainly
South and Central America, India, and Papua New
12
Guinea, but the overall incidence of GI seems to be
1
decreasing, especially in Papua New Guinea. The dis-
EPIDEMIOLOGY AND MODE ease has nearly been eradicated from Australia, with
14
only five cases reported in 2004, and is rare in North
OF TRANSMISSION America and Europe.
15–17

The mode of transmission of granuloma inguinale (GI) ETIOLOGY

is controversial. It is generally considered sexually
transmitted, but fecal contamination and autoinocu-
lation remain a possibility, especially in the setting of
infected children and adults without sexual activity
and primary involvement of remote extragenital
sites.
1,2
Transmission rate between sexual partners is low com-
pared with other sexually transmitted diseases and
was found to be not more than 50%. The incidence of
GI is also relatively low among both prostitutes and
2510 their conjugal partners. Nevertheless, this disease
predomi-
Donovanosis is caused by the organism Klebsiella gran-
ulomatis, previously called Calymmatobacterium gran-
ulomatis. The name has been changed after sequencing
the phoE and 16S ribosomal RNA genes and demon-
strating close homology with Klebsiella pneumoniae and
5,12
Klebsiella rhinoscleromatis.
K. granulomatis is a Gram-negative, nonmotile,
pleomorphic bacterium that stains well with Giemsa,