Pelvic Infections in Women: Belgian guidelines
Ameryckx L.
(UZ Brussel)
Degueldre M.
(CHU St.Pierre)
Donders G.
(VVOG)
Foidart J.M.
(GGOLF-B)
Jacquemyn Y.
(UZ Antwerpen)
Nisolle M.
(CHU de Liège)
Peetermans W.
(UZ Leuven)
Squifflet J.M.
(CU Saint Luc)
Verguts J.
(UZ Leuven, coordinator)
Weyers S.
(UZ Gent)
Outline
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Definition and classification
Etiology, pathogenesis and risk factors
Clinical evaluation
Diagnostic testing
Long term sequelae
Tubo-ovarian abscess
Clinical management
Prevention of PID
Follow up
References
1.
Definition and classification
a. Definition
Pelvic inflammatory disease (PID) is defined as an ascending infection from the endocervix of
the uterus, fallopian tubes or ovaries often related to sexual contact. Therefore, other pelvic
infections caused by surgery, during pregnancy or due to other abdominal processes are not,
strictly considered, ‘PID’ and are not in the scope of this recommendation. This stringent
diagnosis implying the need for sexual contact is controversial because very often only
endogenous intestinal microorganisms can be recovered from the genital tracts of women with
pelvic infections, and their sexual partners do not seem to be infected.
b. Classification
PID has characteristically been considered to have 3 grades of severity based on laparoscopic
findings. PID grade 1 means there is either endometritis or erythema of the salpinx, or a
combination of both. In a grade 2 PID, the salpinges are dark red and swollen (edema). In a
grade 3 PID the salpinx is filled with pus (pyosalpinx) and exudation is found in the pelvis.
Tubo-ovarian abcedation (TOA) is also PID grade 3 according to the definition. A tuboovarian complex is a name used for oedema of the salpinx which is adherent to the ovaria,
uterus, pelvic wall, and/or bowel, but without abscedation. In clinical practice the grading is
not always clear.
2.
Etiology, pathogenesis and risk factors
There are no Belgian data on prevalence, but a recent study showed an average incidence of
120.5 cases of PID with hospitilization per 100.000 women in Sweden over a 15 year period
(1990-2004) with a decreasing trend where incidence is now 62.3 per 100.000 women1
Of women with symptomatic PID, 15-20% suffer complications requiring surgical
intervention. The prevalence of asymptomatic PID is unknown.
Whenever the cervical barrier becomes damaged, bacteria can ascend from the vagina to
infect the upper genital tract2. The importance of this ascending route is emphasized by the
finding that 75% PID of cases start during the first 7 days after menstruation 3;4.
a. Etiology: A number of urogenital pathogens have established roles in PID.
i. Chlamydia trachomatis
In the mid 1970s it became clear that C. trachomatis was a frequent cause of PID. After a
dramatic decline in prevalence of both incidence and complications (neonatal conjunctivitis,
tubal factor infertility, ectopic pregnancy) as was noted in Europe5-9, and in many developed
countries10;11 a resurge of C. trachomatis infected women appeared first in Sweden, and
subsequently in other European countries12-14. This apparent increase may reflect better
detection methods, higher sampling frequencies, or an increase in unsafe sexual practices in at
risk populations15. Also, some formerly unknown strains were detected in Scandinavia that
were not detected using routine PCR techniques12. Recently some fluoroquinolone-resistant
strains have been discovered16.
The incubation period for a C. trachomatis infection is 2-to-3 weeks. Once infected, C.
trachomatis can remain silent for months if left untreated. The PID rate after an untreated
infection is estimated to be 8-to-40%.7 It is estimated that approximately 70% of C.
trachomatis infections remain asymptomatic. Asymptomatic salpingitis can cause tubal
damage and subfertility without any clinical signs.
After initial infection with C. trachomatis the risk of silent progression with intra-tubal
scarring is high, in part due to up-regulation of heat shock proteins18. Chlamydia antigens can
mimic the autologous human antigens triggering reflex production of heat shock proteins that
normally provide a useful defense against nonspecific challenges such as extreme
temperatures or environmental toxins. With recurrent infections and production of heat shock
proteins nonspecific inflammation may be triggered by various causes, resulting in extensive
scarring, even if no active Chlamydial organisms are present. The result is an increased risk of
ectopic pregnancies and infertility18;19. Besides salpingitis, Chlamydia may also cause
mucopurulent cervicitis, urethritis and endometritis.
The diagnostic method of choice for detection of C. trachomatis is polymerase chain reaction’
(PCR)-based testing. These tests have an estimated sensitivity of 86%, a specificity of 99.5%,
and provide the opportunity for simultaneous testing for N gonorrhoea
20;21
. Testing can be
performed on urethral or cervical swabs, or on urine, produced without washing or
desinfecting the urethra, preferably from the first void in the morning, or at least 4 hours after
micturition. Care has to be taken that the first part of the sample is included. Alternative, but
less accurate testing is antigen detection by ELISA. Culture methods have a specificity of
100%, but their sensitivity is only 50 to 80%.
Chlamydial cervicitis or urethritis can be treated by single oral dose of 1 g azithromycin or 7
days of oral doxycycline (100 mg by mouth twice daily). During pregnancy, C. trachomatis
can cause amnionitis and post-partum endometritis. Although off-label, azithromycin can be
used safely during pregnancy, and represents the treatment of choice22.
ii. Neisseria gonorrhoeae
N. gonorrhoeae was the first identified cause of PID. Following availability of penicillin,
gonorrhoea became less frequent. However, worldwide 1/3 of all PID cases are caused by N
gonorrhoeae. The incubation period for a N. gonorrhoeae infection is 2-to-7 days.
Although 30-60% of women harbouring N. gonorrhoeae have no symptoms, such
asymptomatic carriers can transmit the infection to others. If not detected and treated, N.
gonorrhoeae will cause PID in 10-30% of infected women7. Twenty-thirty % of the women
harboring N. gonorrhoeae are also infected with C. trachomatis23. The most frequent
symptoms include a yellow-green leucorrhoea and pelvic pain; on inspection a mucopurulent
cervicitis is often visualized.
Although PCR is very reliable and much faster, culture remains the best test for N.
gonorrhoeae, as it also allows for sensitivity testing for antibiotics.21. Ideally, Thayer-Martin
medium (chocolate agar with antibiotics inhibiting other bacteria) is used, providing 65-85%
sensitivity for asymptomatic infections and 100%, specificity, but a regular chocolate agar can
also be used. Fast transport is crucial, due to the short ex vivo survival time of N.
gonorrhoeae. To increase sensitivity, the endocervical and/or urethral swab should be
inoculated into a specific transport medium.
Treatment options did include: 500 mg ciprofloxacin, 1g azithromycin, or ceftriaxon 125 mg
IM of IV. However, increasing antimicrobial resistance to fluoroquinolones up to 47% in
Belgium has been documented24;25. The CDC recommends ceftriaxone 125 mg IM or IV as
the treatment of choice. In Belgium ceftriaxone is only available in a 1g formulation.
iii. Facultative aerobic Gram negative bacteria
Gram-negative rods, such as Escherichia coli, Enterobacter spp., Klebsiella spp., Proteus spp.
and Gardnerella vaginalis, are often recovered in PID cases34. The etiology is unclear, as
these organisms can also be seen as facultative pathogens and in cluster analysis their
presence in the vagina was not a primary risk factor for PID35.
iv. Aerobic Gram positive cocci
Staphylococcus spp, Streptococcus spp (especially Streptococci Lancefield groups A and B)
and Enterococcus sp. (Streptococci groups D and F) are often found as sole pathogens28, but
as with Gram-negative rods, their exact role in the etiology is unclear. .
v. Anaerobes
Anaerobic bacteria, such as Bacteroides fragilis, Clostridium spp, and Peptostreptococcus,
are present in many PID patients and are always treated26-30. Most, if not all, of these
anaerobic bacteria are highly sensitive to nitro-imidazol. derivates (i.e., metronidazole,
ornidazole, and tinidazole) and to amoxicillin/clavulanic acid.
In the US, several life threatening cases with ascending Clostridium were observed after the
use of vaginal misoprostol to induce an abortion31-33. As only vaginally applied misoprostol
may cause this lethal infection34, it is advised to use it orally, as is common in Europe.
vi. Tuberculosis
Genital tuberculosis characteristically presents as a chronic, latent infection diagnosed in an
infertility evaluation. The infection is often secondary to hematogenous spread from a nongenital source35. The fallopian tubes and endometrium are most often infected. When
associated with ascites and peritonitis, genital tuberculosis can present a diagnostic dilemma
often confused with carcinomatosis peritonitis or ovarian malignancies36-37. Confirmation
requires biopsy with specific endometrial cultures, preferably during menstruation. Specific
cultures of intra-abdominal abscesses may also lead diagnosis. If suspected, detection of
tuberculosis in other organs such as the lungs can be helpful. Patients at high risk are
immigrants, HIV-infected patients, imprisoned women, or patients with a history of alcoholor injection drug use.
vii. Actinomyces
Actinomyces israelii is a Gram-positive anaerobic bacterium usually recovered from the upper
respiratory or gastrointestinal tracts. PID is rarely caused by this organism due to
hematogenous spread from another location, or ascending infection from the vagina in women
with copper-containing intrauterine contraceptive devices (IUCDs)38. Colonization of the
lower genital tract is frequent in the presence of IUCDs and increases with duration of use
40
.
38-
In rare cases severe pelvic infections may occur, mimicking pelvic malignancies41.
Incidental detection of Actinomyces spp. on Pap smears does not need to be treated if
asymptomatic. In contrast, if the IUCD is in place for longer than 4 years, or if the infection is
found on more than one occasion during 12 months, then IUCD removal should be
considered. After removal of the IUCD, infection usually disappears spontaneously without
complications. A new IUCD can be inserted 1 or 2 months later. A. israelii is sensitive to
penicillin, but once endometritis is present, treatment with low dose penicillin should be
continued for weeks to months. Care has to be taken not to misdiagnose pelvic actinomycosis
as a pelvic cancer, because infection can mimic locally extensive ovarian cancer, both on
diagnostic imaging, or during surgical procedures like laparoscopy and laparotomy41-43.
Attempts to remove the ovaries and uterus in patients with actinomyces have lead to lethal
complications44
viii. Mycoplasma
a. Mycoplasma hominis
M. hominis is one of the smallest known bacteria. Because these bacteria do not have a cell
wall, diagnosis cannot be made by microscopic examination of fresh vaginal fluid or Gram
stains. Also, antibiotics inhibiting cell wall synthesis have no effect, and antibiotics targeting
protein synthesis are recommended. The treatment of choice is 1g azithromycin once or
doxycycline 100mg twice daily for 7 days25.
Studies from the 1970s found M. hominis more often in fallopian tubes of women with
clinical PID (4/50), but not in asymptomatic women (0/50) and serologic evidence linked
Mycoplasma with PID45;46. Still, the exact role of M. hominis in PID remains controversial27.
b. Mycoplasma genitalium
Taylor-Robinson and co-workers showed that M. genitalium, a formerly Mycoplasma, was
ubiquitous worldwide and was associated with pelvic infections47;48. Later studies clearly
confirmed the link between M. genitalium and clinical PID in the absence of concomitant
STIs, such as C. trachomatis and gonorrhea47;48. These findings supported different PID
treatment regimens for women harboring M. genitalium, because metronidazole –
doxycycline regimens had success rates of only 35-to-55%
52
. Furthermore, treatment with
cefoxitin and doxycycline plus azithromycin does not provide reliable eradication of M
genitalium53. Hence more studies about the pathogenesis and treatment of this novel
microorganism seem warranted49.
c. Ureaplasma urealyticum
U. urealyticum is part of the normal genital flora of both men and women. It is found in about
70% of sexually active humans.
It had also been described to be associated with a number of diseases in humans, including
non-specific urethritis (NSU), infertility, chorioamnionitis, stillbirth, premature birth, and, in
the perinatal period, pneumonia, bronchopulmonary dysplasia and meningitis.
However, given the relatively low pathogenicity of the organism its role in some of these
diseases remains contentious.
c. Risk factors
The risk of PID is related to the number of lifetime sexual partners of both the woman and her
sexual partners54. Apart from this, the frequency of sexual contact increases the risk of
bacterial vaginosis, a condition linked to STIs, such as C trachomatis, trichomoniasis and
gonorrhea55 and with PID27. (Table 1) PID due to Chlamydia is primarily found in young
women (15-25 years of age). In general PID is seldom encountered in women older than 35
years of age
56;57
. Possible explanations include an increased immunity, differences in sexual
behaviors, or other factors.
Use of barrier methods (e.g., condom, pessary, etc) is largely protective against PID.
However, in some studies barrier contraception reduces transmission of C. trachomatis and N.
gonorrhoeae only by 50%
58;59
. This can be explained by the fact that protection against
transmission is only significant in perfect users, an aim that is seldom achieved even in well
controlled studies incorporating extensive counselling58;59. Oral contraceptives and
intramuscular depot medroxyprogesterone also seem to protect against ascending infection
and PID, but not against Chlamydial cervicitis60;61. Copper-containing IUCDs do not increase
PID risk, unless the device is inserted in women with an STI
62;63
or when an older type of
IUCD was used64 . Randomized studies found a lower PID risk with levonorgestrel-containing
IUCDs than with copper-containing IUCDs65-67
3.
Clinical presentation
a. Medical history
Specific information should be elicited about presence of fever during the last 2 weeks,
general malaise, bilateral lower abdominal pain, or pain when moving or being transported.
Genital symptoms should be evaluated including the amount and characteristics of vaginal
discharge, post-coital bleeding, deep dyspareunia and abdominal pain with radiation to the
interior thighs. Typically, the symptoms appear during the first 7 days after menses 2. Presence
of predisposing and risk factors (described above) increase the likelihood of PID. At least one
third of the patients with PID have irregular vaginal bleeding. If a patient presents with
metrorrhagia, postcoital or intermenstrual bleeding and/or menorrhagia, PID should always be
considered68.
b. Clinical findings
There is no clear consensus on the confirmatory clinical criteria supporting PID diagnosis.
Minimal diagnostic criteria should include: 1) lower abdominal sensitivity and 2) painful
adnexae or cervix on palpation. Urinary infection, lumbar disk disease and torsion of an ovary
have to be excluded. A differential diagnosis has to be made and may alter according to age,
presentation,… (Table 2) Additional criteria supporting PID diagnosis are: T°>38.5 °C,
purulent cervical discharge, pelvic imaging (ultrasound, CT-scan) suggesting tubo-ovarian
abscess, increased inflammatory parameters (e.g., elevated C-reactive protein, leucocytosis
>10.000 /ml, elevated erythrocyte sedimentation rate, etc.), presence of C. trachomatis or N.
gonorrhoeae, or histopathologic evidence of endometritis.
In older studies, an elevated erythrocyte sedimentation rate, temperature above 38°C and
adnexal tenderness were predictive for 65% of laparoscopy-confirmed PID. C-reactive protein
represents a more accurate marker than the erythrocyte sedimentation rate for assessing
inflammatory activity and is typically used for monitoring patients68.
i. Abdominal examination
During abdominal palpation, attention must be given to muscular resistance, rebound
tenderness and pain on percussion. Pain localized in the right upper abdomen suggests
possible perihepatitis with formation of local adhesions, also known as the Fitz-Hugh Curtis
syndrome. In a first episode of PID, the pain never lasts longer than 2 weeks69.
ii. Genital examination
Redness and edema of the vulva, vagina and, most importantly, the cervix are suggestive for
an infectious process. The vaginal discharge can vary from grayish watery and foamy, to
yellow green and muco-purulent. An inflamed cervix has deep red to blue color, appears
edematous and bleeds easily when touched. Typically, thick green-yellow mucus may be
visible in the os. Even when the mucus appears clinically normal, mucopurulent cervicitis can
be diagnosed microscopically even when the mucus appears clinically normal.
Bimanual vagino-abdominal palpation may show motion tenderness of the uterus and pain
upon pushing the uterus towards the abdomen. Tenderness and pain in the adnexal region is
suspicious for severe PID; bilateral pain is more suggestive for this than unilateral tenderness
or pain. Sensitivity of this criterion of uterine and/or adnexal tenderness is 96%, but
specificity of this finding is extremely low (4%)70. Therefore, immediate initiation of
antibiotics based on this symptom alone of uterine or adnexal tenderness would lead to a
tremendous risk of overtreatment and should be discouraged
Clinical diagnosis of PID is imprecise and misses one third of cases proven by laparoscopy.
Therefore, laparoscopic diagnosis remains the ‘gold standard’, and in doubtful cases
laparoscopy is advised before starting therapy. Cultures from vagina, cervix and urethra taken
at the initial visit before starting therapy are sometimes crucial for adjusting the antibiotic
choice if to the patients does not respond to treatment.
iii. Fever
Fever only occurs in 50% of women with PID. Therefore, fever not a reliable sign.
Temperature above 38.5°C is always alarming and requires intensive diagnostic work-up.
4.
Diagnostic testing
a. Lab tests
i. Serum
Signs of acute infection are accompanied by leucocytosis above 10.000/ml. C-reactive protein
is invariably increased and represents an excellent marker to follow the course of the disease
and the effect of treatment. Even when clinical signs and leukocytosis resolve, persistence of
elevated C-reactive protein suggests beginning abscess formation. Human chorionic
gonadotropin (βHCG) should be evaluated to exclude ectopic pregnancy, imminent abortion
or septic abortion, as these conditions may mimic PID.
CA 125 is usually a marker for follow-up in other diseases, it can be used in post-menopausal
women to exclude malignant intra-abdominal processes of ovaries, uterus, stomach, liver or
pancreas, but CA 125 can be also be elevated in patients with endometriosis, PID and
hepatitis, although the former 2 are only sporadically encountered after menopause.
ii. Microbiology
Cervical cultures for gonococci, aerobic bacteria, and PCR for Chlamydia (cervix, urethra
and/or urine) should be performed, as well as urinary cultures. The use of molecular
techniques for diagnosing infections has lead to a tremendous increase in accuracy of
diagnosis and rapidity of obtaining results in comparison to often laborious, less sensitive and
slow techniques of culturing the specimens obtained from patients. Especially mycoplasmata
are very difficult to culture and much more easily detected by molecular techniques 71. In
Australian STD clinics Ureaplasma parvum and urealyticum were recovered in 37% of cases,
Mycoplasma genitalium in 1.3%, and M. hominis in 13.7%, but also unexpected and difficult
to detect infections such as T. vaginalis (3.4%), varicella zoster virus (4.7%), cytomegalovirus
(6%) and herpes virus infections (3.5%) were readily detected in cervical swabs by multiplex
PCR’s72. On the other hand, in only 0.4% Streptococcus agalactiae (GBS) was confirmed, a
very low rate suggesting that some primers may be suboptimal for certain microorganisms
and pointing to the need of supplementary culture techniques in specific infections, such as
GBS and N. gonorrhoeae71;72. Also the transportation fluid and the method of extraction can
have a tremendous influence on the detection rate for microorganisms such as
M.
genitalium73. For M. genitalium culture techniques are too fastidious and difficult, PCR being
the only practical way to detect these organisms71. Another interesting and rapid method for
detecting M. hominis and U. urealyticum is the Mycoplasma Duo kit using A7 differential
agar for the detection of M. hominis and U. urealyticum in clinical samples. Detection of the
mycoplasmata is based on the specific metabolic properties of each organism to hydrolyse
either arginine or urea. The Mycoplasma Duo test showed a significantly higher detection rate
than did culture, although many of the culture-negative results may have been due to the
presence of bacterial overgrowth74. Even when compared with PCR, the Mycoplasma Duo kit
performed very well: a 96% agreement was found between this test and PCR for the detection
of U. urealyticum in neonatal endotracheal aspirates75. The test is easy to get in Belgium and
can be performed in routine laboratories not using DNA-based technology.
In patients with PID, microscopic examination of a fresh endocervical smear reveals more
than 30 leucocytes per high power field, or more than 10 per epithelial cell76. Increased
leucocytosis is very sensitive (91%) and has a high negative predictive value (94.5%) for
diagnosis of cervicitis. However, this examination lacks specificity (26.3%) thereby
erroneously diagnosing PID in 3 out of 4 women. Two additional microscopic criteria can
provide additional help the concomitant finding of abnormal vaginal flora whereby the
lactobacilli are replaced by cocci or anaerobic morphotypes (AVF, Lactobacilli grade 3)77,
and the finding of palisades of leucocytes lining up in the cervical mucus (Fig. 3). Although
the latter sign is considered typical, it has not yet been adequately validated in large clinical
studies. Absence of leukocytosis, certainly if in the presence of Lactobacilli, however, almost
with certainty excludes cervicitis and PID78.
During laparoscopy samples from the retro-uterine pouch of Douglas and endotubal swabs are
recommended for aerobic, anaerobic and Chlamydial cultures or PCR. If there is a suspicion
of tuberculosis, a biopsy, with a specific request for the pathologist, is necessary.
Initially, as PID should be considered a potential STI. Therefore screening for possible
concomitant STI’s is recommended. This includes blood tests for HIV, hepatitis B/C and
syphilis as well as cervical testing for HPV infection. Obviously this is not obligatory for
pelvic infections secondary to a surgical intervention, delivery or known gastrointestinal
infectious process.
Clinical diagnosis of PID is difficult due to the lack of accuracy (sensitivity and specificity) of
all present tests. However, the potential risk for severe sequelae legitimates a low threshold
for a clinical diagnosis. A number of tests may provide further support for PID diagnosis.
b. Imaging techniques
i. Ultrasonographic examination
After clinical examination, pelvic ultrasound is the next step in the PID diagnosis. Neither
sensitivity nor specificity is well defined. The level of severity of the infection is the basis of
the sonographic grading of PID, representing a useful complement to the clinical findings. It
should also be stressed that ultrasound signs can be completely absent, but it may be useful in
the differential diagnosis with other causes of abdominal pain.
1. Mild to moderate PID
Uterus is painful on palpation with the abdominal or endovaginal probe. The adnexal regions
may be normal, with the fallopian tubes not visible or the fallopian tubes are visualized
exhibiting increased vascularity with Doppler flow examination. The tubal wall is thicker than
normal (>5mm) and may show the characteristic “cog wheel sign,” in which the inner lining
of the salpinx appears like a cog wheel (Figure 1). In the pouch of Douglas (retrouterine
pouch) some fluid may be seen.
2. Severe PID
Sonographic findings are more evident, with the uterus extremely sensitive on touch with the
probe. There is a vast amount of exudate present in the abdomen. The fallopian tube is
extended with inhomogeneous purulent fluid, sometimes with fluid-air levels (pyosalpinx)
and pseudo-septation.
In cases of chronic salpingitis, the pyosalpinx will gradually be
replaced by anechogenic fluid and a “beads-on-a-string” image typical for a hydrosalpinx: the
remnants of the endosalpingeal plicae are seen as small excrescences against the tubal wall
(Figure 2). With extension, the tubal wall becomes thinner (<3mm), Later in the process,
peritoneal pseudo cysts form due to inclusion of peritoneal fluid in pockets of adhesions of the
bowel, internal genitals and pelvic wall.
Patients with tubo-ovarian abscess exhibit collections of pus with a thick, hypervascularised
wall surrounding an inhomogeneous echogenic fluid, sometimes with air /fluid levels. When a
tubo-ovarian complex has formed, the tubes, uterus and ovaries are all stuck together and
cannot be moved or palpated separately: they move ‘en bloc’ on pressure from the vaginal
probe.
Pelvic adhesions can be responsible for the “flapping sail” sign, usually reflecting large
amounts of pelvic fluid confined by the loose adhesions. A painful, retroverted and fixated
uterus often result from reduced mobility of the uterus caused by such adhesions. The typical
ultrasonographic appearance of such a fixated retroplicated uterus is sometimes called the
“ear-sign”, due to the appearance of the uterus resembling an auricle.
ii. Computerized tomography (CT)-scan
CT is not considered a first line examination. But by scanning a larger area CT can
provide additional information in selected cases. Indications for a CT scan in the diagnosis of
pelvic inflammatory processes are outlined in Table 3.
Thrombosis of the ovarian vein is most often seen in the postpartum period, (frequency
1/3000), but is also a known complication of pelvic surgery and PID. Eighty to ninety % of
the thromboses are encountered at the right side. To detect this complication CT-scan is
superior to echo-Doppler79.
iii. Nuclear magnetic resonance (NMR)
NMR images showing parametrial inflammation are very specific: T2 weighted images
suppressing fat densities show a fuzzy hyper-intense zone (so called “halo”) with
intensification on T1 weighted images. Abscedation is seen as a thick-walled mass filed with
fluid in the adnexal area. Pyosalpinx also presents a very clear appearance of a twisted and
dilated fluid-filled structure. The content of such abscesses are lightly hyper-intense on T1
weighted images and hypo-intense on T2 weighted images, indicative of blood or
inflammatory debris80.
c. Endometrial biopsy
An endometrial biopsy is a possible diagnostic tool, but there is insufficient evidence to use
this as a routine test.
Acute endometritis mostly appears after surgery or delivery with placental remnants, but is
may also be the departure point for ascending PID. Pathological findings include micro
abscesses and neutrofiles in the endometrial glands.
Chronic endometritis can begin as an acute endometritis but can also occur after insertion of
an IUD or after radiotherapy. Pathological finding is the presence of plasma cells in the
endometrial stroma.
5.
Long-term sequelae
Tubal infertility represents a major worldwide outcome after PID81. The pathogenesis is best
studied in women with recurrent Chlamydial infections causing immune modulation (i.e.,
immune system does not ‘see’ the latent intracellular infection) and subsequent intratubal
scarring. Because such recurrent infections often remain asymptomatic these infections
typically often cause substantially more damage than clinically suspected (cfr supra). A
particular set of signs and symptoms due to intra-abdominal adhesion formation is the socalled Fitz-Hugh-Curtis syndrome (figure 3). This syndrome reflects a peri-hepatitis with
upper abdominal pain, and typical adhesions found on laparoscopy. Other STIs, like
gonorrhea and perhaps M. genitalium (see above), may cause tubal infertility after a single
PID episode, but fertility is usually well preserved in women with a first PID episode who had
prompt treatment.
Ectopic pregnancy represents a second important consequence of mucosal damage to the
fallopian tubes. Ectopic pregnancies are linked to a history of PID, presence of Chlamydia
antibodies82 and Chlamydia induced heat shock protein 60 and 70 reactivity83;84. The tubal
damage or ectopic pregnancy risk after infection with M genitalium is not fully elucidated
yet85, but identification of Mycoplasma at laparoscopy for PID, either in the lower genital
tract or the upper genital tract, is a risk factor for later ectopic pregnancy86. The absolute risk
of EUG remains low at around 1%.87
Chronic pelvic pain is the third major long-term complication of PID. Around 30% of women
suffer from chronic pelvic pains after a symptomatic or asymptomatic PID episode of PID88.
Differential diagnosis includes: interstitial cystitis, pelvic congestion syndrome and
endometriosis.89;90.
6.
Tubo-ovarian abscess
A tubo-ovarian abscess (TOA) is the ultimate attempt of the body to conceal a life threatening
infection.
Pathogenesis. TOA can originate from either ascending PID (primary TOA) or as a
consequence of surgery or an intestinal infectious process. One has to be aware that a TOA
always can mimic or complicate a malignant process, especially in postmenopausal women
(secondary TOA)91. There are no known risk factors that promote TOA development after
PID.
The inflammatory reaction caused by ascending aerobic bacteria causes endothelial damage
and intra-tubal adhesions in which bacteria, debris and leukocytes accumulate. Once large
enough, this accumulation will not allow sufficient oxygen to diffuse into the center of the
abscess. Within 24-to-48 hours anaerobes and facultative anaerobic microorganisms can
thrive in this anaerobic environment (the so-called ‘anaerobic shift’).
Diagnosis. The most prominent clinical findings include abdominal and pelvic pain, present
in over 90% of affected women, followed by fever and leucocytosis in 60-80%92. The “gold
standard” for diagnosis is ultrasonography (see above). TOA, with cystic structures and often
air/fluid levels should be clearly distinguished from a ‘tubo-ovarian complex’, where edema,
adhesions
and
inflammation
are
present,
leading
to
more
heterogeneous
and
hypervascularized sonographic findings. Patients with tubo-ovarian complex often respond
well to sensitive to antimicrobial therapy (>95%), in contrast to patients with TOA (see
below). Differential diagnosis includes dermoid or endometriosis cyst. This can be
particularly difficult, especially if secondary infection is present, as often in the case of
endometriosis.
Management: ubi pus, ibi evacuatur ?
More than 80% of the women who do not respond to appropriate PID therapy have TOAs.
Still, some authors report cure rates as high as 75% with antibiotics alone93. From four to six
centimeters an abscess will still need drainage in about 15%, up to 10 centimeters drainage is
eventually necessary in up to 70%. Therefore, the need for laparoscopic intervention and
timing of this intervention remain controversial.
Surgical drainage is required if the TOA does not respond to medical therapy. This can be
done laparoscopically94, by CT- or ultrasound-guided percutaneous aspiration95;96, or more
recently also by transvaginal puncture97. These procedures should only be done with broad
antibiotic coverage, as the drainage procedure may disseminate infection97. As diagnostic
work-up to exclude malignancy is crucial in post-menopausal women, laparoscopy is always
mandatory in this group.
Conservative treatment is only possible if patient is well informed that close follow up is
needed and surgical intervention may still prove necessary. Resolution of a TOA can take
weeks to months. Weekly follow up with bimanual examination and ultrasonography are
necessary, especially during the first weeks. Patients should be instructed about possible
relapse of the TOA.
The duration of the antibiotic treatment will be depending on clinical progression and CRP.
In our opinion the need for a uni- or bilateral removal of the adnexae depends upon age and
results after antibiotic treatment.
7.
Clinical management
Treatment goals are to treat the most important causative microorganisms and minimize
sequelae of PID. Because most women with early PID do not have major complaints, delayed
diagnosis and effective therapy often increase the likelihood of adhesions and late sequelae. It
is important to examine and treat partners even if they have no definite symptoms. All
partners should be treated with Azithromycine 1 g orally.
a. Antibiotics
Empirical antibiotic therapy based on the expected microorganisms should start before the
cultures results are available. Local resistance patterns vary in different areas. Most empiric
treatment regimens combine agents to treat aerobic and anaerobic bacteria as well as C.
trachomatis.
The indications for intravenous therapy coincide with those for hospital admission (see later).
When the patient is a-febrile and C-reactive protein is decreasing oral therapy is substituted
for 10 to 14 days. Although other regimens may be effective, most guidelines are consistent
with the recommendations in Table 398. In general, therapy should be prolonged to limit the
chance for relapse. Reassessment is recommended after 48 to 72 hours. If the patient is not
responding as expected, reassessment of the patient is mandatory before alternative therapy
and/or hospital admission should be considered. For mild PID antibiotics are given for 14
days, while for severe PID several weeks of therapy may be necessary.
As noted above, increasing antimicrobial resistance, especially to fluoroquinolones, has been
documented for N. gonorrhoeae in many areas including in Belgium. Treatment should
therefore always include ceftriaxone 125 mg IM or IV and this for all cases of PID.
Recent reports demonstrated that moxifloxacin 400mg once daily is effective for mild PID
with proven activity against anaerobic bacteria. This regimen has shown similar cure rates to
ofloxacin plus metronidazole and to ciprofloxacin plus doxycycline and for uncomplicated
PID99;100.
Resistance
by
some
anaerobic
bacteria
(B.
fragilis,
Peptostreptococcus)
and
enterobacteriaceae against clindamycin is increasing25.
Doxycycline is active against gram positive and negative aerobic infections as well as against
C. Trachomatis.
Specific therapy testing is indicated when the microorganisms and their antibiotic sensitivity
are known. However, care has to be taken to assure anaerobic coverage. Also, it is important
to consider the possibility that non-cultivated germs (i.e., those not detected by standard
culture techniques) may also be present, necessitating alternative therapy if the patient does
not improve as expected.
b. Hospitalization
Indications for hospitalization are summarized in Table 4. For PID grade 1 and 2, cure rates
were similar for ambulatory treatment and hospitalization 101. Intravenous fluids are indicated
for patients with vomiting or ileus. Thrombosis prophylaxis is also indicated with low
molecular heparin for hospitalized patients.
c. Indications for laparoscopy
Laparoscopy is not very accurate in PID grades 1 and 2, and is not able to diagnose the
presence of endometritis unless it is combined with hysteroscopy and endometrial sampling
for histological examination. However, in doubtful cases, or when the patient does not
improve or deteriorates, (clinically or by increase of the inflammatory parameters after 72
hours of antibiotic therapy), laparoscopy is indicated. During laparoscopy intra-abdominal
cultures can be taken, and other possible pathology, such as endometriosis, can be assessed.
Excessive rinsing with saline is advised and if abscesses are encountered, these should be
drained and extensively rinsed. In our opinion whenever abscesses are present a drain should
be left postoperatively for at least 24 hours to allow further drainage of the pus and to prevent
new localization of the infection.
8.
Prevention
a. Screening
Standard STI screening and treatment policies offer the potential for substantially reducing a
PID rates102. In high risk groups of women (e.g., sex workers, abused women, women with a
history of PID, women undergoing counseling for
abortion…) routine screening for
Chlamydia and other STIs is recommended103-105 Other groups that is likely to benefit from
screening are teenagers at schools, women attending family planning clinics and/or consulting
for contraception106;107. Women attending the clinic for an abortion or HSG can benefit from
screening for bacterial vaginosis and cervicitis before the procedure.
b. Sexual education
Abstinence is the most secure guarantee of avoiding PID, at least according to the strict
definition wherein PID is considered to be an STD108. The “Abstain, Be faithful and use
Condom” (ABC) recommendation has been successful in some settings such Uganda109 and in
US military clinics110. However, many barriers must be addressed to make safe sex practices
an accepted and commonly adopted approach111.
9.
Follow up
After the initial PID episode, it is important to monitor inflammatory parameters and any
abscess or mass seen on ultrasound. Officially, there is no need to retest for Chlamydia after
recommended treatment. However, some guidelines (i.e., Belgian Societies of Gynecology
and Obstetrics) test of cure testing is strongly advised because persistence of a Chlamydia
infection is seen in 10-15% of cases. Patients with persistent symptoms or doubtful
compliance to therapy should also be tested again 3 weeks post treatment. Earlier re-testing
may lead to false negative (still viable Chlamydia in low numbers) or false positive (shedding
of non viable Chlamydia) results.
Frequent complications of PID include chronic pelvic pain, dyspareunia, infertility (RR x6
after 1 episode, x17 after 2 episodes) and ectopic pregnancy. Every woman experiencing a
PID episode should be aware of these risks. Unfortunately, no study has compared rates of
such long-term sequelae after different treatment regimens.
Table 1. Risk factors for acquiring PID
PID: pelvic inflammatory disease, STD: sexually transmitted disease, AAP: abortus arte
provocatus, D&C: dilatation and curettage, HSG: hysterosalpingography, IUD: intra uterine
device, IVF: in vitro fertilization, IUI: in uterine insemination
Past history PID or STD
New partner
Multiple sex partners
Age: Sexually active teens are 3 times more likely to develop PID than women 25 to 29 years
old.
Instrumentation of the uterus with interruption
AAP / D&C
of cervical barrier
HSG
Insertion IUD within last 6 weeks
IVF/IUI
Table 2. Differential diagnosis of PID (not exhaustive)
The importance can change according to age, presentation,…
Gynaecologic origin
Non gynaecologic origin
Adnexal tumor
Acute enteritis
Congestions / thrombosis
Appendicitis
Dysmenorrhea
Bowel perforation
Ectopic pregnancy
Cancer from bowel, bladder, peritoneum,…
Endometriosis
Cholecystitis
Extruding myoma
Crohn’s disease
Missed abortion
Diverticulitis
Necrosis of myoma
Irritable bowel syndrome
Ovarian / adnexal tortion
Lead intoxication
Ovulation
Lumbar disc disease
Pelvic infection
Nephrolithiasis
Rupture of teratoma
Pyelonefritis
Septic abortion
Radio-enteritis
Uterine or adnexal adhesions
Sickle crisis
Ulcerative colitis
Table 3. Indications for CT-scan in patient suspected of a pelvic infection
Adequate sonography not possible (stenotic vagina)
Uncertain diagnosis on clinical and sonographical grounds
Failing antibiotic therapy
To complete full staging of inflammatory process e.g. perihepatitis (Fitz-Hugh-Curtis)
Detection of possible complications, e.g. septic trombo-phlebitis
Differential diagnosis with other intra-abdominal conditions (e.g. appendicular plastron, dermoid
cyst, ovarian endometriosis…)
Table 4. Antibiotics of choice in women with pelvic infections
Cervicitis
Daycare
Option 1
Option 2
Azithromycin
1 g PO
Single dose
5-nitro-imidazole
2 x 500 mg PO
7 days
Ceftriaxon
1g IM or IV
Single dose
+ Azithromycine
1g PO
Single dose
Salpingitis / PID
duration of therapy may differ according to clinical / hematological evolution (i.e. abscess:
therapy up to 6 weeks recommended)
Ambulatory
Option 1
Ceftriaxon
1g IM or IV
Single dose
Moxifloxacin
400 mg PO
10-14 days
(5-nitro-imidazole)
2 x 500 mg PO
10-14 days
association of 5-nitro-imidazole in case of an overt anaerobic infection can be warranted (i.e.
abscess)
Option 2
Ceftriaxon
1g IM or IV
Single dose
Levofloxacine
500 mg PO
10-14 days
5-nitro-imidazole
2 x 500 mg PO
10-14 days
Hospitalisation
Switch to ambulatory setting possible after 48 hours IV therapy in case of clinical /
hematological improvement
Option 1
Option 2
Option 3
Ceftriaxon
1g IM of IV
Single dose
Levofloxacine
500 mg IV
10-14 days
5-nitro-imidazole
1 g IV
10-14 days
Ceftriaxon
1g IM of IV
Single dose
Amoxi-Clav
4 x 1 g IV
10-14 days
Levofloxacine
500 mg IV
10-14 days
Ceftriaxon
1g IM of IV
Single dose
Amoxi-Clav
4 x 1 g IV
10-14 days
doxycycline
2 x 100 mg PO
10-14 days
5-nitro-imidazole: metronidazole (Flagyl®), ornidazole (Tiberal®), tinidazole (Fasigyn®)
Amoxi-Clav: Augmentin®, Clavucid®, amoxicillin-clavulanic acid generic
Azithromycin : Zitromax®, azithromycin generic
Ceftriaxon: Rocephine®, ceftriaxon generic
Doxycycline: Vibratab®, doxycycline generic
Levofloxacine: Tavanic®
Moxifloxacin: Avelox®
Table 4. Indications for hospitalization and intravenous therapy
Surgical intervention not excluded
Severe clinical picture
PID grade 3 (including tubo-ovarian abscess)
Pregnancy
Failure to respond to oral antibiotics within 48 hours
Immune compromised patients (HIV, transplantation,…)
Intolerance to oral antibiotics
low patient compliance
Figure 1: Cogwheel sign
Figure 2: Beads-on-a-string sign
Courtesy of prof.dr.D.Timmerman
Figure 3: laparoscopic image of the syndrome of Fitz-Hugh-Curtis
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