Pelvic inflammatory disease

Transcription

1 /toag Keywords pelvic inflammatory disease (PID), chlamydia, gonorrhoea, reproductive morbidity, screening Pelvic inflammatory disease Alison Mears and James S Bingham Pelvic inflammatory disease is a common but often uncertain diagnosis, crossing the specialty boundaries of general practice, family planning, accident and emergency medicine, genitourinary medicine and gynaecology. As well as the immediate morbidity it causes, it can commonly lead to potentially serious complications (subfertility, ectopic pregnancy, chronic pelvic pain and psychological morbidity). Despite a number of published guidelines, uncertainty and variation still surround its diagnosis, clinical management and treatment. In this article, we review current guidelines and literature and highlight recent developments and controversies. Author details Alison Mears MRCOG Dip GUM DFFP, SpR in Genitourinary and HIV Medicine, Lydia Department, Guy s and St Thomas Hospital, London, UK. James S Bingham FRCP FRCOG, Consultant in Genitourinary and HIV Medicine, Guy s and St Thomas Hospital, Lambeth Palace Road, London, SE1 7EH, UK. james.bingham@gstt.sthames.nhs.uk (corresponding author) Introduction The term pelvic infection encompasses puerperal sepsis, post-abortion infection, local pelvic infection following surgery and pelvic inflammatory disease (PID). PID is characterised by inflammation of the endometrium, uterus, fallopian tubes and adenexal structures. There is a spectrum of severity ranging from asymptomatic to generalised peritonitis, septicaemia and death. It most frequently occurs secondary to sexually transmitted infections (STIs) in the lower genital tract and is a major cause of morbidity. In the USA, one study has estimated the average per person-lifetime cost of PID may be as high as US$ Making the diagnosis can be problematic because it is recognised that basing it on criteria of clinical signs and symptoms is imprecise 2 and there is no cheap, simple and accurate diagnostic test. This makes PID surveillance difficult. The severity of symptoms may determine the medical setting at which a woman may present. Women with milder symptoms are more likely to present to general practice, family planning or genitourinary medicine clinics, whereas those with more severe symptoms may present to accident and emergency departments or to a gynaecology unit. There have been a few studies 3,4,5 looking at the management of this common condition in various medical settings in the UK. One study demonstrated suboptimal management in accident and emergency departments as compared with genitourinary medicine clinics. 3 Another showed that only 7% of GP practices implemented effective PID management, 4 which is of concern as the prevalence of PID in general practice is 1.7%. 6 PID was highlighted in the Chief Medical Officer s Expert Advisory Committee s findings on chlamydia as an important cause of preventable reproductive morbidity. 7 It is an area of women s sexual health that ought to receive greater attention. Epidemiology It is difficult to assess accurately the epidemiology of PID; diagnosis is inaccurate and cases are probably poorly reported. It is, however, one of the most frequent causes of morbidity in young women and, if diagnoses from general practice are included, the estimated prevalence in women of reproductive age in England and Wales is one in Risk factors for PID are closely associated with those of STI acquisition. The highest rates of PID occur in the years age group. This might be due to a higher number of sexual partners and more frequent partner change or there could be an increased host susceptibility in this age group. 8 Not all women with lower genital tract infection develop PID, so susceptibility may be genetically determined; for instance, with chlamydial infection, an association with human leucocyte antigen-type A31 has been identified. 9 Douching is practised in certain groups, particularly the Afro-Caribbean population in the UK, and this may double the risk of PID. 10 Other risk factors include a past history of STIs, cigarette smoking (two-fold increase) and recent insertion of an intrauterine contraceptive device (IUCD). 11 The association between the oral contraceptive pill and PID is poorly understood. It was thought that it may exert a protective effect against the ascent of infection by progesterone-induced changes in the cervical mucus barrier and endometrial suppression or a direct steroid effect reducing immune-related damage to the tubal mucosa. However, it may just reduce the prevalence of symptomatic infection and not 138

2 Table 1. Bacteria associated with pelvic inflammatory disease Proven association Role less clear Organism Chlamydia trachomatis Neisseria gonorrhoeae Gardnerella vaginalis Anaerobes: Bacteroides sp. Peptostreptococcus and Peptococci sp. Fusobacterium sp. Clostridium bifermentans Mycoplasma hominis Mycoplasma genitalium Ureaplasma urealyticum Streptococcus pneumoniae Escherichia coli Streptococcus pyogenes Haemophilis influenzae Coagulase negative Staphylococci sp. alter the true prevalence of PID. 12 The majority of epidemiological studies on PID have been American and caution should be exercised in extrapolating these findings to the UK population, which may not be matched for contraception or sexual health practices. Aetiology Organisms Ascent of organisms from the lower to the upper genital tract is believed to be the cause of PID.A plethora of organisms has been isolated from the upper genital tract of women with PID, suggesting a polymicrobial nature for the infection, but it remains uncertain which are primary pathogens (Table 1). Chlamydia trachomatis and Neisseria gonorrhoeae have been identified as definite causes of PID 2 and are both increasing in incidence in the UK. Chlamydia is the more common cause and the rate of gonococcal infection in PID may be as high as 14%. Gonococcal PID often has a more acute presentation in terms of duration and severity of symptoms; however, long-term sequelae are more common with C. trachomatis (see Table 2 for sequelae). In over 20% of cases, no organism will be isolated from the upper genital tract. This may imply clearance or overgrowth of original chlamydial or gonococcal infection and anaerobic organisms soon predominate. Certain subtypes of gonococci are associated with PID. Evidence that C. trachomatis, an obligate intracellular bacterium, is a cause of PID consists in identifying it in the upper genital tract and a high prevalence of anti-chlamydial antibodies in women with tubal obstruction. The risk of PID in young women with chlamydia in the lower genital tract is in the region of 10%. 13 Anaerobes are almost universally found in PID and their production of enzymes may assist passage of the bacteria through the cervical mucous plug. A higher rate of bacterial vaginosis has been found in women with PID, but the link is uncertain. Mycoplasma hominis and Ureaplasma Table 2. Complications of Chlamydia trachomatis and Neisseria gonorrhoeae Complication Pelvic inflammatory disease Fitz-Hugh Curtis syndrome (perihepatitis) Tubo-ovarian abscess Sexually acquired reactive arthritis/reiter s syndrome Adult conjunctivitis Transmission to neonate: conjunctivitis, pneumonia Disseminated gonococcal infection and septic arthritis Possible long-term sequelae Chronic pelvic pain Tubal damage: subfertility ectopic pregnancy Psychological morbidity Adhesions, chronic pain Adhesions, chronic pain Fatigue Post-inflammatory joint pain and stiffness; erosive joint damage Persistent locomotor disability Irreversible visual loss, cataracts Nil Potential blindness Damage to the affected joint 139

3 urealyticum have been found in the upper genital tract but it is also uncertain if these are true pathogens. Mycoplasma genitalium is a cause of cervicitis and possibly endometritis in women but its role in PID remains to be ascertained. 14 A role for viruses or other agents has yet to be established. The finding of respiratory tract bacteria in a few cases of PID raises the possibility of a link with orogenital sexual contact. Mycobacterium tuberculosis is mainly seen in immigrants to the UK from developing countries; it can infect the pelvic organs but is not usually found in the lower genital tract. PID and actinomyces Actinomyces-like organisms (ALOs) live in the gastrointestinal system as harmless commensals. When found in the female genital tract they are almost exclusively in association with foreign bodies (IUCD). They can be a rare cause of pelvic infection. The longer the IUCD is in place, the greater the likelihood of finding ALOs on a cervical smear (20% by 5 years). Limited evidence suggests that an IUCD should be removed in symptomatic women and appropriate antibiotics prescribed. However, there is no evidence to support routine removal in asymptomatic women or to support screening those without symptoms. 15 Iatrogenic disease Procedures involving instrumentation of the cervix have the potential to introduce cervical infection to the upper genital tract and can cause PID; for example, termination of pregnancy, hysterosalpingography, evacuation of the uterus or embryo transfer. HIV In the early days of the HIV epidemic it was thought, initially, that concomitant PID might be more severe. However, a number of studies have disputed this and it is the experience of the authors that it is not the case.women with PID who are HIV positive may be treated in the same manner as women without HIV and response rates to treatment are comparable. 16 Pathogenesis The spread of infection to the upper genital structures is canalicular along the mucosal surfaces from the vagina and cervix into the endometrial cavity, fallopian tubes and into the abdominal cavity. 17 Adherence of organisms to spermatozoa may facilitate movement of organisms to the upper genital tract. Loss of the cervical mucus plug at the time of menstruation may allow access of bacteria to the endometrium. The gonococcal strains which result in salpingitis differ from those which cause disseminated gonorrhoea. They enter nonciliated cells, initially, but the ciliated cells soon lose their motility and slough with an active neutrophilic inflammatory response. C. trachomatis attaches to the tubal epithelium and is engulfed in a membrane-lined vacuole. It replicates within the cell, thus protecting it from immune recognition. A Th 1-type response occurs initially with production of a range of cytokines, but much of the inflammatory response is secondary to a delayed type hypersensitivity response to a chlamydial heat-shock protein (hsp). There may be some degree of strain-specific immune protection with gonococcal reinfection and this may reduce the risk of repeated upper genital tract infection. However, with recurrent chlamydial infection, after priming by the initial episode of PID the degree of tubal damage may be greater, possibly mediated by a cross-reaction between chlamydial hsp60 and human hsp The inflammation may cause occlusion of the tubal lumen and, with tissue repair, scarring. Tubo-ovarian abscess formation is a late manifestation but neither N. gonorrhoeae nor C. trachomatis produces this; anaerobic bacteria dominate in these infections. Clinical features The main symptoms and signs of PID are listed in Table 3. Hagdu et al. 19 found vaginal discharge to be present in almost all cases of salpingitis. However, the condition may be asymptomatic. Sometimes PID may not be considered in the differential diagnosis, for example with symptoms such as menorrhagia or spotting while taking the oral contraceptive pill. The latter may be strongly predictive of chlamydial infection and, rather than simply changing the contraceptive pill, women should additionally be screened for STIs. Diagnosis and investigation The symptoms and signs associated with PID may be nonspecific and insensitive, so it is sensible to have a low threshold for initiating treatment. There is no single diagnostic test. It is good practice to perform a pregnancy test on all sexually active women of childbearing age presenting with lower abdominal pain or vaginal bleeding. If urinary tract infection is suspected, a 140

4 Table 3. Clinical features of pelvic inflammatory disease Symptoms Signs Lower abdominal pain Lower abdominal tenderness Deep dyspareunia Adenexal tenderness and/or swelling Abnormal vaginal bleeding Cervical motion pain Abnormal (cervical) discharge Fever (> 38 C) Fever urine dip-stick test should be performed and if positive for leucocytes or nitrites a midstream urine sample should be sent for analysis. Endometrial sampling is not helpful and markers such as erythrocyte sedimentation rate or C- reactive protein, while correlating with the severity of PID, are not specific and neutrophil counts may not be raised in mild disease. Identification of inflammatory cells in a culdocentesis sample supports a diagnosis of PID but the organisms detected may not be those found in the fallopian tubes. Microbiology All patients should have endocervical swabs taken for N. gonorrhoeae (culture) and C. trachomatis (nucleic acid amplification test NAAT). Gonorrhoea can also be identified by a NAAT but, with the gonococcus now resistant to a number of antibiotics in different areas of the world, culture permits antibiotic sensitivity testing. Culture from the urethra increases the yield and sampling from the throat and rectum should be undertaken if the sexual history indicates that these sites have been exposed to infection. Negative tests for these two organisms do not refute a diagnosis of PID but, if positive, will support it. It is wise to offer a woman the opportunity to be screened for other STIs but it is not usual, at present, to screen for M. genitalium. Laparoscopy Laparoscopic findings are subjective and may miss intratubal inflammation where there is little visible hyperaemia on the serosa of the tube. Where the diagnosis remains in doubt, the woman is unwell and there is no response to antibiotics within 72 hours, then laparoscopy is indicated. However routine use is obviated on the basis of risk of morbidity and capacity and cost. Ultrasound scanning Transvaginal ultrasound scanning is the preferred method but its diagnostic sensitivity will depend upon operator experience. Routine use is not justified but it will identify and confirm tubal abscesses. The newer technique, power Doppler imaging, 20 may be sensitive enough to detect tubal hyperaemia suggestive of salpingitis but it would need to be readily available and not delay time to treatment. Differential diagnosis The differential diagnosis of PID is given in Table 4. It is vital to exclude the possibility of an ectopic pregnancy. There may be a history of amenorrhoea with lower abdominal pain, initially unilateral, but it is sensible to perform a pregnancy test in such cases. Systematic questioning should include enquiry about bowel Table 4. Differential diagnosis of pelvic inflammatory disease Differential diagnosis Important points to consider Ectopic pregnancy This must always be considered and excluded; always check date of last menstrual period Ovarian cyst event i.e. bleeding, torsion or rupture Endometriosis Often more chronic symptoms and associated with menstruation. Less likely to cause a fever Appendicitis Pain mainly on the right Irritable bowel syndrome A diagnosis of exclusion Functional pain Pelvic adhesions Past history of previous surgery or infection Urinary tract infection Be aware that chlamydia and gonorrhoea can also cause urinary symptoms Inflammatory bowel disease Pain mainly on the left 141

5 Figure 1. Parental regimen for the management of PID and urinary symptoms, which might suggest gastrointestinal or urinary tract pathology. Management Antibiotic treatment should be commenced as soon as possible, ideally within two days of the onset of symptoms. It should cover N. gonorrhoeae, C. trachomatis and anaerobes. C. trachomatis is rarely resistant but gonococcal resistance, of various types, is common. Knowledge of local strain sensitivities is useful in guiding the choice of antibiotic but, if the infection is believed to have been acquired overseas, then a beta-lactamase antibiotic should not be used as greater than 5% of such strains are likely to produce beta-lactamase. Choice of regimen may be influenced by patient preference, history of allergy and severity of disease. Most patients prefer oral therapy and, if ofloxacin is included in a regimen, a psychiatric history should be taken because of reports of significant psychiatric adverse effects with the drug. Parenteral and oral regimens are delineated in Figures 1 and 2. The combination of doxycycline and metronidazole alone is widely used across genitourinary medicine clinics in the UK but its use has not been assessed in clinical trials. Comparison of different treatments, in the literature, must be interpreted with caution since outcome measurement and assessment of diagnosis is not standardised. Indications for inpatient management with parenteral therapy are severe symptoms or signs, presence of a tuboovarian abscess, clinical failure with oral therapy or an inability to tolerate it and diagnostic uncertainty. However, a large randomised study reviewing reproductive outcomes in outpatient versus inpatient treatment concluded that there was little difference in women with mild to moderate disease. 21 Duration of treatment should be 14 days. Review at 72 hours is advised, particularly with moderate to severe presentations and failure to respond would indicate a change to parenteral therapy, the possible need for surgical intervention or an incorrect diagnosis. Further review at 4 weeks to assess compliance and outcome FIRST-LINE IV REGIMENS cefoxitin 2 g tds IV AND doxycycline 100 mg bd IV (orally if tolerated) clindamycin 900 mg tds AND gentamicin (2 mg/kg loading dose followed by 1.5 mg/kg tds) (a single dose of 7 mg/kg may be used) FOLLOWED BY FOLLOWED BY EITHER doxycycline 100 mg bd PO plus metronidazole 400 mg bd For total of 14 days doxycycline 100 mg bd orally AND metronidazole 400 mg bd orally for total of 14 days KEY bd twice a day IV intravenously qid four times a day tds three times a day OR clindamycin 450 mg qid orally for total of 14 days 142

6 may be useful. Patients should desist from sexual intercourse until they, and their partners, have completed treatment and follow up. An explanation of the condition and the possibility of long-term sequelae should be emphasised, preferably reinforced with written material. Rest in bed in moderate or severe cases should be advised. PID and pregnancy This is not common but when it does occur it is associated with an increase in morbidity for both the mother and fetus. There is no consensus on the optimal antibiotic regimen but treatment should be intravenous and should cover the above-mentioned organisms. 22 The IUCD The World Health Organisation expert working group on recommendations for contraceptive use concluded that there was no additional benefit to be gained by removing an IUCD in a woman diagnosed with mild to moderate PID 23 who had been commenced on antibiotics. Indeed, if the woman wanted it removed, this should take place only after antibiotics have been started. It would, however, be sensible to remove if, at review, there was no clinical improvement or indeed deterioration. Partner notification A number of studies have shown that in adolescent females diagnosed with chlamydia up to 21% have a further chlamydial infection within the ensuing six months. The majority of these infections have been shown to be reinfection rather than persistent or inadequately treated infection. The same is true for gonorrhoea. Repeated chlamydial infection has been shown to increase the risk of PID and long-term sequelae. The relative risk of an ectopic pregnancy following one episode of C. trachomatis is 1, increasing to a relative risk of 11 with three episodes of infection. 24 If only the woman is screened and treated, then she is at high risk of reinfection from her partner. This process should include current and previous partners in the past 6 months. After samples have been taken for chlamydia and gonorrhoea, male partners should be given empirical cover for C. trachomatis (azithromycin 1 g immediately is commonly used) and any Figure 2. Oral regimens for the management of PID FIRST-LINE ORAL/IM REGIMENS ofloxacin 400 mg bd orally metronidazole 400 mg bd orally For 14 days ceftriaxone 250 mg stat IM probenicid 1 g orally cefoxitin 2 g stat IM probenicid 1 g orally FOLLOWED BY KEY bd twice a day IM intramuscularly stat immediately doxycycline 100 mg bd orally metronidazole 400 mg bd orally For 14 days 143

7 other infection identified, such as N. gonorrhoeae, can be treated subsequently. Screening programmes for C. trachomatis The majority of women with chlamydial infection present with atypical symptoms or are asymptomatic and this makes diagnosis difficult. Thus, screening for the organism would be a sensible strategy to reduce the incidence of PID. A study in a health maintenance organisation in Washington State, USA, demonstrated that screening for chlamydia and treating the identified cases led to a 56% reduction in the incidence of PID. 25 Additional evidence demonstrating the effectiveness of prevention is primarily epidemiologic and economic. In Sweden, compulsory reporting of cases, widespread screening, active partner notification and treatment of the identified partners, compulsory education about STIs in schools and substantial changes in sexual mores have all contributed to a marked reduction in the incidence of chlamydia, gonorrhoea and PID. Others have shown that women with multiple chlamydial infections were hospitalised significantly more often for PID and ectopic pregnancy than those infected only once. 26 In addition, screening before instrumentation of the cervix in procedures such as tubal patency tests or insertion of an IUCD seems sensible. While screening programmes have been implemented in Sweden and in some US states, sadly, screening has not been implemented in the UK despite the rising incidence of chlamydial infection. Pilot schemes have demonstrated incidences in the region of 10% in populations tested in the Wirral and at Portsmouth.This was using nucleic acid amplification technology which is still not widely available across the country but, although it is more expensive, it does result in the identification of 30 40% more infections than with the old enzyme immunoassay tests. 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