Chapter 43. Pelvic Inflammatory Disease

Pelvic inflammatory disease (PID) is a complex inflammatory disorder of the female upper genital tract that usually develops as a result of an initiating sexually transmitted infection, but can also be caused by iatrogenic uterine instrumentation.1–6 The term denotes a wide spectrum of histopathologic entities including endometritis, salpingitis, oophoritis, peritonitis, and abscess formation. Clinically, PID can manifest in a wide range of symptoms, from subtle pelvic discomfort to frank peritonitis and hemodynamic shock. A distinct entity called subclinical PID has been recognized as an asymptomatic infection with evidence of upper genital tract inflammation; despite lack of symptoms, subclinical PID is suspected to result in the same long-term reproductive sequelae as its symptomatic counterpart.7–10

Burden of Disease

Surveillance data suggest that lifetime prevalence of PID for women in the United States is 8%,1 with 20% of cases affecting adolescent females.11,12 Estimates of the true burden of this disease, though, are likely inaccurate because this syndrome is not reportable and is substantially underdiagnosed because of atypical presentations. Incidence is decreasing from a peak of 1 million cases annually in the early 1980s to 420,000 cases in the year 2001.6,11,13 Similarly, hospitalization rates have substantially decreased since 1980s, reflecting a shift to outpatient management. Total medical cost of PID was estimated at $2.7 billion for the year 1990,14 but because of the decreased incidence and hospitalization rates, total expenditure in 1998 was $1.88 billion, with long-term reproductive sequelae representing 40% of that sum.15

Risk Factors

Demographic, behavioral, and contraceptive practices have been evaluated in cross-sectional studies as risk factors for PID (Table 43–1). Among demographic risk factors, age younger than 19 years,16–18 lower socioeconomic group,16,19 non-Caucasian race,16,17,20 lack of married status,16,21 and less education17,22 have been associated with increased risk of PID. Behavioral risk factors overlap with those for acquiring STIs. High-risk behaviors include early sexual debut,16,18,19,23 having multiple sexual partners,23–25 and having a current or past STI.16,18–21,26 A history of PID is reported by some19 but not all17,18 authors as an independent risk factor for recurrence. Use of substances like alcohol,18,27 tobacco,17,19,22,28 and cocaine17 may also increase PID risk. Additionally, engaging in sex during menses19,24 and douching29–31 are behaviors that remain controversially associated with PID.

Contraceptive practices also alter the risk of PID. Lack of any contraception is associated with 7.6-fold increased PID risk,24 while inconsistent condom use increases risk by three-fold.17 Intrauterine devices (IUDs) have traditionally been associated with the development of PID,32,33 but recent data demonstrate that the risk is limited to the first 20 days following IUD insertion34 and possibly if the IUD is inserted during concurrent cervicitis.35 IUD placement otherwise, perhaps even in populations with high prevalence of STIs, appears safe.32 Whether hormonal contraception alters PID risk remains unresolved. Both combination oral and progesterone-only injectable forms are associated with increased risk of Chlamydia trachomatis cervicitis.36–38 Oral contraceptive use by a large cohort of women resulted in a nonsignificant reduction in PID risk.36 Use of depot medroxyprogesterone significantly decreased PID risk by 60% among this cohort,36 but was associated with increased risk in a different study.19 Interestingly, case-control data showed that women with subclinical PID diagnosed by endometrial biopsy were 4.3 times more likely to be on oral contraceptives than women with recognized PID,39 whereas use of oral contraception by a large cohort of women with acute PID was associated with a nonsignificant trend toward a reduced pain score.18 These data indicate that the decreased risk associated with hormonal contraceptives may be attributable to a decrease in presenting symptomatology, rather than to an absolute reduction in PID incidence.

Pathogenesis of PID involves a complex interaction between host immune defenses, genetic factors, and bacterial and/or viral virulence factors.5,40 Ascending infection into the upper genital tract occurs either by direct extension from the cervix or by lymphatic spread.41 Any decrease in host immune factors, such as loss of the cervical mucous plug during menses, decreased immunologic endometrial and oviductal secretions detected in adolescence and during the proliferative phase of the menstrual cycle,12,42 and changes in vaginal pH caused by bacterial vaginosis (BV) infection, can enhance the ascension of primary and secondary invaders. Factors that facilitate upward migration of pathogens, such as retrograde menstrual flow and adherence to and transport by sperm, also increase susceptibility to infection.5,12,40 Furthermore, the presence of certain human leukocyte antigen class II alleles can modulate PID risk, indicating that genetic factors contribute to pathogenesis as well.43

PID is a polymicrobial process. C. trachomatis and Neisseria gonorrhoeae are the iniating infection in 40–70% of cases of acute PID.41,44–46 Approximately 25% of women with asymptomatic C. trachomatis or N. gonorrhoeae cervicitis have evidence of endometritis on biopsy and, therefore, are classified as having subclinical PID.7 Other organisms that have been isolated from the upper genital tracts of women with PID include Ureaplasma urealyticum, Mycoplasma hominis, Haemophilus influenzae, Escherichia coli, various streptococci, and HSV-2.44,45,47–49 Recently Mycoplasma genitalium, a causative agent of urethritis in men, is being evaluated as a possible etiologic agent of PID.50–53 BV likely contributes to PID pathogenesis as well. For example, BV-associated organisms are commonly isolated from the upper genital tracts of women with acute PID,27,47,54,55 and 15% of women with BV have endometritis on biopsy.7

The clinical presentation of PID varies greatly, with symptoms ranging from severe, debilitating abdominal or pelvic pain to a more subtle syndrome for which many females may not even seek medical attention. Important components of the patient's history of present illness include description of the pain and associated genitourinary, gastrointestinal, and systemic symptoms. The clinician should also elicit the patient's sexual history, which includes the patient's age at sexual debut, number of lifetime as well as recent partners, frequency of coitus, date of last sexual encounter, history of STIs or prior PID, and the type and frequency of contraceptive use. Furthermore, a thorough menstrual history should be obtained, including information about age at menarche, the date of the last menstrual period, and any atypical symptoms during and since the last menstrual period.

Numerous symptoms can be associated with infection of the upper genital tract in females, but no single symptom is sensitive and specific enough to accurately predict the diagnosis of PID (Table 43–2).56–60 Abdominal or pelvic pain is the most common symptom reported. The pain is often bilateral, dull, and achy in character, classically occurs with or immediately after menses, and can be exacerbated by jarring movements, such as walking or intercourse. Symptoms of lower genital tract infection are often present, including vaginal discharge, burning, or an abnormal odor. Fewer than 50% of all women with PID report fever. Irregular uterine bleeding, either spotting between menses or abnormally heavy and/or painful menses, is a symptom of endometritis. Urinary symptoms occur in approximately 20% of females with PID, while gastrointestinal symptoms, such as decreased appetite, nausea, and vomiting, are less common. Lastly, right upper quadrant pain suggests possible perihepatitis, which is present in 5–10% of adults, but may be more prevalent in adolescents with PID.61

The physical examination should focus on vital signs and on detailed examination of the abdomen and pelvis. Abdominal examination may show diffuse tenderness that is often bilateral, usually greatest in the lower quadrants, and may be accompanied by rebound, guarding, and decreased bowel sounds. On pelvic examination, the presence of a strong odor or vaginal discharge suggests concomitant Trichomonas vaginalis or BV infection. A mucopurulent cervical discharge indicates possible cervicitis, and tenderness of the pelvic organs on bimanual examination signifies upper genital tract involvement. The presence of occult or frank blood on rectal examination, though, makes an alternate diagnosis more likely. Physical examination findings tend to have better sensitivity and specificity profiles than clinical symptoms, but no one sign is pathognomonic for PID (Table 43–3).56–60,62 Adnexal tenderness has the highest sensitivity (95%) of all physical examination findings, but has only intermediate specificity; therefore, its absence can help rule out PID, but its presence does not guarantee the diagnosis. Cervical motion tenderness, a sign classically thought of in association with PID, has even lower sensitivity (82–92%) and just as low specificity as adnexal tenderness for this complex infection. Both mucopurulent cervical discharge and bilateral abdominal tenderness, though, have higher specificities and, thus, are better predictors of PID.59 The other physical examination findings are not as helpful given their limited positive and negative predictive values.

Because the signs and symptoms of PID are so diverse, the differential diagnosis of this syndrome is extensive (Table 43–4). Gynecologic emergencies that can mimic the spectrum of symptoms of PID include ectopic pregnancy, spontaneous or threatened abortion, and ovarian torsion. Other gynecologic conditions include ruptured ovarian cysts, endometriosis, uterine fibroids, pelvic adhesions, and even dysmenorrhea. Gastrointestinal illnesses that share overlapping symptoms with PID are peritonitis, appendicitis, diverticulitis, gastroenteritis, inflammatory bowel disease, and even obstipation. The presence of right upper quadrant pain with PID further broadens the differential to include cholecystitis and hepatitis. Lastly, urinary tract disorders, such as cystitis, pyelonephritis, and ureteral calculi, and miscellaneous causes of abdominal pain, such as pneumonia, sickle cell crisis, and abdominal and/or pelvic trauma, can mimic this infection as well.

Acute Complications: Tubo-Ovarian Abscess and Fitz–Hugh–Curtis Syndrome

Tubo-ovarian abscess (TOA), a serious complication of PID, is characterized as an inflammatory mass involving fallopian tube, ovary, and adjacent structures such as bowel and pelvic peritoneum.4,63 The prevalence of TOA among hospitalized women with PID is estimated to be as high as 17–30%64,65; among outpatients with PID, rates seem to be less than 5%,66,67 although screening for TOA is not universally undertaken and may affect the accuracy of these data. Patients with TOA are not always more toxic appearing than patients with uncomplicated PID64,66 and fewer than 30% have a palpable adnexal mass on examination.4,12,64,66 Acute phase reactants are sometimes, but not always, elevated to a greater extent than in uncomplicated PID.68 If TOA is suspected, an emergent ultrasound is required since the presence of this complication changes PID management.

Fitz–Hugh–Curtis (FHC) syndrome61 denotes acute inflammation of the liver capsule, and occurs in 5–10% of adults58 and in approximately 25% of adolescents69 with PID. Most often associated with N. gonorrhoeae and C. trachomatis, perihepatitis usually results from either direct extension of organisms from the fallopian tubes along the paracolic gutters, or in the case of C. trachomatis, through an exaggerated immune response.70 Clinically, FHC syndrome is characterized by right upper quadrant pain that is typically pleuritic and usually referred to the right shoulder or arm; importantly, the pain is not always temporally associated with concomitant PID pain or symptoms of a lower genital tract infection.71 Liver associated enzymes are either normal or mildly elevated, thus helping differentiate this disorder from hepatitis and gall stone disease. Adjunctive tests, such as CBC, ESR, or CRP are inconsistently elevated, while ultrasonography and tests for N. gonorrhoeae and C. trachomatis can help establish the diagnosis.61 Perihepatitis makes the diagnosis of concurrent PID even more enigmatic, but it should be considerd in the differential diagnosis in sexually active females, especially adolescents, who have right upper quadrant pain with or without concurrent pelvic symptoms.

Long-Term Complications: Infertility, Ectopic Pregnancy, Chronic Pelvic Pain

Infertility, ectopic pregnancy, and chronic pelvic pain (CPP) are long-term complications of PID and account for a significant portion of the economic burden of this syndrome.14 Case-control studies have shown that women who delay treatment longer than 3 days have a 2–3.5-fold higher rate of infertility and/or ectopic pregnancy compared to women with PID who seek care early.72 After one episode of PID, the risk of infertility and ectopic pregnancy increases ten-fold and seven-fold, respectively73; furthermore, this risk doubles with each successive episode.73,74 CPP afflicts approximately 20–35% of women who have had PID75,76 and leads to substantial morbidity. Retrospective chart reviews indicate that CPP is the main indication of 12% of the 590,000 hysterectomies performed in the United States each year,1 while prospective cohort data show that women who develop CPP after PID have significantly reduced physical and mental health scores.77

The diagnosis of PID is challenging because the syndrome can encompass variable combinations of a wide spectrum of clinical entities. Thus, the presentation of PID can vary greatly: symptoms are protean and no physical examination finding is pathognomonic for the disease. Furthermore, no single diagnostic gold standard exists, thus clinical diagnosis retains central importance. Not surprisingly then, because of the complex nature of this syndrome, PID is diagnosed correctly by clinical findings alone only 65% of the time.78 Combinations of diagnostic criteria that seek to improve the sensitivity or specificity of the clinical diagnosis do so at the expense of the other.

CDC Criteria for Diagnosis of PID

In the past, CDC diagnostic criteria for PID required the presence of three mandatory components: abdominal pain, adnexal tenderness, and cervical motion tenderness.79 The sensitivity of all three criteria, though, was shown to be only 83%,62 indicating that many cases of true PID were misclassified. In order to maximize the sensitivity of the clinical criteria, reduce the number of missed or delayed diagnoses, and decrease reproductive sequelae, the current CDC guidelines48 recommend suspecting PID in any sexually active female at risk for STIs who has experienced pelvic or abdominal pain, if at least one of the minimum criteria is present on pelvic examination: cervical motion or uterine or adnexal tenderness (Table 43–5). The presence of any of the adjunctive clinical criteria, such as temperature > 101°F, abnormal vaginal discharge, positive saline microscopy of vaginal secretions, elevated ESR or CRP, or documented infection with N. gonorrhoeae or C. trachomatis, can be used to enhance the specificity of the minimum criteria, but are not required to make the diagnosis of PID.

Proposed Diagnostic Approach

Every clinician should have a low threshold for suspecting PID in any sexually active female with current or recent abdominal or pelvic pain. In order to improve the accuracy of this diagnosis, though, providers should utilize a systematic approach (Table 43–6). Important historical components include information about the patient's pain and other associated symptoms, a complete sexual, contraceptive and menstrual history, and a screen for PID risk factors. The physical examination should focus on vital signs and a detailed examination of the abdomen and pelvis. The minimum laboratory evaluation for every patient suspected of having PID includes a urine pregnancy test, saline microscopy of vaginal secretions, and PCR tests for N. gonorrhoeae and C. trachomatis. A normal wet mount has 94.5% negative predictive value for the presence of PID,80 while positive N. gonorrhoeae and C. trachomatis. PCR tests are highly predictive of endometritis in the right clinical setting.60,62 Adjunctive tests such as a CBC, ESR, and CRP can be obtained, but should not delay the diagnosis, since these values are not uniformly elevated in all cases of PID.58,59,81 Normal results of all three tests, though, have been shown to have a negative predictive value of 100%.82 Finally, every female diagnosed with this infection should be offered HIV testing.48

Adjuvant modalities, such as ultrasound, MRI, endometrial biopsy, and laparoscopy, play a minor role in the initial diagnosis of PID given their costs, risks, and limited availability. None of these entities have perfect sensitivity and specificity profiles. Transvaginal ultrasonography has only 81% sensitivity and 78% specificity when compared to laparoscopy,83 but the addition of color flow Doppler greatly improves the positive and negative predictive value of this imaging modality.84 MRI has 95% sensitivity and 89% specificity in diagnosing PID,83 while the sensitivity of endometrial biopsy is 92% and its specificity is 87% when compared to laparoscopy.85 Laparoscopy itself, once considered the gold standard for the diagnosis of PID, has low accuracy in early or mild disease,86–89 and when compared to fimbrial biopsy, has only 27% sensitivity and 92% specificity.87 The CDC recommends that use of these diagnostic techniques be limited to patients not responding to initial therapy or to those in whom an alternate emergent diagnosis cannot be excluded.48 Furthermore, because endometritis and salpingitis can occur concomitantly or in exclusion of one other, the CDC recommends that an endometrial biopsy be performed in every woman with negative laparoscopic findings.48

Outpatient versus Inpatient Treatment of PID

In recent years there has been a shift to outpatient management of PID. A recent large multicenter randomized controlled trial, called the PID Evaluation and Clinical Health (PEACH) Study, has provided evidence to substantiate this change in management.75 The study randomized 831 women with mild to moderate PID to either initial inpatient treatment with intravenous cefoxitin and doxycycline or outpatient treatment consisting of a single IM dose of cefoxitin and oral doxycycline.90 There were no significant differences between the inpatient and outpatient groups in terms of long-term outcomes, such as infertility (17.9% versus 18.4%), frequency of PID recurrence (16.6% versus 12.4%), CPP (29.8% versus 33.7%), and ectopic pregnancy (0.3 versus 1%).75 There was, however, a trend toward improved eradication of endometritis at 30 days in the inpatient group (45.9% versus 37.6%, p = 0.09).75 Interestingly, a large portion of both treatment groups experienced clinical sequelae, which raises questions about the accuracy of the initial diagnosis and clinical cure rates of the antibiotic regimens utilized in this study. The equivalent outcomes between both groups, though, demonstrate that hospitalization of every female with PID is not warranted.

The CDC suggests hospitalization if a surgical emergency (such as appendicitis) cannot be excluded by the initial workup, or if the patient is pregnant, has not responded to oral antibiotics, is unable to follow or tolerate an outpatient oral regimen, has severe illness, nausea, vomiting, or high fever, or if the patient has a TOA.48 An implicit yet critically important part of outpatient management is the ability and volition of the patient to engage in close 72-hour follow-up in order to evaluate treatment response. This factor is especially salient to the care of adolescents who may have limited resources to coordinate appropriate follow-up. No current data exist, however, that demonstrate superiority of outcomes for hospitalized adolescents; thus the decision to hospitalize teens with PID should be based on the above criteria. Additionally, no definitive recommendation exists to hospitalize women in their later reproductive years either, despite data from a small cross-sectional study of hospitalized women with PID showing that women older than 35 years had a more complicated course than their younger counterparts.91

CDC-Recommended Regimens

The CDC currently recommends several parenteral and oral regimens for the treatment of PID (Table 43–7).48,92 Total treatment duration is 14 days. Parenteral therapy, if initiated, can be discontinued 24 hours after clinical improvement, and oral doxycycline or clindamycin should be instituted for the remainder of treatment. Intravenous doxycycline is associated with painful phlebitis and should be avoided whenever possible.48,75 Outpatient regimens include a single IM dose of a third-generation cephalosporin plus a 14-day course of doxycycline, with or without metronidazole. Coverage of anaerobes is suggested but not mandated by the CDC48,92 because conflicting data show that while anaerobic gram-negative rods can result in endometritis,20 many of the antibiotic regimens that do not cover anaerobes have good clinical and microbial cure rates.25 Regimens utilizing either a single dose93 or a 7-day course94 of azithromycin have shown equivalent clinical cure rates compared to current oral regimens but are not yet endorsed by the CDC because of growing concern for emerging macrolide resistance.

Because of increasing prevalence of quinolone-resistant N. gonorrhoeae (QRNG), the CDC no longer recommends the use of fluoroquinolones for treatment of gonococcal infections, including associated conditions such as PID. 92,95 Currently, therefore, cephalosporins are the only class of antibiotics that is approved for outpatient management of PID, which significantly complicates treatment of this infection in patients with severe allergic reactions to penicillin or other beta-lactam antibiotics. Spectinomycin is an alternate choice in this situation, but is not available in the United States. Therefore, patients allergic to penicillin should either be hospitalized and treated with clindamycin and gentamycin, or if there is low suspicion for N. gonorrhoeae, can be managed as outpatients with azithromycin, as long as cultures, antimicrobial-sensitivity testing, and close follow-up are undertaken.

While management of FHC Syndrome is similar to that of uncomplicated PID,61 treatment of TOA differs significantly. CDC guidelines mandate that all females with TOA be hospitalized and that parenteral regimens include anaerobic coverage.48,92 Length of treatment is generally for 14–21 days. No evidence exists that parenteral therapy for the entire duration of treatment results in superior outcomes. Most clinicians use clindamycin instead of doxycycline for oral therapy in order to achieve improved anaerobic coverage.48,92 Drainage or surgery is indicated if medical therapy does not attain clinical improvement.48,63,65

Management of PID in Special Populations: HIV-Positive Females and Adolescents

There is conflicting data on whether HIV-positive females suffer more severe manifestations of PID,96–99 thus, the CDC does not currently mandate more aggressive management or hospitalization of all HIV-positive patients with PID.48,92 Old retrospective studies showed slower response rates to treatments, increased rates of surgery, and longer hospitalization stays for HIV-positive women with PID,98,100 but more current data support similar outcomes between HIV-positive and HIV-negative women, except possibly for those with a low-CD4 count.96,97,101

Treatment of youth also deserves special consideration. Incidence of PID is 5–10-fold greater in adolescents than in adults,11,12 a finding that may be partially related to increased risk-taking behavior among this population.102 Adolescents, though, also have decreased secretion of cervical immunoglobulins, lower overall serologic immunity and increased cervical ectopy, all of which allow pathogens to adhere more readily to the columnar cells of the endocervix and initiate an ascending infection.11,12,40,42 Additional risk factors for PID among adolescents include having older sexual partners, a history of involvement with protective services, and a history of suicide attempts.18 Clinicians who care for adolescents should also realize that teens have decreased access to health care, which makes them less likely to initiate care or engage in necessary follow-up.103,104 Health care providers should use increased sensitivity when treating adolescents with PID: offering compassionate and honest care,105 seeing the patient alone for at least part of the visit, and ensuring confidentiality103 are factors that can make a difference in outcomes among adolescents with this infection.

Primary and Secondary Prevention of PID

Central to primary prevention of PID is universal screening for C. trachomatis and, in some US cities, for N. gonorrhoeae as well. Unequivocal data exist that universal screening decreases the prevalence of STIs, PID, and ectopic pregnancy.106,107 Promotion of barrier methods is another strategy to decrease the incidence of PID. Inconsistent condom use has been shown to increase risk of PID threefold,17 and there is some evidence from the PEACH trial that consistent use can decrease recurrence of this complex infection and its long-term sequelae.108

Recurrent PID is estimated to comprise up to 47% of all cases.109 Secondary prevention strategies seek to improve not only eradication of the primary episode, but also patient adherence and partner treatment rates as well. Evidence shows that clinicians manage PID correctly only 35–60% of the time.110–112 Most antibiotic errors involve the duration of doxycycline, the choice of azithromycin or cefixime as first-line therapy, or inadequate ceftriaxone dose.110 Furthermore, adequate follow-up instructions are given less than 30% of the time.110,111 A subset of the PEACH trial evaluated treatment adherence using pill bottle electronic monitoring devices: results showed that patients took only 70% of the total prescribed doses of doxycycline, 17% of which were taken within the optimal time period.113 Retrospective data indicate that 25% of adolescents being treated for recurrent PID reported noncompliance with their initial regimen, while 70% did not tell their partners to get treated.109 Different partner treatment initiatives have been studied and show equivalent outcomes.114 In sum, in order to decrease recurrence of this complex infection and its devastating repercussions, health care providers absolutely need to ensure that every patient treated for PID is prescribed the correct antibiotic regimen, is given careful instructions for treatment adherence, and has both appropriate follow-up as well as a concrete plan for getting her partner treated.

• Right upper quadrant pain should raise suspicion for Perihepatitis associated with PID.
• Tubo-ovarian abscess occurs in up to one-third of women hospitalized for treatment of PID; <30% of women with a toa will have a pulpable adneral mass.