Pelvic Inflammatory Disease PDF

PELVIC INFLAMMATORY DISEASE. Arben Santo, David Stephen. LEARNING OBJECTIVES. See the pathology syllabi for learning objectives. REFERENCES. 1. Kumar V, Abbas AK, Aster JC. Pathologic Basis of Disease, 10e, Elsevier, 2020, pages 988-989. 2. Goljan EF. Rapid Review Pathology, 5e, Elsevier, 2018, pag...

PELVIC INFLAMMATORY DISEASE. Arben Santo, David Stephen. LEARNING OBJECTIVES. See the pathology syllabi for learning objectives. REFERENCES. 1. Kumar V, Abbas AK, Aster JC. Pathologic Basis of Disease, 10e, Elsevier, 2020, pages 988-989. 2. Goljan EF. Rapid Review Pathology, 5e, Elsevier, 2018, pages 639-640. CASE PRESENTATION: DIANE PHILLIPS. An 18-year-old girl presents with a one-week history of severe bilateral lower abdominal pain, fever, and chills. She has had some nausea and several episodes of vomiting. Her last menstrual period was 7 days earlier. She has been sexually active for the past three years and has had unprotected intercourse with several partners. She denies irregular bleeding, dysmenorrhea and dyspareunia. Physical examination reveals an ill-appearing young patient and a temperature of 38.6°C (101.48°F), a pulse of 94 beats per minute, blood pressure 124/82 mm Hg and a respiratory rate of 22 breaths per minute. On physical examination, the abdomen is slightly distended with rebound tenderness, and negative psoas and Murphy signs. Her vagina is pink and moist with no external lesions. There is a purulent discharge from the cervical os, and the cervix appears indurated. The uterus is in the midline position and is soft and tender to palpation. There is bilateral adnexal fullness and moderate tenderness. Laboratory studies reveal a leukocyte count of 16,700 cells/mm3 (normal: 4,000-10,000 cells/mm3), with a left shift, erythrocyte sedimentation rate of 56 mm/hr (normal: <20 mm/hr), C-reactive protein of 4.7 mg/dL (normal: <1 mg/dL), and a negative rapid plasma reagin test. Urinalysis is negative β-hCG. A vaginal wet mount reveals increased numbers of neutrophils. A cervical swab results positive for both C. trachomatis and N. gonorrhoeae. A transvaginal sonography identifies mild enlargement of the uterus, presence of fluid within the endometrial cavity, bilaterally increased tubal wall thickness, bilaterally enlarged ovaries and presence of fluid of moderate volume in the rectovaginal pouch (cul-de-sac). The patient was admitted and received two days of intravenous antibiotic therapy, but her fever did not decrease. A diagnostic laparoscopy was performed. About 5 cm3 of yellow, purulent fluid was drained from the pelvis. The fallopian tubes were reddened and swollen, with visible yellow exudates on the tubal surface, but with no adhesions and grossly open edematous fimbriae. A diagnosis of pelvic inflammatory disease was made. 1 DEFINITION. Pelvic inflammatory disease (PID) refers to acute infection of the upper genital tract structures in women, involving any or all of the uterus, fallopian tubes, and ovaries (endocervicitis, endometritis, salpingitis); this is often accompanied by involvement of the neighboring pelvic organs (pelvic peritonitis). By convention, PID is initiated by a sexually transmitted agent, which ascends into the upper genital tract. EPIDEMIOLOGY. Based on the National Health and Nutrition Examination Survey 2013–2014 data, 4.4% of women (2.5 million) 18 to 44 years of age in the United States reported a history of PID. PID occurs most frequently in women ages 15 to 25 years. RISK FACTORS. Risk factors for PID include age younger than 25 years, new or multiple sex partners, unprotected sexual intercourse, intercourse with a symptomatic partner, young age at onset of sexual activity (younger than 15 years), or a history of STDs. • Women who douche may have a higher risk of getting PID than women who do not douche. This is because douching upsets the bacterial ecology, can cause bacterial vaginosis, and enhances bacterial invasion of the uterus. ETIOLOGY. Typically, the first time a patient is diagnosed with PID, it is from a sexually transmitted organism, most commonly Chlamydia trachomatis or Neisseria gonorrhoeae. Later, microorganisms that comprise the vagina flora such as Prevotella spp., Peptostreptococcus spp., Mobiluncus spp., Gardnerella vaginalis, and Mycoplasma hominis, participate in the compromise of normal host immunity. Regardless of the initiating pathogen, PID assumes the features of a mixed (facultative and anaerobic) polymicrobial infection. • Tuboovarian abscesses, which virtually always contain a mixture of facultative and anaerobic bacteria (“polymicrobial PID”). • The current thought is that gonococci and chlamydia may initially penetrate the cervical barrier and cause mucopurulent endocervicitis that damages the endocervical canal, allowing endogenous organisms to access the upper genital tract. The initial gonococcal or chlamydial infection may then be replaced by competing anaerobic or facultative infection. PATHOGENESIS. Most cases of PID arise from the ascension of microorganisms from the lower genital tract. There is a canalicular upward spread along the mucosal surfaces. The initial infection involves the mucosa and not the muscularis. The only existing barrier between the lower and upper genital tract is thickened cervical mucus. The endocervical canal functions as a barrier protecting the normally sterile upper genital tract from the organisms of the dynamic vaginal ecosystem. With menses the cervical mucus thins, potentially allowing bacteria to ascend to the upper reproductive tract. • Diagnostic and therapeutic procedures that disrupt the protective cervical barrier, such as dilatation and curettage, induced abortion, insertion of an intrauterine device and hysterosalpingography introduce bacteria into the endometrial cavity. • Endocervical infection with sexually transmitted pathogens can disrupt this barrier. Disturbance of this barrier provides vaginal bacteria access to the upper genital organs, infecting the endometrium, then endosalpinx, ovarian cortex, pelvic peritoneum, and their underlying stroma. 2 • Disturbance of the cervical barrier provides vaginal bacteria access to the upper genital organs, infecting the endometrium, then endosalpinx, ovarian cortex, pelvic peritoneum, and their underlying stroma CLINICAL PRESENTATION. Acute salpingitis and PID present with a wide spectrum of manifestations ranging from overt clinical infection (overt PID) in 40% of cases, to unrecognized subclinical infection (subclinical PID) in 60% of cases. 1. Subclinical salpingitis. The diagnosis of subclinical salpingitis in clinical practice is difficult. Individuals with subclinical infection are identified in studies of women with documented infertility secondary to tubal scarring and adhesions. Even though tubal scarring and adhesions suggest PID, these individuals give no history of PID. However, in detailed interviews, these individuals frequently report medical visits for low abdominal or pelvic pain and abnormal uterine bleeding. Most of individuals with subclinical salpingitis and PID have a documented C. trachomatis infection. Some consider the gold standard for the diagnosis of subclinical PID to be an endometrial biopsy demonstrating endometritis (i.e., presence of neutrophils in superficial endometrium and a few plasma cells in the endometrial stroma). 2. Acute overt salpingitis. The classical clinical and laboratory findings in acute salpingitis are presented in Table 1. If women with the clinical diagnosis of acute salpingitis were to undergo routine laparoscopy, visual evidence of acute tubal inflammation would confirm the diagnosis. Acute overt salpingitis (PID) ranges from mild to severe presentations. Approximately 36% of women with acute overt salpingitis have a mild-to-moderate form of the disorder, and only 4% have a severe form of PID. (A) Mild-to-moderate PID. The most common symptoms in patients with mild-to-moderate PID include (i) bilateral lower abdominal pain, (ii) cervical motion tenderness and/or (iii) uterine/adnexal tenderness during pelvic examination. 3 Cervical motion tenderness is diagnosed when cervical manipulation induces pain. Intermenstrual bleeding and urinary frequency are also present in a lower percentage. Nausea and vomiting, which reflect the peritoneal involvement in the infectious-inflammatory process, are infrequent (10%) in mildto-moderate PID. The most common clinical physical findings include (i) mucopurulent or purulent vaginal discharge, and (ii) temperature > 38°C. A palpable adnexal mass is present in 50% of patients. (B) Severe PID. Severe PID is associated with peritonitis or tuboovarian abscess. The clinical picture described in the case presentation (Diane Phillips) can be characterized as a case of severe PID. Patients with severe PID appear very ill, with fever and chills, nausea and vomiting, purulent vaginal discharge, and rebound tenderness or abdominal guarding. Peripheral leukocytosis, elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are common laboratory findings as well. LABORATORY STUDIES. Leukocytosis is present in less than 50% of patients. An elevated ESR or elevated CRP is present in most of patients. Cervical cultures for C. trachomatis and N. gonorrheae should be done during the speculum examination. Laboratory studies should include a urine or serum pregnancy test. IMAGING STUDIES. Most commonly, the ultrasonographic results for acute PID are normal, because salpingitis alone is not usually associated with imaging findings. Sometimes salpingitis is associated with an increase of the tubal wall thickness greater than 5 mm. Hydrosalpinx and pyosalpinx are depicted as fluid- or debriscontaining tubal distention. Additionally, ultrasonography can reveal fluid in the cul-de-sac. LAPAROSCOPY. In everyday practice the diagnosis of PID is based primarily on clinical findings. Laparoscopy is not typically performed unless the patient has failed any antibiotic therapy. The laparoscopic findings in women with acute salpingitis (PID) cluster into two general categories: (i) free exudate (peritonitis) in the pelvis; or (ii) tubal occlusion without free exudate. 1. Free exudate in the pelvis. Some infections may rapidly produce peritonitis. Patients with this pattern are characterized laparoscopically by a free exudate in the pelvis and abdomen associated with patent tubes and absence of tubal adhesions. Women with free exudate tend to present with signs of peritonitis, peripheral blood leukocytosis, and with the presence of N. gonorrhoeae in the lower and upper genital tract. These associations suggest that when the tubes are patent, exudate flows from the tubes into the pelvis and abdomen, causing peritonitis, while tubal occlusion blocks exudate from reaching the peritoneum. 2. Tubal occlusion without free exudate. Some infections produce tubal occlusion without peritonitis. These patients show tubal adhesions in laparoscopy, tubal abscess, and a palpable adnexal mass on physical examination. PATHOLOGY. Acute salpingitis is a spectrum of infections of the upper genital tract that includes endometritis, salpingitis, oophoritis, and peritonitis. 1. Endometritis. The endometrial infection by C. trachomatis and N. gonorrhoeae is manifested by neutrophilic infiltration of the endometrial surface, by large numbers of plasma cells in the endometrial stroma, and lymphoid aggregates with germinal centers. 2. Salpingitis. The mucosa of the normal fallopian tube forms a complicated maze-like pattern of folds, termed plicae, that branch but do not join. Tubal folds are lined by ciliated columnar epithelium. 4 (A) Acute suppurative salpingitis. This is a purulent inflammation of the fallopian tube with more severe changes in the mucosa than other layers of the tube. Grossly the fallopian tube is swollen, edematous and congested. Fibrin exudate may lay over the tubal serosa. Histologically, the mucosa (plicae) is greatly swollen and densely infiltrated by neutrophils. The tubal epithelium undergoes necrosis in severe disease and may shed. The lumen is filled with pus. (B) Chronic salpingitis. Repeated bouts of acute salpingitis lead to chronic interstitial salpingitis. Grossly, the fallopian tube is thickened and congested with adhesions on the surface, often binding the tube and ovary closely together. Histologically, fibrin exudation into the tubal lumen during the acute salpingitis results in plicae adhering to each other. Subsequent organization and healing lead to permanent adhesions between the plicae, producing epithelium-lined dilated channels. Within plicae, large collections of chronic inflammatory cells accumulate with proliferating lymphocytes forming germinal centers. (C) Natural history of salpingitis. Salpingitis and other components of the PID typically have remissions and exacerbations and are difficult to eradicate. As a result of this cycle of events, acute salpingitis leads to chronic salpingitis, quiescence and then an exacerbation of the acute episode again. The outcome of salpingitis depends largely on the severity of the initial acute inflammation and the tendency to develop acute exacerbations. If the initial acute inflammation is mild, complete resolution can occur. If the initial acute inflammation is severe, resolution does not occur, and the inflammatory process becomes chronic, and scarring takes place. Scarring may cause folds of epithelium to become densely adherent to each other. This produces a complicated multicystic system, exaggerated by continued mucus secretion by the epithelium. The chronic inflammatory process may eventually subside. The plicae remain fused by fibrosis, but the inflammatory infiltrate is minimal or absent. (D) Complications of salpingitis. • Pyosalpinx develops if the fimbrial end of the fallopian tube becomes occluded, and the release of the purulent tubal content is prevented. A pyosalpinx is characterized by thinning of the tubal wall and a lumen filled with pus. • Hydrosalpinx results when the purulent exudate is resorbed concurrently with the quiescence of the inflammatory process, and clear fluid replaces pus. 3. Oophoritis and tubo-ovarian abscess. During the evolution of salpingitis the fimbria frequently become attached to the surface of the ovary. Pathogenic microorganisms can then gain access to the ovary by direct extension. They may establish themselves in a ruptured Graafian follicle. Oophoritis and tubo-ovarian abscess result. • A tubo-ovarian abscess is a loculated mass consisting of adherent ovarian, tubal, uterine, omental, and sometimes intestinal tissues. The locules contain purulent material and are surrounded by a wall of fibrous and granulation tissue. Microscopically there is marked edema and congestion of the ovarian 5 tissues surrounding areas of suppurative inflammation. The acute inflammatory exudate is gradually replaced by lymphocytes, plasma cells and granulation tissue. Fibrosis and the development of pelvic adhesions follow. 4. Peritonitis. Pelvic peritonitis results if the purulent exudate escapes from the tubes or ovaries into the peritoneal cavity. A purulent exudate accumulates in the cul-de-sac. The peritoneal fluid of the cul-desac, aspirated by culdocentesis, displays an elevated leukocyte count. Culdocentesis refers to the extraction of fluid from the rectouterine pouch posterior to the vagina through a needle. • As a result of pelvic peritonitis, contiguous pelvic structures may become involved in the inflammatory process. A pelvic abscess forms in the rectouterine pouch. The inflammatory exudate becomes organized forming adhesions between the fallopian tube, ovary, uterus, bowel and bladder. The fibrotic adhesions glue the adjacent structures of the pelvis to one another. MICROBIOLOGICAL DIAGNOSIS OF PID. There are numerous testing modalities for gonococcal infections including Gram stain, culture, immunochemical, and molecular detection. 1. Microscopy of a direct smear. The classic test for gonococcal infections has been Gram stain of the swab specimen from endocervix. Microscopic demonstration of neutrophils containing intracellular Gram-negative kidney-shaped diplococci under oil immersion (1000×) provides presumptive diagnosis of gonorrhea. • The test for Chlamydia infections is Giemsa stain of the swab specimen from endocervix. Microscopic examination demonstrates intracellular inclusions in epithelial cells. • The presence of Clue cells in the smear of vaginal secretions can be used to confirm bacterial vaginosis. Clue cells are detached epithelial cells to which bacteria have bound, giving the epithelial cell a “fuzzy” appearance on microscopy. 2. Culture. Culture testing from sites of exposure is strongly recommended for PID. Culture remains important for its ability to assess antibiotic susceptibilities of the isolate when resistance is suspected. The two most commonly used media for the growth of N. gonorrhoeae are Thayer-Martin and MartinLewis media. 3. Immunochemical confirmatory identification. It has become necessary to confirm a clinical isolate identified as Neisseria gonorrhoeae from culture using a second test. GonoGen II is a monoclonal antibody-based colorimetric test intended for the confirmatory identification of Neisseria gonorrhoeae from culture. Organisms from a suspected isolate of N. gonorrhoeae are suspended in solubilizing buffer. The buffer is mixed with the GonoGen II reagent and applied to a well on the test tray. A positive reaction is visible as a red dot. If the isolate is not N. gonorrhoeae no reaction will be visible. • A number of enzyme immunoassays (EIA) are available for the detection of chlamydial antigens in clinical specimens. These products use either monoclonal or polyclonal antibodies to detect chlamydial 6 lipopolysaccharide. Most EIAs take several hours to perform. The sensitivity profiles of the commercially available C. trachomatis EIAs range from 65% to 75% compared with NAA assays. 4. Serological tests. Serological tests used for screening of syphilis and other STDs do not work for the diagnosis of genital tract infections caused by N. gonorrhoeae and C. trachomatis. 5. Molecular tests. The diagnostic test of choice for N. gonorrhoeae and C. trachomatis infection of the genitourinary tract is nucleic acid amplification test (NAAT) of vaginal swabs. They are more sensitive than culture, offer testing on a wider range of specimen types and are less demanding in specimen quality, transportation and storage. The CDC recommends screening of asymptomatic persons suspected of having N. gonorrhoeae infection using urine NAAT for males and cervical or urine NAAT for females. • The major limitation of NAATs is that they detect only the genetic material; they cannot determine whether the bacteria causing infection are living or resistant to antibiotics. Thus, the test cannot be used to determine whether treatment is effective, and an antibiotic is killing the bacteria. Another limitation is that NAAT testing does not provide antibiotic sensitivities of the organism. EXTRAGENITAL MANIFESTATIONS OF PID. Both C. trachomatis and N. gonorrheae may enter the abdominal cavity proper and cause inflammation of the serosal surfaces, periappendicitis and perihepatitis. 1. Periappendicitis. Periappendicitis involves inflammation of the periappendicular serosa associated with PID. The appendicular mucosa is not involved. The appendix is adherent to the right fallopian tube in almost all cases indicating a direct spread of organisms from the infected tube to the appendiceal serosa. Clinically periappendicitis mimics acute appendicitis. Patients complain of fever and right lower abdominal pain. Physical examination reveals rebound tenderness in the right lower quadrant. Laboratory tests show elevated ESR and C-reactive protein levels. 2. Perihepatitis. Perihepatitis, also known as Fitz-Hugh-Curtis syndrome, features inflammation of the liver capsule and the adjacent parietal peritoneum associated with PID. Fibrous deposits develop in the acute stages on the liver capsule, which later become organized and form “violin-string” fibrotic adhesions between the liver capsule and the abdominal wall. The clinical signs of perihepatitis are an acute, sharp, pleuritic type, right-upper quadrant abdominal pain associated occasionally with a friction rub. Laboratory tests (leukocytosis, elevated ESR and CRP) are within the ranges seen in other cases of PID. Laparoscopy is the technique of choice for the diagnosis of perihepatitis. CHRONIC SEQUELAE OF PID. Pelvic inflammatory disease has significant long-term sequelae that have a profound adverse impact on the general and reproductive health of young women. These sequelae include (i) infertility, (ii) chronic pelvic pain and (iii) ectopic pregnancy. 7 • With each repeated episode of PID the rate of infertility, chronic pelvic pain, and ectopic pregnancy increase two-fold. Infertility and ectopic abortion result from tubal scarring and occlusion. Chronic pelvic pain is due to the presence of diffuse fibrotic intraperitoneal adhesions involving the fallopian tubes, ovaries, uterus, bladder, bowel, and omentum. 8