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Home , Cervicitis, Salpingitis

CLINICAL PRACTICE

• Pelvic inflammatory disease: Clinical update

JOSEPH H. RIDGIK, D.O. FACOOG Stratford, New Jersey NEAL POCK, D.O. Tucson, Arizona

Pelvic inflammatory fallopian tubes and pelvis. Eighty-nine years later, disease (PID), with an estimated 10 our understanding of the pathophysiology of this million new cases annually, is currently disease has been enhanced and elaborated via elec- the leading cause of in the tron microscopy and immunofluorescence tagging United States. Acute PID refers to the of pathogens, but the basic theory proposed by acute syndrome (unrelated to pregnancy Kelly remains unchallenged. In a comparison of or surgery) attributed to the ascent of endometrial biopsy specimens with peritoneal fluid microorganisms from the vagina and cytology performed at the time of laparoscopic diag- endocervix to the , nosis of PID, Paavonen and associates 2 concluded fallopian tubes, and/or contiguous that "nonpuerperal is an entity asso- structure. The clinical picture of PID ciated with pelvic inflammatory disease, most ranges from acute overwhelming febrile likely representing an intermediate stage between illness, which is life threatening, to and acute ." Keith and co- chronic diffuse abdominal discomfort, workers3 used electron microscopy and fluorscein- which is easily mistaken for a conjugated monoclonal antibodies to demonstrate genitourinary or gastrointestinal that trichomonads and sperm act as vectors to complaint. For simplicity, the term PID transport a variety of pathogenic from the will be used rather than the specific and vagina into the fallopian tubes and pel- involved site, such as endometrium, vis. Another mechanism of transport proposed by endometritis, etc. This paper provides a these authors is a pressure differential between the review of the pathophysiology of PID cervix and a negative intraperitoneal pressure, and a clinical update on diagnosis and which causes an "insuck" effect, thus facilitating a treatment, with a great degree of rapid transport of these pathogens into the fallo- emphasis placed on the pian tube and pelvic cavity. organism, because of the prevalence of this bacteria in the United States and Diagnosis throughout the world. Attention will be Differential diagnoses in patients suspected of hav- focused on the life cycle, incidence, ing acute PID include , ruptured clinical appearance, and suggested , torsion of the ovary, acute appen- therapeutic guidelines. dicitis, acute endometritis, septic abortion, endo- metriosis, acute intestinal obstruction, acute pyelonephritis, and puerperal sepsis. In 1898, Kelly proposed that pelvic inflam- Lower abdominal pain is the most frequent matory disease (PID) was the result of an ascending symptom in patients with laparoscopically con- that began in the vagina and cervix, then firmed acute salpingitis. 4 Acute symptoms most spread over the surface of the endometrium into the often appear during or immediately after menses,

Pelvic inflammatory disease: Clinical update 142/87 TABLE 1. CLINICAL CRITERIA FOR DIAGNOSIS OF SALPINGITIS.6 office might be an alternative to laparoscopy for All three signs are necessary for diagnosis: establishing a diagnosis of acute PID. Their re- Direct abdominal tenderness with or without search has shown that the presence of plasma cell rebound tenderness endometritis in the biopsy specimen has a sen- Thnderness on motion of cervix and Adnexal tenderness sitivity of 89 percent and a positive predictive value of 43 percent in diagnosis of PID when compared to Plus one or more of these signs must be present: findings at the time of diagnostic laparoscopy. Positive gram stain of the endocervix for gram-negative intracellular diplococci Based on the degree of infiltration and aggregation Thmperature >38 C. of plasma cells in the endometrial stroma, biopsy Leukocytosis >10,000/cu. mm. specimens from this study were graded histo- Purulent material (white blood cells present) obtained from peritoneal cavity on culdocentesis or laparoscopy logically as mild, moderate, or severe endometritis. Pelvic abscess or inflammatory complex on bimanual or The single-strip endometrial biopsy technique sonographic examination. may well provide a safe and simple diagnostic tool for detecting early stages of ascending pelvic infec- tion before the appearance of visible laparoscopic findings. An area for productive future PID study when an intrauterine environment rich in mucus might be directed at exploring the possibility and and cellular debris provide a ready media for the quantitations of false-negative results at the time growth and spread of ascending organisms. The of diagnostic laparoscopy. severity and clinical course of the pelvic infection In the United States, the most frequent an- are dependent upon the particular strain and vir- aerobes to be isolated from the fallopian tubes and ulence of the infective organism and are altered by pelvis of patients with PID are C. trachomatis and the patients general health and resistance to the N. gonorrhoeae.8 Chlamydia have now specific pathogen. Pyogenic organisms, such as surpassed and herpes as "the most prev- , Escherichia coli, Strep- alent sexually transmitted disease in the United tococcus viridans, Bacterioides fragilis, and Pep- States today."9 Estimates from the Centers for Dis- tostreptococcus, often have an acute febrile course, ease Control place the number of reported cases of while Chlamydia-associated PID is characterized PID at 3 million annually, with unreported cases by a protracted course of vague lower genital tract estimated to be 10 million annually.19 symptoms .5 Because of this high incidence, it is important to Hager and coauthors6 suggested revised clinical understand the life cycle of C. trachomatis. The criteria for confirming the presence of PID, as out- organism is a nonmotile, gram-negative, metabolic lined in Table 1. obligate—an intracellular parasite. It replicates Early cervical infections that can lead to the within the cytoplasm of the host cell and forms development of PID must be differentiated from characteristic intracellular inclusion bodies, which vaginal and lower genitourinary tract infections stain dark brown with immunoperoxidase tech- before proper treatment can be initiated. The pres- niques using McCoy cell cultures. Unlike , ence of malodorous associated Chlamydia organisms contain both RNA and DNA with mucopurulent cervicitis is suggestive of and have a cell wall similar to the gram-negative infection. To establish this bacteria.11 Their entire life cycle requires approx- diagnosis, Brunham and associates 7 have recom- imately 3 days. The infecting (rigid-walled) ele- mended the following objective criteria: (1) positive mentary body (EB) attaches to the host cell wall swab test (yellow-colored endocervical mucus); and and is ingested via phagocytosis into the host cell (2) the presence of 10 or more polymorphonuclear body. The EB is encapsulated in a phagocytic vesi- leukocytes per microscopic field (at x 1,000 magni- cle derived from the host cells surface membrane. fication). These authors state that the specimen It is within this vesicle that the EB undergoes should be obtained directly from the endocervical reorganization or metamorphosis into an initial canal and should be free from vaginal con- reticulated body (RB). Chlamydiae cannot syn- taminants. Slides demonstrating large amounts of thesize adenosine triphosphate and, therefore, vaginal epithelial cells or flora should be excluded. must depend upon the host cell to supply the energy Differential diagnosis of vaginal discharges should for replication as well as the essential amino acids include tests for , Candida (hence the term metabolic obligate). The initial RB albicans, and Gardnerella vaginalis, as well as N. remains in the phagosome as a metabolically active gonorrhoeae. but noninfectious, replicating form. Dividing by Paavonen and associates 2 have suggested that single binary fission, the initial RB produces the single-strip endometrial biopsy performed in the final reticulate body and then undergoes a resting

143/88 Feb. 1987/Journal of AOAJvol. 87/no. 2 phase for 18 to 24 hours. Condensation or meta- collection kit which contains a single glass slide morphosis into the rigid-walled EB now occurs, with a circular well for plating the specimen, two causing rupture of the phagosome with lysis of the Dacron swabs, and an acetone fixative. The spec- host cell wall and release of the infective EB. The imen to be examined is taken directly from the life cycle begins once again with attachment of the columnar epithelium in the endocervical canal and rigid-walled EB to a new host cell wal1.12 should not include debris from the vaginal surfaces. Often, polymicrobial infections of synergistic The surface of the cervix is cleansed of excess vaginal organisms, including Peptococcus, Pep - mucus and debris with the largest swab, then the tostreptococcus, Bacterioides, Streptococcus, Staph- smaller swab is used to collect the endocervical ylococcus, and , are found in PID. cells. The cell specimen is applied directly to the When an abscess is present, enteric gram-negative surface of the small circular well on the slide and rods (E. Coll, Klebsiella, Pseudomonas, and Hemo- then air dried and fixed with the acetone. In the philus influenzae) frequently are found. One laboratory, the slide is treated with a reagent con- should be aware that the bacterial flora changes taining monoclonal antibodies that are tagged with during different stages in the progression of cer- fluorescein isothiocyanate. These antibodies are vicitis into PID, and that these changes often alter specific to the principal membrane protein of all 15 the reported symptomatology and observed clinical of the known serotypes of C. trachomatis. The slide response to treatment. 8 According to Brunham,815 is then rinsed and analyzed. The stain remains percent of the women with acute PID fail to respond attached to both the intracellular and extracellular to the initial antimicrobial treatment, and another elementary bodies. Positive specimens appear as 15 percent are rendered infertile by the first infec- an "apple-green starry sky or Milky Way" collec- tion. Twenty percent have a recurrent episode of tion of stained EB and RB. Unfortunately, the in- PID. Of those women who do become pregnant, 8 terpretation of these slides is technically difficult percent have ectopic pregnancy. Therefore, PID and requires considerable judgement and experi- must always be viewed as a serious threat to the ence by the lab technician reading them. There- patients fertility. fore, the laboratory in our institution no longer C. trachomatis has now surpassed N. gonor- uses this test. The Micro Trak process is better rhoeae as the most frequently diagnosed pathogen suited for use by a smaller hospital laboratory that in cases of infertility due to tubal occlusive dis- would perform fewer numbers of tests. The start-up ease. 10 The presence of an elevated C. trachomatis costs are less than Chlamydiazme, but, unlike that antibody titer has a high predictive value for hydro- process, Micro Trak is not approved for surgical salpinx and peritubal diseases. In one study, 73 specimens. percent of women with distal tubal occlusion had The Chlamydiazme procedure is much better high titers from C. trachomatis antibodies, while suited for batching of large numbers of tests. The women with normal fertility had no antibodies for endocervical specimen is collected on a Dacron the organism.13 Punnonen and coworkers 14 found swab. Instead of applying the specimen to a slide, positive C. trachomatis titers in 91 percent of the swab is placed in a specimen transport tube women with infertility from tubal occlusion; of containing a storage reagent; it is then capped and even greater interest, they also found that 50 per- sent to the laboratory, where it may be stored in the cent of infertile women with normal his- refrigerator for up to 5 days without loss of ac- tiosalpingographic findings had elevated titers for curacy. The cells on the swab are dislodged into C. trachomatis. solutions, and a single treated plastic bead is added In the past, diagnosis of C. trachomatis infections to the transport tube. This bead has monoclonal was dependent upon standard culture techniques. rabbit antibodies on its surface; these are specific to The specimen was spread across pretreated single- all 15 serotypes of C. trachomatis. The bead is cell thickness tissue cultures containing McCoy washed and the rabbit IgG is tagged with labeled cells. Incubation was technically difficult and re- peroxidase (horseradish and goat) immunofluores- quired 48 to 72 hours. The cells then were stained cence stain. The tubes are batched in groups of 20 with iodine, Giemsa stain, or fluorescent-labeled and read by standard colometric equipment, which antibodies and analyzed. The procedure was expen- is attached to a computer printer. Large numbers of sive, time consuming, and not generally available tests are easily processed in this way, and the high in hospital laboratories. However, two commercial initial cost is recoupable if a sufficient number of processes for the detection of Chlamydia—Micro tests are performed. Trak (Syva Co.) and Chlamydiazyme (Abbott Labo- For the sake of completeness, some special cases ratories)—have become available recently. of PID should be mentioned. The first is PID sec- The Micro Trak process consists of a specimen ondary to the use of an . Patients

Pelvic inflammatory disease: Clinical update 144/89 TABLE 2. STAGING OF SALPINGITIS BY LAPAROSCOPY.6 erythromycin (250 mg. 4 times daily) for at least 14 Stages of disease Signs days. For uncomplicated gonococcal infections, the rec- Mild Erythema, edema, no spontaneous pur- ulent exudate, tube freely movable ommended treatments10 include the following: aq- Moderate Gross purulent material evident, erythema ueous procaine penicillin G (4.8 million units and edema more marked. Tubes may not injected intramuscularly, at 2 sites) with oral pro- be freely movable, and fimbria stoma may not be patent. benecid (1.0 gm.); or oral amoxcillin (3.0 gm.) or Severe Pyosalpinx or inflammatory complex, or ampicillin (3.5 gm.), either with oral probenecid abscesst (1.0 gm.); or oral tetracycline hydrochloride (500 mg. 4 times a day for 7 days). Oral doxycycline The tubes may require manipulation to produce purulent exudate. tThe size of any pelvic abscess should be measured. hyclate (100 mg. twice daily for 7 days) may be substituted for the tetracycline hydrochloride. Other forms of tetracycline are not more effective than tetracycline hydrochloride, and all using this type of contraception have a five-fold tetracyclines are ineffective as single-dose therapy. increased risk of developing acute salpingitis as Because 45 percent of patients documented as compared to women using other contraceptive having gonorrhea have a coexisting Chlamydial methods.5,15 Genital Mycoplasma and Ureaplasma infection,10 for these patients a combination of oral urealyticum (formerly called T-strain Mycoplasma) amoxicillin (3.0 gm.) or ampicillin (3.5 gm.) with organisms have been cultured in up to 13 percent of oral probenecid (1.0 gm.) is given as initial therapy, female patients with acute salpingitis. These or- which is followed by 7 days of tetracycline hydro- ganisms are often implicated in puerperal infec- chloride (500 mg. 4 times a day). tion, spetic abortion, low birth weight, nongonococ- All outpatients should be reevaluated in 48 to 72 cal , spontaneous abortion, and infer- hours, and a culture for test of cure should be per- tility.16 formed. If an intrauterine contraceptive device is in Postpartum endometritis occurs in 34 percent of place, it is usually removed during this follow-up women with antepartum C. trachomatis cervical visit. Patients who fail to respond to or who have a infections. 17 Modes of transmission of organisms minimal or poor response to outpatient that cause postpartum puerperal sepsis (E. coli, therapy should be hospitalized immediately. Other Bacterioides, Peptostreptococcus, and Clostridium) indications for inpatient treatment of acute PID include direct extension from vagina and cervix, include: uncertain diagnosis; temperature >101 de- lymphatic transmission, and septic thrombi.18 grees F. (a sign of acute systemic illness); suspected Other single etiologic agents for PID include acute surgical abdomen (suspected ectopic preg- type IL° Actinomyces in asso- nancy, possible appendicitis, or bowel obstruction); ciation with the use of intrauterine devices, 20 and upper peritoneal signs (Fitz-Hugh-Curtis syn- Enterobacteriaceae.21 drome); suspected tubo-ovarian or pelvic abscess with fluid in the cul-de-sac; known or suspected Treatment pregnancy; and cases in which outpatient manage- Successful treatment of PID is difficult under the ment is impractical because of noncompliance or best of circumstances, and careful diagnosis via inability of the patient to take oral medication t° cultures and testing is important to the selection of Once the patient is hospitalized, recommended appropriate antibiotic therapies. Failure of treat- combinations8,10 of antimicrobial treatment for ment is often due to the continued use of inap- acute PID include the following: intravenous cefox- propriate antibiotic agents for a prolonged period of itin (2 gm. every 6 hours) with intravenous dox- time despite a lack of clinical improvement. ycycline (100 mg. every 12 hours); or intravenous Outpatient therapy for diagnosed Chlamydia-as- clindamycin (600 mg. each 6 hours) with intra- sociated infections, as recommended by the Centers venous gentamicin or tobramycin (2 mg./kg. bolus for Disease Control,1° includes oral tetracycline hy- followed by 1.5 mg./kg. each 8 hours); or intra- drochloride (500 mg. 4 times a day for 7 full days) venous doxycycline (200 mg. bolus followed by 100 and oral doxycycline hyclate (100 mg. twice daily mg. each 12 hours) plus intravenous metronidazole for 7 full days). If the patient is pregnant, the rec- (1 gm. every 12 hours). ommended therapy includes intramuscular spec- Brunham8 has suggested the following criteria tinomycin (2 gm. daily) plus oral erythromycin for clinical staging of acute PID: stage I, acute (500 mg. taken on an empty stomach 4 times a day salpingitis without ; stage II, acute sal- for at least 7 days). The patient who can not tolerate pingitis with peritonitis; stage III, acute salpingitis this regimen should take a decreased dosage of oral with tubal abscess; and stage IV, ruptured tubo-

145/90 Feb. 1987/Journal of AGA/vol. 87/no. 2 ovarian abscess. Stage I patients are managed ini- 5. GjØnnaess, H., et al.: Pelvic inflammatory disease. Etiologic studies with emphasis on chlamydial infection. Obstet Gynecol 59:550-5, May 82 tially as outpatients on single-drug therapy, while 6. Hager, WD., et al.: Criteria for diagnosis and grading of salpingitis patients with stage II disease are hospitalized and (editorial). Obstet Gynecol 61:113-4, Jan 83 treated with multiple parenteral . Pa- 7. Brunham, R.C., et al.: Mucopurulent cervicitis. The ignored counter- tients with stage III and stage IV disease require part in women of urethritis in men. N Engl J Med 311:1-6, 5 Jul 84 8. Brunham, R.C.: Therapy for acute pelvic inflammatory disease. A surgical intervention as well as a regimen of multi- critique of recent treatment trials. Obstet Gynecol 148:235-40, 1 Feb 84 ple parenteral antibiotics. Laparoscopic staging of 9. Norman, R.A.: Chlamydia infections. The disease of the 80s. Osteo PID is often necessary in choosing the appropriate Med News 11:1 10. Sexually transmitted disease treatment guidelines 1982. MMWR medical or surgical therapy. Laparoscopic classi- 34:35S-43S, 18 Oct 85 fication criteria, as delineated by Hager and 11. Brown, E.R., and Nair, V.: Laboratory identification of s"xually trans- coauthors,6 are listed in Table 2. mitted diseases. J Reproduct Med 30S:237-43, Mar 85 12. Faro, S.: Chlamydia trachomatis infection in women. J Reproduct Med 30S:273-8, Mar 85 Summary 13. Judson, F.N.: Assessing the number of genital chlamydial infections In conclusion, one should be extremely careful in in the United States. J Reproduct Med 30S:269-72, Mar 85 14. Punnonen, R., et al.: Chlamydial serology in infertile women by establishing a diagnosis. Pelvic inflammatory dis- immunofluorescence. J Fertil Steril 31:656-9, 19 Jun 79 ease has a wide range of clinical presentations; 15. Ory, H.W.: A review of the association between intrauterine devices and acute pelvic inflammatory disease. J Reproduct Med 20:200-4, Apr 78 depending upon the stage of the disease and the 16. Friberg, J.: Diagnosis of genital Mycoplasma and Ureaplasma infec- causative organism, the patient may be acutely ill tions. J Reproduct Med 30S:256-61, Mar 85 or mildly uncomfortable. One should know the lim- 17. Moore, D.B., et al.: Increased frequency of serum antibodies to Chlamydia trachomatis in infertility due to distal tubal disease. Lancet itations of the tests and the cultures routinely used 2:574-7, 11 Sep 82 and should not hesitate to confirm ones clinical 18. Pritchard, J.A., MacDonald, P.C., and Gant, N.F.: Williams Obstetrics. impressions with laparoscopy or dilatation and Ed. 17. Appleton-Century-Crofts, Norwalk, Connecticut, 1984 19. Paavonen, J., et al.: Endometritis and acute salpingitis associated curettage. The patient should not be undertreated; with Chlamydia trachomatis and type two. Obstet PID often has multiple infective organisms under- Gynecol 65:288-91, Feb 85 20. Schmidt, W.A., et al.: Actinomycins and intrauterine contraceptive lying the clinical picture, and it may be necessary devices. The clinicopathologic study. Diagn Gynecol Obstet 2:165-77, Fall to employ more than one antibiotic and several 80 stages of therapy, including hospitalization, before 21. Thompson, S.E., et al.: The microbiology and therapy of acute pelvic inflammatory disease in hospitalized patients. Obstet Gynecol the patient is cured. Chlamydia trachomatis has 136:179-86, 15 Jan 80 now surpassed N. gonorrhoeae as the most frequent causative organism of PID; its symptoms and clinical course are more subtle and require dif- Accepted for publication in June 1986. Updating, as necessary, ferent antibiotics and a longer duration of treat- has been done by the authors. ment to effect a cure.

Dr. Ridgik is an associate professor of clinical obstetrics/ gynecology, University of Medicine and Dentistry of New Jersey, 1. Kelly, H.: Operative gynecology. Appleton-Century-Crofts, New York, School of Osteopathic Medicine, Stratford, New Jersey. At the 1898 time this paper was written, Dr. Pock was a resident in 2. Paavonen, J., et al.: Comparison of endometrial biopsy and peritoneal obstetrics/gynecology at Kennedy Memorial Hospitals-Univer- fluid cytologic testing with laparoscopy in the diagnosis of acute pelvic sity Medical Center, Stratford, New Jersey. He is now in the inflammatory disease. Am J Obstet Gynecol 151:645-50, 1 Mar 85 private practice of obstetrics and gynecology in Tucson, Arizona. 3. Keith, L.G., et al.: On the causation of pelvic inflammatory disease. Am J Obstet Gynecol 149:215-24, 15 May 84 Dr. Ridgik, University of Medicine and Dentistry of New Jersey, 4. Jacobson, L.: Differential diagnosis of acute pelvic inflammatory dis- School of Osteopathic Medicine, 40 East Laurel Road, Suite 225, ease. Am J Obstet Gynecol 138:1006-11, 1 Dec 80 Stratford, New Jersey 08084.

Pelvic inflammatory disease: Clinical update 146/91