The Missing Piece: Pelvic and Abdominal Pain in a 40-Year-Old Cisgender Female

CASE A 40-year-old cisgender female with a medical history significant for Roux-en-Y gastric bypass presented to her primary care clinic with acute right upper quadrant abdominal pain. She had no associated nausea, vomiting, diarrhea, constipation, hematochezia, melena, fevers, or chills. On physical examination, vital signs were within normal limits, and she had marked right upper quadrant abdominal tenderness without guarding or rebound tenderness. Murphy's sign was absent. The patient's aspartate transaminase (AST) was 35 U/L; alanine transaminase (ALT), 28 U/L; alkaline phosphatase, 136 U/L; total bilirubin, less than 0.2 mg/dL; and white blood cell (WBC) count, 4300 cells/μL. An abdominal ultrasound showed a possible abdominal wall hernia but no cholelithiasis or biliary duct dilatation. A computed tomography (CT) scan of the abdomen was obtained to further evaluate, revealing faint ground-glass attenuation along the inferior aspect of the liver with a small amount of perihepatic fluid (Fig. 1).FIGURE 1: Computed tomography of the patient's abdomen showing a small amount of perihepatic fluid (arrows).At the time of her presentation, the patient had also been undergoing evaluation for chronic pelvic pain and menorrhagia. Sixteen months prior, the patient had presented to an emergency department with acute right lower quadrant abdominal pain, intermenstrual vaginal bleeding, and fevers. Abdominal imaging including ultrasound and CT of the abdomen and pelvis at that time showed no identifiable cause for her abdominal pain. A pelvic examination and testing for sexually transmitted infections (STIs) were not performed. The patient's abdominal pain improved but did not resolve, and due to persistent indolent symptoms, endometrial biopsy was obtained 1 week after the development of acute right upper quadrant pain and was notable for evidence of chronic endometritis (Fig. 2).FIGURE 2: Endometrial biopsy showing numerous plasma cells infiltrating the endometrial stroma (hematoxylin and eosin stain).WHAT IS YOUR DIAGNOSIS? Testing for sexually transmitted infections was performed. Serologic testing for HIV, hepatitis B, hepatitis C, and syphilis was negative. Urine nucleic acid amplification testing was negative for Neisseria gonorrhoeae and Chlamydia trachomatis and positive for M. genitalium. She was treated with moxifloxacin (400 mg) once daily for 14 days. Within 48 hours of starting treatment, both her acute and chronic abdominal pain had improved and resolved quickly with treatment. Repeat urine nucleic acid amplification for M. genitalium was negative 71 days after completing therapy. DISCUSSION M. genitalium was initially isolated from urethral specimens from men with nongonococcal urethritis (NGU) in 1981.1 A fastidious and slow-growing organism, M. genitalium is extremely difficult to culture, thus limiting the ability to study this organism prior to the advent of molecular assays such as polymerase chain reaction (PCR). M. genitalium is a sexually transmitted infection, causing urethritis in persons assigned male at birth and cervicitis among persons assigned female at birth.2–6M. genitalium has also been associated with pelvic inflammatory disease (PID), with a possible causative relationship, although data on this are limited.5,6 Similar to other STIs, M. genitalium infection has been associated with HIV infection, possibly enhancing HIV transmission when coinfection is present.7–9 PID occurs as a complication of ascending infection of the genital tract, resulting in salpingitis, endometritis, tubo-ovarian abscess, and, occasionally, peritonitis.10 PID can result in significant long-term sequelae including infertility, ectopic pregnancy, and chronic pelvic pain, particularly when treatment is delayed.11–14 Although traditionally thought to be primarily the result of untreated sexually transmitted infections like gonorrhea and chlamydia, it is now clear that the microbiology of PID is more complex, and C. trachomatis and N. gonorrhoeae account for fewer than half of PID cases in most studies.15M. genitalium infection generally causes mild indolent symptoms similar to chlamydia, as compared to gonorrhea, or can be asymptomatic. The implications of asymptomatic infection for this organism remain unclear. Some studies have reported an association between M. genitalium infection and adverse pregnancy outcomes and infertility, although a causative relationship has not been established.5,16 The use of serology for diagnosis is a limiting factor in these studies. Perihepatitis (Fitz-Hugh-Curtis syndrome) is a rare complication of PID involving inflammation and adhesions of the liver capsule resulting from the sexually transmitted infection in PID ascending beyond the pelvis. This generally presents as right upper quadrant abdominal pain. To date, there has been only one other reported case of perihepatitis associated with M. genitalium infection.17 Treatment of M. genitalium infection has been complicated by the lack of accurate and commercially available diagnostic testing until 2019, the limited number of effective antimicrobials, the emergence of antibiotic resistance over the past several years, and the lack of commercially available resistance testing in the US. The standard outpatient empiric treatment regimens recommended by the US Centers for Disease Control and Prevention (CDC) 2021 STI Treatment Guidelines for urethritis, cervicitis, and PID include ceftriaxone plus doxycycline and, for PID, the addition of metronidazole to target C. trachomatis, N. gonorrhoeae, and anaerobic organisms.18 In areas where doxycycline- or tetracycline-resistant M. genitalium is prevalent, this may not provide effective coverage when M. genitalium is the causative pathogen. Lacking a cell wall, cephalosporins are ineffective against M. genitalium, and doxycycline demonstrates a cure rate of only 30% to 45%, which does not necessarily correlate with detected antimicrobial resistance.19 Azithromycin has inherent activity against M. genitalium, although resistance has grown over the past decade, with macrolide resistance detected in more than 50% of M. genitalium infections in many countries.20 Furthermore, studies have demonstrated induced macrolide resistance after treatment with azithromycin.21 Moxifloxacin is one of the few fluoroquinolones with demonstrated efficacy against M. genitalium,22 although fluoroquinolones are associated with potential for adverse effects including Clostridioides difficile infection, QT prolongation, tendon rupture, hepatotoxicity, and drug interactions. Fluoroquinolone resistance is also increasing globally.22,23 Despite the low cure rates with doxycycline monotherapy mentioned above, in studies where doxycycline is used as part of a two-step antibiotic regimen, where selection of the second antibiotic is guided by a resistance assay (eg, doxycycline followed by moxifloxacin or azithromycin), doxycycline appears to reduce the bacterial load of M. genitalium, making the second antibiotic more effective and increasing cure rates.20,24 Improved point-of-care diagnostic assays that can both diagnose M. genitalium and detect resistance will allow for more targeted effective therapy. This resistance-guided therapy strategy has been used successfully in Australia25 and has now been incorporated into the US CDC 2021 STI Treatment Guidelines.18 Unfortunately, there are no resistance assays with FDA approval in the US for M. genitalium. For urethritis and cervicitis, the current CDC guidelines recommend sequential treatment with doxycycline (100 mg) twice daily for 7 days followed by moxifloxacin (400 mg) once daily for 7 days if M. genitalium resistance testing is unavailable or if resistance testing is available and macrolide resistance is detected.18 If resistance testing is available and no macrolide resistance is detected, azithromycin can be substituted for moxifloxacin with a 1 g initial dose followed by 500 mg once daily for 3 additional days.18 For treatment of PID caused by M. genitalium, moxifloxacin (400 mg) once daily for 14 days has been effective.18 This case illustrates the importance of taking a sexual history, obtaining STI testing, and considering PID when evaluating a female patient with pelvic or abdominal pain. Also highlighted is the need to consider M. genitalium as an additional STI to test for in the setting of chronic indolent PID. Given the often-subtle presentation of PID, clinicians should have a low threshold to perform a pelvic examination and STI testing to minimize the potential for long-term sequelae including chronic pain and infertility. The case also adds to the evidence supporting M. genitalium as a cause of PID and its complications, including perihepatitis. Further studies are needed to guide recommendations regarding testing and treatment for M. genitalium in the setting of PID, and resistance testing is needed in the US to guide effective treatment. Additionally, a greater understanding of M. genitalium as an STI is needed to inform further decisions regarding public health and prevention efforts.