Gonococcal Arthritis

Gonorrhea is a sexually transmitted infection (STI) of epithelium and commonly manifests as cervicitis, urethritis, proctitis, and conjunctivitis. If untreated, infections at these sites can lead to local complications such as endometritis, salpingitis, tuboovarian abscess, bartholinitis, peritonitis, and perihepatitis in female patients; periurethritis and epididymitis in male patients; and ophthalmia neonatorum in newborns. Disseminated gonococcemia is an uncommon event whose manifestations include skin lesions, tenosynovitis, arthritis, and (in rare cases) endocarditis or meningitis. (Harrison’s Principles of Internal Medicine, 17 Edition Volume 1, p.914) (Harrison’s Principles of Internal Medicine, 18 Edition) Neisseria gonorrhoeae is a gram-negative, nonmotile, non-spore-forming organism that grows singly and in pairs (i.e., as monococci and diplococci, respectively). Gonococci, like all other Neisseria species, are oxidase positive. They are distinguished from other neisseriae by their ability to grow on selective media and to utilize glucose but not maltose, sucrose, or lactose. (Harrison’s Principles of Internal Medicine, 17 Edition Volume 1, p.914) (Harrison’s Principles of Internal Medicine, 18 Edition) Neisseria gonorrhoeae is one of the most common causes of infectious polyarthritis. (Harrison’s Principles of Internal Medicine, 17 Edition Volume 1, p.2169) (Harrison’s Principles of Internal Medicine, 18 Edition) INTRODUCTION

Disseminated gonococcal arthritis (DGI) or gonococcal arthritis results from gonococcal bacteremia. In the 1970s, DGI occurred in ∑0.5–3% of persons with untreated gonococcal mucosal infection. (Harrison’s Principles of Internal Medicine, 17 Edition Volume 1, p.918) (Harrison’s Principles of Internal Medicine, 18 Edition) Although its incidence has declined in recent years, gonococcal arthritis has accounted for up to 70% of episodes of infectious arthritis in persons <40 years of age in the United States. Arthritis due to N. gonorrhoeae is a consequence of bacteremia arising from gonococcal infection or, more frequently, from asymptomatic gonococcal mucosal colonization of the urethra, cervix, or pharynx. Women are at greatest risk during menses and during pregnancy and overall are two to three times more likely than men to develop disseminated gonococcal infection (DGI). Persons with complement deficiencies, especially of the terminal components, are prone to recurrent episodes of gonococcemia. Strains of gonococci that are most likely to cause DGI include those which produce transparent colonies in culture, have the type IA outer- membrane protein, or are of the AUH-auxotroph type. (Harrison’s Principles of Internal Medicine, 17 Edition Volume 2, p ) (Harrison’s Principles of Internal Medicine, 18 Edition) Gonorrhea predominantly affects young, nonwhite, unmarried, less educated members of urban populations. (Harrison’s Principles of Internal Medicine, 17 Edition Volume 1, p.914) (Harrison’s Principles of Internal Medicine, 18 Edition) EPIDEMIOLOGY

Women are at greatest risk during menses and during pregnancy and overall are two to three times more likely than men to develop disseminated gonococcal infection (DGI). Persons with complement deficiencies, especially of the terminal components, are prone to recurrent episodes of gonococcemia. Strains of gonococci that are most likely to cause DGI include those which produce transparent colonies in culture, have the type IA outer-membrane protein, or are of the AUH-auxotroph type. (Harrison’s Principles of Internal Medicine, 17 Edition Volume 2, p.2172) (Harrison’s Principles of Internal Medicine, 18 Edition) Menstruation is a risk factor for dissemination, and approximately two-thirds of cases of DGI are in women. In about half of affected women, symptoms of DGI begin within 7 days of onset of menses. Complement deficiencies, especially of the components involved in the assembly of the membrane attack complex (C5 through C9), predispose to neisserial bacteremia, and persons with more than one episode of DGI should be screened with an assay for total hemolytic complement activity. (Harrison’s Principles of Internal Medicine, 17 Edition Volume 1, p.918) (Harrison’s Principles of Internal Medicine, 18 Edition) Gonorrhea predominantly affects young, nonwhite, unmarried, less educated members of urban populations. (Harrison’s Principles of Internal Medicine, 17 Edition Volume 1, p.914) (Harrison’s Principles of Internal Medicine, 18 Edition) RISK FACTOR

The most common manifestation of DGI is a syndrome of fever, chills, rash, and articular symptoms. Small numbers of papules that progress to hemorrhagic pustules develop on the trunk and the extensor surfaces of the distal extremities. Migratory arthritis and tenosynovitis of the knees, hands, wrists, feet, and ankles are prominent. (Harrison’s Principles of Internal Medicine, 17 Edition Volume 2, p.2171) (Harrison’s Principles of Internal Medicine, 18 Edition) The clinical manifestations of DGI have sometimes been classified into two stages: a bacteremic stage, which is less common today, and a joint-localized stage with suppurative arthritis. A clear-cut progression usually is not evident. Patients in the bacteremic stage have higher temperatures, and chills more frequently accompany their fever. Painful joints are common and often occur together with tenosynovitis and skin lesions. Polyarthralgias usually include the knees, elbows, and more distal joints; the axial skeleton is generally spared. Skin lesions are seen in ∑75% of patients and include papules and pustules, often with a hemorrhagic component (Picture 1). These lesions are usually on the extremities and number between 5 and 40.Picture 1 (Harrison’s Principles of Internal Medicine, 17 Edition Volume 1, p.918) (Harrison’s Principles of Internal Medicine, 18 Edition) CLINICAL MANIFESTATIONS

Acute urethritis is the most common clinical manifestation of gonorrhea in males. The usual incubation period after exposure is 2–7 days, although the interval can be longer and some men remain asymptomatic. Urethral discharge and dysuria, usually without urinary frequency or urgency, are the major symptoms. The discharge initially is scant and mucoid but becomes profuse and purulent within a day or two. Most symptomatic men with gonorrhea seek treatment and cease to be infectious. The remaining men, who are largely asymptomatic, accumulate in number over time and constitute about two-thirds of all infected men at any point in time. Together with men incubating the organism (who shed the organism but are asymptomatic), they serve as the source of spread of infection (Harrison’s Principles of Internal Medicine, 17 Edition Volume 1, p.916) (Harrison’s Principles of Internal Medicine, 18 Edition) Mucopurulent cervicitis is the most common STI diagnosis in American women and may be caused by N. gonorrhoeae. Women infected with N. gonorrhoeae usually develop symptoms. However, the women who either remain asymptomatic or have only minor symptoms may delay in seeking medical attention. These minor symptoms may include scant vaginal discharge issuing from the inflamed cervix (without vaginitis or vaginosis per se) and dysuria (often without urgency or frequency) that may be associated with gonococcal urethritis. (Harrison’s Principles of Internal Medicine, 17 Edition Volume 1, p ) (Harrison’s Principles of Internal Medicine, 18 Edition)

Suppurative arthritis involves one or two joints, most often the knees, wrists, ankles, and elbows (in decreasing order of frequency); other joints occasionally are involved. Most patients who develop gonococcal septic arthritis do so without prior polyarthralgias or skin lesions; in the absence of symptomatic genital infection, this disease cannot be distinguished from septic arthritis caused by other pathogens. (Harrison’s Principles of Internal Medicine, 17 Edition Volume 1, p.918) (Harrison’s Principles of Internal Medicine, 18 Edition) Gonococcal endocarditis, although rare today, was a relatively common complication of DGI in the preantibiotic era, accounting for about one-quarter of reported cases of endocarditis. Another unusual complication of DGI is meningitis. (Harrison’s Principles of Internal Medicine, 17 Edition Volume 1, p ) (Harrison’s Principles of Internal Medicine, 18 Edition)

Forty-nine patients with disseminated gonococcal infection (DGI) hospitalized at Boston City and University Hospitals over a 7-year period were studied. Patients with clinical manifestations of DGI and with cervical, urethral, rectal, pharyngeal, synovial or blood cultures positive for Neisseria gonorrhoeae were separated into two groups based on the presence or absence of suppurative arthritis. There were 19 cases of suppurative arthritis (Group II) and 30 cases with only tenosynovitis, skin lesions, or both (Group I). Blood cultures were positive only in Group I patients (43%) and synovial fluid cultures only in Group II patients (47%). Polyarthralgia was the most common initial symptom in both groups of patients. Twenty-six Group I patients had tenosynovitis (87%), while only 4 Group II patients (21%) had tenosynovitis (p less than 0.001). The knee was the most commonly involved suppurated joint. Twenty-seven Group I patients (90%) had skin lesions compared to 8 Group II patients (42%) (p less than 0.001). Some of these lesions progressed on treatment; some patients were unaware of their lesions. Genitourinary symptoms were unusual in both groups of patients. Eleven women (33%) were menstruating or were pregnant at the onset of DGI. Thirteen patients had histories suggestive of previous gonococcal infections; one had recurrent DGI. This patient and one other were found to have complement abnormalities. There were no cases of endocarditis or meningitis. Four patients had unexplained liver function abnormalities. All patients recovered uneventfully. (O'Brien JP et al: Disseminated gonococcal infection: A prospective analysis of 49 patients and a review of pathophysiology and immune mechanisms. Medicine)

The differential diagnosis of the bacteremic stage of DGI includes reactive arthritis, acute rheumatoid arthritis, sarcoidosis, erythema nodosum, drug-induced arthritis, and viral infections (e.g., hepatitis B and acute HIV infection). The distribution of joint symptoms in reactive arthritis differs from that in DGI (Picture 2).Picture 2 (Harrison’s Principles of Internal Medicine, 17 Edition Volume 1, p.918) (Harrison’s Principles of Internal Medicine, 18 Edition) It is important to differentiate reactive arthritis from disseminated gonococcal disease, both of which can be venereally acquired and associated with urethritis. Unlike reactive arthritis, gonococcal arthritis and tenosynovitis tend to involve both upper and lower extremities equally, to lack back symptoms, and to be associated with characteristic vesicular skin lesions. (Harrison’s Principles of Internal Medicine, 17 Edition Volume 2, p.2114) (Harrison’s Principles of Internal Medicine, 18 Edition) DIFFERENTIAL DIAGNOSIS

The cutaneous lesions and articular findings are believed to be the consequence of an immune reaction to circulating gonococci and immune-complex deposition in tissues. Thus, cultures of synovial fluid are consistently negative, and blood cultures are positive in <45% of patients. Synovial fluid may be difficult to obtain from inflamed joints and usually contains only 10,000– 20,000 leukocytes/µL. (Harrison’s Principles of Internal Medicine, 17 Edition Volume 2, p.2172) (Harrison’s Principles of Internal Medicine, 18 Edition) Because it is difficult to isolate gonococci from synovial fluid and blood, specimens for culture should be obtained from potentially infected mucosal sites. Cultures and gram-stained smears of skin lesions are occasionally positive. All specimens for culture should be plated onto Thayer- Martin agar directly or in special transport media at the bedside and transferred promptly to the microbiology laboratory in an atmosphere of 5% CO 2, as generated in a candle jar. NAA- based assays are extremely sensitive in detecting gonococcal DNA in synovial fluid. A dramatic alleviation of symptoms within 12–24 h after the initiation of appropriate antibiotic therapy supports a clinical diagnosis of the DGI syndrome if cultures are negative. (Harrison’s Principles of Internal Medicine, 17 Edition Volume 2, p.2172) (Harrison’s Principles of Internal Medicine, 18 Edition) DIAGNOSIS

True gonococcal septic arthritis is less common than the DGI syndrome and always follows DGI, which is unrecognized in one-third of patients. A single joint such as the hip, knee, ankle, or wrist is usually involved. Synovial fluid, which contains >50,000 leukocytes/µL, can be obtained with ease; the gonococcus is only occasionally evident in gram-stained smears, and cultures of synovial fluid are positive in <40% of cases. Blood cultures are almost always negative. (Harrison’s Principles of Internal Medicine, 17 Edition Volume 2, p.2172) (Harrison’s Principles of Internal Medicine, 18 Edition) A rapid diagnosis of gonococcal infection in men may be obtained by Gram's staining of urethral exudates (Picture 3). The detection of gram-negative intracellular monococci and diplococci is usually highly specific and sensitive in diagnosing gonococcal urethritis in symptomatic males but is only ∑50% sensitive in diagnosing gonococcal cervicitis. Samples should be collected with Dacron or rayon swabs. Part of the sample should be inoculated onto a plate of modified Thayer-Martin or other gonococcal selective medium for culture. It is important to process all samples immediately because gonococci do not tolerate drying. If plates cannot be incubated immediately, they can be held safely for several hours at room temperature in candle extinction jars prior to incubation. If processing is to occur within 6 h, transport of specimens may be facilitated by the use of nonnutritive swab transport systems such as Stuart or Amies medium. For longer holding periods (e.g., when specimens for culture are to be mailed), culture media with self-contained CO 2 -generating systems (such as the JEMBEC or Gono-Pak systems) may be used.Picture 3 (Harrison’s Principles of Internal Medicine, 17 Edition Volume 1, p.919) (Harrison’s Principles of Internal Medicine, 18 Edition)

PMNs are often seen in the endocervix on a Gram's stain, and an abnormally increased number (30 PMNs per field in five 1000x oil-immersion microscopic fields) establishes the presence of an inflammatory discharge. Unfortunately, the presence or absence of gram-negative intracellular monococci or diplococci in cervical smears does not accurately predict which patients have gonorrhea, and the diagnosis in this setting should be made by culture or another suitable nonculture diagnostic method. The sensitivity of a single endocervical culture is ∑80–90%. If a history of rectal sex is elicited, a rectal wall swab (uncontaminated with feces) should be cultured. A presumptive diagnosis of gonorrhea cannot be made on the basis of gram-negative diplococci in smears from the pharynx, where other Neisseria species are components of the normal flora. (Harrison’s Principles of Internal Medicine, 17 Edition Volume 1, p.919) (Harrison’s Principles of Internal Medicine, 18 Edition) Nucleic acid probe tests are being substituted for culture for the direct detection of N. gonorrhoeae in urogenital specimens. A common assay is as sensitive as conventional culture techniques. A disadvantage of non-culture-based assays is that N. gonorrhoeae cannot be grown from the transport systems. Thus a culture-confirmatory test and formal antimicrobial susceptibility testing, if needed, cannot be performed. Nucleic acid amplification tests (NAATs), including Roche Amplicor, Gen-Probe APTIMA Combo2, and BD ProbeTec ET, offer an advantage: urine samples can be tested with a sensitivity similar to that obtained when urethral or cervical swab samples are assessed by culture and other non-NAATs. (Harrison’s Principles of Internal Medicine, 17 Edition Volume 1, p.919) (Harrison’s Principles of Internal Medicine, 18 Edition)

Blood should be cultured in suspected cases of DGI. The use of Isolator blood culture tubes may enhance the yield. The probability of positive blood cultures decreases after 48 h of illness. Synovial fluid should be inoculated into blood culture broth medium and plated onto chocolate agar rather than selective medium because this fluid is not likely to be contaminated with commensal bacteria. Gonococci are infrequently recovered from early joint effusions containing 80,000 leukocytes/µL. The organisms are seldom recovered from blood and synovial fluid of the same patient. (Harrison’s Principles of Internal Medicine, 17 Edition Volume 1, p.919) (Harrison’s Principles of Internal Medicine, 18 Edition)

Initial treatment consists of ceftriaxone (recommended, 1 g IV or IM every 24 h ) or cefotaxime (1 g IV every 8 h) or ceftizoxime (1 g IV every 8 h) to cover possible penicillin-resistant organisms. Once local and systemic signs are clearly resolving and if the sensitivity of the isolate permits, the 7-day course of therapy can be completed with an oral agent such as ciprofloxacin (500 mg twice daily). If penicillin-susceptible organisms are isolated, amoxicillin (500 mg three times daily) may be used. Suppurative arthritis usually responds to needle aspiration of involved joints and 7–14 days of antibiotic treatment. Arthroscopic lavage or arthrotomy is rarely required. Patients with DGI should be treated for Chlamydia trachomatis infection unless this infection is ruled out by appropriate testing. (Harrison’s Principles of Internal Medicine, 17 Edition Volume 2, p.2172) (Harrison’s Principles of Internal Medicine, 18 Edition) (Harrison’s Principles of Internal Medicine, 17 Edition Volume 1, t.137-1) (Harrison’s Principles of Internal Medicine, 18 Edition, t.144-1) TREATMENT