Five days after the onset of her most recent menstrual cycle, a 24-year-old woman begins to experience fever and chills. Soon thereafter, many of her joints become painful, including those in her knees, elbows, wrists, ankles, hands, and feet. These symptoms persist over the next 24 hours, during which a small number of reddish sores (papules) appear on several fingers and the palms of her hands. By the time she gets to a physician (the next day), some of the papules have developed into painful, hemorrhagic pustules. Her vital signs are T = 38.5 C, P = 80, R = 16, BP = 130/70 mm Hg. On physical examination, it is noted that the pustules on her extremities are surrounded by a distinct red areola and that a few papules have also developed on her trunk. Except for the apparently inflamed joints, there are no other remarkable findings. On taking the patient's history, the physician finds that she has been sexually active with multiple partners but has not experienced any noticeable signs or symptoms typical of common STDs. She uses birth control pills; most of her partners don't bother with condoms.

Question 2.1: What is your preliminary diagnosis?

The patient's history suggests that a sexually transmitted disease is possible, even though she has not experienced any typical STD symptoms (e.g., urethritis or cervicitis). Moreover, the absence of such symptoms does not rule out an STD because many gonococcal and chlamydial infections in women are asymptomatic. The fever and chills imply that an infection is occurring. The combination of fever, chills, polyarthralgias, and small numbers of papules that develop into pustules is characteristic of disseminated gonococcal infection (DGI).

Question 2.2: What tests should you perform?

DGI is related to gonococcal bacteremia, so blood cultures for Neisseria gonorrhoeae (and other pathogens in case your diagnosis is wrong) should be ordered. You could also culture fluid from the pustules. Because asymptomatic gonorrhea is suspected here, it would be a good idea to get Gram stains and cultures of cervical and/or urethral smears. To be really thorough, you can also analyze synovial fluid (leukocyte count with differential) and attempt to culture it. Note that all specimens for culturing of N. gonorrhoeae should be plated directly onto Thayer-Martin agar or placed in special transport media at the bedside and transferred promptly to the microbiology lab.

Test Results:

The blood, synovial fluid, and pustule fluid cultures are all negative. However, the lab is able to culture N. gonorrhoeae from the cervical swab. A few Gram-negative cocci in pairs are visible in the Gram stain of this sample. The WBC for the synovial fluid is 12,000 leukocytes per (L, 90% of which are neutrophils and 10% mononuclears.

Question 2.3: Are the negative culture results consistent with the diagnosis?

Actually, they are. Blood cultures are positive in fewer than 50% of DGI cases. Cultures of skin lesions and synovial fluid are almost always negative. There are several plausible explanations for this. First, the gonococci may just be present in numbers that are too low to be detected by culturing. Second, the nutritional requirements of these organisms may be unusual, so it may not be possible to isolate them using standard gonococcal culture media. Third, cell wall fragments (e.g., pieces of peptidoglycan) or immune complexes (consisting of gonococcal antigens and host antibodies) may be deposited in synovial tissue and cause inflammation in the absence of intact, living bacteria. Immune-related or hypersensitivity phenomena caused by gonococcal antigens may also account for "sterile" skin lesions.

Question 2.4: How did this infection get started?

The patient has an asymptomatic gonococcal infection (or colonization) of the cervical mucosa. N. gonorrhoeae probably entered her bloodstream during menses. Women are at greatest risk of DGI during menses and pregnancy. More then 50% of DGI cases in women begin within 7 days of the onset of menses. Complement deficiencies, especially of the components involved in assembly of the membrane attack complex (C5 through C9) also predispose one to gonococcal bacteremia. Up to 13% of patients with DGI have these deficiencies. Any patient who experiences recurrent DGI should be screen for complement deficiencies.

Question 2.5: What is the prevalence of this disease?

DGI occurs in up to 3% of persons with untreated gonococcal mucosal infection. (In most cases, the infection untreated because it is asymptomatic.) DGI may arise from asymptomatic mucosal colonization of the urethra, cervix, or pharynx. The low frequency of occurrence probably is attributable to a relatively low proportion of N. gonorrhoeae strains that are likely to disseminate in the bloodstream. DGI strains resist the antibacterial action of human serum and generally do not incite inflammation at genital sites (thus the asymptomatic cases), probably because these strains produce only limited quantities of chemotactic factors. Most N. gonorrhoeae strains do not have serum resistance and, as a result, are far less likely to persist in the bloodstream.

Question 2.6: Is this the only type of joint disease associated with this agent?

No, N. gonorrhoeae can also cause frank (suppurative) arthritis, which usually affects only a single joint (typically in the hip, knee, ankle, or wrist). It is said that this true septic arthritis always follows a disseminated infection. However, most victims do not experience the usual symptoms of DGI (fever, chills, polyarthralgias, etc.) prior to developing the frank arthritis, and this has led to two schools of thought at to what is actually happening in these cases. One approach has been to classify DGI into two stages, the bacteremic stage (with or without the usual symptoms) and a joint-localized stage that results in suppurative arthritis. The opposing view is that, because there is seldom a clear-cut progression, a disseminated infection may lead to either of two entirely distinct syndromes. In any event, the frank arthritis occurs far less frequently than DGI. Synovial fluid is easy to obtain during the frank arthritis and typically contains >50,000 leukocytes per (L. Gonococci are only occasionally visible in Gram-stained smears of synovial fluid, and cultures are positive in <40% of cases. Blood cultures are almost always negative.

Question 2.7: How should you treat this?

The initial treatment should consist of ceftrioxone (1 g IV or IM every 24 hrs), to cover possible penicillin-resistant strains. Once local and systemic signs are clearly resolving, the 7-day course of therapy can be completed with an oral agent such as cefixime (400 mg bid) or ciprofloxacin (500 mg bid) or, if penicillin-resistant strains are isolated, amoxicillin (500 mg tid). Suppurative arthritis usually responds to needle aspiration of involved joints and 7-14 days of antibiotic therapy. Arthroscopic lavage or arthrotomy is rarely required.